Inhibitors of APOL1 and methods of using same

Abstract

The disclosure provides at least one entity chosen from compounds of Formula (I) pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, compositions comprising the same, and methods of using the same, including use in treating APOL1 mediated kidney disease.

Description

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

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

[0003] FSGS is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function. NDKD is a disease characterized by hypertension and progressive decline in kidney function. Human genetics support a causal role for the G1 and G2 APOL1 variants in inducing kidney disease. Individuals with two APOL1 risk alleles are at increased risk of developing endstage kidney disease (ESKD), including FSGS, human immunodeficiency virus (HIV)-associated nephropathy, NDKD, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See, P. Dummer et al., Semin Nephrol. 35(3): 222-236 (2015).

[0004] APOL1 is a 44 kDa protein that is only expressed in humans, gorillas, and baboons. APOL1 is produced mainly by the liver and contains a signal peptide that allows for 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 (T. b. brucei). APOL1 G1 and G2 variants confer additional protection against trypanosoma species that cause sleeping sickness. Although normal plasma concentrations of APOL1 are relatively high and can vary at least 20-fold in humans, circulating APOL1 is not causally associated with kidney disease.

[0005] However, APOL1 in the kidney is thought to be responsible for the development kidney diseases, including FSGS and NDKD. Under certain circumstances, APOL1 protein synthesis can be increased by approximately 200-fold by pro-inflammatory cytokines such as interferons or tumor necrosis factor-a. In addition, several studies have shown that APOL1 protein can form pH-gated Na+ / K+ pores in the cell membrane, 2021213758   13 Oct 2026 resulting in a net efflux of intracellular K+, ultimately resulting in activation of local and systemic inflammatory responses, cell swelling, and death.

[0006] The risk of ESKD is substantially higher in people of recent sub-Saharan African ancestry as compared to those of European ancestry and in the U.S., ESKD is responsible for nearly as many lost years of life in women as from breast cancer and more lost years of life in men than from colorectal cancer. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using blockers of the renin angiotensin system), and patients with FSGS and heavy proteinuria may be offered high dose steroids. Corticosteroids induce remission in a minority of patients and are associated with numerous and at times, severe, side effects, and are often poorly tolerated. These patients, and particularly individuals of recent sub-Saharan African ancestry with two APOL1 risk alleles, experience faster disease progression leading to ESKD.

[0007] Thus, there is an unmet medical need for treatment for APOL1 mediated kidney diseases, including FSGS, NDKD, and ESKD. It is an object of the present invention to go some way to meeting this need, and / or to at least provide the public with a useful choice. In view of evidence that APOL1 plays a causative role in inducing and accelerating the progression of kidney disease, inhibition of APOL1 should have a positive impact on patients with APOL1 mediated kidney disease, particularly those who carry two APOL1 risk alleles (i.e., are homozygous or compound heterozygous for the G1 or G2 alleles). [0007a] In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents, or such sources of information, is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

[0008] One aspect of the disclosure provides at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, which can be employed in the treatment of diseases mediated by APOL1, such as FSGS and NDKD. 2021213758   13 Oct 2026

