APOL1 INHIBITORS AND METHODS OF USING SAME - Patent application

Abstract

The present disclosure provides a compound of formula (I): TIFF2023512213000281.tif4771 Provided are at least one entity selected from pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, compositions comprising them, and methods of using them, including their use in treating APOL1-mediated kidney diseases.

Description

[Technical Field]

[0001] This application claims the benefit of priority from U.S. Provisional Patent Application No. 62 / 967,276 filed on 29 January 2020, U.S. Provisional Patent Application No. 63 / 038,278 filed on 12 June 2020, and U.S. Provisional Patent Application No. 63 / 040,166 filed on 17 June 2020, which are incorporated herein by reference.

[0002] This disclosure provides compounds that inhibit apolipoprotein L1 (APOL1) and methods for using those compounds to treat APOL1-mediated kidney diseases, including focal segmental glomerulosclerosis (FSGS) and / or non-diabetic nephropathy (NDKD). In some embodiments, FSGS and / or NDKD are associated with common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del). [Background technology]

[0003] FSGS is a disease of podocytes (glomerular visceral epithelial cells) involved in proteinuria and progressive decline in renal function. NDKD is a disease characterized by hypertension and progressive decline in renal function. Human genetics supports the causal roles of APOL1 variants G1 and G2 in inducing kidney disease. Individuals with both APOL1 risk alleles are at increased risk of developing FSGS, human immunodeficiency virus (HIV)-associated nephropathy, NDKD, arterial nephrosclerosis, lupus nephritis, microalbuminuria, and end-stage kidney disease (ESKD), including chronic kidney disease. See P. Dummer et al., Semin Nephrol. 35(3):222-236 (2015).

[0004] APOL1 is a 44kDa protein expressed only in humans, gorillas, and baboons. APOL1 is primarily produced by the liver and contains a signaling peptide that enables its secretion into the bloodstream, where it circulates bound to a subset of high-density lipoproteins. APOL1 is responsible for protection against the invasive parasite Trypanosoma Brucei Brucei (TbBrucei). G1 and G2 variants of APOL1 provide additional protection against the Trypanosoma species that cause sleeping sickness. Normal plasma concentrations of APOL1 are relatively high, and can vary by at least 20-fold in humans, but circulating APOL1 is not causally associated with kidney disease.

[0005] However, APOL1 in the kidney is thought to be responsible for the development of kidney diseases, including FSGS and NDKD. Under certain circumstances, APOL1 protein synthesis can be increased by approximately 200 times by interferon or pro-inflammatory cytokines such as tumor necrosis factor-α. Furthermore, APOL1 protein is gated to the cell membrane at pH Na + / K + It forms pores, resulting in intracellular K + Several studies have shown that net elimination occurs, ultimately activating local and systemic inflammatory responses, cell swelling, and cell death.

[0006] The risk of ESKD is significantly higher in recent sub-Saharan Africans compared to people of European and American descent, and ESKD accounts for nearly the same number of years lost in women as in breast cancer and in men as in colorectal cancer. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using renin-angiotensin system blockers), and patients with FSGS and severe proteinuria may be offered high-dose corticosteroids. Corticosteroids induce remission in a small number of patients but are associated with numerous, sometimes severe, side effects and are often poorly tolerated. These patients, particularly recent sub-Saharan Africans with two APOL1 risk alleles, experience faster disease progression, leading to ESKD. Therefore, there is an unmet medical need for the treatment of APOL1-mediated kidney diseases, including FSGS, NDKD, and ESKD. Given the evidence that APOL1 plays a causal role in inducing and promoting the progression of kidney disease, inhibition of APOL1 should have a positive effect on patients with APOL1-mediated kidney disease, particularly those carrying two APOL1 risk alleles (i.e., homozygous or compound heterozygous for the G1 or G2 allele). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] P.Dummer et al.,Semin Nephrol.35(3):222-236(2015) [Overview of the Initiative] [Means for solving the problem]

[0008] One aspect of the present disclosure provides at least one entity selected from compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, which are used for the treatment of APOL1-mediated diseases such as FSGS and NDKD.

[0009] Therefore, a first aspect of the present invention relates to a compound of formula (I), [ka] We provide a compound selected from the pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, wherein, (i) Ring A is a 3- to 7-membered ring, and the ring is a cyclic alkyl or heterocyclic ring. (ii) Q is N or CR 5 And, (iii) Each R1 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • -OC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)OC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups • C1-C6 linear, branched, and cyclic haloalkoxy groups, • Benzyloxy group, benzylamino group, or benzylthio group • 3-6 member heterocycloalkenyl groups, • 3-6 member heterocycloalkyl groups, and • 5- and 6-membered heteroaryl groups, or The two R1 groups, together with the carbon atoms to which they are bonded, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group. (iv) Each R2 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups, (v)m is selected from 0, 1, 2, 3, and 4, (vi)n is selected from 0, 1, 2, 3, 4, and 5. (vii)X is selected from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, and the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with one to four groups independently selected from the following: o C1-C6 alkyl groups, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, (viii)Y is selected from divalent amino, divalent oxygen, divalent C1-C8 linear, branched, and cyclic alkyl groups, divalent C1-C8 linear, branched, and cyclic alkoxy groups, divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, where the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with one to three groups independently selected from the following: o C1-C6 alkyl groups optionally substituted with hydroxyl, o C3-C6 cyclic alkyl, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, Alternatively, divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups may be optionally fused with C3-C6 cyclic alkyl groups. (ix)o is selected from 0, 1, 2, 3, and 4. (x)p is selected from 0, 1, 2, 3, and 4. (xi) R3 and R4 are selected independently from the following: Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 linear and branched alkoxy groups optionally substituted with C3-C6 cyclic alkyl groups or 3-6 membered heterocycles. • A C1-C6 cyclic alkyl group which is optionally substituted with one to four groups independently selected from the following: o halogen group, o Hydroxy, o Oxo, o C1-C6 linear and branched alkoxy groups, o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, and o Amide group, • A heterocyclic group which is arbitrarily substituted with one to four groups independently selected from the following: o halogen group, o Oxo, o Hydroxy, and o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, • An aryl group which is optionally substituted with one to four groups which are optionally substituted with halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups which are optionally substituted with one or two groups which are optionally substituted with hydroxyl groups and C1-C6 linear and branched alkoxy groups, • A heteroaryl group optionally substituted with one to four groups independently selected from hydroxyl and C1-C6 linear alkyl groups, and · C 1- C7 linear and branched alkyl groups, which are optionally substituted with one to five groups independently selected from the following: 1- C7 linear and branched alkyl groups, o Amino group, o Hydroxy, o Oxo, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups. o C3-C6 cyclic alkyl group, which is optionally substituted with one or two groups independently selected from a halogen group, a C1-C6 linear and branched alkoxy group, a C1-C6 linear and branched alkyl group optionally substituted with one or two hydroxyl groups, and a hydroxyl group, o C2-C6 linear and branched alkynyl groups, o C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group which is optionally substituted with one or two groups which are optionally substituted with halogen groups, hydroxy, hydroxy and C1-C6 linear and branched alkyl groups which are optionally substituted with one or two o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 membered heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups, and, o A 4-10 member heteroaryl group, which is optionally substituted with one to three groups independently selected from a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkyl group, which is optionally substituted with one to three groups independently of a halogen group, a halogen group, and a C1-C6 linear and branched alkoxy group. Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4-10 membered heterocyclyl group which is optionally substituted with one to four groups independently selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and hydroxy and C1-C6 linear and branched alkyl groups, and C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with one to four groups independently selected from o Amide groups optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently selected from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups. o A 4-10 member heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups independently selected from halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups, and (xii) R5 does not exist, or is selected from the following: Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • C1-C6 linear and branched alkyl groups, In the formula, if R5 is not present, Q is a bridgehead atom.

[0010] In one aspect of the present disclosure, the compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb) are selected from compounds 1 to 286 and compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives.

[0011] In some embodiments, the disclosure provides pharmaceutical compositions comprising compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, at least one entity selected from these. In some embodiments, the pharmaceutical composition may comprise at least one compound selected from compounds 1-286 and compounds 287-465, pharmaceutically acceptable salts of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. These compositions may further comprise at least one additional pharmaceutically active ingredient and / or at least one carrier.

[0012] Another aspect of the present disclosure provides a method for treating FSGS and / or NDKD, comprising administering to a subject requiring it at least one entity selected from the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, or a pharmaceutical composition comprising at least one entity. In some embodiments, the method comprises administering at least one entity selected from compounds 1-286 and compounds 287-465, any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives.

[0013] In some embodiments, the treatment method involves administering at least one additional activator, as the same pharmaceutical composition or a different composition, to a subject requiring it, at least one entity selected from the compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. In some embodiments, the method involves administering at least one entity selected from compounds 1-286 and compounds 287-465, any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, together with at least one additional activator, as the same pharmaceutical composition or a different pharmaceutical composition. A method for inhibiting APOL1 is also provided, comprising administering to a subject requiring it at least one entity selected from the compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), a pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, or a pharmaceutical composition comprising at least one entity. In some embodiments, a method for inhibiting APOL1 comprises administering at least one entity selected from the compounds 1-286 and compounds 287-465, a pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, or a pharmaceutical composition comprising at least one entity. [Brief explanation of the drawing]

[0014] [Figure 1] The plate layout in Figure 1 shows a plate map of ARP for dose-response. [Modes for carrying out the invention]

[0015] definition As used herein, the term "APOL1" means the apolipoprotein L1 protein, and the term "APOL1" means the apolipoprotein L1 gene.

[0016] The term "APOL1-mediated renal disease" refers to a disease or condition that impairs renal function and may be caused by APOL1. In some embodiments, APOL1-mediated renal disease is associated with patients who have two APOL1 risk alleles, for example, being homozygous or compound heterozygous for the G1 or G2 allele. In some embodiments, APOL1-mediated renal disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterial nephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0017] As used herein, the term “FSGS” means focal segmental glomerulosclerosis, a disease of the podocytes (glomerular visceral epithelial cells) that causes proteinuria and progressive decline in renal function. In some embodiments, FSGS is associated with two APOL1 risk alleles.

[0018] As used herein, the term “NDKD” means non-diabetic kidney disease characterized by severe hypertension and progressive decline in renal function. In some embodiments, NDKD is associated with two APOL1 risk alleles.

[0019] The terms “ESKD” and “ESDD” are used interchangeably to refer to end-stage renal disease or end-stage nephropathy. ESKD / ESDD is the final stage of kidney disease, i.e., renal failure, meaning that the kidneys no longer function well enough for the patient to survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESD is associated with two APOL1 risk alleles.

[0020] The term “compound,” when referring to the compounds of this disclosure, means a collection of molecules having the same chemical structure, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemic compounds, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variation may exist between the constituent atoms of the molecules. Therefore, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom may also contain a smaller amount of isotopic substitutions having one or more hydrogen atoms at one or more of the designated deuterium positions in its structure. The relative amount of such isotopic substitutions in the compounds of this disclosure will depend on several factors, including the isotopic purity of the reagents used to prepare the compounds and the efficiency of isotopic incorporation in the various synthetic steps used to prepare the compounds. However, as stated above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotope substitutions is 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 overall.

[0021] As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” Generally, the term “substituted,” whether preceded by the term “optionally,” refers to the substitution of a hydrogen radical in a given structure with the radical of a particular substituent. Unless otherwise indicated, an “optionally substituted” group may have substituents at each substituted position of the group, and if two or more positions in any given structure may be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at all positions. The substituent combinations envisioned herein result in the formation of stable or chemically feasible compounds.

[0022] The term "isotopic replacement" refers to species whose chemical structures differ only in their isotopic compositions. In addition, unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 replacement of carbon by 14 C, except for

[0023] compounds having this structure are within the scope of this disclosure.

[0024] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by the migration of an atom or group, such as a hydrogen atom, within the molecule.

[0025] As used herein, "stereoisomers" refer to enantiomers and diastereomers.

[0026] As used herein, "deuterated derivative" has the same chemical structure as the reference compound, but with deuterium atoms ( "D" or " 2This refers to compounds having one or more hydrogen atoms substituted with "H". It will be recognized that some variation in the natural isotopic abundance occurs in the synthesized compounds depending on the origin of the chemicals used in the synthesis. Despite this variation, the concentrations of naturally occurring stable hydrogen isotopes are small and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein. Therefore, unless otherwise specified, when referring to "deuterated derivatives" of the compounds in this disclosure, at least one hydrogen is substituted with deuterium in a manner well 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 in 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) for each deuterium atom.

[0027] As used herein, the term “isotope enrichment factor” means the ratio of the isotopic abundance to the natural abundance of a particular isotope.

[0028] As used herein, the terms “alkyl” or “aliphatic” mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a non-aromatic monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but has a single bond to the rest of the molecule. Unless otherwise specified, alkyl groups contain 1 to 20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 10 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 8 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 6 alkyl carbon atoms, in some embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms, and in yet other embodiments, alkyl groups contain 1 to 3 alkyl carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, linear or branched, and substituted or unsubstituted alkyl groups. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are linear. In some embodiments, alkyl groups are branched.

[0029] The terms "cycloalkyl," "carbocyclic," or "cyclic alkyl" refer to fusion, spirocyclic, or monocyclic C atoms. 3-8 Hydrocarbons, or non-aromatic spirocyclic, bicyclic, bridging bicyclic, tricyclic, or bridging tricyclic C molecules that are either fully saturated or contain one or more unsaturated units. 4-14 This refers to hydrocarbons, where any individual ring in the aforementioned bicyclic ring system has 3 to 7 members. Suitable cycloalkyl groups include cycloalkyls, bicyclic cycloalkyls (e.g., decalin), norbornyl, cross-linked bicycloalkyls such as [1.1.1]bicyclopentyl or [2.2.2]bicyclooctyl, or cross-linked tricyclics such as adamantyl. In some embodiments, the cyclo group is substituted. In some embodiments, the cyclo group is unsubstituted.

[0030] As used herein, the term “heteroalkyl” means an aliphatic group in which one, two, or three carbon atoms are independently substituted with one or more oxygen, sulfur, and / or nitrogen atoms. In some embodiments, one or two carbon atoms may be substituted with phosphorus and / or silicon. Heteroalkyl groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and may include “heterocyclic,” “heterocyclyl,” or “heterocyclic” groups. In some embodiments, the heteroalkyl group is an aminoalkyl group. In some embodiments, the heteroalkyl group is a thioalkyl group. In some embodiments, the heteroalkyl group is an alkoxy group. In some embodiments, the heteroalkyl group has a combination of two or more heteroatoms independently selected from oxygen, nitrogen, phosphorus, and sulfur.

[0031] As used herein, the term “alkenyl” means a linear (i.e., unbranched), branched, substituted, or unsubstituted hydrocarbon chain containing one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon containing one or more unsaturated units but not aromatic (referred to herein as a “cyclic alkenyl”). In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is linear. In some embodiments, the alkenyl group is branched.

[0032] As used herein, the terms “heterocycle,” “heterocyclyl,” or “heterocyclic” mean a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, a “heterocycle,” “heterocyclyl,” or “heterocyclic” group has 3 to 14 ring members, one or more of which are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, boron, and silicon. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one to three heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one to three heteroatoms that are nitrogen. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has one heteroatom that is a sulfur atom. In some embodiments, the heterocycle has two heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocycle has three heteroatoms independently selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted.

[0033] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, boron, and silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, any quaternized form of basic nitrogen, or, for example, N(3,4-dihydro-2H-pyrrolyl, etc.), NH(pyrrolidinyl, etc.), or NR). + This means one or more non-carbon atoms selected from (including the substituted nitrogen atoms of heterocyclic rings, such as N-substituted pyrrolidinyls).

[0034] As used herein, the term “unsaturated” means that a part of a compound has one or more unsaturated units or degree. Unsaturation is a state in which all available valence bonds in a compound are not filled by substituents, and therefore the compound contains double or triple bonds.

[0035] As used herein, the terms “alkoxy” or “thioalkyl” refer to an alkyl group, as already defined, where one carbon atom of the alkyl group is replaced with an oxygen (”alkoxy”) or sulfur (”thioalkyl”) atom, provided that the oxygen or sulfur atom is bonded between two carbon atoms. “Cyclic alkoxy” refers to a monocyclic, spirocyclic, bicyclic, bridging bicyclic, tricyclic, or bridging tricyclic hydrocarbon containing at least one alkoxy group but not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl. In some embodiments, the “alkoxy” and / or “thioalkyl” groups are substituted. In some embodiments, the “alkoxy” and / or “thioalkyl” groups are unsubstituted.

[0036] As used herein, the terms “haloalkyl” and “haloalkoxy” mean linear or branched alkyl or alkoxy groups that are optionally substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyl groups such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2-.

[0037] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodine, respectively.

[0038] The term "aminoalkyl" refers to an alkyl group that is substituted with an amino group or contains an amino group.

[0039] As used herein, the term “alkylsulfonyl” refers to an alkyl group, as already defined, where one carbon atom of the alkyl group and the substituents of the carbon atom are substituted with sulfur atoms, and the sulfur atoms are further substituted with two oxo groups. The alkylsulfonyl group may be linear or branched. In some embodiments, the alkylsulfonyl group is substituted with the alkyl moiety of the alkylsulfonyl group. In some embodiments, the alkylsulfonyl group is unsubstituted with the alkyl moiety of the alkylsulfonyl group.

[0040] As used herein, “amino” refers to a group that is a primary, secondary, or tertiary amine.

[0041] As used herein, the "carbonyl" group refers to a C=O group.

[0042] As used herein, the "cyano" or "nitrile" group refers to -C≡N.

[0043] As used herein, the "hydroxy" group refers to the -OH group.

[0044] As used herein, the "thiol" group refers to the -SH group.

[0045] As used herein, "tert" and "t-" refer to the third degree, respectively.

[0046] As used herein, "Me" refers to a methyl group.

[0047] As used herein, the “amide” group refers to a carbonyl group, as already defined, in which the carbonyl carbon is bonded to an amino group, as already defined. When a chemical group is said to be substituted by an amide group, that chemical group may be bonded to a carbonyl carbon or an amino nitrogen of the amide group.

[0048] As used herein, the “carbamate” group refers to a carbonyl group, as already defined, in which the carbon of the carbonyl group is bonded to an amino group and a divalent oxygen, as already defined. When a chemical group is said to be substituted by a carbamate group, that chemical group may be bonded to a divalent oxygen or the amino nitrogen of the carbamate group.

[0049] As used herein, “aromatic group” or “aromatic ring” refers to a chemical group comprising a conjugated planar ring system having a delocalized pi electron orbital consisting of [4n+2]p orbital electrons, where n is an integer between 0 and 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0050] The term "aryl," used alone or as part of a larger term such as "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, and each ring in bicyclic and tricyclic ring systems contains 3 to 7 ring members. The term "aryl" also refers to heteroaryl ring systems as defined below herein. A non-limiting example of an aryl group is the phenyl ring. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0051] The term "heteroaryl," used alone or as part of a larger term in "heteroarylalkyl" or "heteroarylalkoxy," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in bicyclic and tricyclic ring systems contains 3 to 7 ring members. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having five ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, the heteroaryl group is unsubstituted.

[0052] Non-limiting examples of protecting groups useful for nitrogen-containing groups such as amine groups include, for example, t-butylcarbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzylcarbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding (a process generally referred to as "protecting") and removing (a process generally referred to as "deprotecting") such amine protecting groups are well known and available in the art, for example, PJ Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition (John Wiley & Sons, New York, 1999) and 4, which are incorporated herein by reference in their entirety. th It is available from Edition (John Wiley & Sons, New Jersey, 2014).

[0053] Some, but not limited to, suitable solvents that may be used in this disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (SiO), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0054] Some, but not limited to, suitable bases that may be used in this disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (NaOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N;TEA), diisopropyl-ethylamine (i-Pr2EtN;DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe;NaOCH3).

[0055] This disclosure includes pharmaceutically acceptable salts of the disclosed compounds. Salts of the compounds are formed between an acid and a compound with a basic group such as an amino functional group, or between a base and a compound with an acidic group such as a carboxyl functional group.

[0056] As used herein, the term “pharmaceutically acceptable” means a component that, within the bounds of sound medical judgment, is suitable for use in contact with human and other mammalian tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. “pharmaceutically acceptable salt” means any non-toxic salt that can directly or indirectly provide the compounds of this disclosure to a recipient upon administration. Preferred pharmaceutically acceptable salts are disclosed, for example, in SMBerge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0057] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, capries, acrylates, formates, isobutyrates, caprinates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dicarboxylates, hexin-1,6-dicarboxylates. These include carboxylates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylenesulfons, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfons, propanesulfons, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed from mineral acids such as hydrochloric acid and hydrobromic acid, and those formed from organic acids such as maleic acid.

[0058] pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4This includes alkyl) 4 salts. This disclosure also assumes quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Preferred non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons and aryl sulfons. Other preferred non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

[0059] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0060] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to the amount of compound administered that produces the desired effect (e.g., improvement of symptoms of FSGS and / or NDKD, reduction of the severity or symptoms of FSGS and / or NDKD, and / or progression or reduction of symptoms of FSGS and / or NDKD). The exact amount of the effective dose depends on the therapeutic purpose and will be verifiable by those skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0061] As used herein, the term “treatment” and its derivatives refer to the slowing or cessation of disease progression. As used herein, “treatment” and its derivatives include, but are not limited to, complete or partial remission, a lower risk of renal failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events). Improvement or reduction in the severity of any of these symptoms can be readily assessed according to methods and techniques known or subsequently developed in the art.

[0062] When the terms “about” and “approximately” are used in relation to the dose, volume, or weight percentage of an ingredient in a composition or dosage form, they include a specific dose, volume, or weight percentage value or range of dose, volume, or weight percentage that is recognized by those skilled in the art as providing an equivalent pharmacological effect to that obtained by a particular dose, volume, or weight percentage.

[0063] As used herein, the term “ambient conditions” means room temperature, ambient conditions, and uncontrolled humidity conditions.

[0064] At least one entity selected from the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and / or any of the aforementioned deuterated derivatives, may be administered once daily, twice daily, or three times daily, for example, for the treatment of FS. In some embodiments, the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb) are selected from compounds 1 to 286 and compounds 287 to 465, any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. In some embodiments, at least one entity selected from the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives is administered once daily. In some embodiments, at least one entity selected from compounds 1 to 286, any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives is administered once daily. In some embodiments, at least one entity selected from the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and / or any of the aforementioned deuterated derivatives is administered twice daily. In some embodiments, at least one entity selected from compounds 1-286 and compounds 287-465, any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and / or any of the aforementioned deuterated derivatives, is administered twice daily. In some embodiments, at least one entity selected from compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and / or any of the aforementioned deuterated derivatives, is administered three times daily.In some embodiments, at least one entity selected from compounds 1-286 and compounds 287-465, any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and / or any of the aforementioned deuterated derivatives, is administered three times a day.