[0009] Thus, one aspect of the disclosure provides compounds chosen from compounds of Formula (I): (I), pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)    Ring A is a 3- to 7-membered ring, wherein the ring is a cyclic alkyl or a heterocycle; (ii) Q is N or CR5; (iii)   each R1 is independently chosen from halogen groups, hydroxy, 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 groups, -C(O)NHaryl groups, -NHC(O)heteroaryl groups, -C(O)NHheteroaryl groups, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2aryl groups, -S(O)2NHaryl groups, 2021213758   13 Oct 2026 •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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, benzylamino, or benzylthio groups, •  3- to 6-membered heterocycloalkenyl groups, •  3- to 6-membered heterocycloalkyl groups, and •  5- and 6-membered heteroaryl groups; or two R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group; (iv) each R2 is independently chosen from • halogen groups, • hydroxy, • 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 groups, •  -C(O)NHaryl groups, • -NHC(O)heteroaryl groups, 2021213758   13 Oct 2026 • -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, • -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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; (v) m is chosen from 0, 1, 2, 3, and 4; (vi) n is chosen from 0, 1, 2, 3, 4, and 5; (vii) X is chosen from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with one to four groups independently chosen from: o      C1-C6 alkyl groups, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino; 2021213758   13 Oct 2026 (viii) Y is chosen 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, wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with one to three groups independently chosen from o     C1-C6 alkyl groups optionally substituted with hydroxy, o      C3-C6 cyclic alkyl, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino, or wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally fused to a C3-C6 cyclic alkyl; (ix)    o is chosen from 0, 1, 2, 3, and 4; (x)    p is chosen from 0, 1, 2, 3, and 4; (xi)   R3 and R4 are independently chosen from: • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 linear and branched alkoxy groups optionally substituted with a C3- C6 cyclic alkyl group or a 3- to 6-membered heterocycle; •  C1-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from: o halogen groups, o hydroxy, o oxo, o C1-C6 linear and branched alkoxy groups, o C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and 2021213758   13 Oct 2026 o amido groups, • heterocyclic groups optionally substituted with one to four groups independently chosen from: o halogen groups, o oxo, o hydroxy, and o  C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and •  C1-C7 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy, o oxo, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and branched alkoxy groups, C1-C6 linear and branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy, o  C2-C6 linear and branched alkynyl groups, 2021213758   13 Oct 2026 o  C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkyl groups, 2021213758   13 Oct 2026 o amide groups optionally substituted with one to four groups indepedently chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with one to four groups indepedently chosen 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 chosen from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (xii)   R5 is absent or is chosen from: • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and •  C1-C6 linear and branched alkyl groups, wherein when R5 is absent, Q is a bridgehead atom.

[0010] In one aspect of the disclosure, the compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), are chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. 2021213758   13 Oct 2026

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

[0012] Another aspect of the disclosure provides methods of treating FSGS and / or NDKD comprising administering to a subject in need thereof, at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing or a pharmaceutical composition comprising the at least one entity. In some embodiments, the methods comprise administering at least one entity chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

[0013] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV) (Va), and (Vb),, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, or as separate compositions. In some embodiments, the methods comprise administering at least one entity chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing with at least one additional active agent either in the same pharmaceutical composition or in a separate pharmaceutical composition.

[0014] Also provided are methods of inhibiting APOL1, comprising administering to a subject in need thereof, at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those 10 2021213758   13 Oct 2026 compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing or a pharmaceutical composition comprising the at least one entity. In some embodiments, the methods of inhibiting APOL1 comprise administering at least one entity chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing or a pharmaceutical composition comprising the at least one entity. [0014a] More specifically, in a first aspect, the present invention provides a compound chosen from compounds of Formula (I): pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)    Ring A is a 4- to 6-membered ring wherein the ring is a cyclic alkyl or a heterocycle; (ii) Q is N or CR5; (iii) each R1 is independently chosen from • halogen groups, • hydroxy, • thiol, • amino, • cyano, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic thioalkyl groups, and •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic haloalkyl groups; (iv) each R2 is independently chosen from 2021213758   13 Oct 2026 • halogen groups, • hydroxy, • thiol, • amino, and • cyano; (v) m is chosen from 1, 2, and 3; (vi) n is chosen from 1, 2, and 3; (vii) X is chosen from divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, wherein the divalent alkyl groups are optionally substituted with one to four groups independently chosen from: o      C1-C6 alkyl groups, o     halogen groups, o     hydroxy, and o     amino; (viii) Y is chosen from divalent amino, divalent oxygen, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkoxy groups, and divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic aminoalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, and divalent aminoalkyl groups are optionally substituted with one to three groups independently chosen from o     C1-C6 alkyl groups optionally substituted with hydroxy, o      C3-C6 cyclic alkyl, o     halogen groups, o     hydroxy, and o     amino; (ix)    o is 0 or 1; (x)     p is 0 or 1; (xi)   R3 is chosen from: • hydrogen, •  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, •  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted with a C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle; 2021213758   13 Oct 2026 •  C3-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from: o halogen groups, o  hydroxy, o oxo, o  C1-C6 linear and C3-C6 branched alkoxy groups, o  C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o amido groups, • heterocyclic groups optionally substituted with one to four groups independently chosen from: o halogen groups, o oxo, o hydroxy, and o  C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and •  C1-C7 linear and C3-C7 branched alkyl groups, wherein the alkyl groups are optionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy, o oxo, o cyano, o carboxylic acid, 2021213758   13 Oct 2026 o halogen groups, o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and C3-C6 branched alkoxy groups, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy, o  C2-C6 linear and C3-C6 branched alkynyl groups, o  C2-C6 linear and C3-C6 branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and C3-C6 branched alkoxy groups, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and C3-C6 branched alkoxy groups; (xii)   R4 is chosen from: 2021213758   13 Oct 2026 • hydrogen, •  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, •  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted with a C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle; •  C3-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from: o halogen groups, o  hydroxy, o oxo, o  C1-C6 linear and C3-C6 branched alkoxy groups, o  C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o amido groups, • heterocyclic groups optionally substituted with one to four groups independently chosen from: o halogen groups, o oxo, o hydroxy, and o  C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and •  C1-C7 linear and C3-C7 branched alkyl groups, wherein the alkyl groups are substituted with one to five groups independently chosen from: o amino groups, 2021213758   13 Oct 2026 o hydroxy, o oxo, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and C3-C6 branched alkoxy groups, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy, o  C2-C6 linear and C3-C6 branched alkynyl groups, o  C2-C6 linear and C3-C6 branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and C3-C6 branched alkoxy groups, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted 16 2021213758   13 Oct 2026 with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and C3-C6 branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkyl groups, o amide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, o carboxamide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted 2021213758   13 Oct 2026 with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and (xiii)  R5 is absent or is chosen from: • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and •  C1-C6 linear and C3-C6 branched alkyl groups, wherein when R5 is absent, Q is a bridgehead atom. [0014b] In a second aspect, the present invention provides a compound chosen from compounds of Formula (I): pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein (i)    Ring A is chosen from: (ii) Q is N or CR5; (iii) each R1 is independently chosen from • halogen groups, • hydroxy, • thiol, •  amino, •  cyano, 2021213758   13 Oct 2026 •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic thioalkyl groups, and •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic haloalkyl groups; (iv)   each R2 is independently chosen from •  halogen groups, •  hydroxy, •   thiol, •  amino, and •  cyano; (v)    m is chosen from 1, 2, and 3; (vi)    n is chosen from 1, 2, and 3; (vii)   X is chosen from divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, wherein the divalent alkyl groups are optionally substituted with one to four groups independently chosen from: o  C1-C6 alkyl groups, o halogen groups, o hydroxy, and o amino; (viii) Y is chosen from divalent amino, divalent oxygen, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkoxy groups, and divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic aminoalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, and divalent aminoalkyl groups are optionally substituted with one to three groups independently chosen from o  C1-C6 alkyl groups optionally substituted with hydroxy, o  C3-C6 cyclic alkyl, o halogen groups, o hydroxy, and o amino; (ix) o is 0 or 1; 2021213758   13 Oct 2026 (x) p is 0 or 1; (xi) R3 and R4 are independently chosen from: • hydrogen, •  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, •  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted with a C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle; •  C3-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from: o halogen groups, o hydroxy, o oxo, o  C1-C6 linear and C3-C6 branched alkoxy groups, o  C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o amido groups, • heterocyclic groups optionally substituted with one to four groups independently chosen from: o halogen groups, o oxo, o hydroxy, and o  C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and 2021213758   13 Oct 2026 •  C1-C7 linear and C3-C7 branched alkyl groups, wherein the alkyl groups are optionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy, o oxo, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and C3-C6 branched alkoxy groups, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy, o  C2-C6 linear and C3-C6 branched alkynyl groups, o  C2-C6 linear and C3-C6 branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and C3-C6 branched alkoxy groups, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and 2021213758   13 Oct 2026 o 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and C3-C6 branched alkoxy groups; or R3 and R4, 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 chosen from • hydroxy, • oxo, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C 1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkyl groups, • amide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, • carboxamide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, and heterocyclic groups, •  4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and •  4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and (xii)   R5 is hydrogen. 2021213758   13 Oct 2026 [0014c] In a third aspect, the present invention provides a compound chosen from compounds of Formula (IIIa) compounds of Formula (IIIb): pharmaceutically acceptable salts of any of the foregoing, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 is independently chosen from: • halogen groups, • hydroxy, • thiol, • amino, • cyano, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic thioalkyl groups, and •  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic haloalkyl groups, (ii) each R2 is independently chosen from: 2021213758   13 Oct 2026 • halogen groups, • hydroxy, • thiol, • amino, and • cyano, (iii) m is chosen from 0, 1, 2, and 3; (iv) n is chosen from 0, 1, 2, and 3; (v)    R3 and R4 are independently chosen from: • hydrogen, •  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, •  C3-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and amido groups, • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and C3-C6 branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o carboxylic acid, o halogen groups, 2021213758   13 Oct 2026 o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and C3-C6 branched alkynyl groups, o  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, or R3 and R4, 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 chosen from: o hydroxy, o oxo, 2021213758   13 Oct 2026 o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and (vi)   each R5 is independently chosen from • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and • C1-C6 linear and C3-C6 branched alkyl groups. 2021213758   13 Oct 2026 [0014d] In a fourth aspect, the present invention provides a compound chosen from compounds of Formula (IV): (IV) pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 and R2 is independently chosen from: • fluoro, • chloro, • bromo, • cyano, • methyl, • cyclopropyl, • ethyl, • isopropyl, • propen-2-yl, and • methoxy; (ii)    R3 and R4 are independently chosen from: • hydrogen, •  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, •  C3-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and amido groups, 2021213758   13 Oct 2026 • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and C3-C6 branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and C3-C6 branched alkynyl groups, o  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), 2021213758   13 Oct 2026 o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and 2021213758   13 Oct 2026 o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and (iii) each R5 is independently chosen from: • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and • C1-C6 linear and C3-C6 branched alkyl groups. [0014e] In a fifth aspect, the present invention provides a compound chosen from Compounds 1 to 286 (see Table 1 below) and Compounds 287 to 465 (see Table 2 below), pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. [0014f] In a sixth aspect, the present invention provides a pharmaceutical composition comprising the compound, salt, or deuterated derivative according to any of the first to fifth aspects and a pharmaceutically acceptable carrier. [0014g] In a seventh aspect, the present invention provides a method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, salt, or deuterated derivative according to any of the first to fifth aspects or the pharmaceutical composition according to the sixth aspect. [0014h] In an eighth aspect, the present invention provides a method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, salt, or deuterated derivative according to any of the first to fifth aspects or the pharmaceutical composition according to the sixth aspect. [0014i] In a ninth aspect, the present invention provides use of the compound, salt, or deuterated derivative according to any of the first to fifth aspects in the manufacture of a medicament for treating APOL1 mediated kidney disease. [0014j] In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be 2021213758   13 Oct 2026 readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims. Definitions [0014k] The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification and claims which include the term “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise”, “comprises”, and “comprised” are to be interpreted in a similar manner.