[0065] In some embodiments, at least one entity selected from compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb) in amounts of 2 mg to 1500 mg, 5 mg to 1000 mg, 10 mg to 500 mg, 20 mg to 300 mg, 20 mg to 200 mg, 30 mg to 150 mg, 50 mg to 150 mg, 60 mg to 125 mg, or 70 mg to 120 mg, 80 mg to 115 mg, 90 mg to 110 mg, 95 mg to 110 mg, or 100 mg to 105 mg, (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), a pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives is administered once, twice, or three times a day. In some embodiments, at least one entity selected from compounds 1-286 and compounds 287-465 in amounts of 2 mg to 1500 mg, 5 mg to 1000 mg, 10 mg to 500 mg, 20 mg to 300 mg, 20 mg to 200 mg, 30 mg to 150 mg, 50 mg to 150 mg, 60 mg to 125 mg, or 70 mg to 120 mg, 80 mg to 115 mg, 90 mg to 110 mg, 95 mg to 110 mg, or 100 mg to 105 mg, pharmaceutically acceptable salts of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives is administered once, twice, or three times a day.

[0066] A person skilled in the art will recognize that, when the amount of a compound is disclosed, the relative amount of the pharmaceutically acceptable salt form of the compound is equal to the concentration of the free base of the compound. The amounts of compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "at least one compound in 10 mg selected from the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), and their pharmaceutically acceptable salts" includes 10 mg of the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), and concentrations of pharmaceutically acceptable salts of the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb) equivalent to 10 mg of the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb). Compounds and compositions

[0067] In addition to compounds, deuterated derivatives, solvates, and pharmaceutically acceptable salts of compounds of formula (I), in some embodiments, at least one entity of the present disclosure is a compound of formula (Ia), [ka] A pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives are selected, in the formula, (i) Each R1 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • -OC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)OC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups • C1-C6 linear, branched, and cyclic haloalkoxy groups, • Benzyloxy group, benzylamino group, or benzylthio group • 3-6 member heterocycloalkenyl groups, • 3-6 member heterocycloalkyl groups, and • 5- and 6-membered heteroaryl groups, or The two R1 groups, together with the carbon atoms to which they are bonded, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group. (ii) Each R2 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups, (iii)m is selected from 0, 1, 2, 3, and 4, (iv)n is selected from 0, 1, 2, 3, 4, and 5, (v)X is selected from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, and the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with at least one group selected from the following: o C1-C6 alkyl groups, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, (vi) Y is selected from divalent C1-C8 linear, branched, and cyclic alkyl groups, divalent C1-C8 linear, branched, and cyclic alkoxy groups, divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with at least one group selected from the following: o C1-C6 alkyl groups, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, (vii)o is selected from 0, 1, 2, 3, and 4, (viii)p is selected from 0, 1, 2, 3, and 4, (ix) R3 and R4 are selected independently from the following: Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups, which are optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkoxy groups, and C1-C6 cyclic alkyl groups, which are optionally substituted with at least one group selected from amide groups. • A heterocyclic group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • An aryl group which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and an aryl group which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • A heteroaryl group optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with at least one group selected from hydroxyl, amino, and C1-C6 linear, branched, and cyclic alkoxy groups. o Amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups, which are optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and (vi) Each R5 is selected independently from the following: Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • C1-C6 linear and branched alkyl groups.

[0068] In some embodiments, R3 is hydrogen or methyl.

[0069] In some embodiments, R3 is hydrogen.

[0070] In some embodiments, each R1 is selected independently from the halogen group.

[0071] In some embodiments, each R1 is a fluoropolymer.

[0072] In some embodiments, each R2 is independently selected from halogen groups and methyl groups.

[0073] In some embodiments, each R2 is selected independently of the halogen group.

[0074] In some embodiments, each R2 is fluorocarbon.

[0075] In some embodiments, m is 1 or 2.

[0076] In some embodiments, m is 2.

[0077] In some embodiments, n is 1 or 2.

[0078] In some embodiments, o is 1.

[0079] In some embodiments, p is 1.

[0080] In some embodiments, o is 0.

[0081] In some embodiments, p is 0.

[0082] In some embodiments, R5 is hydrogen.

[0083] In some embodiments, at least one entity is a compound of formula (II), [ka] A pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives are selected, in the formula, (i) Each R1 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • -OC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)OC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups • C1-C6 linear, branched, and cyclic haloalkoxy groups, • Benzyloxy group, benzylamino group, or benzylthio group • 3-6 member heterocycloalkenyl groups, • 3-6 member heterocycloalkyl groups, and • 5- and 6-membered heteroaryl groups, or The two R1 groups, together with the carbon atoms to which they are bonded, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group. (ii) Each R2 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups, (iii)m is selected from 0, 1, 2, 3, and 4, (iv)n is selected from 0, 1, 2, 3, 4, and 5, (v) R3 and R4 are selected independently from the following: Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups, which are optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkoxy groups, and C1-C6 cyclic alkyl groups, which are optionally substituted with at least one group selected from amide groups. • A heterocyclic group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • An aryl group which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and an aryl group which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • A heteroaryl group optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with at least one group selected from hydroxyl, amino, and C1-C6 linear, branched, and cyclic alkoxy groups. o Amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups, which are optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and (vi) Each R5 is selected independently from the following: Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • C1-C6 linear and branched alkyl groups.

[0084] In some embodiments, each R1 is independently selected from a halogen group and C1-C6 linear and branched alkyl groups, each R2 is independently selected from a halogen group and C1-C6 linear and branched alkyl groups, m is selected from 0, 1, 2, and 3, and n is 1 or 2.

[0085] In some embodiments, each R1 is independently selected from a halogen group and a methyl group, each R2 is independently selected from a halogen group and a methyl group, m is 0, 1, or 2, and n is 1 or 2.

[0086] In some embodiments, each R1 is a fluoropolymer.

[0087] In some embodiments, each R2 is fluorocarbon.

[0088] In some embodiments, m is 0, 1, or 2.

[0089] In some embodiments, m is 2.

[0090] In some embodiments, m is 0.

[0091] In some embodiments, n is 1 or 2.

[0092] In some embodiments, n is 1.

[0093] In some embodiments, R5 is selected from hydrogen, amino, alkyl, and halo.

[0094] In some embodiments, R5 is selected from hydrogen and C1-C6 linear alkyl groups.

[0095] In some embodiments, R5 is hydrogen.

[0096] In some embodiments, R3 is selected from hydrogen and C1-C6 linear or branched alkyl groups.

[0097] In some embodiments, R3 is selected from hydrogen and methyl.

[0098] In some embodiments, R4 is selected from the following: C1-C6 linear and branched alkyl groups, which are optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups.

[0099] In some embodiments, R4 is selected from the following: C1-C6 linear and branched alkyl groups, which are optionally substituted with at least one group selected from the following: o Hydroxy, o Amide groups, which are optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups, and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, and o A 5 or 6-membered heteroaryl group, which is optionally substituted with one or two groups selected from hydroxyl and C1-C6 linear and branched alkyl groups.

[0100] In some embodiments, R4 is selected from the following: C1-C6 linear and branched alkyl groups, which are optionally substituted with at least one group selected from the following: o Hydroxy, o Amide group optionally substituted with one or two groups selected from C1-C6 linear alkyl groups, A 5- or 6-membered heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear alkyl groups.

[0101] In some embodiments, R3 and R4, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following. o Hydroxy, o C1-C6 linear alkyl groups, and o An amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups.

[0102] In some embodiments, at least one entity is a compound of formula (IIIa), [ka] Compound of formula (IIIb) [ka] A selection from any of the aforementioned pharmaceutically acceptable salts, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, in the formula, (i) Each R1 is independently selected from the following: • Halogen group, · hydroxy, · thiol, · amino, · cyano, · -OC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, · -C(O)OC1-C6 straight-chain, branched, and cyclic alkyl groups, · -NHC(O)C1-C6 straight-chain, branched, and cyclic alkyl groups, · -C(O)NHC1-C6 straight-chain, branched, and cyclic alkyl groups, · -NHC(O)aryl group, · -C(O)NHaryl group, · -NHC(O)heteroaryl group, · -C(O)NHheteroaryl group, · -NHS(O)2C1-C6 straight-chain, branched, and cyclic alkyl groups, · -S(O)2NHC1-C6 straight-chain, branched, and cyclic alkyl groups, · -NHS(O)2aryl group, · -S(O)2NHaryl group, · -NHS(O)2heteroaryl group, · -S(O)2NHheteroaryl group, · -NHC(O)NHC1-C6 straight-chain, branched, and cyclic alkyl groups, · -NHC(O)NHaryl group, · -NHC(O)NHheteroaryl group, · C1-C6 straight-chain, branched, and cyclic alkyl groups, · C2-C6 straight-chain, branched, and cyclic alkenyl groups, · C1-C6 straight-chain, branched, and cyclic hydroxyalkyl groups, · C1-C6 straight-chain, branched, and cyclic alkoxy groups, · C1-C6 straight-chain, branched, and cyclic thioalkyl groups, · C1-C6 straight-chain, branched, and cyclic haloalkyl groups, · C1-C6 straight-chain, branched, and cyclic haloaminoalkyl groups, • C1-C6 linear, branched, and cyclic halothioalkyl groups • C1-C6 linear, branched, and cyclic haloalkoxy groups, • Benzyloxy group, benzylamino group, or benzylthio group • 3-6 member heterocycloalkenyl groups, • 3-6 member heterocycloalkyl groups, and • 5- and 6-membered heteroaryl groups, or The two R1 groups, together with the carbon atoms to which they are bonded, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group. (ii) Each R2 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C4 linear, branched, and cyclic alkyl groups, · C2-C4 linear, branched, and cyclic alkenyl groups, · C1-C4 linear, branched, and cyclic hydroxyalkyl groups, · C1-C4 linear, branched, and cyclic alkoxy groups, · C1-C4 linear, branched, and cyclic thioalkyl groups, · C1-C4 linear, branched, and cyclic haloalkyl groups, · C1-C4 linear, branched, and cyclic haloaminoalkyl groups, · C1-C4 linear, branched, and cyclic halothioalkyl groups, and · C1-C4 linear, branched, and cyclic haloalkoxy groups, (iii) m is selected from 0, 1, [2, 3], and 4, [[ID=!]]The number "2" in the original text is enclosed in brackets. In the translation, it is enclosed in square brackets as well, following the same format for special handling of numbers within brackets. (iv) n is selected from 0, 1, 2, 3, 4, and 5, (v) R3 and R4 are independently selected from the following, · hydrogen, · C1-C6 linear and branched alkylsulfonyl groups, · C1-C6 cyclic alkyl groups optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy and C1-C6 linear and branched alkoxy groups, and amide groups, · heterocyclic groups optionally substituted with at least one group selected from halogen groups, hydroxy, hydroxy and C1-C6 linear and branched alkoxy groups, · aryl groups optionally substituted with at least one group selected from halogen groups, hydroxy, hydroxy and C1-C6 linear and branched alkoxy groups, [[ID=!]]The repeated "hydroxy" in the original text is translated as "hydroxy" again in the translation to maintain the exact text structure. · heteroaryl groups optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with at least one group selected from hydroxyl, amino, and C1-C6 linear, branched, and cyclic alkoxy groups. o Amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups, which are optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and (vi) Each R5 is a compound independently selected from the following: Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • C1-C6 linear and branched alkyl groups.

[0103] In some embodiments, each R1 is independently selected from a halogen group and C1-C6 linear and branched alkyl groups, each R2 is independently selected from a halogen group and C1-C6 linear and branched alkyl groups, m is selected from 0, 1, 2, and 3, and n is 1 or 2.

[0104] In some embodiments, each R1 is independently selected from a halogen group and a methyl group, each R2 is independently selected from a halogen group and a methyl group, m is 0, 1, or 2, and n is 1 or 2.

[0105] In some embodiments, each R1 is a fluoropolymer.

[0106] In some embodiments, each R2 is fluorocarbon.

[0107] In some embodiments, m is 0, 1, or 2.

[0108] In some embodiments, m is 2.

[0109] In some embodiments, m is 0.

[0110] In some embodiments, n is 1 or 2.

[0111] In some embodiments, n is 1.

[0112] In some embodiments, R5 is selected from hydrogen, amino, alkyl, and halo.

[0113] In some embodiments, R5 is selected from hydrogen and C1-C6 linear alkyl groups.

[0114] In some embodiments, R5 is hydrogen.

[0115] In some embodiments, R3 is selected from hydrogen and C1-C6 linear or branched alkyl groups.

[0116] In some embodiments, R3 is selected from hydrogen and methyl.

[0117] In some embodiments, R4 is selected from C1-C6 linear and branched alkyl groups that are optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups.

[0118] In some embodiments, R4 is selected from C1-C6 linear and branched alkyl groups that are optionally substituted with at least one group selected from the following: o Hydroxy, o Amide groups, which are optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups, and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, and o A 5 or 6-membered heteroaryl group, which is optionally substituted with one or two groups selected from hydroxyl and C1-C6 linear and branched alkyl groups.

[0119] In some embodiments, R4 is selected from C1-C6 linear and branched alkyl groups that are optionally substituted with at least one group selected from the following: o Hydroxy, o Amide group optionally substituted with one or two groups selected from C1-C6 linear alkyl groups, A 5- or 6-membered heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear alkyl groups.

[0120] In some embodiments, R3 and R4, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following. o Hydroxy, o C1-C6 linear alkyl groups, and o An amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups.

[0121] In some embodiments, at least one entity of the present disclosure is a compound of formula (IV), [ka] A pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives are selected, in the formula, (i) Each R1 and R2 is independently selected from the following: Fluoro, Chlorophyll, Bromo, · Cyano, Methyl, • Cyclopropyl, • Ethyl, • Hydroxypropyl, Isopropyl, • Propen-2-yl, • Dihydrofuran, • Fran, and • Methoxy, (ii) R3 and R4 are selected independently from the following: Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups, which are optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkoxy groups, and C1-C6 cyclic alkyl groups, which are optionally substituted with at least one group selected from amide groups. • A heterocyclic group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • An aryl group which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and an aryl group which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • A heteroaryl group optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with at least one group selected from hydroxyl, amino, and C1-C6 linear, branched, and cyclic alkoxy groups. o Amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups, which are optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and (iii) Each R5 is Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • Independently selected from C1-C6 linear and branched alkyl groups.

[0122] In some embodiments, R3 is hydrogen, and R4 is independently selected from the following: • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups, which are optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkoxy groups, and C1-C6 cyclic alkyl groups, which are optionally substituted with at least one group selected from amide groups. • A heterocyclic group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • An aryl group which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and an aryl group which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • A heteroaryl group optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups.

[0123] In some embodiments, R4 is independently selected from a halogen group, a C1-C6 linear and branched alkyl group optionally substituted with one or two groups selected from a halogen group, a hydroxyl group, a hydroxyl group, and a C1-C6 linear and branched alkyl group, and an amide group, and R3 is independently selected from the following: • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups, which are optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkoxy groups, and C1-C6 cyclic alkyl groups, which are optionally substituted with at least one group selected from amide groups. • A heterocyclic group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • An aryl group which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and an aryl group which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • A heteroaryl group optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups.

[0124] In some embodiments, R3 and R4, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following. o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with at least one group selected from hydroxyl, amino, and C1-C6 linear, branched, and cyclic alkoxy groups. o Amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups, which are optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups.

[0125] In some embodiments, in at least one entity selected from the compounds of formulas (I), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, each R1 and R2 is independently selected from fluoro, chloro, bromo, cyano, and methyl.

[0126] In some embodiments, at least one entity of the present disclosure is selected from compounds 1 to 286 illustrated in Table 1, and any pharmaceutically acceptable salts of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. The dashed lines in the compounds of Table 1 (i.e., [ka] ) indicates a bond between two atoms and represents the mixed stereochemical position of a group of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32]

[0127] In some embodiments, at least one entity of the present disclosure is selected from compounds 287-465 illustrated in Table 2, and any pharmaceutically acceptable salts of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. The dashed lines in the compounds in Table 2 (i.e., [ka] ) indicates a bond between two atoms and shows the mixed stereochemical position of a set of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14]

[0128] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), compounds 1-286 (Table 1) and compounds 287-465 (Table 2), pharmaceutically acceptable salts of any of these compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. In some embodiments, a pharmaceutical composition comprising at least one compound selected from formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), compounds 1-286 and compounds 287-465, pharmaceutically acceptable salts of any of these compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives is administered to a patient in need.

[0129] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, at least one pharmaceutically acceptable is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0130] The pharmaceutical compositions of this disclosure can be used in combination therapy, and it will be understood that the pharmaceutical compositions described herein may further include at least one other effective therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound selected from the compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvated compounds, and any of the aforementioned deuterated derivatives may be administered as a separate composition simultaneously with, before, or after, a composition comprising at least one other effective therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound selected from compounds 1-286 (Table 1) and compounds 287-465 (Table 2), tautomers of those compounds, any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvated compounds, and any of the aforementioned deuterated derivatives may be administered as a separate composition simultaneously with, before, or after, a composition comprising at least one other effective therapeutic agent.

[0131] As described above, the pharmaceutical compositions disclosed herein may optionally further include at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. When used herein, the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersing aids, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except for any conventional carrier being incompatible with the compounds of this disclosure by, for example, producing some undesirable biological effect or interacting in a detrimental manner with any other component(s) of the pharmaceutical composition, its use is intended to be within the scope of this disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates, glycine, sorbic acid, and potassium sorbate), partially glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (sodium carboxymethylcellulose). This includes, but is not limited to, ethylcellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogenic substance-removed water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants.

[0132] In some embodiments of this disclosure, the compounds and pharmaceutical compositions described herein are used to treat APOL1-mediated kidney disease. In some embodiments, APOL1-mediated kidney disease is selected from ESKD, FSGS, HIV-associated nephropathy, NDKD, arterial nephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated kidney disease treated with the compounds, deuterated derivatives, pharmaceutically acceptable salts, and / or compositions of the present invention is FSGS. In some embodiments, the APOL1-mediated kidney disease treated with the compounds, deuterated derivatives, pharmaceutically acceptable salts, and / or compositions of the present invention is NDKD. In some embodiments, the APOL1-mediated kidney disease treated with the compounds, deuterated derivatives, pharmaceutically acceptable salts, and / or compositions of the present invention is ESKD. In some embodiments, a patient having the APOL1-mediated kidney disease treated with the compounds, deuterated derivatives, pharmaceutically acceptable salts, and / or compositions of the present invention has two APOL1 risk alleles. In some embodiments, patients with APOL1-mediated kidney disease are homozygous for the APOL1 gene risk allele G1:S342G:I384M. In some embodiments, patients with APOL1-mediated kidney disease are homozygous for the APOL1 gene risk allele G2:N388del:Y389del. In some embodiments, patients with APOL1-mediated kidney disease are heterozygous for both the APOL1 gene risk alleles G1:S342G:I384M and G2:N388del:Y389del.

[0133] In some embodiments, the disclosed method involves administering at least one entity selected from the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, to a patient in need. In some embodiments, the compound of formula (I) is selected from compounds 1 to 286 (Table 1) and compounds 287 to 465 (Table 2), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. In some embodiments, the aforementioned patient in need has a genetic variant of APOL1, namely G1:S342G:I384M and G2:N388del:Y389del.

[0134] Another embodiment of the present disclosure provides a method for inhibiting APOL1 activity, comprising contacting the aforementioned APOL1 with at least one entity selected from the compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. In some embodiments, the method for inhibiting APOL1 activity comprises contacting the aforementioned APOL1 with at least one entity selected from the compounds 1 to 286 (Table 1) and compounds 287 to 465 (Table 2), any pharmaceutically acceptable salt of any of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. Non-exclusive exemplary embodiments 1. Compound of formula (I), [ka] A compound selected from the pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, wherein, (i) Ring A is a 3- to 7-membered ring, and the ring is a cyclic alkyl or heterocyclic ring. (ii) Q is N or CR 5And, (iii) Each R1 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • -OC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)OC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups • C1-C6 linear, branched, and cyclic haloalkoxy groups, • Benzyloxy group, benzylamino group, or benzylthio group • 3-6 member heterocycloalkenyl groups, • 3-6 member heterocycloalkyl groups, and • 5- and 6-membered heteroaryl groups, or The two R1 groups, together with the carbon atoms to which they are bonded, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group. (iv) Each R2 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups, (v)m is selected from 0, 1, 2, 3, and 4, (vi)n is selected from 0, 1, 2, 3, 4, and 5. (vii)X is selected from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, and the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with one to four groups independently selected from the following: o C1-C6 alkyl groups, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, (viii)Y is selected from divalent amino, divalent oxygen, divalent C1-C8 linear, branched, and cyclic alkyl groups, divalent C1-C8 linear, branched, and cyclic alkoxy groups, divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, where the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with one to three groups independently selected from the following: o C1-C6 alkyl groups optionally substituted with hydroxyl, o C3-C6 cyclic alkyl, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, Alternatively, divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups may be optionally fused with C3-C6 cyclic alkyl groups. (ix)o is selected from 0, 1, 2, 3, and 4. (x)p is selected from 0, 1, 2, 3, and 4. (xi) R3 and R4 are selected independently from the following: Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 linear and branched alkoxy groups optionally substituted with C3-C6 cyclic alkyl groups or 3-6 membered heterocycles. • A C1-C6 cyclic alkyl group which is optionally substituted with one to four groups independently selected from the following: o halogen group, o Hydroxy, o Oxo, o C1-C6 linear and branched alkoxy groups, o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, and o Amide group, • A heterocyclic group which is arbitrarily substituted with one to four groups independently selected from the following: o halogen group, o Oxo, o Hydroxy, and o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, • An aryl group which is optionally substituted with one to four groups which are optionally substituted with halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups which are optionally substituted with one or two groups which are optionally substituted with hydroxyl groups and C1-C6 linear and branched alkoxy groups, • A heteroaryl group optionally substituted with one to four groups independently selected from hydroxyl and C1-C6 linear alkyl groups, and · C 1- C7 linear and branched alkyl groups, which are optionally substituted with one to five groups independently selected from the following: 1- C7 linear and branched alkyl groups, o Amino group, o Hydroxy, o Oxo, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups. o C3-C6 cyclic alkyl group, which is optionally substituted with one or two groups independently selected from a halogen group, a C1-C6 linear and branched alkoxy group, a C1-C6 linear and branched alkyl group optionally substituted with one or two hydroxyl groups, and a hydroxyl group, o C2-C6 linear and branched alkynyl groups, o C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group which is optionally substituted with one or two groups which are optionally substituted with halogen groups, hydroxy, hydroxy and C1-C6 linear and branched alkyl groups which are optionally substituted with one or two o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 membered heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups, and, o A 4-10 member heteroaryl group, which is optionally substituted with one to three groups independently selected from a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkyl group, which is optionally substituted with one to three groups independently of a halogen group, a halogen group, and a C1-C6 linear and branched alkoxy group. Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4-10 membered heterocyclyl group which is optionally substituted with one to four groups independently selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, including hydroxyl, amino, C1-C6 linear, branched, and cyclic alkoxy groups, oxo 、 and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkyl groups, C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently selected from o Amide groups optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently selected from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups. o A 4-10 member heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups independently selected from halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups, and (xii) R5 does not exist, or is selected from the following: Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • C1-C6 linear and branched alkyl groups, In the formula, if R5 is absent, Q is the bridgehead atom in the compound. 2. The compound, deuterated derivative, or pharmaceutically acceptable salt described in Embodiment 1, wherein ring A is a 4- to 6-membered ring. 3. The compound, deuterated derivative, or pharmaceutically acceptable salt described in Embodiment 2, wherein ring A is a four-membered ring. 4. The compound, deuterated derivative, or pharmaceutically acceptable salt described in Embodiment 2, wherein ring A is cyclobutyl. 5. Ring A is [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound described in Embodiment 2. 6.Q is CR 5The compound, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 4. 7. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 6, wherein each R1 is independently selected from the following. • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkoxy groups. 8. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 7, wherein each R1 is independently selected from a halogen group and a C1-C6 linear, branched, and cyclic haloalkyl group. 9. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 8, wherein each R1 is independently selected from fluoro and CF3. 10. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 9, wherein each R1 is fluoro. 11. Compounds, deuterated derivatives, or pharmaceutically acceptable salts according to Embodiments 1 to 10, wherein each R2 is independently selected from the following. • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups. 12. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 11, wherein each R2 is independently selected from a halogen group. 13. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 12, wherein each R2 is fluoro. 14. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 13, wherein m is 2. 15. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 14, wherein n is 1. 16. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 15, wherein X is selected from divalent C1-C8 linear, branched, and cyclic alkyl groups, and the divalent alkyl group is optionally substituted with one to four groups selected from the following. o C1-C6 alkyl groups, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o Amino. 17. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 16, wherein X is selected from -CH2- and -CH2-CH2-. 18. Y is selected from divalent amino, divalent oxygen, divalent C1-C8 linear, branched, and cyclic alkyl groups, and divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, and the divalent alkyl groups and divalent aminoalkyl groups are optionally substituted with one to three groups independently selected from the following: o C1-C6 alkyl groups optionally substituted with hydroxyl, o C3-C6 cyclic alkyl, o Oxo, and o Hydroxy, Alternatively, a compound, salt, or deuterated derivative according to any one of Embodiments 1 to 17, wherein a divalent alkyl group, a divalent alkoxy group, a divalent aminoalkyl group, and a divalent thioalkyl group are optionally fused with a C3-C6 cyclic alkyl group. 19.Y is, [ka] A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 18, selected from the above. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 19, wherein 20.o is 0. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 19, wherein 21.o is 1. 22. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 21, wherein p is 0. 23. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 21, wherein p is 1. 24. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 23, wherein R3 is hydrogen and R4 is selected from the following. Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 linear and branched alkoxy groups optionally substituted with C3-C6 cyclic alkyl groups or 3-6 membered heterocycles. • A C1-C6 cyclic alkyl group which is optionally substituted with one to four groups independently selected from the following: o halogen group, o Hydroxy, o Oxo, o C1-C6 linear and branched alkoxy groups, o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, and o Amide group, • A heterocyclic group which is arbitrarily substituted with one to four groups independently selected from the following: o halogen group, o Oxo, o Hydroxy, and o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, • A heteroaryl group optionally substituted with one to four groups independently selected from hydroxyl and C1-C6 linear alkyl groups, and · C 1- C7 linear and branched alkyl groups, which are optionally substituted with one to five groups independently selected from the following: 1- C7 linear and branched alkyl groups, o Amino group, o Hydroxy, o Oxo, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups. o C3-C6 cyclic alkyl group, which is optionally substituted with one or two groups independently selected from a halogen group, a C1-C6 linear and branched alkoxy group, a C1-C6 linear and branched alkyl group optionally substituted with one or two hydroxyl groups, and a hydroxyl group, o C2-C6 linear and branched alkynyl groups, o C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 membered heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups, and, o A 4-10 membered heteroaryl group, wherein one to three groups are optionally substituted with a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkyl group, which are optionally substituted with one to three groups independently of a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkoxy group. 25. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 23, wherein R3 and R4, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocyclyl group which is optionally substituted with one to four groups independently selected from the following. o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and hydroxy and C1-C6 linear and branched alkyl groups, and C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with one to four groups independently selected from o Amide groups optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently selected from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups. o A 4-10 member heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups independently selected from a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkyl group, which is optionally substituted with one or two groups independently selected from a hydroxyl group and a C1-C6 linear and branched alkoxy group. 26. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 25, wherein R5 is independently selected from hydrogen, a halogen group, and a C1-C6 linear and branched alkyl group. 27. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 26, wherein R5 is independently selected from hydrogen, fluoro, and methyl. 28. Compounds of formulas (Va) and (Vb), [ka] Selected from the pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, where R 1 , R 2 , R 3 , R 4 The compound, salt, or deuterated derivative according to Embodiment 1, wherein , Y, and p are as defined in Embodiment 1. 29. The compounds, deuterated derivatives, or pharmaceutically acceptable salts described in Embodiment 28, wherein each R1 is independently selected from the following. • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkoxy groups. 30. Compounds, deuterated derivatives, or pharmaceutically acceptable salts according to Embodiment 28 or 29, wherein each R1 is independently selected from a halogen group and a C1-C6 linear, branched, and cyclic haloalkyl group. 31. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 28-30, wherein each R1 is independently selected from fluoro and CF3. 32. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 28 to 31, wherein each R1 is fluoro. 33. R2 is a compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 28 to 32, selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups. 34. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 28 to 33, wherein R2 is selected from halogen groups. 35. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 28 to 34, wherein R2 is fluoro. 36.Y is selected from divalent amino, divalent oxygen, divalent C1-C8 linear, branched, and cyclic alkyl groups, and divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, and the divalent alkyl groups and divalent aminoalkyl groups are optionally substituted with one to three groups independently selected from the following: o C1-C6 alkyl groups optionally substituted with hydroxyl, o C3-C6 cyclic alkyl, o Oxo, and o Hydroxy, Alternatively, a compound, salt, or deuterated derivative according to any one of Embodiments 28 to 35, wherein a divalent alkyl group, a divalent alkoxy group, a divalent aminoalkyl group, and a divalent thioalkyl group are optionally fused to a C3-C6 cyclic alkyl group. 37.Y is, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 28 to 36, selected from the above. 38. A compound, salt, or deuterated derivative according to any one of embodiments 28 to 37, wherein p is 0. 39. A compound, salt, or deuterated derivative according to any one of Embodiments 28 to 37, wherein p is 1. 40. A compound, salt, or deuterated derivative according to any one of Embodiments 28 to 39, wherein R3 is hydrogen and R4 is selected from the following. Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 linear and branched alkoxy groups optionally substituted with C3-C6 cyclic alkyl groups or 3-6 membered heterocycles. • A C1-C6 cyclic alkyl group which is optionally substituted with one to four groups independently selected from the following: o halogen group, o Hydroxy, o Oxo, o C1-C6 linear and branched alkoxy groups, o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, and o Amide group, • A heterocyclic group which is arbitrarily substituted with one to four groups independently selected from the following: o halogen group, o Oxo, o Hydroxy, and o C1-C6 linear and branched alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxyl and C1-C6 linear and branched alkoxy groups, • A heteroaryl group optionally substituted with one to four groups independently selected from hydroxyl and C1-C6 linear alkyl groups, and · C 1- C7 linear and branched alkyl groups, which are optionally substituted with one to five groups independently selected from the following: 1- C7 linear and branched alkyl groups, o Amino group, o Hydroxy, o Oxo, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups. o C3-C6 cyclic alkyl group, which is optionally substituted with one or two groups independently selected from a halogen group, a C1-C6 linear and branched alkoxy group, a C1-C6 linear and branched alkyl group optionally substituted with one or two hydroxyl groups, and a hydroxyl group, o C2-C6 linear and branched alkynyl groups, o C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 membered heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups, and, o A 4-10 membered heteroaryl group, wherein one to three groups are optionally substituted with a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkyl group, which are optionally substituted with one to three groups independently of a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkoxy group. 41. A compound, salt, or deuterated derivative according to any one of Embodiments 28 to 39, wherein R3 and R4, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocyclyl group which is optionally substituted with one to four groups independently selected from the following. o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with one or two groups independently selected from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and hydroxy and C1-C6 linear and branched alkyl groups, and C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with one to four groups independently selected from o Amide groups optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with one to four groups independently selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently selected from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups. o A 4-10 member heterocyclyl group, which is optionally substituted with one or two groups independently selected from halogen groups, hydroxyl groups, and C1-C6 linear and branched alkyl groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups independently selected from a halogen group, a hydroxyl group, and a C1-C6 linear and branched alkyl group, which is optionally substituted with one or two groups independently selected from a hydroxyl group and a C1-C6 linear and branched alkoxy group. 42. Compound of formula (Ia), [ka] A compound selected from the pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, wherein, (i) Each R1 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • -OC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)OC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups • C1-C6 linear, branched, and cyclic haloalkoxy groups, • Benzyloxy group, benzylamino group, or benzylthio group • 3-6 member heterocycloalkenyl groups, • 3-6 member heterocycloalkyl groups, and • 5- and 6-membered heteroaryl groups, or The two R1 groups, together with the carbon atoms to which they are bonded, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group. (ii) Each R2 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups, (iii)m is selected from 0, 1, 2, 3, and 4, (iv)n is selected from 0, 1, 2, 3, 4, and 5, (v)X is selected from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, and the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with at least one group selected from the following: o C1-C6 alkyl groups, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, (vi) Y is selected from divalent C1-C8 linear, branched, and cyclic alkyl groups, divalent C1-C8 linear, branched, and cyclic alkoxy groups, divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with at least one group selected from the following: o C1-C6 alkyl groups, o aryl group, o Heteroaryl group, o halogen group, o Hydroxy, and o amino, (vii)o is selected from 0, 1, 2, 3, and 4, (viii)p is selected from 0, 1, 2, 3, and 4, (ix) R3 and R4 are selected independently from the following: Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups, which are optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkoxy groups, and C1-C6 cyclic alkyl groups, which are optionally substituted with at least one group selected from amide groups. • A heterocyclic group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • An aryl group which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and an aryl group which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • A heteroaryl group optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with at least one group selected from hydroxyl, amino, and C1-C6 linear, branched, and cyclic alkoxy groups. o Amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups, which are optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and (vi) Each R5 is a compound independently selected from the following: Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • C1-C6 linear and branched alkyl groups. 43. The compound, salt, or deuterated derivative according to Embodiment 42, wherein R3 is hydrogen or methyl. 44. A compound, salt, or deuterated derivative according to Embodiment 42 or 43, wherein R3 is hydrogen. 45. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 44, wherein each R1 is independently selected from a halogen group. 46. ​​A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 42 to 45, wherein each R1 is fluoro. 47. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 46, wherein each R2 is independently selected from a halogen group and a methyl group. 48. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 47, wherein each R2 is independently selected from a halogen group. 49. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 48, wherein each R2 is fluoro. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 49, wherein m is 1 or 2. 51. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 50, wherein m is 2. 52. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 51, wherein n is 1 or 2. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 52, wherein 53.o is 1. 54. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 53, wherein p is 1. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 52 or 54, wherein 55.o is 0. 56. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 51 or 53, wherein p is 0. 57. A compound, salt, or deuterated derivative according to any one of Embodiments 42 to 56, wherein R5 is hydrogen. 58. Compound of formula (II), [ka] A pharmaceutically acceptable salt, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives are selected, in the formula, (i) Each R1 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, • -OC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)OC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C6 linear, branched, and cyclic alkyl groups, • C2-C6 linear, branched, and cyclic alkenyl groups, • C1-C6 linear, branched, and cyclic hydroxyalkyl groups, • C1-C6 linear, branched, and cyclic alkoxy groups, • C1-C6 linear, branched, and cyclic thioalkyl groups, • C1-C6 linear, branched, and cyclic haloalkyl groups, • C1-C6 linear, branched, and cyclic haloaminoalkyl groups • C1-C6 linear, branched, and cyclic halothioalkyl groups • C1-C6 linear, branched, and cyclic haloalkoxy groups, • Benzyloxy group, benzylamino group, or benzylthio group • 3-6 member heterocycloalkenyl groups, • 3-6 member heterocycloalkyl groups, and • 5- and 6-membered heteroaryl groups, or The two R1 groups, together with the carbon atoms to which they are bonded, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group. (ii) Each R2 is independently selected from the following: • Halogen group, • Hydroxyl • Thiol, • Amino, · Cyano, -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, • -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)aryl group, -C(O)NH aryl group, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, • -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2 aryl group, -S(O)2NH aryl group, -NHS(O)2 heteroaryl group, -S(O)2NH heteroaryl group, -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, -NHC(O)NH aryl group, -NHC(O)NH heteroaryl group, • C1-C4 linear, branched, and cyclic alkyl groups, • C2-C4 linear, branched, and cyclic alkenyl groups, • C1-C4 linear, branched, and cyclic hydroxyalkyl groups, • C1-C4 linear, branched, and cyclic alkoxy groups, • C1-C4 linear, branched, and cyclic thioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkyl groups • C1-C4 linear, branched, and cyclic haloaminoalkyl groups • C1-C4 linear, branched, and cyclic halothioalkyl groups, • C1-C4 linear, branched, and cyclic haloalkoxy groups, (iii)m is selected from 0, 1, 2, 3, and 4, (iv)n is selected from 0, 1, 2, 3, 4, and 5, (v) R3 and R4 are selected independently from the following: Hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups, which are optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkoxy groups, and C1-C6 cyclic alkyl groups, which are optionally substituted with at least one group selected from amide groups. • A heterocyclic group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • An aryl group which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and an aryl group which is optionally substituted with at least one group selected from C1-C6 linear and branched alkyl groups. • A heteroaryl group optionally substituted with at least one group selected from C1-C6 linear alkyl groups, and • C1-C6 linear and branched alkyl groups, wherein the alkyl group is optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Carboxylic acid, o halogen group, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o C optionally substituted with one or two groups selected from halogen groups and hydroxyl groups 3- C6 cyclic alkyl group, o C1-C6 linear and branched alkynyl groups, o C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxyl group, o C1-C6 linear and branched alkylsulfonyl groups, o An aryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, an aryl group which is optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, o Carbonyl-(4-methylpiperazine-1-yl), o carbonyl-(N-morpholino), o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, Alternatively, R3 and R4, together with the nitrogen atom to which they are bonded, may form a 4- to 10-membered heterocyclyl group which is optionally substituted with at least one group selected from the following: o Hydroxy, o Oxo, o C1-C6 linear, branched, and cyclic alkyl groups, which are optionally substituted with at least one group selected from hydroxyl, amino, and C1-C6 linear, branched, and cyclic alkoxy groups. o Amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o A carboxamide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups, which are optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and (vi) Each R5 is a compound independently selected from the following: Hydrogen, • Halogen group, • Hydroxyl • Thiol, • Amino acids, and • C1-C6 linear and branched alkyl groups. 59. (i) Each R1 is independently selected from the following: • Halogen groups, and • C1-C6 linear, branched, and cyclic alkyl groups, (ii) Each R2 is independently selected from the following: • Halogen groups, and • C1-C6 linear, branched, and cyclic alkyl groups, (iii)m is selected from 0, 1, 2, and 3, (iv) The compound, salt, or deuterated derivative according to Embodiment 58, wherein n is 1 or 2. 60. (i) Each R1 is independently selected from the following: • Halogen groups, and Methyl, (ii) Each R2 is independently selected from the following: • Halogen groups, and Methyl, (iii)m is 0, 1, or 2, and (iv) The compound, salt, or deuterated derivative according to Embodiment 58 or 59, wherein n is 1 or 2. 61. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 60, wherein each R1 is fluoro. 62. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 61, wherein each R2 is fluoro. 63. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 62, wherein m is 0, 1, or 2. 64. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 63, wherein m is 2. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 63, wherein m is 0. 66. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 65, wherein n is 1 or 2. 67. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 65, wherein n is 1. 68. A compound, salt, or deuterated derivative according to any one of Embodiments 58 to 67, wherein R5 is selected from hydrogen, amino, alkyl, and halo. 69. A compound, salt, or deuterated derivative according to any one of embodiments 58 to 67, wherein R5 is selected from hydrogen and a C1-C6 linear alkyl group. 70. A compound, salt, or deuterated derivative according to any one of Embodiments 58 to 69, wherein R5 is hydrogen. 71. A compound, salt, or deuterated derivative according to any one of Embodiments 58 to 70, wherein R3 is selected from hydrogen and C1-C6 linear and branched alkyl groups. 72. A compound, salt, or deuterated derivative according to any one of Embodiments 58 to 71, wherein R3 is selected from hydrogen and methyl. 73. R4 is a compound, salt, or deuterated derivative according to any one of embodiments 58 to 72, selected from the following: C1-C6 linear and branched alkyl groups, which are optionally substituted with at least one group selected from the following: o Amino group, o Hydroxy, o Cyano, o Amide group, which is optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o A 4-10 member heterocyclyl group, optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups, and a 4-10 member heterocyclyl group optionally substituted with one or two groups selected from C1-C6 linear and branched alkoxy groups, and o A 4-10 member heteroaryl group, which is optionally substituted with one or two groups selected from halogen groups, hydroxy, hydroxy, and C1-C6 linear and branched alkyl groups. 74. R4 is a compound, salt, or deuterated derivative according to any one of Embodiments 58 to 73, selected from the following: C1-C6 linear and branched alkyl groups, which are optionally substituted with at least one group selected from the following: o Hydroxy, o Amide groups, which are optionally substituted with one or two groups selected from C1-C6 linear, branched, and cyclic alkyl groups, and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, and o A 5 or 6-membered heteroaryl group, which is optionally substituted with one or two groups selected from hydroxyl and C1-C6 linear and branched alkyl groups. 75. R4 is a compound, salt, or deuterated derivative according to any one of embodiments 58 to 74, selected from the following: C1-C6 linear and branched alkyl groups, which are optionally substituted with at least one group selected from the following: o Hydroxy, o Amide group optionally substituted with one or two groups selected from C1-C6 linear alkyl groups, A 5- or 6-membered heteroaryl group optionally substituted with one or two groups selected from C1-C6 linear alkyl groups. 76. A compound, salt, or deuterated derivative according to any one of Embodiments 58 to 70, wherein R3 and R4, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group independently selected from the following. o Hydroxy, o C1-C6 linear alkyl groups, and o An amide group optionally substituted with at least one group selected from C1-C6 linear, branched, and cyclic alkyl groups. 77. Compounds selected from compounds 1-286 (Table 1), their pharmaceutically acceptable salts, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. 78. Compounds selected from compounds 287-465 (Table 2), their pharmaceutically acceptable salts, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives. 79. A pharmaceutical composition comprising a compound, salt, deuterated derivative, and a pharmaceutically acceptable carrier described in any one of Embodiments 1 to 78. 80. A method for treating APOL1-mediated renal disease, comprising administering to a patient in need of it a compound, salt, deuterated derivative according to any one of Embodiments 1 to 78 or a pharmaceutical composition according to Embodiment 79. 81. The method according to Embodiment 80, wherein APOL1-mediated renal disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterial nephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. 82. The method according to Embodiment 80, wherein APOL1-mediated renal disease is FSGS. 83. The method according to Embodiment 80, wherein APOL1-mediated renal disease is NDKD. 84. The method according to Embodiment 80, wherein the APOL1-mediated renal disease is ESKD. 85. The method according to any one of embodiments 80 to 84, wherein APOL1-mediated renal disease is associated with an APOL1 genetic allele selected from homozygous G1:S342G:I384M and homozygous G2:N388del:Y389del. 86. The method according to any one of embodiments 80 to 84, wherein APOL1-mediated kidney disease is associated with compound heterozygous G1:S342G:I384M and G2:N388del:Y389del APOL1 genetic alleles. 87. A method for inhibiting APOL1 activity, comprising contacting the aforementioned APOL1 with a compound, salt, or deuterated derivative described in any one of Embodiments 1 to 78, or with a pharmaceutical composition described in Embodiment 79. 88. The method according to Embodiment 87, wherein APOL1 is associated with an APOL1 genetic allele selected from homozygous G1:S342G:I384M and homozygous G2:N388del:Y389del. 89. The method according to Embodiment 87, wherein APOL1 is associated with the compound heterozygous G1:S342G:I384M and G2:N388del:Y389delAPOL1 genetic alleles. General synthesis scheme

[0135] Another aspect of this disclosure provides methods for preparing compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), compounds 1-286 and 287-465, pharmaceutically acceptable salts of any of these compounds, any of the aforementioned solvates, any of the aforementioned deuterated derivatives, and intermediates for preparing any of the aforementioned. Throughout the synthesis schemes and descriptions for preparing compounds of formula (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), compounds 1-286 (Table 1) and 287-465 (Table 2), pharmaceutically acceptable salts of any of these compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, the following abbreviations are used. Abbreviation AIBN = Azobisisobutyronitrile ARP = Assay Ready Plate BBBPY = 4,4'-di-tert-butyl-2,2'-dipyridyl CBzCl = Benzyl chloroformate CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazine DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propane-2-amine DMAP = dimethylaminopyridine DMA = Dimethylacetamide DME = Dimethoxyethane DMEM = Dulbecco's modified Eagle culture medium DMF = Dimethylformamide DMSO = Dimethyl sulfoxide DPPA = Diphenylphosphoryl azide alkyl = ethyl acetate EtOH = Ethanol FBS = Fetal Bovine Serum FLU = Fluorescence Value HATU = [dimethylamino(triazolo[4,5-b]pyridine-3-yloxy)methylene]-dimethyl-ammonium(phosphate hexafluoride ion) HDMC = N-[(5-chloro-3-oxide-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HBSS = Hank's equilibrium salt solution IPA = Isopropyl alcohol LDA = Lithium diisopropylamide LED = Light-emitting diode MeOH = methanol MTBE = Methyl tert-butyl ether NMM = N-methylmorpholine NMP = N-methylpyrrolidine PBS = Phosphate-buffered saline Pd(dppf)2Cl2=[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(III) dichloride PP = Polypropylene PTSA = p-toluenesulfonic acid monohydrate T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphospholinane-2,4,6-trioxide TEA = Triethylamine Tet = Tetracycline TFA = Trifluoroacetic Acid THF = Tetrahydrofuran THP = Tetrahydropyran TMSS = Tris(trimethylsilyl)silane

[0136] Scheme 1 provides a process suitable for the preparation of indole of formulas 1-4. In some embodiments, X 1 is a halogen. In some embodiments, the halogen is Cl, I, or Br. 1 , R 2, m and n are as defined above. Using any suitable conditions for coupling alkynes, the aryl halides of formula 1-1 and the alkynes of formula 1-2 can be converted to obtain the aminoaryl alkynes of formula 1-3. For example, in some embodiments, the coupling is carried out in the presence of a catalytic system of CuI or Pd(PPh3)2Cl2. In some embodiments, the reaction is carried out in the presence of at least one base. In some embodiments, the at least one base is DIPEA or NEt3. In some embodiments, the conversion of the compounds of formula 1-3 to the indoles of formula 1-4 is achieved by treatment with CuI or PdCl2 in at least one polar solvent in the presence of heating. In some embodiments, the at least one polar solvent is selected from DMF and MeCN. In some embodiments, the heating is greater than 100°C. Scheme 1 [ka]

[0137] Scheme 2 describes a process for the preparation of formula I. The indoles of formulas 1-4 may react with the carbonyl compounds of formula 2-1 to obtain the compounds of formula 2-2. Compound 2-1 is any ketone or aldehyde suitable for forming the compounds of formula 2-2 when reductively coupled with the compounds of formulas 1-4. For example, X' may be CH, or X' may be absent (o=0). In some embodiments, the reaction is carried out in the presence of at least one acid and at least one reducing agent. In some embodiments, the acid is selected from trifluoroacetic acid and methanesulfonic acid. In some embodiments, the reducing agent is Et3SiH. The reaction may be carried out in a solvent such as dichloromethane. The process for the preparation of the compounds of formula I involves the coupling of the carboxylic acid of formula 2-2 and amines 1-5 using any suitable method for forming an amide bond. Scheme 2 [ka]