[0015] The term “APOL1” as used herein means apolipoprotein L1 protein and the term “APOL1” means apolipoprotein L1 gene.

[0016] The term “APOL1 mediated kidney disease” refers to a disease or condition that impairs kidney function and can be attributed to APOL1. In some embodiments APOL1 mediated kidney disease is associated with patients having two APOL1 risk alleles, e.g., are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, the APOL1 mediated kidney disease is chosen from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0017] The term “FSGS” as used herein means focal segmental glomerulosclerosis, which is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function. In some embodiments FSGS is associated with two APOL1 risk alleles.

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

[0019] The terms “ESKD” and “ESRD” are used interchangeabley to refer to end stage kidney disease or end stage renal disease. ESKD / ESRD is the last stage of kidney disease, i.e., kidney failure, and means that the kidneys have stopped working well enough for the patient to survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0020] The term “compound,” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except 2021213758   13 Oct 2026 that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0021] As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0022] The term “isotopologue” refers to a species in which the chemical structure differs from only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C or 14C are within the scope of this disclosure.

[0023] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the present 2021213758   13 Oct 2026 compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

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

[0025] “Stereoisomer” as used herein refers to enantiomers and diastereomers.

[0026] As used herein, “deuterated derivative” refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom (“D” or “2H”). It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of compound of the disclosure, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%). In some embodiments, the deuterated derivatives of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium) at least 4500, (67.5 % deuterium incorporation), at least 5000 (75% deuterium incorporation) at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation, at least 6466.7 (97% deuterium incorporation, or at least 6600 (99% deuterium incorporation).

[0027] The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0028] The term “alkyl” or “aliphatic” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic that has a single point of attachment 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, and in some embodiments, 33 2021213758   13 Oct 2026 alkyl groups contain 1 to 4 alkyl carbon atoms, and in yet other embodiments alkyl groups contain 1 to 3 alkyl carbon atoms. Nonlimiting examples of alkyl groups include, but are not limited to, linear or branched, and substituted or unsubstituted alkyl. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are straight-chain. In some embodiments, alkyl groups are branched.