[0138] Scheme 3 describes a process for preparing the compound of formula (II), in which, in some embodiments, the compound of formula 3-2 is prepared from indoles of formulas 1-4 and ketones of formula 3-1. In some embodiments, the reaction is carried out in the presence of at least one acid and at least one reducing agent. In some embodiments, the acid is selected from trifluoroacetic acid and methanesulfonic acid. In some embodiments, the reducing agent is Et3SiH. In some embodiments, the reaction is carried out in at least one solvent. In some embodiments, the solvent is dichloromethane. In some embodiments, as described in Scheme 3, the process for preparing the compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), and (IV) includes reacting the compound of formula 3-2 with an amine of formula 1-5 in the presence of at least one amide coupling agent (e.g., HATU, CDMT, HDMC, or T3P) and at least one suitable base (e.g., DIPEA or TEA). In some embodiments, the amide coupling agent is selected from HATU, CDMT, HDMC, and T3P. In some embodiments, the appropriate base is selected from DIPEA and TEA. In some embodiments, HATU and triethylamine in at least one solvent are used. In some embodiments, the solvent is DMF. Compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), and (IV) may be prepared from compounds of formulas 1-5 and 3-2 using other suitable conditions for amide bond formation. Scheme 3 [ka]

[0139] The process for preparing the compounds of formulas 4-3 and 4-5 is shown in Scheme 4. LG 1 is any suitable leaving group, such as p-nitrophenol. In some embodiments, LG 1If the group is a p-nitrophenol group, the amine of formula 4-1 may be converted to the intermediate of formula 4-2 by treatment with any suitable reagent for the formation of a p-nitrophenol carbamate. For example, the reaction may be carried out in the presence of a p-nitrophenol carbonate or (4-nitrophenyl)carbonochloride. The reaction may be carried out in a basic solvent such as pyridine. Under alternative conditions, the compound of formula 4-2 may be prepared by treatment with a p-nitrophenol carbonate in a solvent such as DMF in the presence of a base such as DIPEA. Adding the amine of formula 1-5 to a solution of the intermediate of formula 4-2 yields the compound of formula 4-3. In some embodiments, the reaction may be carried out in the presence of a base such as triethylamine and a solvent such as DMF. The reaction may be carried out at room temperature or with additional heat. Scheme 4 [ka]

[0140] Scheme 5 shows a process for preparing the compound of formula 5-2. The amine of formula 4-1 can react with an alkyl halide when formula 5-1 is present in the presence of a base and a solvent. In some embodiments, the base may be triethylamine. In some embodiments, the solvent may be DMF. In some embodiments, the reaction may be carried out at room temperature. Scheme 5 [ka]

[0141] Scheme 6 shows the process for preparing the amines of formulas 6-3 and 6-6. The amines of formulas 6-3 and 6-6 can be used as the compounds of formula 4-1 in schemes 4 and 5. PG 1is any suitable nitrogen protecting group, such as CBz or Boc. Compounds of formula 6-2 can be prepared from indoles of formulas 1-4 and ketones of formula 6-2 using any conditions suitable for carrying out reductive alkylation. Acids and reducing agents can be used in the reductive alkylation step. In some embodiments, the acids used are trifluoroacetic acid and methanesulfonic acid. In some embodiments, the reducing agent may be triethylsilane. Compounds of formula 6-3 can be prepared from 6-2 using any suitable conditions for removing the nitrogen protecting group. For example, PG 1 When is CBz, the compound of formula 6-3 is obtained by hydrocracking using hydrogen gas and palladium on a carbon catalyst. In some embodiments, the reaction is carried out in a solvent mixture such as THF and methanol. The compound of formula 6-6 can be prepared from the indole of formula 1-4 and the aldehyde of formula 6-5 using the process described for the preparation of the compound of formula 6-3. Scheme 6 [ka]

[0142] Scheme 7 shows a process for preparing the compound of formula 7-3. The compound of formula 7-2 can be prepared from 1-4 and 7-1 using any suitable conditions for reductive alkylation. The compound of formula 7-3 can be prepared using any suitable method for the reduction of the nitrile group to an amine. In some embodiments, hydrogenation using a catalyst such as Raney nickel may be used. The reaction may be carried out in a solvent such as a solution of ammonia in methanol. The reaction may be carried out under high pressure, e.g., in a hydrogen atmosphere at 60 psi. In some alternative embodiments, reduction using LiAlH4 may be used. The reaction may be carried out in a solvent such as THF. The reaction may be carried out in the presence of heating (e.g., 60°C). The compound of formula 7-3 may be used as the compound of formula 4-1. Scheme 7 [ka]

[0143] Scheme 8 shows the process for preparing the compound of formula 8-3 from the alcohol of formula 8-1. LG 2 is any suitable activated alcohol that forms a carbonate. The compound of formula 8-2 can be prepared from the alcohol of formula 8-1 using any suitable reagent for the preparation of carbamates. For example, LG 2 If is p-nitrophenol, the compound of formula 8-2 can be prepared by treatment with p-nitrophenol carbonate or (4-nitrophenyl)carbonochloride as in 8-1. The reaction is carried out in the presence of a suitable base, such as triethylamine or pyridine. A solvent such as dichloromethane may be used. The compound of formula 8-3 can be prepared from the carbamate of formula 8-2 and the amines of formulas 1-5 in the presence of a base and a solvent. In some embodiments, a base such as pyridine and a solvent such as DMF may be used. The reaction may be carried out in the presence of heating. For example, the reaction may be carried out at 80°C. Scheme 8 [ka]

[0144] Scheme 9 shows a process for preparing the alcohol of formula 9-3. The alcohol of formula 9-3 may be used as the compound of formula 8-1. PG 2 is any suitable alcohol protecting group. For example, PG 2 The group may be an acetate group. The compound of formula 9-2 can be prepared by reductive alkylation of the compound of formula 9-1 with indole of formula 1-4. Any suitable conditions for reductive alkylation may be used. In some embodiments, reducing agents such as Et3SiH may be used. Acids such as TFA may be used. The reaction may be carried out in a solvent such as dichloromethane. The compound of formula 9-3 may be prepared from the compound of formula 9-2 using a suitable method for removing the alcohol protecting group. For example, PG 2If the group is an acetate group, the compound of formula 9-3 may be obtained by treatment with a base such as K2CO3 in a solvent such as methanol. Scheme 9 [ka]

[0145] Scheme 10 shows a process for preparing the compound of formula 10-3. Ring A in the compound of formula 10-3 contains a nitrogen atom. The compound of formula 10-3 may be prepared from amine 10-3 and the isocyanate of formula 10-2. In some embodiments, the reaction may be carried out in the presence of a base such as DIPEA. In some embodiments, the reaction is carried out in a solvent such as DMSO. Scheme 10 [ka] [Examples]

[0146] The following examples are provided so that the disclosures described herein may be understood more fully. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way. Example 1 Compound Synthesis General purification and analytical methods

[0147] Unless otherwise specified, all final products were purified as needed by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: 10–100% MeCN in H2O, modifier: 0.2% formic acid or 0.1% trifluoroacetic acid).

[0148] The product was analyzed by LCMS method A, B, or C. LCMS m / z and retention times were collected.

[0149] LC-MS method A: HPLC Sunfire C18 column. Gradient: 2-98% MeCN / H2O over 3.8 minutes. TFA modifier.

[0150] LCMS method B: ULC CSH C18 column. Gradient: 5-95% MeCN / H2O. TFA modifier.

[0151] LC-MS method: C:UPLC CSH C18 column. Gradient: 10-60% MeCN / H2O. TFA modifier. Preparation of S1-S3 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid (S1), 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [TRANS] (S2), and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [CIS] (S3) [ka] Step 1. Synthesis of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline (C2)

[0152] To a flask containing 2,4-difluoro-6-iodoaniline C2 (134 g, 525.5 mmol), NEt3 (1.3 L), followed by DMF (250 mL), 1-ethynyl-4-fluorobenzene (83.5 g, 695.1 mmol), CuI (20.5 g, 107.6 mmol), and PdCl2(PPh3)2 (25 g, 35.6 mmol) were added. 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 under vacuum. The product mixture was filtered through a silica gel plug (eluent: CH2Cl2), followed by a second silica plug filtration (eluent: 30-40% ethyl acetate in heptane). Silica gel chromatography (gradient: 0-20% siRNA in heptane) yielded the product (87g, 60%) as a pale yellow solid. 1 H NMR (300MHz, CDCl3) 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)ppm. LCMS m / z 248.0[M+H] + . Step 2. Synthesis of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (C3)

[0153] To a solution of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline C2 (46 g, 167.5 mmol) in DMF (600 mL), CuI (1.9 g, 10.0 mmol) was added, 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 NaCl solution, dried over Na2SO4, and concentrated under vacuum to obtain the product, which was used in subsequent steps without further purification (41 g, 87%). 1 H NMR (300MHz, CDCl3) 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)ppm. LCMS m / z 248.0[M+H] +. Step 3.3 - Synthesis of [5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutancarboxylic acid (S1)

[0154] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (100 mg, 0.4045 mmol) in CH2Cl2 (5 mL), 3-oxocyclobutanecarboxylic acid (47 mg, 0.4119 mmol), Et3SiH (235 mg, 2.021 mmol), and TFA (230 mg, 2.017 mmol) were added. The reaction mixture was stirred overnight at room temperature, then concentrated and redissolved in a water / ethyl acetate mixture. The organic layer was washed with NaHCO3(aq) and then Na2SO4. 4. Dried with 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutancarboxylic acid (trifluoroacetate) (40 mg, 21%). 1 H NMR (300MHz, DMSO-d6) δ12.20(s, 1H), 11.72(d, J=3.9Hz, 1H), 7.71-7.29(m, 5H), 7.00(ddt, J=11.7, 9.8, 2.1 Hz, 1H), 4.14-3.83 (m, 1H), 3.26-2.91 (m, 1H) 2H, 2.77-2.54 (m, 2H, obscured by solvent peak) ppm. LCMS m / z 346.22 [M+H] + . Preparation of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [TRANS](S2) and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [CIS](S3)

[0155] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (20 mg, 80.90 mmol) and 3-oxocyclobutanecarboxylic acid (13.9 mg, 121.8 mmol) in CH2Cl2 (160 mL), Et3SiH (65 mg, 407.0 mmol) was added. TFA (31 mL, 402.4 mmol) was slowly added via an additive funnel while monitoring the temperature. A slight exothermic reaction (2-3°C) was observed during the addition. After 1 hour, the temperature rose to 24°C. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and then quenched with saturated NaHCO3 to obtain pH 7. The organic layer was separated and washed with brine. The solvent was removed under reduced pressure. Dichloromethane (25 mL) was added, and the solid was pulverized. The mixture was filtered, and the solvent was removed under reduced pressure. The mixture contained the product as a mixture of cis and trans isomers. The product was obtained by silica gel chromatography (gradient: 0-20% MeOH in dichloromethane).

[0156] SFC analysis was used to identify cis and trans isomers by chromatography. Column: Daicel Chilalpak® AD-H, 4.6 × 100 mm. Mobile phase: 20% methanol (containing 5 mM ammonia), 80% carbon dioxide. Flow rate: 5 mL / min.

[0157] Peak A (first elution peak, retention time 0.86 min). Trans isomer.

[0158] Peak B (second elution peak, retention time 0.98 min). Cis isomer.

[0159] Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [trans]S2 (8.49g, 30%) 1H NMR (300MHz, acetone-d6) δ10.71(s, 1H), 7.79-7.56(m, 2H), 7.45(dd, J=9.8, 2.2Hz, 1H), 7.39 -7.21(m, 2H), 6.85(ddd, J=11.1, 9.6, 2.2Hz, 1H), 4.14(pd, J=9.3, 1.3Hz, 1H), 3.29(dddd, J =9.4, 7.3, 3.6, 1.3Hz, 1H), 2.89-2.56(m, 4H)ppm. LCMS m / z 346.07 [M+H] + .

[0160] 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [CIS]S3 (11.7g, 42%). 1 H NMR (400MHz, acetone-d6) δ10.69(s, 1H), 7.74-7.56(m, 3H), 7.37-7.21(m, 2H), 6.84(ddd, J=11.1, 9.6, 2.2Hz, 1H ), 3.89(tt, J=10.2, 8.5Hz, 1H), 3.19(tt, J=9.6, 8.4Hz, 1H), 2.85-2.71(m, 2H), 2.69-2.55(m, 2H), 2.05(m, J= 2.2Hz, 2H)ppm. Preparation S4 1-Ethynyl-4-fluorobenzene-2,3,5,6-d4(S4) [ka] Step 1. Synthesis of 1-bromo-4-fluorobenzene-2,3,5,6-d4(S5)

[0161] CH 2Cl2A solution of bromine (34.8 g, 218 mmol, 1.1 equivalents) in (40 mL) was added dropwise to a solution of 1-fluorobenzene-2,3,4,5,6-d5C4 (20 g, 200 mol, 1 equivalent) and FeCl3 (0.6 g, 3.7 mmol, 0.02 equivalents) in CH2Cl2 (40 mL) at 18-20°C. After stirring at room temperature for 1.5 hours, the mixture was washed with water (3 × 50 mL), sodium thiosulfate solution (0.72 M, 50 mL), and additional water (50 mL). The organic layer was dried over sodium sulfate and filtered. Small runs of this reaction (5 g of 1-fluorobenzene-2,3,4,5,6-d5) treated in the same manner were combined for distillation to remove the solvent. The combined organic layers were evaporated under atmospheric distillation to remove dichloromethane, and then distilled to obtain a colorless oil product (33.3g, yield 75%, bp150-152). o C) was obtained. Step 2. Synthesis of ((4-fluorophenyl-2,3,5,6-d4)ethynyl)trimethylsilane (C6)

[0162] (Trimethylsilyl)acetylene (32.9 mL, 232.5 mmol, 1.3 equivalents), copper(I) iodide (3.5 g, 18.6 mmol, 0.1 equivalent), and PdCl2(PPh3)2 (6.5 g, 9.3 mmol, 0.05 equivalents) were added at room temperature to a mixture of 1-bromo-4-fluorobenzene-2,3,5,6-d4C5 (33.3 g, 186.0 mmol, 1 equivalent) in NEt3 (310 mL). The mixture was purged with nitrogen for 10 minutes and then stirred at 70-80°C for 18 hours. After cooling to room temperature, the mixture was diluted with HCl (300 mL), filtered through celite®, and washed with HCl (2 × 100 mL). The filtrate was concentrated under reduced pressure at 30°C to obtain the product (45.3 g) as a dark brown oil, which was then used. Step 3. Synthesis of 1-ethynyl-4-fluorobenzene-2,3,5,6-d4(S4)

[0163] Potassium carbonate (128.5 g, 930 mmol, 5 equivalents) was added at room temperature to a mixture of ((4-fluorophenyl-2,3,5,6-d4)ethynyl)trimethylsilane C6 (45.3 g, 186 mmol, 1 equivalent) in MeOH (620 mL). The mixture was stirred at room temperature for 2 hours. The mixture was filtered through celite® and washed with MeOH (50 mL) and hexane (3 × 50 mL). The filtrate was diluted with water (2000 mL) and separated. The aqueous layer was extracted with hexane (3 × 500 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure (50 mbar, 5°C) to obtain the product (30 g, theoretical yield 23.09 g) as dark oil. (Note: 1-Ethynyl l-4-fluorobenzene-2,3,5,6-d4 is volatile and was co-distilled with other solvents (MeOH, hexane) under reduced pressure or atmospheric pressure. Crude 1-ethynyl l-4-fluorobenzene-2,3,5,6-d4S4 was used in the next step without column purification to minimize losses during solvent evaporation.) compound 1 N-(2-amino-2-oxo-ethyl)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxamide(1) [ka]

[0164] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutane-carboxylic acid (130 g, 376.5 mmol) in DMF (920 mL), HATU (217 g, 570.7 mmol) was added, and the mixture was stirred for 10 minutes. The reaction mixture was cooled to 5°C on an ice bath. 2-aminoacetamide (hydrochloride) (48 g, 434.2 mmol) and DIPEA (197 mL, 1.131 mol) were slowly added via an addition funnel while maintaining a temperature below 30°C. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated NaHCO3 (2 L), and siRNA (1 L) was added. The product crystallized during quenching. The solid was removed by filtration and washed with water (1 L). The filtrate layer was separated and washed with ethyl acetate (1 L), and the combined organic layers were then washed with water (2 L) and brine (2 L). The product precipitated from the organic layer, and the solid was filtered. The filtrate was concentrated under reduced pressure to 90% of its original volume (excluding any additional product). The combined solid was slurryed in 4:1 water / acetone (500 mL) for 12 hours. The solid was filtered, washed with water (400 mL), and dried overnight in a vacuum oven at 55°C. N-(2-amino-2-oxo-ethyl)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxamide (109.75 g, 72%). 1 H NMR (300MHz, methanol-d4) δ7.56-7.44(m, 2H), 7.32(dd, J=9.7, 2.2Hz, 1H), 7.20(t, J=8.8Hz, 2H), 6.74(ddd, J=1 1.0, 9.6, 2.2Hz, 1H), 4.18-4.02(m, 1H), 3.88(s, 2H), 3.25(dtd, J=9.2, 4.9, 2.3Hz, 1H), 2.75-2.56(m, 4H)ppm. LCMS m / z 402.24 [M+H] + SFC analysis showed a trans / cis ratio of 99:1 (column: Daicel Chilalpak® AD-H, 10 × 250 mm, mobile phase: 40% MeOH (containing 5 mM ammonia), 70% carbon dioxide. Flow rate: 75 mL / min).

[0165] Trans stereochemistry was confirmed by single-crystal X-ray analysis. Compound 2-45

[0166] Compound 2-45 (Table 3) was prepared from S2 and a commercially available amine by HATU coupling as described in standard procedure A. Standard Procedure A. HATU Coupling of Amines

[0167] 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutane-carboxylic acid S2 (25 mg, 0.07 mmol) in DMF (2 mL) was mixed with amine (0.07 mmol), HATU (approx. 36 mg, 0.09 mmol), and Et3N (approx. 7.3 mg, 10.1 uL, 0.07 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron). Gradient: MeCN in H2O containing 0.1% trifluoroacetic acid. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] compound 46 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-(2-hydroxyethyl)cyclobutanecarboxamide (46) [ka]

[0168] A 250 mL round-bottom flask was filled with a magnetic stirring rod, 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxylic acid (5.63 g, 16.3 mmol), DMF (30 mL), DIPEA (8.5 g, 65.77 mmol), ethanolamine (2.2 g, 36.02 mmol), and HATU (12 g, 31.56 mmol). The reaction mixture was stirred at room temperature. The mixture was diluted with water (approximately 250 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic extract was washed with water (200 mL) and brine (approximately 200 mL) and dried over MgSO4. The mixture was filtered and concentrated under vacuum to reduce the volume to approximately 50 mL. The product formed a white precipitate, which was collected via vacuum filtration using a Buchner funnel. The filtered cake was washed with HCl, collected, and dried under vacuum to obtain 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-(2-hydroxyethyl)cyclobutanecarboxamide (4.86 g, 77%). 1H NMR (300 MHz, acetone) δ10.69(s, 1H), 7.77-7.51(m, 2H), 7.41(dd, J=9.8, 2.2 Hz, 1H), 7.36-7.21(m, 2H), 7.11(s, 1H), 6.85(ddd, J=11.1, 9.7, 2.2 Hz, 1H), 4.25-3.99(m,1H), 3.94(td, J=5.5, 0.7Hz, 1H), 3.60(q, J=5.5Hz, 2H), 3.34(q, J=5.6Hz, 2H), 3.29-3.11(m,1H), 2.71-2.46(m, 4H)ppm. LCMS m / z 389.29 [M+H] + Compound 47-48

[0169] Compounds 47-48 (Table 4) were prepared by coupling S2 with a suitable commercially available amine according to standard procedure A. [Table 4-1] [Table 4-2] Compound 49-82

[0170] Compounds 49-82 (Table 5) were prepared from S2 and a suitable commercial amine by HATU coupling according to standard procedure A. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] Compound 83-161

[0171] Compounds 83-161 (Table 6) were prepared from S2 and a suitable commercial amine by HATU coupling according to standard procedure A. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17] [Table 6-18] Compound 162-234

[0172] Compounds 162-234 (Table 7) were prepared from S2 and a suitable commercial amine by HATU coupling according to standard procedure A. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 Table 7-11 Table 7-12 Table 7-13 Table 7-14 Table 7-15 Table 7-16 Table 7-17 Table 7-18 Table 7-19 Table 7-20 Table 7-21 Table 7-22 [Table 7-23] compound 235 N-(2-amino-2-oxo-ethyl)-3-[5,7-difluoro-2-(2,3,5,6-tetoledoterio-4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxamide(235) [ka] Step 1. 2,4-difluoro-6-((4-fluorophenyl-2,3,5,6-d4)ethynyl)aniline (C8)

[0173] A mixture of crude 2,4-difluoro-6-iodaniline C7 (59.7 g, 58% purity, 135.8 mmol, 1 equivalent) and crude 1-ethynyl-4-fluorobenzene-2,3,5,6-d4C56 (28.1 g, 60% purity, 135.80 mmol, 1 equivalent) in NEt3 (550 mL) was purged with nitrogen for 10 minutes. Cul (5.2 g, 27.2 mmol, 0.2 equivalents) and Pd(PPh3)Cl2 (9.5 g, 13.6 mmol, 0.1 equivalents) were added. The mixture was stirred at room temperature for 20 hours, and then concentrated under reduced pressure at 40°C. The residue was purified twice with silica gel (800 g of silica gel, dry-loaded, eluted each time with a gradient of 0-10% dichloromethane in heptane) to obtain product C8 (40.5 g) as a brown solid, which was used in subsequent processes without further purification. (This substance still contained some unreacted 2,4-difluoro-6-iodoaniline (40% based on LC-MS)). Step 2. 5,7-Difluoro-2-(4-Fluorophenyl-2,3,5,6-d4)-1H-Indole(C9)

[0174] A solution of 2,4-difluoro-6-((4-fluorophenyl-2,3,5,6-d4)ethynyl)aniline C8 (39.5 g, 60% purity, 157.2 mmol, 1 equivalent) in DMF (400 mL) was purged with nitrogen for 10 minutes. CuI (3.0 g, 15.7 mmol, 0.1 equivalent) was added, and the mixture was purged with nitrogen for another 10 minutes. The mixture was heated at 145 °C for a further 20 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure at 60 °C to remove most of the DMF. The residue was diluted with water (500 mL) and t-butyl methyl ether (300 mL). The mixture was filtered through Celite® and washed with t-butyl methyl ether (100 mL). The filtrate layers were separated, and the aqueous layer was extracted with t-butyl methyl ether (2 × 200 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure at 40°C. Purification by silica gel chromatography (gradient: 0-10% ethyl phosphate in heptane) yielded 5,7-difluoro-2-(4-fluorophenyl-2,3,5,6-d4)-1H-indole as an orange-brown solid (19 g, yield 80%). (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl-2,3,5,6-d4)-1H-indole-3-yl)cyclobutan-1-carboxylic acid (C10)

[0175] Trifluoroacetic acid (30.64 mL, 400.09 mmol, 6.02 equivalents) was added dropwise at room temperature to a solution of compound C9 (16.7 g, 66.47 mmol, 1 equivalent), 3-oxocyclobutanecarboxylic acid (11.38 g, 99.71 mmol, 1.5 equivalents), and triethylsilane (64.3 mL, 402.28 mmol, 6.05 equivalents) in dichloromethane (200 mL). After stirring at room temperature for 20 hours, the reaction mixture was concentrated to approximately 100 mL under reduced pressure, the solid (cis isomer C11) was filtered, and washed with dichloromethane (2 × 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified twice using an InterChim autochromatography system (330 g Sorbtech silica gel column). Elution was performed each time with a gradient of 0-10% ethyl acetate in dichloromethane to obtain compound C10 (19.3 g, yield 83%) as a pale yellow oil. (1r,3r)-N-(2-amino-2-oxoethyl)-3-(5,7-difluoro-2-(4-fluorophenyl-2,3,5,6-d4)-1H-indole-3-yl)cyclobutan-1-carboxamide(235)

[0176] HATU (24.0 g, 63.15 mmol, 1.5 equivalents) was added to a solution of compound C10 (19.3 g, 42.1 mmol, 1 equivalent) in DMF (200 mL), and the mixture was sparged with nitrogen for 10 minutes. The mixture was cooled to 5°C in an ice bath, and glycinamide hydrochloride (5.12 g, 46.31 mmol, 1.1 equivalents) was added, followed by the dropwise addition of N,N-diisopropylethylamine (22.0 mL, 126.3 mmol, 3 equivalents). The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (250 mL) was added, and the mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with saturated brine (400 mL), filtered, and concentrated under reduced pressure at 40°C. The residue was purified using an InterChim autochromatography system (330 g SorbTech silica gel column) and eluted under a gradient of 0-100% ethyl acetate in heptane to obtain crude compound 236 (30 g) as a yellow solid. This material (30 g) was dissolved in a mixture of ethyl acetate (600 mL) and water (200 mL). The layers were separated, and the organic layer was washed with water (200 mL) and saturated brine (200 mL). The organic layer was concentrated under reduced pressure to obtain a pale yellow viscous solid (21 g), which was pulverized twice in a 4:1 mixture of water and acetone (250 mL) to obtain compound 235 (13.9 g, purity 95%) as an off-white solid. This substance was further purified by SFC separation. Column: Daicel Chilalpak® AD-H, 20 × 250 mm; Mobile phase: 30% methanol (containing 0.15% diethylamine), 70% carbon dioxide. Flow rate: 65 mL / min. The second elution peak was product compound 235 (7.5 g, 99.9% purity), obtained as a white solid. The cis isomer of compound 235 was isolated at the first elution peak and obtained as a yellow solid (1.8 g, 95.8% purity).

[0177] Compound 235 was further purified by SFC with additional time. Column: Achiral, 20 × 250 mm; Mobile phase: 45% methanol, 65% carbon dioxide. Flow rate: 75 mL / min. Compound 236-273

[0178] Compounds 236-273 (Table 8) were prepared from S3 and a suitable commercial amine by HATU coupling according to standard procedure A. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13] Compound 274-277

[0179] Compounds 274-277 (Table 9) were prepared from S3 and a suitable commercial amine by HATU coupling according to standard procedure A. [Table 9-1] [Table 9-2] compound 278 Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxamide (278) [ka] Step 1.3 - Synthesis of [5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarbonitrile (C12)

[0180] 5,7-Difluoro-2-(4-fluorophenyl)-1H-indole (200 mg, 0.81 mmol) was collected in CH2Cl2 (10 mL) and 3-oxocyclobutane carbonitride (100 mg, 1.1 mmol) was added. Et3SiH (800 mg, 6.9 mmol) and TFA (600 mg, 5.3 mmol) were also added. The reaction mixture was stirred overnight. The reaction mixture was concentrated and diluted with saturated NaHCO3 / ethyl acetate. The organic layer was dried over brine and Na2SO4, then concentrated to obtain a solid. The product was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid). 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarbonitrate (trifluoroacetate) (220 mg, 55%). 1 H NMR (300MHz, DMSO-d6) δ11.81(s, 1H), 7.73-7.47(m, 2H), 7.47-7.23(m, 3H), 7.14-6.90(m, 1H), 3.8 2(tt, J=10.2, 8.2Hz, 1H), 3.36-3.22(m, 1H), 2.86-2.66(m, 2H), 2.57(ddd, J=11.8, 9.0, 2.3Hz, 2H). LCMS m / z 327.08 [M+H] + Step 2.3 - Synthesis of [5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxamide (278)

[0181] 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarbonitrile (C12) (50 mg, 0.1066 mmol) was dissolved in DMSO (2 mL), and K2CO3 (15 mg, 0.11 mmol) and hydrogen peroxide (5 mg, 0.15 mmol) were added. The foamy reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, filtered, and concentrated. The product was obtained by purification by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid). 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarboxamide (trifluoroacetate) (4 mg, 7%). 1 H NMR (300MHz, methanol-d4) δ9.56(s, 1H), 6.11(dd, J=9.9, 2.2Hz, 1H), 6.08-5.88(m, 2H), 5.88-5.57(m, 2H), 5.40-5 .03(m, 1H), 2.24(tt, J=10.3, 8.3Hz, 1H), 1.72-1.42(m, 1H), 1.31-1.06(m, 2H), 0.95(qd, J=8.3, 2.6Hz, 2H)ppm. LCMS m / z 345.28 [M+1] + Compound 279-280

[0182] Compounds 279 and 280 (Table 10) were prepared from 3-[7-fluoro-2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [cis / transmix] and a suitable commercial amine using standard method A. 3-[7-fluoro-2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-indole-3-yl]cyclobutanecarboxylic acid [cis / transmix] was prepared from 7-fluoro-2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-indole and 3-oxocyclobutanecarboxylic acid using the method for the preparation of S1 described above. [Table 10] Compound 281-286

[0183] Compounds 281-286 (Table 11) were prepared from suitable acids and commercially available amines by HATU coupling according to standard method A. [Table 11-1] [Table 11-2]

[0184] Table 12 lists all the amines used in the preparation of the compounds in Table 3-11. The amines in Table 12 were either commercially purchased or prepared by standard literature processes. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] Preparation S5 [ka] Step 1. Synthesis of [3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]acetate (C12)

[0185] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (5 g, 20 mmol) in dichloromethane (25 mL), (3-oxocyclobutyl) acetate (3.8 g, 0.030 mol) was added, followed by Et3SiH (12 g, 100 mmol) and trifluoroacetic acid (12 g, 110 mmol). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic phase was separated and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0-40% ethyl acetate in heptane) to obtain the product: [3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]acetate (7 g, 67%). LCMS m / z 360.2 [M+H] + . Step 2.3 - Synthesis of [5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanol (C13)

[0186] To a solution of [3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]acetate C12 (7 g, 12 mmol) in methanol (60 mL), potassium carbonate (2.2 g, 16 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was then partitioned between ethyl acetate and brine. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate in heptane to obtain the product: 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanol (4 g, 95%). 1 H NMR (300MHz, DMSO-d6) δ11.67(d, J=7.4 Hz, 1H), 7.75-7.15(m, 5H), 6.99(t, J=10.5 Hz, 1H), 4.43(d, J=7.0 Hz, 1H), 3.99 (dd, J=13.0, 7.0Hz, 1H), 2.57 (d, J=8.5Hz, 2H), 2.21 (p, J=10.8, 10.2Hz, 2H). LCMS m / z 318.2 [M+H] + . Step 3.3 - Synthesis of [5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanone (S5)

[0187] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanol C13 (500 mg, 1.1 mmol) in dichloromethane (25 mL), 3-oxo-1,3-dihydro-1λ5,2-benziodoxol-1,1,1-triyltriacetate (580 mg, 1.4 mmol) was added. The mixture was stirred at room temperature for 3 hours. The precipitate was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0-50% ethyl ammonium in heptane) to obtain the product: 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanol (200 mg, 37%). 1H NMR (400MHz, DMSO-d6) δ11.83(s, 1H), 7.67-7.59(m, 2H), 7.37(t, J=8.8 Hz, 2H), 7.16(dd, J=9.8, 2.2 Hz, 1H), 7.07-6.97(m, 1H), 3.92(p, J=8.2 Hz, 1H), 3.53-3.41(m, 2H), 3.31-3.25(m, 1H). LCMS m / z 316.3 [M+H] + . Preparation S6 [ka] Step 1. Synthesis of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl)carbamate (C14)

[0188] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole S1 (5.05 g, 20.4 mmol) in dichloromethane (100 mL) under a nitrogen atmosphere, benzyl N-(3-oxocyclobutyl)carbamate (4.9 g, 22 mmol) was added, followed by Et3SiH (20 mL, 130 mmol) and trifluoroacetic acid (9.5 mL, 120 mmol). The mixture was stirred overnight at room temperature. The mixture was then concentrated under vacuum and partitioned between ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic phase was separated and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0-100% ethyl acetate in heptane) to obtain the isomer mixture product. A mixture of isomers (6.5 g, 14 mmol) was separated by chiral SFC separation (column: Daicel Chilalpak® AD-H, 20 × 250 mm, mobile phase: 40% methanol (containing 5 mM ammonia), 60% carbon dioxide, flow rate: 75 mL / min) to obtain the trans isomer: benzyl (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)carbamate (1.1 g, 52%). 1H NMR (300MHz, acetone-d6) δ7.64-7.57(m, 2H), 7.43-7.24(m, 7H), 6.90-6.80(m, 2H), 5.10( 2, 2H), 4.35(d, J=6.9Hz, 1H), 4.21-4.07(m, 1H), 2.81-2.74(m, 2H), 2.50-2.40(m, 2H). LCMS m / z 451.24 [M+H] + . Step 2. Synthesis of (1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanamine (S6)

[0189] To a solution of benzyl N-[(1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]carbamate C14 (1.7 g, 3.8 mmol) in MeOH (20 mL) and THF (5 mL), 10% palladium was added on a carbon catalyst (1 g, 50% water). The reaction mixture was placed on a Parr shaker at 30 psi for 6 hours. The mixture was then filtered through Celite®. The filtrate was removed under vacuum, and the resulting mixture was ground with DCM (10 mL) to obtain the product: (1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanamine (948.2 mg, 75%). 1 H NMR (300MHz, methanol-d4) δ7.51 (ddt, J=8.3, 5.2, 2.5 Hz, 2H), 7.26 (dtd, J=8.8, 6.8, 2.2Hz, 3H), 6.78 (ddd, J=11.1, 9.6, 2.1 Hz, 1H), 4.25(p, J=9.0Hz, 1H), 3.96(dddt, J=8.2, 7.0, 3.5, 1.9H, 1H), 2.97-2.80(m, 2H), 2.50(ddt, J=12.5, 9.6, 3.3Hz, 2H). LCMS m / z 317.13 [M+H] + . Preparation S7 [ka] Preparation of 4-nitrophenyl ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)carbamate (S7)

[0190] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanamine S6 (600 mg, 1.9 mmol) in THF (20 mL), bis(4-nitrophenyl)carbonate (285 mg, 0.937 mmol), followed by Et3N (200 mg, 2.0 mmol), was added. The reaction mixture was stirred at room temperature for several hours. The mixture was then concentrated under vacuum to obtain the product: 4-nitrophenyl((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)carbamate (600 mg, 12%). LCMS m / z 482.27 [M+H] + . Preparation S8 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]cyclobutancarboxylic acid (S8) [ka] Step 1. Synthesis of ethyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]cyclobutanecarboxylate (S15)

[0191] 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (750 mg, 3.034 mmol) and ethyl 3-formylcyclobutane carboxylate (2.4 g, 15.37 mmol) were dissolved in CH2Cl2 (8 mL), and Et3SiH (1.8 g, 15.48 mmol) and TFA (1.7 g, 14.91 mmol) were added. The reaction mixture was stirred overnight at room temperature. The organic solvent (including TFA) was removed under reduced pressure. The resulting crude product was quenched with aqueous NaHCO3 and extracted with ethyl. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography using hexane and ethyl ethyl 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]cyclobutane carboxylate (1.1 g, 90%). 1 H NMR(300 MHz, acetone-d6)δ10.70(s, 1H), 7.74(dddd, J=8.4, 7.5, 5.2, 3.1Hz, 2H), 7.39-7.15(m, 3H), 6.82(ddd, J=11.1, 9.7, 2.2Hz, 1H), 4.03(qd, J=7.1, 2.6Hz , 2H), 3.11-2.93(m, 2H), 2.93-2.78(m, 1H), 2.79-2.48(m, 1H), 2.26-2.10 (m, 2H), 1.97-1.77(m, 2H), 1.43-1.20(m, 1H), 1.16(td, J=7.1, 1.5Hz, 3H). LCMS m / z 388.35 [M+H] + .

[0192] Step 2.3 - Synthesis of [[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]cyclobutancarboxylic acid (S8)

[0193] Ethyl 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]cyclobutanecarboxylate C15 (1 g, 1.862 mmol) was dissolved in THF (10 mL) and water (10 mL), and then LiOH (90 mg, 3.758 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was then concentrated and diluted with water and ethyl acetate. The organic layer was neutralized with 1 N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The organic layer was then concentrated and purified by silica gel chromatography (0-20% MeOH in gradient DCM) to obtain the product: 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]cyclobutanecarboxylic acid (800 mg, quantitative). 1 H NMR (300MHz, acetone-d6) δ10.71(s, 1H), 7.88-7.64(m, 2H), 7.43-7.08(m, 3H), 6.82(ddd, J=11.0, 9.7, 2.2Hz, 1H), 3.15-3. 04(m, 1H), 3.01-2.94(m, 1H), 2.94-2.79(m, 1H), 2.79-2.48(m, 1H), 2.29-2.11(m, 2H), 1.90(qdd, J=9.4, 5.3, 2.4Hz, 2H). LCMS m / z 360.31 [M+H] + . Preparation S9 (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl(4-nitrophenyl)carbonate(S9) [ka] Step 1. Synthesis of (1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutan-1-ol (C16)

[0194] To a solution of [3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]acetate C12 (700 mg, 1.2 mmol) in MeOH (10 mL), K2CO3 (200 mg, 1.4 mmol) was added at room temperature. The mixture was then separated between siRNA and saturated sodium bicarbonate aqueous solution. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by chiral SFC separation (column: Daicel Chilalpak® OJ-H, 20 × 250 mm, mobile phase: 20% isopropanol (containing 5 mM ammonia), 80% carbon dioxide, flow rate: 75 mL / min) to obtain the trans isomer. (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutan-1-ol (100 mg, 46%). 1 H NMR (300MHz, acetone- d6)δ10.67(s, 1H), 7.81-7.51(m, 2H), 7.51-7.07(m, 3H), 6.99-6.62(m, 1H), 4.58(dt, J= 6.9, 3.5Hz, 1H), 4.13(ttd, J=9.2, 7.9, 1.1Hz, 2H), 2.79-2.55(m, 2H), 2.50-2.25(m, 2H). LCMS m / z 318.28 [M+H] + . Step 2. Synthesis of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl(4-nitrophenyl)carbonate (S9)

[0195] To a solution of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutan-1-ol C16 (2000 mg, 6.30 mmol) in DCM (20 mL), (4-nitrophenyl)carbonochloride (2 g, 10 mmol) was added, followed by pyridine (750 mg, 9.5 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate. The solution was washed with 2 M aqueous NaOH (x3) and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the product: (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl(4-nitrophenyl)carbonate. LCMS m / z 483.26 [M+H] + . Preparation of S10 and S11 ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methanamine (S10) and ((1s,3s)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methanamine (S11) [ka] Step 1.3 Synthesis of (5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutan-1-carbonitrile (C17)

[0196] A 250 mL round-bottom flask was filled with a magnetic stirring rod, 5,7-difluoro-2-(4-fluorophenyl)-1H-indole S1 (3.8 g, 13.8 mmol), 3-oxocyclobutane carboninitrile (1.7 g, 17.8 mmol), DCM (100 mL), and Et3SiH (9.6 g, 82.5 mmol), and then TFA (9.5 g, 83.3 mmol) was added dropwise via syringe. After 16 hours, additional 3-oxocyclobutane carboninitrile (1.7 g, 17.8 mmol), Et3SiH (9.6 g, 82.5 mmol), and TFA (9.5 g, 83.3 mmol) were added, and the mixture was stirred for a further 20 hours. The reaction was then determined to be complete by LC-MS, and then carefully reverse-quenched over a solution of saturated NaHCO3 aqueous solution. Once a neutral pH was achieved, the mixture was poured into a separatory funnel and extracted with DCM (2 × 500 mL). The organic extracts were then combined, dried over MgSO4, filtered through a celite bed, and concentrated under vacuum to obtain the title compound as a mixture of approximately 1:1 cis / trans.

[0197] Upon standing, a solid formed, which was pulverized with DCM (approximately 50 mL). The resulting white solid was then collected via vacuum filtration using a Buchner funnel. The solid was determined to be the cis product, and the filtrate was primarily trans. The filtrate (trans) material was pre-absorbed onto Celite and further purified via SiO2 chromatography (120 g) using heptane / ethyl acetate (8:1) as the eluent to obtain pure trans-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarbonitriel C17 (1.7 g, 26%). LCMS m / z 327.28 [M+H] + and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanecarbonitric C18 (2.2g, 45%). LCMS m / z 327.28 [M+H] + . Synthesis of ((1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methanamine (S10)

[0198] Under a nitrogen atmosphere, at 0 °C, to a solution of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutane-1-carbonitrile C17 (901 mg, 2.62 mmol) in anhydrous THF (29 mL) was slowly added lithium aluminum hydride (2 M in 5.7 mL, 11 mmol). The reaction mixture was stirred at 0 °C for an additional 10 minutes, slowly warmed to room temperature, and then heated to 60 °C for 1 hour. The reaction was then cooled to room temperature and slowly added to a cold solution of 1 M aqueous Rochelle salt. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with DCM to afford the product. ((1r,3r)-3-(5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (535 mg, 57%). 1 1H NMR (300 MHz, acetone-d6) δ 7.66 - 7.55 (m, 2H), 7.41 (ddd, J = 9.9, 5.6, 2.2 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.84 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.10 - 3.95 (m, 1H), 3.42 (s, 1H), 2.82 (d, J = 7.3 Hz, 1H), 2.68 - 2.48 (m, 3H), 2.25 - 2.16 (m, 2H). LCMS m / z 331.33 [M+H] + . Synthesis of (1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (S11)

[0199] Under an argon atmosphere at 0°C, (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutan-1-carbonitrile C18 (3 g, 9 mmol) was added in several portions to a solution of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutan-1-carbonitrile C18 (45 mL) in anhydrous THF (45 mL). The reaction mixture was stirred at 0°C for a further 10 minutes, slowly heated to room temperature, and then heated to 60°C for 1 hour. The reaction mixture was then cooled to room temperature and slowly quenched with aqueous sodium sulfate solution. The mixture was filtered through a Celite® pad, washed with ethyl acetate, and concentrated under vacuum. The residue was ground with DCM to obtain the product: ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methaneamine (3 g, 95%). 1 H NMR (400MHz, DMSO-d6) δ11.62(s, 1H), 7.57(dd, J=8.5, 5.5 Hz, 2H), 7.46(dd, J=10.0, 2.2Hz, 1H), 7.34(t, J=8.7Hz, 2H), 7.01-6.91(m, 1H), 3.59(q, J=9.6, 8.9 Hz, 1H), 2.56-2.50(m, 2H), 2.3-2.22(m, 3H), 2.02-1.97(m, 2H). LCMS m / z 331.0 [M+H] + . Preparation S12 [ka] Preparation of 4-nitrophenyl (((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)carbamate (S12)

[0200] To a solution of bis(4-nitrophenyl)carbonate (2.2 g, 7.3 mmol) in DCM (40 mL), DIPEA (2 mL, 10 mmol) was added, followed by a solution of ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methaneamine S10 (1.89 g, 5.72 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 hour, then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the product: (((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)-methyl)carbamate (2.3 g, 81%). LCMS m / z 496.22[M+H] + . Preparation S13 [ka] Step 1.3 Synthesis of (5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutan-1-carbonitrile (C19)

[0201] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (200 mg, 0.81 mmol) and 3-oxocyclobutane carbonitride (100 mg, 1.1 mmol) in DCM (10 mL), Et3SiH (800 mg, 6.9 mmol) was added, followed by trifluoroacetic acid (600 mg, 5.3 mmol). The mixture was then stirred overnight and separated between saturated sodium bicarbonate aqueous solution and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the product: 3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutane-1-carbonitride (220 mg, 55%). 11H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 7.73 - 7.47 (m, 2H), 7.47 - 7.23 (m, 3H), 7.14 - 6.90 (m, 1H), 3.82 (tt, J = 10.2, 8.2 Hz, 1H), 3.36 - 3.22 (m, 1H), 2.86 - 2.66 (m, 2H), 2.57 (ddd, J = 11.8, 9.0, 2.3 Hz, 2H). LCMS m / z 327.08 [M+H] + Step 2. Synthesis of (3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (C20)

[0202] To a suspension of Raney nickel (50 mg, 0.9 mmol) in methanol (50 mL) was added 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarbonitrile C19 (2.5 g, 4.7 mmol), followed by addition of ammonia solution (400 mL, 7M in methanol). The mixture was stirred at room temperature for 2 days under a hydrogen atmosphere (60 psi). The mixture was filtered and the filtrate was concentrated in vacuo to give the product. (3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (1.2 g, 77%). 1 1H NMR (300 MHz, methanol-d4): δ 6.25 (ddd, J = 8.6, 5.4, 2.7 Hz, 2H), 6.01 - 5.85 (m, 3H), 5.46 (ddd, J = 11.4, 9., 2.1 Hz, 1H), 2.52 (dq, J =., 7.7 Hz, 1H), 1.69 (d, J = 6.1 Hz, 2H), 1.28 (td, J = 7.3,., 3.9 Hz, 3H), 0.88 - 0.69 (m, 2H). LCMS m / z 331.37 [M+H] + . Step 3. Synthesis of ethyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methyl)carbamate (C21)

[0203] To a solution of (3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methanamine C2O (423 mg, 1.06 mmol) and ethyl chloroformate (0.135 mL, 1.41 mmol) in DCM (6 mL), Et3N (0.450 mL, 3.23 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with water. The aqueous layer was extracted with DCM, and the combined organic matter was successively washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (gradient: 0-100% ethyl hexane) to obtain the product: ethyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)carbamate (315 mg, 70%). LCMS m / z 403.42[M+H]+. Step 4. Synthesis of 1-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)-N-methylmethanamine (C22)

[0204] To a solution of ethyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)carbamate C21 (309 mg, 0.73 mmol) in THF (4 mL) at 0°C, LiAlH4 (1.3 mL, 2.99 mmol, 2.3 M in 2-methyltetrahydrofuran) was added. The reaction mixture was heated to room temperature, stirred for 2 hours, then quenched with an aqueous solution of Rochelle salt and extracted with RINKAN. The organic layer was successively washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the product: 1-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)-N-methylmethanamine (219 mg, 73%). LCMS m / z 344.92 [M+H] + . Step 5. Synthesis of 4-nitrophenyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)methyl)carbamate (S13)