[0029] The terms “cycloalkyl,” “carbocycle,” or “cyclic alkyl” refer to a fused, spirocyclic, or monocyclic C3-8 hydrocarbon or a spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic C4-14 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, wherein any individual ring in said bicyclic ring system has 3 to 7 members. Suitable cycloalkyl groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl, [1.1.1]bicyclo-pentyl, or [2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl. In some embodiments, cyclogroups are substituted. In some embodiments, cyclogroups are unsubstituted.

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

[0031] The term “alkenyl” as used herein, means a straight-chain (i.e., unbranched), branched, substituted or unsubstituted hydrocarbon chain that contains one or more units of saturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that contains one or more units of unsaturation, but which is not aromatic (referred to herein as, “cyclic alkenyl”). In some embodiments, alkenyl groups are substituted. In some embodiments, alkenyl groups are unsubstituted. In some embodiments, alkenyl groups are straightchain. In some embodiments, alkenyl groups are branched.

[0032] The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring 34 2021213758   13 Oct 2026 members is an independently chosen heteroatom. In some embodiments, the “heterocycle”, “heterocyclyl”, or “heterocyclic” group has 3 to 14 ring members in which one or more ring members is a heteroatom independently chosen 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 chosen 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 that are each independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocycle has three heteroatoms that are each independently selected from nitrogen and oxygen. In some embodiments, heterocycles are substituted. In some embodiments, heterocycles are unsubstituted.

[0033] The term “heteroatom” means one or more non-carbon atoms selected from oxygen, sulfur, nitrogen, phosphorus, boron, and silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

[0034] The term “unsaturated”, as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all of the available valance bonds in a compound are satisfied by substituents and thus the compound contains double or triple bonds.

[0035] The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, wherein one carbon of the alkyl group is replaced by an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom, respectively, provided that the oxygen and sulfur atoms are linked between two carbon atoms. A “cyclic alkoxy” refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group, but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl. In some embodiments, “alkoxy” and / or 35 2021213758   13 Oct 2026 “thioalkyl” groups are substituted. In some embodiments, “alkoxy” and / or “thioalkyl” groups are unsubstituted.

[0036] The terms “haloalkyl” and “haloalkoxy,” as used herein, means a linear or branched alkyl or alkoxy, as the case may be, which is substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyls, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, -OCF2-.

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

[0038] The term “aminoalkyl” means an alkyl group which is substituted with or contains an amino group.

[0039] As used herein, the term “alkylsulfonyl” refers to an alkyl group, as previously defined, wherein one carbon atom of the alkyl group, and the carbon atom’s substituents, are replaced by a sulfur atom, and wherein the sulfur atom is further substituted with two oxo groups. An alkylsulfonyl group may be linear or branched. In some embodiments, alkylsulfonyl groups are substituted at the alkyl portion of the alkylsulfonyl group. In some embodiments, alkylsulfonyl groups are unsubstituted at the alkyl portion of the alkylsulfonyl group.

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

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

[0042] As used herein, a “cyano” or “nitrile” group refer to -C=N.

[0043] As used herein, a “hydroxy” group refers to -OH.

[0044] As used herein, a “thiol” group refers to -SH.

[0045] As used herein, “tert” and “t-” each refer to tertiary.

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

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

[0048] As used herein, a “carbamate” group refers to a carbonyl group, as previously defined, wherein the carbon of the carbonyl group is bonded to an amino group, as 36 2021213758   13 Oct 2026 previously defined, and a divalent oxygen. When a chemical group is said to be substituted by a carbamate group, that chemical group may be bonded to the divalent oxygen or to the amino nitrogen of the carbamate group.

[0049] As used herein, “aromatic groups” or “aromatic rings” refer to chemical groups that contain conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer ranging from 0 to 6. Nonlimiting examples of aromatic groups include aryl and heteroaryl groups.

[0050] The term “aryl” used alone or as part of a larger moiety as in “arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. The term “aryl” also refers to heteroaryl ring systems as defined herein below. Nonlimiting examples of aryl groups include phenyl rings. In some embodiments, aryl groups are substituted. In some embodiments, aryl groups are unsubstituted.