[0205] To a solution of bis(4-nitrophenyl)carbonate (308 mg, 1.01 mmol) in DCM (5 mL), Et3N (295 μL, 2.12 mmol) was added, followed by a solution of 1-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)-N-methylmethanamine C22 (290 mg, 0.84 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 hour, then partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the product: 4-nitrophenyl((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)(methyl)carbamate (266 mg, 62%). LCMS m / z 510.24[M+H]+. Preparation S14 [ka] Preparation of 3-(3-(bromomethyl)cyclobutyl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (S14)

[0206] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (380 mg, 1.5 mmol) in DCM (5 mL), 3-(bromomethyl)cyclobutanone (250 mg, 1.5 mmol), Et3SiH (900 mg, 7.7 mmol), and TFA (525 mg, 4.60 mmol) were added. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was then diluted with ethyl acetate (approximately 100 mL) and washed with saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0-40% ethyl acetate in heptane) to obtain the product: 3-(3-(bromomethyl)cyclobutyl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (504 mg, 34%). LCMS m / z 394.38[M+H] + . Preparation S15 [ka] Step 1. Synthesis of methyl 2-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)acetate (C23)

[0207] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (460 mg, 1.9 mmol) and 2-(3-oxocyclobutyl) acetate (291 mg, 2.05 mmol) in DCE (5 mL), triethylsilane (1.2 mL, 7.5 mmol) was added, followed by methanesulfonic acid (365 μL, 5.63 mmol) at 70°C. The mixture was heated at 70°C for 2 hours, and additional methyl 2-(3-oxocyclobutyl) acetate (291 mg, 2.05 mmol) was added. The mixture was stirred at 70°C for an additional 2 hours. After cooling to room temperature, the mixture was diluted with DCM (80 mL) and washed with saturated sodium carbonate aqueous solution and brine. The organic layer was separated and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0-10% ethyl hexane) to obtain the product. Methyl 2-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl) acetate (450.7 mg, 65%). LCMS m / z 374.19[M+H] + Step 2. Synthesis of 2-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)acetic acid (S15)

[0208] A solution of methyl 2-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]acetate C23 (488 mg, 1.30 mmol) in THF (10 mL) was mixed with saturated LiOH aqueous solution (5 mL). The mixture was then heated to 50°C and stirred overnight. The mixture was then cooled to ambient temperature and concentrated in vacuum. The resulting residue was then diluted with DCM (approximately 50 mL), acidified to pH 3 with 10% HCl, and the aqueous layer was extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to obtain the product: 2-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)acetic acid (508 mg, quantitative). 1 H NMR (300MHz, chloroform-d) δ8.05(s, 1H), 7.57-7.39(m, 2H), 7.29-7.16(m, 4H), 6.87-6.6 4(m, 1H), 3.86-3.72(m, 2H), 2.80-2.47(m, 3H), 2.06(q, J=10.8, 9.2Hz, 1H), 1.88(td, J =5.7, 4.9, 3.1Hz, 2H). LCMS m / z 360.19[M+H] + . Preparation S16 [ka] Step 1.3 - Synthesis of [5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclopentanecarboxylate (C24)

[0209] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (501 mg, 1.89 mmol) and ethyl 3-oxocyclopentane carboxylate (390 mg, 2.5 mmol) in 70°C DCE (8 mL), methanesulfonic acid (201 μL, 3.10 mmol) and triethylsilane (1 mL, 6 mmol) were added. The mixture was heated at 180°C for 1 hour. Then, additional ethyl 3-oxocyclopentane carboxylate (390 mg, 2.5 mmol), methanesulfonic acid (201 μL, 3.10 mmol), and triethylsilane (1 mL, 6 mmol) were added, and the mixture was stirred at 90°C for 3 days. Water (100 mL) was added to the mixture, and the aqueous layer was extracted with DCM (3 × 70 mL). The product was obtained by purification using silica gel chromatography (gradient: 0-100% ammonium ethyl in heptane). Ethyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclopentanecarboxylate (300 mg, 40%). 1 H NMR (300MHz, chloroform-d) δ8.13(s, 1H), 7.61-7.42(m, 2H), 7.36-7.01(m, 3H), 6.76(ddd, J=10.8, 9.4, 2.1Hz, 1H), 5.97-5.20(m, 1H), 4.24-4.06(m, 2H), 3.61-3.30(m, 1H), 3.23-2.91(m, 1H), 2.25(ddt, J =15.2, 6.5, 2.7 Hz, 2H), 2.13-2.01(m, 3H), 1.36-1.27(m, 3H). LCMS m / z 388.1[M+H] + . Step 2.3 - Synthesis of [5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclopentancarboxylic acid (S16)

[0210] A solution of ethyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclopentanecarboxylate C24 (290 mg, 0.74 mmol) and LiOH (360 mg, 15 mmol) in MeOH (3 mL), THF (4 mL), and water (4 mL) was heated overnight at 50 °C. The mixture was concentrated under vacuum. Water (30 mL) was added to the residue, and the pH was subsequently adjusted to 1 with HCl. The mixture was extracted with DCM (3 × 30 mL), the combined organic phase was washed with brine, and concentrated under vacuum to obtain the product: 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclopentanecarboxylic acid (264 mg, 99%). 1 ¹H NMR (300 MHz, chloroform-d): δ 8.04 (s, 1H), 7.61-7.38 (m, 2H), 7.27-7.06 (m, 3H), 6.76 (dddd, J=10.6, 9.3, 2.1, 1.0 Hz, 1H), 3.57-3.33 (m, 1H), 3.30-2.95 (m, 1H), 2.55-1.83 (m, 6H). LCMS m / z 360.07 [M+H] + . Preparation S17 [ka] Step 1.3 Synthesis of (5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)azetidine-1-carboxylate (C25)

[0211] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (500 mg, 1.35 mmol) and benzyl 3-oxoazetidine-1-carboxylate (277 mg, 1.35 mmol) in DCM (15 mL), Et3SiH (470 mg, 4.0 mmol) and TFA (310 mg, 2.71 mmol) were added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was dissolved in RINKAN (approximately 50 mL) and washed with saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0-100% RINKAN in heptane) to obtain the product. Benzyl 3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)azetidine-1-carboxylate (536 mg, 84%). LCMS m / z 524.04 [M+H] + . Step 2.3 Synthesis of (azetidine-3-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (S17)

[0212] A mixture of 10% by weight of Pd / C (20 mg) in MeOH (10 mL) and benzyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]azetidine-1-carboxylate C25 (500 mg, 1.1 mmol) in MeOH (20 mL) was placed under a hydrogen atmosphere. The resulting mixture was stirred at ambient temperature for 3 hours. The mixture was filtered through Celite® and concentrated under vacuum. The residue was purified by reverse-phase chromatography (column C18, gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product: 3-(azetidine-3-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (380 mg, 81%). 1H NMR (300MHz, methanol-d4) δ7.63-7.48(m, 2H), 7.41(dd, J=9.5, 2.1Hz, 1H), 7.37-7.18(m, 2H), 6.85( ddd, J=11.0, 9.6, 2.1Hz, 1H), 4.70-4.52(m, 1H), 4.45(dd, J=11.0, 9.1Hz, 2H), 4.36-4.17(m, 2H). LCMS m / z 303.26[M+H] + . compound 287 3-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]amino]propanamide(287) [ka] Preparation of 3-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]amino]propanamide (287)

[0213] To a solution of 3-aminopropanamide (14 mg, 0.11 mmol) and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanone S5 (30 mg, 0.1 mmol) in DMF (2.5 mL), triacetoxy(sodio)boron (24 mg, 0.11 mmol) was added, followed by acetic acid (4 mg, 0.01 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was then filtered, and the filtrate was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product: 3-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]amino]propanamide (12 mg, 25%). LCMS m / z 388.16[M+H] + . compound 288 2-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]amino]acetamide(288) [ka] Preparation of 2-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]amino]acetamide (288)

[0214] To a solution of 2-aminoacetamide (12 mg, 0.11 mmol) and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanone S5 (30 mg, 0.1 mmol) in DMF (2.5 mL), triacetoxy(sodio)boron (24 mg, 0.11 mmol) was added, followed by acetic acid (4 mg, 0.01 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was then filtered, and the filtrate was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product: 2-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]amino]acetamide (9 mg, 19%). LCMS m / z 374.15[M+H] + . compound 289 N-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]-2-hydroxyacetamide(289). [ka] N-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]-2-hydroxyacetamide(289). Standard Procedure B: N-Alkylation Method

[0215] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutanamine S6 (50 mg, 0.16 mmol) in DMF (2 mL), 2-chloro-N-(hydroxymethyl)acetamide (29 mg, 0.24 mmol) was added, followed by Et3N (32 mg, 44 μL, 0.32 mmol). The reaction mixture was stirred overnight at room temperature. The product was purified by reverse-phase HPLC (method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product: N-[3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]-2-hydroxyacetamide (3.8 mg, 4.6%). LCMS m / z 404.18[M+H] + . Compound 290-294

[0216] Compounds 290-294 (see Table 13) were prepared in a single step from compound S6 using the standard method described for the synthesis of compound 289. Alkyl halides were obtained from commercially available sources. Any modifications to this method are shown in Table 13 and the accompanying footnotes. [Table 13-1] [Table 13-2] compound 295 1-((1r,3S)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)-3-((S)-1-hydroxypropan-2-yl)urea(295) [ka] Preparation of 1-((1r,3S)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)-3-((S)-1-hydroxypropan-2-yl)urea (295) Standard Procedure C: Urea Formation

[0217] To a solution of (4-nitrophenyl)N-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]carbamate S7 (50 mg, 0.1 mmol) in DMF (2 mL), (2S)-2-aminopropan-1-ol (7.8 mg, 0.1039 mmol) was added, followed by Et3N (10.5 mg, 14.5 μL, 0.104 mmol). The reaction mixture was stirred overnight at room temperature. The product was purified by reverse-phase HPLC (method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid). 1-((1r,3S)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)-3-((S)-1-hydroxypropan-2-yl)urea (19.7 mg, 36%). LCMS m / z 418.15[M+H] + . Compound 296-298

[0218] Compounds 296-298 (see Table 14) were prepared in a single step from intermediate S7 using the standard procedure described for the synthesis of compound 295. The amines were obtained from a commercially available source. Any modifications to this method are shown in Table 14 and the accompanying footnotes. [Table 14] compound 299 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]-N-(2-hydroxyethyl)cyclobutan-1-carboxamide(299) [ka] Preparation of 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]-N-(2-hydroxyethyl)-cyclobutan-1-carboxamide (299) Standard Procedure D: Amide Coupling with HATU

[0219] To a solution of 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]cyclobutancarboxylic acid S8 (30 mg, 0.08 mmol) and a solution of 2-aminoethanol (6.6 mg, 0.11 mmol) in DMF (2 mL), HATU (38 mg, 0.10 mmol) was added, followed by Et3N (16.9 mg, 0.167 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered. The product was obtained by purification by reverse-phase HPLC (method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid). 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]methyl]-N-(2-hydroxyethyl)cyclobutan-1-carboxamide (2.2 mg, 5.1%). LCMS m / z 403.17[M+H] + . Compound 300-348

[0220] Compounds 300-348 (see Table 15) were prepared in a single step from compound S8 using the standard procedure described for the synthesis of compound 299. The amines were obtained from a commercially available source. Any modifications to this method are shown in Table 15 and the accompanying footnotes. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7] [Table 15-8] [Table 15-9] [Table 15-10] [Table 15-11] [Table 15-12] [Table 15-13] Compound 349 (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamate(349) [ka] Preparation of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamate (349) Standard Procedure E: Carbamate Coupling Method

[0221] To a solution of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl(4-nitrophenyl)carbonate 9 (50 mg, 0.1 mmol) in DMF (2 mL), 2-amino-2-(hydroxymethyl)propane-1,3-diol (19 mg, 0.16 mmol) was added, followed by pyridine (16 mg, 0.21 mmol). The mixture was heated overnight at 80°C. The mixture was filtered and purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product. (1r,3S)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamate (12 mg, 20%). LCMS m / z 465.26[M+H] + . Compound 350-390

[0222] Compounds 350–390 (see Table 16) were prepared from intermediate S9 using a suitable amine and the carbamate coupling method described for compound 349. The amine was obtained from a commercially available source. Any modifications to this method are shown in Table 16 and the accompanying footnotes. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8] [Table 16-9] [Table 16-10] [Table 16-11] Compound 391 1-(((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)-3-methylurea(391) [ka] Preparation of 1-(((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)-3-methylurea (391) Standard Procedure G: Carbamate Coupling Method

[0223] To a solution of 4-nitrophenyl (((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)carbamate S12 (50 mg, 0.1 mmol) and Et3N (0.03 mL, 0.2 mmol) in THF (2 mL), methamamine (0.075 mL, 0.15 mmol, 2 M in THF) was added. The reaction mixture was stirred at 80°C for 2 hours, treated with 1 M aqueous HCl, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under vacuum, and purified by reverse-phase HPLC (Method: C18 WatersSunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product. 1-(((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)-3-methylurea (18 mg, 36%). LCMS m / z 388.15[M+H] + . Compound 392-426

[0224] Compounds 392-426 (see Table 17) were prepared in a single step from compound S12 using the standard procedure described for the synthesis of compound 391. The amines were obtained from a commercially available source. Any modifications to this method are shown in Table 17 and the accompanying footnotes. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7] [Table 17-8] [Table 17-9] [Table 17-10] [Table 17-11] Compound 427 1-((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)-1-methyl-3-((1-methyl-1H-imidazole-4-yl)methyl)urea(427) [ka] Preparation of 1-((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)-1-methyl-3-((1-methyl-1H-imidazole-4-yl)methyl)urea (427) Standard Procedure H: Urea Coupling Method

[0225] A solution of 4-nitrophenyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)(methyl)carbamate S13 (22 mg, 0.032 mmol), (1-methyl-1H-imidazole-4-yl)methanamine (5 mg, 0.045 mmol), and Et3N (14 μL, 0.097 mmol) in THF (1 mL) was refluxed in a sealed test tube for 2 days, cooled to room temperature, and purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product. 1-((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)-1-methyl-3-((1-methyl-1H-imidazole-4-yl)methyl)urea (5 mg, 26%). LCMS m / z 482.29[M+H] + . Compound 428-432

[0226] Compounds 428-432 (see Table 18) were prepared in a single step from compound S13 using the standard procedure described for the synthesis of compound 427. The amines were obtained from a commercially available source. Any modifications to this method are shown in Table 18 and the accompanying footnotes. [Table 18-1] [Table 18-2] compound 433 2-(((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)amino)acetamide(433) [ka] Preparation of 2-(((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)amino)acetamide (433) Standard Procedure I: Alkylation Method

[0227] A mixture of 3-[3-(bromomethyl)cyclobutyl]-5,7-difluoro-2-(4-fluorophenyl)-1H-indole S14 (25 mg, 0.063 mmol), 2-aminoacetamide (4.7 mg, 0.063 mmol), and K2CO3 (18 mg, 0.13 mmol) in DMF (0.3 mL) was heated at 80°C for 12 hours. The mixture was then diluted with DMSO (approximately 0.5 mL) and purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product: 2-(((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)amino)acetamide (2 mg, 6%). LCMS m / z 388.19 [M+H] + Compound 434-444

[0228] Compounds 434-444 (see Table 19) were prepared in a single step from compound S14 using the standard procedure described for the synthesis of compound 433. The amines were obtained from a commercially available source. Any modifications to this method are shown in Table 19 and the accompanying footnotes. [Table 19-1] [Table 19-2] [Table 19-3] Compound 445 2-((((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)amino)acetamide(445) [ka] Preparation of 2-((((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)amino)acetamide (445) Standard Procedure J: Alkylation Method

[0229] To a solution of ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methanamine S10 (0.050 g, 0.15 mmol) in DMF (4 mL), 2-bromoacetamide (22 mg, 0.16 mmol) was added, followed by Et3N (30 mg, 0.30 mmol). The reaction mixture was stirred overnight at room temperature, filtered, and purified by reverse-phase HPLC (Method: C18 WatersSunfire column (30 × 150 mm, 5 microns), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product 2-((((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl)cyclobutyl)methyl)amino)acetamide (35 mg, 42%). 1 H NMR (300MHz, acetone-d6) δ10.70(s, 1H), 7.61(ddq, J=8.5, 5.3, 1.7Hz, 2H), 7.41(dt, J=9.8, 2.3Hz, 1H), 7.27(tdd, J=9.1, 4.1, 2.1Hz, 2H), 6.84(dd d, J=11.1, 9.5, 2.0Hz, 1H), 4.07(d, J=26.5Hz, 2H), 3.85(s, 1H), 3.45(dd , J=41.3, 7.9Hz, 2H), 2.95(s, 1H), 2.78-2.57(m, 2H), 2.57-2.26(m, 2H). LCMS m / z 388.16[M+H] + . Compound 446-451

[0230] Compounds 446-451 (see Table 20) were prepared in a single step from compound S10 using the standard method described for the synthesis of compound 445. Alkyl bromides were obtained from commercially available sources. Any modifications to this method are shown in Table 20 and the accompanying footnotes. [Table 20-1] [Table 20-2] Compound 452 2-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]-N-[1-(hydroxymethyl)cyclobutyl]acetamide(452) [ka] Preparation of 2-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]-N-[1-(hydroxymethyl)cyclobutyl]acetamide (452) Standard procedure K: Amide coupling method

[0231] To a solution of 2-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]acetic acid S15 (15 mg, 0.042 mmol) and (1-aminocyclobutyl)methanol (6 mg, 0.06 mmol) in DMSO (1 mL), HATU (30 mg, 0.08 mmol) and Et3N (30 μL, 0.2 mmol) were added. The reaction mixture was stirred at ambient temperature for 12 hours. The product was obtained by purification by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid). 2-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclobutyl]-N-[1-(hydroxymethyl)cyclobutyl]acetamide (12.5 mg, 67%). 1H NMR (300MHz, chloroform-d) δ7.51 (ddd, J=8.8, 7.1, 5.3 Hz, 2H), 7.30 (dd, J=9.8, 2.3Hz, 1H), 7.21 (td, J=9.2, 8.8, 2.2 Hz, 2H), 6.81-6.64(m, 1H), 3.70(d, J=6.9Hz, 3H), 2.63(d, J=14.2Hz, 1H), 2.50 (t, J=7.9Hz, 2H), 2.29(d, J=7.0Hz, 2H), 2.27-1.99(m, 6H), 2.00-1.74(m, 2H). LCMS m / z 443.18[M+H] + . Compound 453-462

[0232] Compounds 453-462 (see Table 21) were prepared in a single step from compound S15 using the standard method described for the synthesis of compound 452. The amines were obtained from a commercially available source. Any modifications to this method are shown in Table 21 and the accompanying footnotes. [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5] [Table 21-6] compound 463 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]cyclopentanecarboxamide (463) [ka] Preparation of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]cyclopentanecarboxamide (463)

[0233] Triethylamine (40 μL, 0.3 mmol) was added to a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]cyclopentancarboxylic acid S16 (22 mg, 0.061 mmol), (2R)-2-aminopropan-1-ol (7 mg, 0.09 mmol), and HATU (45 mg, 0.12 mmol) in DMSO (1 mL). The mixture was stirred at room temperature for 12 hours. The mixture was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product. 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]cyclopentanecarboxamide (15.8 mg, 62%). LCMS m / z 417.18[M+H] + . compound 464 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-ethyl-azetidine-1-carboxamide (464) [ka] Preparation of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-ethylazetidine-1-carboxamide (464)

[0234] A solution of 3-(azetidine-3-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole(trifluoroacetate) S17 (12 mg, 0.029 mmol) and isocyanate ethane (10 mg, 0.1 mmol) in DMSO (1 mL) was mixed with DMSO (20 μL, 0.1 mmol). The mixture was stirred at room temperature for 1 hour and purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product: 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-ethyl-azetidine-1-carboxamide (7 mg, 64%). LCMS m / z 374.14[M+H] + . compound 465 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-(2,2-difluoroethyl)azetidine-1-carboxamide (465) [ka] Preparation of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-(2,2-difluoroethyl)azetidine-1-carboxamide (465)

[0235] A solution of 3-(azetidine-3-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole(trifluoroacetate) S17 (20 mg, 0.05 mmol) and 1,1-difluoro-2-isocyanate-ethane (9 mg, 0.08 mmol) in DMSO (1 mL) was mixed with DIPEA (40 μL, 0.2 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to obtain the product: 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-yl]-N-(2,2-difluoroethyl)azetidine-1-carboxamide (20.5 mg, 99%). 1 H NMR (300MHz, methanol-d4) δ7.60-7.42(m, 2H), 7.35-7.16(m, 3H), 6.80(ddd, J=11.0, 9.6, 2.2 Hz, 1H), 5.88(tt, J=56.5, 4.2 Hz, 1H), 4.39(td, J=7.7, 2.2Hz, 2H), 4.29-3.99(m, 3H), 3.52(td, J=14.8, 4.2Hz, 2H). LCMS m / z 410.07[M+H] + . Example 2. Assay for detecting and measuring the properties of APOL1 inhibitors of compounds Acute APOL1 thallium assay using inducible stable clones of HEK293 cells

[0236] The apolipoprotein L1 (APOL1) protein forms potassium-permeable cation pores in the cell membrane. APOL1 risk variants (G1 and G2) induce a greater potassium flux than G0 in HEK293 cells. This assay utilizes the permeability of thallium (Tl+) through ligand-dependent potassium channels. The dye generates a bright fluorescence signal upon binding with Tl+, which occurs through the potassium channels. The intensity of the Tl+ signal is proportional to the number of open potassium channels. Therefore, it provides a functional indicator of potassium channel activity. During the initial dye loading step, the Tl+ indicator dye, as an acetoxymethyl (AM) ester, enters the cells via passive diffusion. Cytoplasmic esterases cleave the AM ester, releasing its active thallium-sensitive form. The cells are then stimulated with Tl+. The increase in fluorescence in the assay represents the influx of Tl+ into the cell, particularly through potassium channels (i.e., through APOL1 pores), providing a functional measurement of potassium channel / pore activity. The thallium assay is performed on cells expressing G1 APOL1. Reagents and materials

[0237] APOL1 cell line (HEK T-Rex stably inducible cell line) o HEK T-Rex System Tetracycline (Tet)-inducible mammalian expression system. To regulate transcription, we stably express the Tet repressor. Expression under the full-length CMV promoter. APOL1 stable inducible cell line. Clone used: G1 DC3.25

[0238] tissue culture medium o Cell culture medium DMEM + 10% FBS + P / S + 5 μg / mL blastosidine + 1 μg / mL puromycin 500 mL of DMEM + 55 mL of FBS + 5 mL of P / S + 280 μL of blastosidine S HCl (10 mg / mL) + 56 μL of puromycin (10 mg / mL) o Cell assay medium • DMEM containing 2% FBS + PenStrep

[0239] [Table 25]

[0240] [Table 26]

[0241] Equipment and facilities Nuaire cell culture food, catalog number 540-600 o 37°C / 5% CO incubator for connection to a robotic arm, Liconic: STX110 o Molecular Devices FLIPR Tetra High-throughput cell screening system, catalog number FT0324, Molecular Devices ThermoFisher MultiDrop 384, catalog number 5840300 Biotek Microfill, catalog number ASF1000A-4145 BioRad TC10 cell counter, catalog number 145-0010 Assay procedure

[0242] Cells scaled up from frozen vials APOL1 G1 3.25 (HEK293 T-Rex) Frozen Vial: 5 million cells per vial Step 1, Day 1: Thaw the frozen vial in T-225. Step 2, Day 5: (If 85% confluent): 3 x 10 per flask 6 Divide one T-225 molecule into individual cells. Step 3, Day 8: Divide the cells to be set up for assay plates as described below.

[0243] cell culture T-Rex APOL1 HEK cells are divided twice a week to maintain a confluence state of less than 85% of the culture flask surface area. Cells can be retained up to passage 25. o Cell culture medium • DMEM high glucose + 10% FBS, + P / S, + 5 μg / mL blastosidine, + 1 μg / mL puromycin 500 mL of DMEM, + 55 mL of FBS, + 5 mL of P / S, + 280 μL of blastosidine 10 mg / mL, + 56 μL of puromycin 10 mg / mL o Assay medium Invitrogen Opti-MEM Reduced Serum Medium

[0244] Day 1 Preparation of cell assay plates The culture medium is removed by aspiration to x cm 2 It is removed from the T flask. Wash the cell monolayer with PBS 1X at room temperature. Remove the PBS by aspiration. Cells are trypsinated using trypsin. o Incubate the flask at room temperature for 2-3 minutes. Next, add complete DMEM medium. Then, transfer the cell suspension to a 50 mL Falcon polypropylene tube. Next, count the cells using a Biorad TC10 cell counter and centrifuge the required amount of cells at 1200 RPM for 5 minutes. The required amount is 1.3 x 10⁶ 6 These are APOL1 T-Rex HEK cells at a cell / mL density. o Suspend the pellet in the assay medium. Using MultiDrop, add 20 μL to each well of a 384-well black, clear, flat-bottomed poly-D coated plate (corresponding to a total of 26,000 cells per well). The tetracycline prepared in the following section is added to the cells before seeding to induce APOL1 expression. The plates are left at room temperature for 20-30 minutes before being incubated at 37°C and 5% CO2. Preparation of tetracycline o Tetracycline stock is prepared in H2O at a concentration of 1 mg / mL, dispensed, and stored at -20°C. o On the day the cells are seeded for the assay, prepare the tetracycline working concentration as follows: Transfer 50 μL of stock to 5 mL of assay medium, dilute the tetracycline stock with 100X dilution to obtain an intermediate stock of 10 μg / mL. • When adding to cell plates with Biomek, or when adding directly to cells, prepare tetracycline at 4X and then impart 1X tetracycline concentration according to Table 22 below. [Table 22]

[0245] Day 2 Thallium loading dye and cell loading preparation FLIPR (Registered Trademark) Potassium Assay Kit R8223 o Preparation of loading buffer: 1. Remove one vial each of Component A (dye) and Component C (Pluronic®) from the freezer and allow them to equilibrate at room temperature. 2. For the bulk kit, prepare Component B by mixing 200 mL of 20 mM HEPES and 1X HBSS with pH 7.4. 3. Dissolve the contents of Component C vial in DMSO and mix thoroughly by vortexing. 4. Mix the vial of Component A (dye) with 10 mL of Component B buffer (HBSS 20 mM HEPES). 5. Combine the Component C solution from Step 3 and the Component A solution from Step 4, and vortex for 1-2 minutes until the contents of the vial are dissolved. Note: It is important that the contents are completely dissolved to ensure reproducibility between experiments. 6. If using only the bulk kit, combine the solution from step 5 with the remaining 190 mL of prepared Component B buffer, and then mix thoroughly. o Add 200 μL of probenecid (equivalent to a final concentration of 2.5 mM in the assay plate) and 20 μL of 100 mM ouabain (equivalent to 100 μM in the assay plate) to every 10 mL of prepared dye. Add 25 μL of loading dye to each well of an assay plate containing 25 μL of dye. Link to a robotic arm (multidrop or microfiber). o Incubate at room temperature for 30 minutes. Preparation of drug plates and transfer of compounds to assay plates. The compound is seeded onto an assay-ready plate (ARP). The plate layout in Figure 1 shows a plate map of the ARP for dose-response. The compound is hydrated with 20 μL of HBSS containing 20 mM HEPES. The compound is transferred to the assay plate 30 minutes after loading the thallium-sensitive dye, as described in the preparation of the thallium-loading dye above. The compound is diluted at a ratio of 1:500 relative to its final concentration. The compound is transferred using a FLIPR. Mixing: 3 strokes, 10 μl at a speed of 5 μl / sec, height 20 μl. Aspiration: 10 μl at a speed of 5 μl / sec, height 5 μl; tip-up speed 20 mm / sec. Dispensing: 10 μl at a speed of 5 μl / sec, height 10 μl; liquid removal speed 20 mm / sec. o Incubate at room temperature for 30 minutes. Preparation of thallium sulfate source plate Prepare a 5X thallium sulfate solution in a 1X chloride buffer. For a 5 mL 5X thallium source plate: 1 mL of free 5X chloride, 0.5 mL of Tl2SO4 50 mM (final equivalent concentration of 2 mM), and 3.5 mL of H2O. Dispense into 384-well Corning PP round-bottom plates (Costar, catalog number 3656). o 12.5 μL per well is required for each assay plate + dead volume. o Gently rotate it. Start the assay with FLIPR 384-Head. parameters o Excitation: 470-495 nm; Emission: 515-575 nm. o Addition amount: 12.5μL. o Aspiration: 12.5 μl at a speed of 20 μl / sec, height 5 μl, tip-up speed 20 mm / sec. Dispensing: 12.5 μl at a rate of 20 μl / sec, height 40 μl; liquid removal rate 20 mm / sec. o Read the baseline for 10 seconds and transfer 12.5 μL to the assay plate. Read every second for 60 seconds. When adding thallium, leave the tip attached to the head. Data Analysis o Statistics file: Export slope (speed) between 17 seconds and 32 seconds. Analyze using (without Tet DMSO) and (with Tet DMSO) controls (setting up stimulation and neutral controls, respectively). o Calculate the inhibitory thallium rate relative to the control. o Data is, 50 This is reported as the (half-maximal inhibitory concentration) and the maximum inhibitory rate. APOL1 recombinant protein-based blue trypanosome lysis assay

[0246] Blue trypanosoma is a bloodstream parasite to which humans, gorillas, and baboons are immune due to the presence of the APOL1 protein in their HDL particles. The protein is taken up by the parasite via the TbHpHb receptor located in its flagellar pocket and bound by the Hpr protein contained in the HDL particles, which induces receptor endocytosis by the parasite.

[0247] Following endocytosis, the formed vesicles containing HDL particles mature from early endosomes to late endosomes and then to lysosomes. Simultaneous pH changes within the vesicle lumen lead to the insertion of APOL1 protein into the late endosome / lysosome membrane, resulting in lysosomal membrane permeabilization and, further downstream, trypanosome lysis. Blue trypanosomes are sensitive to lysis by all three APOL1 variants (G0, G1, and G2).

[0248] The blue trypanosoma lysis assay is a parasite lysis assay using recombinant APOL1 protein variants, followed by fluorescence detection of viability by adding AlamarBlue reagent to the assay well, which is a common metabolic redox indicator (AlamarBlue assay).

[0249] In short, the AlamarBlue active compound, a blue, water-soluble, non-toxic, and cell-permeable molecule, can be reduced to resorphine, a red compound, via various metabolic pathways, which can then be measured by absorbance or fluorescence. The assay allows for the calculation of viability at the end of lysis (the percentage of viable trypanosomes remaining in each well) compared to the untreated state by interpolating fluorescence values ​​(FLU) on a standard curve with a known amount of seeded trypanosomes / well. Reagents and materials

[0250] Blue Trypanosoma (ATCC, catalog number PRA-382) o Lister 427 VSG 221 Blood flow type

[0251] [Table 27]

[0252] [Table 28]

[0253] [Table 29]

[0254] [Table 30]

[0255] [Table 31]

[0256] [Table 32]

[0257] equipment E1-Clip Tip Pipette, 12 Channels, Adjustable, 2-125 μL, Catalog Number 4672070BT ThermoFisher MultiDrop 384, catalog number 5840300 o Multidrop Agilent Bravo, catalog number G5409A o Bravo o SpectraMax M5

[0258] Assay-Ready Plate (ARP) There are two formats for ARP. Diluted 2.5 times to 10 mM final highest concentration. Diluted 3 times to 5 mM final highest concentration. Both have a dose-response score of 10. • 0.1% DMSO was finalized in a black assay plate. The compound is diluted 1000-fold on a black assay plate. Each plate is designed in two sets for 14 compounds. o Last Black assay plate: • Row 1: Culture medium only (without APOL1) (100% viability) • Columns 2-23: APOL1 (approximately EC1) of 0.05 μg / mL 90 (10% survival rate with APOL 1) · Row 24: 0.1μg / mL APOL1(EC 100 )(approximately 0% survival) Assay procedure Trypanosoma bluis culture Protocol A

[0259] Step 1, Day 1 o Heat the cells at 35°C for no more than 2 minutes. o Gently resuspend one vial in 20 mL of pre-warmed culture medium and culture in a T75 flask at 37°C and 5% CO2. Do not remove the freeze-protectant.

[0260] Step 2, Day 4 o Centrifuge at 800xg for 5 minutes at room temperature. Resuspend in 1 mL of culture medium. o Dilute 1:25 times (10 μL / 240 μL medium). o Count the blood cells using a blood cell counter (after adding the parasites). Leave it for 1-2 minutes until the parasites settle down. • The number is approximately 100 viable motile parasites per 16 grids, or approximately 25 × 10 6 It should be an individual parasite / flask. o 1 × 10 in 20 mL of culture medium 6 Add the parasites to the T75 flask and subculture the parasites. o 2.33 × 10 in 46.6 mL of culture medium 6 Add the parasites to the T175 flask and subculture the parasites. • For every T75 flask, you should prepare enough to fill approximately 1.5 × 384 well assay plates. • For every T175 flask, you should prepare enough to fill approximately 3.8 × 384 well assay plates.

[0261] Step 3, Day 6 Centrifuge at 800xg for 5 minutes. • Resuspend each starting flask in 3 mL of assay medium (without phenol red and FBS). • Resuspend in 7 mL of assay medium (without phenol red and FBS) per 175 flask. Dilute 1:25 times. o Count using a hemocytometer. • All T75 flask settings are approximately 75 × 10 6 There should be one parasite / flask (doubling time = 8.7 hours) + (Check the time). • All T175 flask settings are approximately 175 × 10 6 There should be one parasite / flask (doubling time = 8.7 hours) + (Check the time). • 46 x 10 per 384-well plate 6 This many parasites are needed (120,000 parasites per well). Protocol B

[0262] Step 1, Day 1 Thaw the cells at 35°C for no more than 2 minutes. o Gently resuspend one vial in 20 mL of pre-warmed culture medium and culture in a T75 flask at 37°C and 5% CO2. Do not remove the freeze-protectant.

[0263] Step 2, Day 2 o Centrifuge at 800xg for 5 minutes at room temperature. Resuspend in 1 mL of culture medium. o Dilute 1:25 times (10 μL / 240 μL medium). Leave it for 1-2 minutes until the parasites settle down. • The number is approximately 100 viable motile parasites per 16 grids, or approximately 8 × 10 6 It should be an individual parasite / flask. o 1.25 × 10⁶ per 20 mL of culture medium in a T75 flask 6 Add individual parasites and subculture the parasites. • Approximately 1.5 × 384 well assay plates are required for each T75 flask configuration. • Approximately 3.8 × 384 well assay plates are required for each T175 flask configuration.

[0264] Step 3, Day 5 Centrifuge at 800xg for 5 minutes. Resuspend each T75 starting flask in 3 mL of assay medium (without phenol red and FBS). Resuspend each T175 starting flask in 7 mL of assay medium (without phenol red and FBS). Dilute 1:25 times. o Count using a hemocytometer. Each T75 flask measures approximately 75 x 10°C per flask. 6 It should have one parasite (checking doubling time: 7.7 hours) + 1 hour). Each T175 flask measures approximately 175 x 10°C per flask. 6 It should have one parasite (checking doubling time: 7.7 hours) + 1 hour). Dissolution assay settings

[0265] APOL1 G1 protein Remove aliquots of 1.2 mg / mL APOL1 protein stock from -70°C. o Determine the amount needed for the experiment: • 11.5 mL of APOL1 0.1 μg / mL is required per 384-well plate. For control, 0.5 mL of APOL1 0.2 μg / mL is required per 384-well plate. o Perform the first 1:10 dilution (10 μL / 90 μL) in the assay medium (currently 120 μg / mL). • At a final concentration of 0.05 μg / mL, the EC is approximately 50 APOL1 is used for this purpose. This value needs to be determined for each new lot of protein used. Add 30 mL / well of 0.1 μg / mL 2X APOL1 solution. Solution A: For a 2X stock solution containing 0.1 μg / mL, 8.33 μL (120 μg / mL) out of 10 mL was measured. For solution B, 16.67 μL (120 μg / mL) out of 10 mL was measured against a 2X stock control containing 0.2 μg / mL.

[0266] Multidrop o Black assay plate (384-well black wells with transparent bottom, catalog number 3762). Dispense 30 μL / well of assay medium into one row (without APOL1). Columns 2-23: Dispense 30 μL / well of solution A (0.1 μg / mL APOL1). Dispense 30 μL / well of solution B (0.2 μg / mL APOL1) into a 24-row fountain. o Storage plate (Polypropylene storage plate, Corning® catalog number 3656). Rows 1-24: Dispense 80 μL of assay medium (without APOL1) per well (30 mL of medium / plate).

[0267] Bravo: Compound Transfer Place the storage plate, assay-ready plate (ARP), and black assay plate on the deck. Transfer 20 μL from the storage plate to ARP and mix. Transfer 6 μL from ARP to a black assay plate and mix. • The black assay plate is ready for trypanosome addition.

[0268] Trypanosome addition: Once the compound has been added to the black assay plate, begin collecting trypanosomes as described in step 3 of the blue trypanosome culture section. Count the trypanosomes in assay medium (without phenol red and FBS), 5 × 10 6 Prepare at / mL. • 384-well plate (46 x 10 6 5 x 10 per plate 6 9.2 mL of trypanosomes / mL is required. Using an E1-Clip multichannel 12-channel 2-125μL adjustable pipette, 24μL of 5×10¹³ solution was added to each well of a 384-well plate. 6 Add the trypanosome mix. Once the addition is complete, gently tap the plate on the surface to ensure that the liquid is present in each well. Place the plate on the plate shaker for about 10 seconds and shake to ensure even distribution and that no droplets remain on any edge. Place in an incubator overnight (16 hours) at 37°C and 5% CO2. o Each well contains 60 μL of the following: 30 μL of 2X APOL1 medium, 6 μL of 10X compound, and 24 μL of trypanosome solution.

[0269] Adding AlamarBlue After 16 hours (overnight) in the incubator, take the required amount of AlamarBlue (2.3 mL / plate) from the bottle stored in the refrigerator and warm it briefly in a 37°C water bath. Add 6 μL / well using an E1-Clip multichannel 12-channel 2-125 μL adjustable pipette. Protect from light and incubate the plate at 37°C and 5% CO2 for 2.5 hours.

[0270] Read using SpectraMax (Softmax Pro 6.4 software, excitation: 555nm, emission: 585nm). Efficacy data for compounds 1-286

[0271] The compounds of formulas (I), (II), (IIIa), (IIIb), and (IVa) are useful as inhibitors of APOL1 activity. Table 23 below shows the IC50 of compounds 1-286 obtained using the above procedure (assays described in Examples 2A and 2B). 50 This explains the following. In Table 23 below, the following meanings apply: IC 50 Regarding the values, "+++" means <0.25 μm, "++" means 0.25 μm - 1.0 μm, and "+" means greater than 1.0 μm. ND = Not determined. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] [Table 23-7] Efficacy data for compounds 287-465

[0272] The compounds of formulas (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb) are useful as inhibitors of APOL1 activity. Table 24 below shows the IC50 of compounds 287-465 obtained using the above procedure (assays described in Examples 2A and 2B). 50 This explains the following. In Table 24 below, the following meanings apply. IC 50 Regarding the following: "+++" means <0.25μm, "++" means 0.25μm-1.0μm, and "+" means greater than 1.0μm. ND = Not determined. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] Other Embodiments

[0273] This disclosure provides merely exemplary embodiments of the disclosure. Those skilled in the art will readily recognize that various changes, modifications, and variations can be made from this disclosure and the claims without departing from the spirit and scope of the disclosure as defined in the following claims.

Claims

1. A compound of formula (I), 【Chemistry 58】 A compound selected from a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing, wherein: (i) Ring A is a 3- to 7-membered ring, said ring being a cyclic alkyl or heterocyclic ring; (ii) Q is N or CR ５ and (iii) Each R １ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -OC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)OC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ６ linear, branched, and cyclic alkyl groups; ・C ２ -C ６ linear, branched, and cyclic alkenyl groups; ・C １ -C ６ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ６ linear, branched, and cyclic alkoxy groups; ・C １ -C ６ linear, branched, and cyclic thioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ６ linear, branched, and cyclic halothioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkoxy groups; a benzyloxy group, a benzylamino group, or a benzylthio group, a 3- to 6-membered heterocycloalkenyl group, 3-6 membered heterocycloalkyl groups, and 5- and 6-membered heteroaryl groups, or Two R's １ The groups, together with the carbon atoms to which they are attached, form a C ４ -C ８ forming a cycloalkyl group, an aryl group, or a heteroaryl group, (iv) Each R ２ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ４ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ４ linear, branched, and cyclic alkyl groups; ・C ２ -C ４ linear, branched, and cyclic alkenyl groups; ・C １ -C ４ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ４ linear, branched, and cyclic alkoxy groups; ・C １ -C ４ linear, branched, and cyclic thioalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ４ linear, branched, and cyclic halothioalkyl groups, and ・C １ -C ４ linear, branched, and cyclic haloalkoxy groups; (v) m is selected from 0, 1, 2, 3, and 4; (vi) n is selected from 0, 1, 2, 3, 4, and 5; (vii) X is a divalent C １ -C ８ Linear, branched, and cyclic alkyl groups and divalent C １ -C ８ selected from linear, branched, and cyclic thioalkyl groups, wherein said divalent alkyl and divalent thioalkyl groups are optionally substituted with one to four groups independently selected from: o C １ -C ６ alkyl groups, an aryl group, a heteroaryl group, a halogen group, o hydroxy, and o Amino, (viii) Y is a divalent amino, divalent oxygen, divalent C １ -C ８ Straight-chain, branched, and cyclic alkyl groups, divalent C １ -C ８ Linear, branched, and cyclic alkoxy groups, divalent C １ -C ８ Linear, branched, and cyclic aminoalkyl groups, and divalent C １ -C ８ selected from linear, branched, and cyclic thioalkyl groups, wherein said divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with one to three groups independently selected from the following: C optionally substituted with hydroxy １ -C ６ alkyl groups, o C ３ -C ６ Cyclic alkyl, an aryl group, a heteroaryl group, a halogen group, o hydroxy, and o Amino, Alternatively, the divalent alkyl group, the divalent alkoxy group, the divalent aminoalkyl group, and the divalent thioalkyl group may be C ３ -C ６ optionally fused to a cyclic alkyl; (ix) o is selected from 0, 1, 2, 3, and 4; (x) p is selected from 0, 1, 2, 3, and 4; (xi) R ３ and R ４ are independently selected from: hydrogen, ・C １ -C ６ linear and branched alkylsulfonyl groups, ・C ３ -C ６ C optionally substituted with a cyclic alkyl group or a 3- to 6-membered heterocycle １ -C ６ linear and branched alkoxy groups, ・C １ -C ６ A cyclic alkyl group optionally substituted with one to four groups independently selected from the following: １ -C ６ a cyclic alkyl group represented by the formula: a halogen group, o hydroxy, oxo, o C １ -C ６ linear and branched alkoxy groups, o C １ -C ６ Straight chain and branched alkyl groups, including hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ straight-chain and branched alkyl groups, and an amide group, heterocyclic groups optionally substituted with one to four groups independently selected from: a halogen group, oxo, o hydroxy, and o C １ -C ６ Straight chain and branched alkyl groups, including hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ linear and branched alkyl groups, aryl groups, including halogen groups, hydroxy, and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ an aryl group optionally substituted with one to four groups independently selected from: straight-chain and branched alkyl groups; Hydroxy and C １ -C ６ a heteroaryl group optionally substituted with one to four groups independently selected from straight chain alkyl groups, and ・C １－ C ７ C is a straight-chain and branched alkyl group optionally substituted with one to five groups independently selected from the following: １－ C ７ linear and branched alkyl groups, an amino group, o hydroxy, oxo, o cyano, carboxylic acids, a halogen group, o an amide group, C １ -C ６ Linear, branched, and cyclic alkyl groups and C １ -C ６ an amide group optionally substituted with one or two groups independently selected from linear, branched, and cyclic hydroxyalkyl groups; o C ３ -C ６ A cyclic alkyl group, which is selected from the group consisting of a halogen group, C １ -C ６ Linear and branched alkoxy groups, optionally substituted with one or two hydroxy groups １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkyl groups, and hydroxy ３ -C ６ cyclic alkyl groups, o C ２ -C ６ straight-chain and branched alkynyl groups, C optionally substituted with at least one hydroxy ２ -C ６ linear and branched alkoxy groups, o C １ -C ６ linear and branched alkylsulfonyl groups, o Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ an aryl group optionally substituted with one or two groups independently selected from: straight-chain and branched alkyl groups; carbonyl-(4-methylpiperazin-1-yl), carbonyl-(N-morpholino), o 4-10 membered heterocyclyl group, including halogen, oxo, hydroxy, C １ -C ６ Linear and branched alkoxy groups, and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups independently selected from: straight-chain and branched alkyl groups; and o 4-10 membered heteroaryl groups, including halogen, hydroxy, and hydroxy, halogen, and C １ -C ６ C optionally substituted with one to three groups independently from straight-chain and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one to three groups independently selected from: straight-chain and branched alkyl groups; Or, R ３ and R ４ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl group optionally substituted with one to four groups independently selected from: o hydroxy, oxo, o C １ -C ６ Linear, branched, and cyclic alkyl groups, including hydroxy, amino, C １ -C ６ Linear, branched, and cyclic alkoxy groups, oxo 、 and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkyl groups; ３ -C ６ C optionally substituted with one to four groups independently selected from: １ -C ６ linear, branched, and cyclic alkyl groups; o C １ -C ６ an amide group optionally substituted with one to four groups independently selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ a carboxamide group optionally substituted with one to four groups independently selected from linear, branched, and cyclic alkyl groups; o oxo, C １ -C ６ C optionally substituted with one to four groups independently selected from linear, branched, and cyclic alkyl groups, and heterocyclic groups; １ -C ６ linear, branched, and cyclic alkoxy groups; o 4-10 membered heterocyclyl groups, including halogen, hydroxy, and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups independently selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ straight-chain and branched alkyl groups; and a 4- to 10-membered heteroaryl group optionally substituted with one or two groups independently selected from the group consisting of: (xii) R ５ is absent or is chosen from: hydrogen, - halogen groups, Hydroxy, thiols, Amino, and ・C １ -C ６ linear and branched alkyl groups, In the formula, R ５ is absent, then Q is a bridgehead atom.

2. Ring A is 【Chemistry 59】 2. The compound of claim 1, a deuterated derivative, or a pharmaceutically acceptable salt thereof, selected from:

3. Q is CR ５ 3. The compound, deuterated derivative, or pharmaceutically acceptable salt of claim 1 or claim 2, wherein:

4. Each R １ is a halogen group and C １ -C ６ 4. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 3, wherein the haloalkyl groups are independently selected from straight-chain, branched, and cyclic haloalkyl groups.

5. Each R １ Fluoro and CF ３ 5. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 4, independently selected from:

6. Each R ２ 6. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5, wherein is independently selected from a halogen group.

7. Each R ２ The compound, salt, or deuterated derivative of any one of claims 1 to 6, wherein is fluoro.

8. 8. The compound, salt, or deuterated derivative of any one of claims 1 to 7, wherein m is 2.

9. 9. The compound, salt, or deuterated derivative of any one of claims 1 to 8, wherein n is 1.

10. X is divalent C １ -C ８ 16. The compound, salt, or deuterated derivative of any one of claims 1 to 15, wherein the divalent alkyl group is selected from linear, branched, and cyclic alkyl groups, and wherein the divalent alkyl group is optionally substituted with one to four groups selected from the following: o C １ -C ６ alkyl groups, an aryl group, a heteroaryl group, a halogen group, o hydroxy, and o Amino.

11. X is -CH ２ - and -CH ２ -CH ２ The compound, salt, or deuterated derivative of any one of claims 1 to 10, selected from:

12. Y is a divalent amino, a divalent oxygen, a divalent C １ -C ８ Linear, branched, and cyclic alkyl groups, and divalent C １ -C ８ selected from linear, branched, and cyclic aminoalkyl groups, wherein the divalent alkyl groups and divalent aminoalkyl groups are optionally substituted with one to three groups independently selected from the following: C optionally substituted with hydroxy １ -C ６ alkyl groups, o C ３ -C ６ Cyclic alkyl, o oxo, and o hydroxy, Alternatively, the divalent alkyl group, the divalent alkoxy group, the divalent aminoalkyl group, and the divalent thioalkyl group are each selected from the group consisting of C ３ -C ６ 12. The compound, salt, or deuterated derivative of any one of claims 1 to 11, optionally fused to a cyclic alkyl.

13. Y, 【Transformation 60】 13. The compound, salt, or deuterated derivative of any one of claims 1 to 12, selected from:

14. 14. The compound, salt, or deuterated derivative of any one of claims 1 to 13, wherein o is 0 or 1.

15. 15. The compound, salt, or deuterated derivative of any one of claims 1 to 14, wherein p is 0 or 1.

16. R ３ is hydrogen, and R ４ 16. The compound, salt, or deuterated derivative of any one of claims 1 to 15, wherein is selected from: hydrogen, ・C １ -C ６ linear and branched alkylsulfonyl groups, ・C ３ -C ６ C optionally substituted with a cyclic alkyl group or a 3- to 6-membered heterocycle １ -C ６ linear and branched alkoxy groups, ・C １ -C ６ A cyclic alkyl group optionally substituted with one to four groups independently selected from the following: １ -C ６ a cyclic alkyl group represented by the formula: a halogen group, o hydroxy, oxo, o C １ -C ６ linear and branched alkoxy groups, o C １ -C ６ Straight chain and branched alkyl groups, including hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ straight-chain and branched alkyl groups, and an amide group, heterocyclic groups optionally substituted with one to four groups independently selected from: a halogen group, oxo, o hydroxy, and o C １ -C ６ Straight chain and branched alkyl groups, including hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ linear and branched alkyl groups, Hydroxy and C １ -C ６ a heteroaryl group optionally substituted with one to four groups independently selected from straight chain alkyl groups, and ・C １－ C ７ C is a straight-chain and branched alkyl group optionally substituted with one to five groups independently selected from the following: １－ C ７ linear and branched alkyl groups, an amino group, o hydroxy, oxo, o cyano, carboxylic acids, a halogen group, o an amide group, C １ -C ６ Linear, branched, and cyclic alkyl groups and C １ -C ６ an amide group optionally substituted with one or two groups independently selected from linear, branched, and cyclic hydroxyalkyl groups; o C ３ -C ６ A cyclic alkyl group, which is selected from the group consisting of a halogen group, C １ -C ６ Linear and branched alkoxy groups, optionally substituted with one or two hydroxy groups １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkyl groups, and hydroxy ３ -C ６ cyclic alkyl groups, o C ２ -C ６ straight-chain and branched alkynyl groups, C optionally substituted with at least one hydroxy ２ -C ６ linear and branched alkoxy groups, carbonyl-(4-methylpiperazin-1-yl), carbonyl-(N-morpholino), o 4-10 membered heterocyclyl group, including halogen, oxo, hydroxy, C １ -C ６ Linear and branched alkoxy groups, and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups independently selected from: straight-chain and branched alkyl groups; and o 4-10 membered heteroaryl groups, including halogen, hydroxy, and hydroxy, halogen, and C １ -C ６ C optionally substituted with one to three groups independently from straight-chain and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one to three groups independently selected from: straight-chain and branched alkyl groups;

17. R ３ and R ４ together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl group optionally substituted with one to four groups independently selected from: o hydroxy, oxo, o C １ -C ６ Linear, branched, and cyclic alkyl groups, including hydroxy, amino, C １ -C ６ Linear, branched, and cyclic alkoxy groups, oxo 、 and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkyl groups; ３ -C ６ C optionally substituted with one to four groups independently selected from: １ -C ６ linear, branched, and cyclic alkyl groups; o C １ -C ６ an amide group optionally substituted with one to four groups independently selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ a carboxamide group optionally substituted with one to four groups independently selected from linear, branched, and cyclic alkyl groups; o oxo, C １ -C ６ C optionally substituted with one to four groups independently selected from linear, branched, and cyclic alkyl groups, and heterocyclic groups; １ -C ６ linear, branched, and cyclic alkoxy groups; o 4-10 membered heterocyclyl groups, including halogen, hydroxy, and hydroxy and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups independently selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, and C １ -C ６ C optionally substituted with one or two groups independently selected from linear and branched alkoxy groups; １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups independently selected from: straight-chain and branched alkyl groups;

18. R ５ 18. The compound, salt, or deuterated derivative of any one of claims 1 to 17, wherein is independently selected from hydrogen, fluoro, and methyl.

19. The compound is a compound of formula (V-a) and (V-b), 【Chemistry 61】 a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing, wherein R １ , R ２ , R ３ , R ４ 2. The compound, salt, or deuterated derivative of claim 1, wherein Y, p, and p are as defined in claim 1.

20. The compound is a compound of formula (Ia): 【Transformation 62】 a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing, wherein: (i) Each R １ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -OC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)OC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ６ linear, branched, and cyclic alkyl groups; ・C ２ -C ６ linear, branched, and cyclic alkenyl groups; ・C １ -C ６ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ６ linear, branched, and cyclic alkoxy groups; ・C １ -C ６ linear, branched, and cyclic thioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ６ linear, branched, and cyclic halothioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkoxy groups; a benzyloxy group, a benzylamino group, or a benzylthio group, a 3- to 6-membered heterocycloalkenyl group, 3-6 membered heterocycloalkyl groups, and 5- and 6-membered heteroaryl groups, or Two R's １ The groups, together with the carbon atoms to which they are attached, form a C ４ -C ８ forming a cycloalkyl group, an aryl group, or a heteroaryl group, (ii) Each R ２ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ４ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ４ linear, branched, and cyclic alkyl groups; ・C ２ -C ４ linear, branched, and cyclic alkenyl groups; ・C １ -C ４ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ４ linear, branched, and cyclic alkoxy groups; ・C １ -C ４ linear, branched, and cyclic thioalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ４ linear, branched, and cyclic halothioalkyl groups, and ・C １ -C ４ linear, branched, and cyclic haloalkoxy groups; (iii) m is selected from 0, 1, 2, 3, and 4; (iv) n is selected from 0, 1, 2, 3, 4, and 5; (v) X is a divalent C １ -C ８ Linear, branched, and cyclic alkyl groups and divalent C １ -C ８ selected from linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl and divalent thioalkyl groups are optionally substituted with at least one group selected from: o C １ -C ６ alkyl groups, an aryl group, a heteroaryl group, a halogen group, o hydroxy, and o Amino, (vi) Y is a divalent C １ -C ８ Straight-chain, branched, and cyclic alkyl groups, divalent C １ -C ８ Linear, branched, and cyclic alkoxy groups, divalent C １ -C ８ Linear, branched, and cyclic aminoalkyl groups, and divalent C １ -C ８ linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with at least one group selected from the following: o C １ -C ６ alkyl groups, an aryl group, a heteroaryl group, a halogen group, o hydroxy, and o Amino, (vii) o is selected from 0, 1, 2, 3, and 4; (viii) p is selected from 0, 1, 2, 3, and 4; (ix) R ３ and R ４ are independently selected from: hydrogen, ・C １ -C ６ linear and branched alkylsulfonyl groups, ・C １ -C ６ Cyclic alkyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ C optionally substituted with at least one group selected from linear and branched alkyl groups, and amide groups １ -C ６ cyclic alkyl groups, Heterocyclic groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a heterocyclic group optionally substituted with at least one group selected from: a linear and branched alkyl group; Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with at least one group selected from linear and branched alkyl groups; ・C １ -C ６ a heteroaryl group optionally substituted with at least one group selected from a linear alkyl group, and ・C １ -C ６ Linear and branched alkyl groups, said alkyl groups being optionally substituted with at least one group selected from: an amino group, o hydroxy, o cyano, carboxylic acids, a halogen group, o an amide group, C １ -C ６ Linear, branched, and cyclic alkyl groups and C １ -C ６ an amide group optionally substituted with one or two groups selected from linear, branched, and cyclic hydroxyalkyl groups; C optionally substituted with one or two groups selected from halogen groups and hydroxy ３－ C ６ cyclic alkyl groups, o C １ -C ６ straight-chain and branched alkynyl groups, C optionally substituted with at least one hydroxy １ -C ６ linear and branched alkoxy groups, o C １ -C ６ linear and branched alkylsulfonyl groups, o Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; carbonyl-(4-methylpiperazin-1-yl), carbonyl-(N-morpholino), o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from linear and branched alkyl groups; Or, R ３ and R ４ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group selected from: o hydroxy, oxo, o C １ -C ６ Linear, branched, and cyclic alkyl groups, including hydroxy, amino, C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkoxy groups １ -C ６ linear, branched, and cyclic alkyl groups; o C １ -C ６ an amide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ a carboxamide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ Linear, branched, and cyclic alkoxy groups, including C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups, and heterocyclic groups; １ -C ６ linear, branched, and cyclic alkoxy groups; o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; (vi) each R ５ teeth, hydrogen, - halogen groups, Hydroxy, thiols, Amino, and ・C １ -C ６ 10. The compound, salt, or deuterated derivative of claim 1, independently selected from straight-chain and branched alkyl groups.

21. The compound is a compound of formula (II): 【Transformation 63】 a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing, wherein: (i) Each R １ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -OC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)OC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ６ linear, branched, and cyclic alkyl groups; ・C ２ -C ６ linear, branched, and cyclic alkenyl groups; ・C １ -C ６ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ６ linear, branched, and cyclic alkoxy groups; ・C １ -C ６ linear, branched, and cyclic thioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ６ linear, branched, and cyclic halothioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkoxy groups; a benzyloxy group, a benzylamino group, or a benzylthio group, a 3- to 6-membered heterocycloalkenyl group, 3-6 membered heterocycloalkyl groups, and 5- and 6-membered heteroaryl groups, or Two R's １ The groups, together with the carbon atoms to which they are attached, form a C ４ -C ８ forming a cycloalkyl group, an aryl group, or a heteroaryl group, (ii) Each R ２ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ４ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ４ linear, branched, and cyclic alkyl groups; ・C ２ -C ４ linear, branched, and cyclic alkenyl groups; ・C １ -C ４ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ４ linear, branched, and cyclic alkoxy groups; ・C １ -C ４ linear, branched, and cyclic thioalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ４ linear, branched, and cyclic halothioalkyl groups, and ・C １ -C ４ linear, branched, and cyclic haloalkoxy groups; (iii) m is selected from 0, 1, 2, 3, and 4; (iv) n is selected from 0, 1, 2, 3, 4, and 5; (v) R ３ and R ４ are independently selected from: hydrogen, ・C １ -C ６ linear and branched alkylsulfonyl groups, ・C １ -C ６ Cyclic alkyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ C optionally substituted with at least one group selected from linear and branched alkyl groups, and amide groups １ -C ６ cyclic alkyl groups, Heterocyclic groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a heterocyclic group optionally substituted with at least one group selected from: a linear and branched alkyl group; Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with at least one group selected from linear and branched alkyl groups; ・C １ -C ６ a heteroaryl group optionally substituted with at least one group selected from a linear alkyl group, and ・C １ -C ６ Linear and branched alkyl groups, said alkyl groups being optionally substituted with at least one group selected from: an amino group, o hydroxy, o cyano, carboxylic acids, a halogen group, o an amide group, C １ -C ６ Linear, branched, and cyclic alkyl groups and C １ -C ６ an amide group optionally substituted with one or two groups selected from linear, branched, and cyclic hydroxyalkyl groups; C optionally substituted with one or two groups selected from halogen groups and hydroxy ３－ C ６ cyclic alkyl groups, o C １ -C ６ straight-chain and branched alkynyl groups, C optionally substituted with at least one hydroxy １ -C ６ linear and branched alkoxy groups, o C １ -C ６ linear and branched alkylsulfonyl groups, o Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; carbonyl-(4-methylpiperazin-1-yl), carbonyl-(N-morpholino), o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from linear and branched alkyl groups; Or, R ３ and R ４ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group selected from: o hydroxy, oxo, o C １ -C ６ Linear, branched, and cyclic alkyl groups, including hydroxy, amino, C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkoxy groups １ -C ６ linear, branched, and cyclic alkyl groups; o C １ -C ６ an amide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ a carboxamide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ Linear, branched, and cyclic alkoxy groups, including C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups, and heterocyclic groups; １ -C ６ linear, branched, and cyclic alkoxy groups; o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; (vi) each R ５ are independently selected from: hydrogen, - halogen groups, Hydroxy, thiols, Amino, and ・C １ -C ６ Straight-chain and branched alkyl groups. halogen groups, and methyl, (iii) m is 0, 1, or 2; and (iv) The compound, salt, or deuterated derivative of claim 1, wherein n is 1 or 2.

22. The compound is a compound of formula (IIIa): 【Chemistry 64】 Compound of formula (IIIb) 【Transformation 65】 a pharmaceutically acceptable salt of any of the foregoing, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing, wherein: (i) Each R １ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -OC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)OC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ６ linear, branched, and cyclic alkyl groups; ・C ２ -C ６ linear, branched, and cyclic alkenyl groups; ・C １ -C ６ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ６ linear, branched, and cyclic alkoxy groups; ・C １ -C ６ linear, branched, and cyclic thioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ６ linear, branched, and cyclic halothioalkyl groups; ・C １ -C ６ linear, branched, and cyclic haloalkoxy groups; a benzyloxy group, a benzylamino group, or a benzylthio group, a 3- to 6-membered heterocycloalkenyl group, 3-6 membered heterocycloalkyl groups, and 5- and 6-membered heteroaryl groups, or Two R's １ The groups, together with the carbon atoms to which they are attached, form a C ４ -C ８ forming a cycloalkyl group, an aryl group, or a heteroaryl group, (ii) Each R ２ are independently selected from: - halogen groups, Hydroxy, thiols, ・ Amino, ・ Cyano, -NHC(O)C １ -C ６ linear, branched, and cyclic alkyl groups; -C(O)NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHC(O)aryl groups, -C(O)NH aryl groups, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, -NHS (O) ２ C １ -C ６ linear, branched, and cyclic alkyl groups; -S (O) ２ NHC １ -C ６ linear, branched, and cyclic alkyl groups; -NHS (O) ２ aryl groups, -S (O) ２ NH aryl group, -NHS (O) ２ heteroaryl groups, -S (O) ２ NH heteroaryl group, ・ -NHC(O)NHC １ -C ４ linear, branched, and cyclic alkyl groups; -NHC(O)NH aryl groups, -NHC(O)NH heteroaryl groups, ・C １ -C ４ linear, branched, and cyclic alkyl groups; ・C ２ -C ４ linear, branched, and cyclic alkenyl groups; ・C １ -C ４ linear, branched, and cyclic hydroxyalkyl groups; ・C １ -C ４ linear, branched, and cyclic alkoxy groups; ・C １ -C ４ linear, branched, and cyclic thioalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloalkyl groups; ・C １ -C ４ linear, branched, and cyclic haloaminoalkyl groups; ・C １ -C ４ linear, branched, and cyclic halothioalkyl groups, and ・C １ -C ４ linear, branched, and cyclic haloalkoxy groups; (iii) m is selected from 0, 1, 2, 3, and 4; (iv) n is selected from 0, 1, 2, 3, 4, and 5; (v) R ３ and R ４ are independently selected from: hydrogen, ・C １ -C ６ linear and branched alkylsulfonyl groups, ・C １ -C ６ Cyclic alkyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ C optionally substituted with at least one group selected from linear and branched alkyl groups, and amide groups １ -C ６ cyclic alkyl groups, Heterocyclic groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a heterocyclic group optionally substituted with at least one group selected from: a linear and branched alkyl group; Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with at least one group selected from linear and branched alkyl groups; ・C １ -C ６ a heteroaryl group optionally substituted with at least one group selected from a linear alkyl group, and ・C １ -C ６ Linear and branched alkyl groups, said alkyl groups being optionally substituted with at least one group selected from: an amino group, o hydroxy, o cyano, carboxylic acids, a halogen group, o an amide group, C １ -C ６ Linear, branched, and cyclic alkyl groups and C １ -C ６ an amide group optionally substituted with one or two groups selected from linear, branched, and cyclic hydroxyalkyl groups; C optionally substituted with one or two groups selected from halogen groups and hydroxy ３－ C ６ cyclic alkyl groups, o C １ -C ６ straight-chain and branched alkynyl groups, C optionally substituted with at least one hydroxy １ -C ６ linear and branched alkoxy groups, o C １ -C ６ linear and branched alkylsulfonyl groups, o Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; carbonyl-(4-methylpiperazin-1-yl), carbonyl-(N-morpholino), o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from linear and branched alkyl groups; Or, R ３ and R ４ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group selected from: o hydroxy, oxo, o C １ -C ６ Linear, branched, and cyclic alkyl groups, including hydroxy, amino, C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkoxy groups １ -C ６ linear, branched, and cyclic alkyl groups; o C １ -C ６ an amide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ a carboxamide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ Linear, branched, and cyclic alkoxy groups, including C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups, and heterocyclic groups; １ -C ６ linear, branched, and cyclic alkoxy groups; o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; (vi) each R ５ teeth, hydrogen, - halogen groups, Hydroxy, thiols, Amino, and ・C １ -C ６ 2. The compound, salt, or deuterated derivative of claim 1, wherein the alkyl group is selected from straight-chain and branched alkyl groups.

23. The compound is a compound of formula (IV): 【Chemical Formula 66】 a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing, wherein: (i) Each R １ and R ２ are independently selected from: Fluoro, ・ Chrollo, ・ Bromo, ・ Cyano, methyl, cyclopropyl, ethyl, hydroxypropyl, isopropyl, propen-2-yl, dihydrofuran, Franc, and methoxy, (ii) R ３ and R ４ are independently selected from: hydrogen, ・C １ -C ６ linear and branched alkylsulfonyl groups, ・C １ -C ６ Cyclic alkyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ C optionally substituted with at least one group selected from linear and branched alkyl groups, and amide groups １ -C ６ cyclic alkyl groups, Heterocyclic groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a heterocyclic group optionally substituted with at least one group selected from: a linear and branched alkyl group; Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with at least one group selected from linear and branched alkyl groups; ・C １ -C ６ a heteroaryl group optionally substituted with at least one group selected from a linear alkyl group, and ・C １ -C ６ Linear and branched alkyl groups, said alkyl groups being optionally substituted with at least one group selected from: an amino group, o hydroxy, o cyano, carboxylic acids, a halogen group, o an amide group, C １ -C ６ Linear, branched, and cyclic alkyl groups and C １ -C ６ an amide group optionally substituted with one or two groups selected from linear, branched, and cyclic hydroxyalkyl groups; C optionally substituted with one or two groups selected from halogen groups and hydroxy ３－ C ６ cyclic alkyl groups, o C １ -C ６ straight-chain and branched alkynyl groups, C optionally substituted with at least one hydroxy １ -C ６ linear and branched alkoxy groups, o C １ -C ６ linear and branched alkylsulfonyl groups, o Aryl groups, including halogen groups, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ an aryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; carbonyl-(4-methylpiperazin-1-yl), carbonyl-(N-morpholino), o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from linear and branched alkyl groups; Or, R ３ and R ４ together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group selected from: o hydroxy, oxo, o C １ -C ６ Linear, branched, and cyclic alkyl groups, including hydroxy, amino, C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkoxy groups １ -C ６ linear, branched, and cyclic alkyl groups; o C １ -C ６ an amide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ a carboxamide group optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups; o C １ -C ６ Linear, branched, and cyclic alkoxy groups, including C １ -C ６ C optionally substituted with at least one group selected from linear, branched, and cyclic alkyl groups, and heterocyclic groups; １ -C ６ linear, branched, and cyclic alkoxy groups; o 4-10 membered heterocyclyl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heterocyclyl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; o 4-10 membered heteroaryl groups, including halogen, hydroxy, hydroxy and C １ -C ６ C optionally substituted with one or two groups selected from linear and branched alkoxy groups １ -C ６ a 4- to 10-membered heteroaryl group optionally substituted with one or two groups selected from: straight-chain and branched alkyl groups; (iii) Each R ５ teeth, hydrogen, - halogen groups, Hydroxy, thiols, Amino, and ・C １ -C ６ 2. The compound, salt, or deuterated derivative of claim 1, wherein the alkyl group is selected from straight-chain and branched alkyl groups.

24. A compound selected from compounds 1-286 (Table 1), a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing.

25. A compound selected from compounds 287-465 (Table 2), a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing.

26. A pharmaceutical composition comprising a compound, salt, deuterated derivative of any one of claims 1 to 25 and a pharmaceutically acceptable carrier.

27. A method of treating an APOL1-mediated kidney disease, comprising administering to a patient in need thereof a compound, salt, deuterated derivative of any one of claims 1 to 25 or a pharmaceutical composition of claim 26.

28. 28. The method of claim 27, wherein the APOL1-mediated kidney disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

29. 28. The method of claim 27, wherein the APOL1-mediated kidney disease is associated with an APOL1 genetic allele selected from homozygous G1:S342G:I384M and homozygous G2:N388del:Y389del.

30. 28. The method of claim 27, wherein the APOL1-mediated kidney disease is associated with compound heterozygous G1:S342G:I384M and G2:N388del:Y389del APOL1 genetic alleles.

31. 27. A method of inhibiting APOL1 activity, comprising contacting said APOL1 with a compound, salt, or deuterated derivative according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26.

32. 32. The method of claim 31, wherein the APOL1 is associated with an APOL1 genetic allele selected from homozygous G1:S342G:I384M and homozygous G2:N388del:Y389del.

33. 32. The method of claim 31, wherein the APOL1 is associated with compound heterozygous G1:S342G:I384M and G2:N388del:Y389del APOL1 genetic alleles.

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