[0051] The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroarylalkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, heteroaryl groups are substituted. In some embodiments, heteroaryl groups have one or more heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl groups have one heteroatom. In some embodiments, heteroaryl groups have two heteroatoms. In some embodiments, heteroaryl groups are monocyclic ring systems having five ring members. In some embodiments, heteroaryl groups are monocyclic ring systems having six ring members. In some embodiments, heteroaryl groups are unsubstituted.

[0052] Non-limiting examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods of adding (a process generally referred to as “protecting”) and removing (process generally referred to as “deprotecting”) such amine protecting groups are well-known in the art and available, for example, in P. J. Kocienski, Protecting 37 2021213758   13 Oct 2026 Groups, Thieme, 1994, which is hereby incorporated by reference in its entirety and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999) and 4th Edition (John Wiley & Sons, New Jersey, 2014).

[0053] Non-limiting examples of suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, 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-methyl pyrrolidone (NMP).

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

[0055] The disclosure includes pharmaceutically acceptable salts of the disclosed compounds. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

[0056] The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1 to 19.

[0057] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, 38 2021213758   13 Oct 2026 besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, P -hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0058] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, nonlimiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0059] The terms “patient” and “subject” are used interchangeably and refer to an animal including a human.

[0060] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to that amount of compound that produces the desired effect for which it is administered (e.g., improvement in symptoms of FSGS and / or NDKD, lessening the severity of FSGS and / NDKD or a symptom of FSGS and / or NDKD, and / or reducing progression of FSGS and / or NDKD or a symptom of FSGS and / or NDKD). The exact 39 2021213758   13 Oct 2026 amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0061] As used herein, the term “treatment” and its cognates refer to slowing or stopping disease progression. “Treatment” and its cognates as used herein, include, but are not limited to the following: complete or partial remission, lower risk of kidney failure (e.g. ESRD), and disease-related complications (e.g. edema, susceptibility to infections, or thrombo-embolic events). Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0062] The terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.

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

[0064] The at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing may be administered once daily, twice daily, or three times daily, for example, for the treatment of FSGS. In some embodiments, the compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), are chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered once daily. In some embodiments, at least one entity chosen from Compounds 1 to 286, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing is administered once daily. In some embodiments, at least one entity chosen from 2021213758   13 Oct 2026 compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered twice daily. In some embodiments, at least one entity chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered twice daily. In some embodiments, at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing are administered three times daily. In some embodiments, at least one entity chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered three times daily.

[0065] In some embodiments, 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 of at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing are administered once daily, twice daily, or three times daily. In some embodiments, 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 of at least one entity chosen from Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing are administered once daily, twice daily, or three times daily.

[0066] One of ordinary skill in the art would recognize that, when an amount of compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of the compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based upon the free base form of the reference compound. For example, “10 mg of at least one compound chosen from 41 2021213758   13 Oct 2026 compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), and pharmaceutically acceptable salts thereof” includes 10 mg of compound of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), and a concentration of a pharmaceutically acceptable salt of compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), equivalent to 10 mg of compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), Compounds and Compositions

[0067] In addition to compounds, deuterated derivatives, solvates, and pharmaceutically salts of compounds of Formula (I), in some embodiments, at least one entity of the disclosure is chosen from compounds of Formula (Ia): (Ia) pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 is independently chosen from • halogen groups, • hydroxy, • 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 groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, 2021213758   13 Oct 2026 •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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, benzylamino, or benzylthio groups, •  3- to 6-membered heterocycloalkenyl groups, •  3- to 6-membered heterocycloalkyl groups, and •  5- and 6-membered heteroaryl groups; or two R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group; (ii) each R2 is independently chosen from • halogen groups, • hydroxy, • thiol, • amino, • cyano, •  -NHC(O)C1-C6 linear, branched, and cyclic alkyl groups, 2021213758   13 Oct 2026 •  -C(O)NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHC(O)aryl groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, • -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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 chosen from 0, 1, 2, 3, and 4; (iv) n is chosen from 0, 1, 2,3 4, and 5; (v) X is chosen from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with at least one group chosen from o      C1-C6 alkyl groups, o      aryl groups, 2021213758   13 Oct 2026 o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino; (vi) Y is chosen 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 chosen from o      C1-C6 alkyl groups, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino; (vii)   o is chosen from 0, 1, 2, 3, and 4; (viii)  p is chosen from 0, 1, 2, 3, and 4; (ix) R3 and R4 are independently chosen from • hydrogen, • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups 2021213758   13 Oct 2026 optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and 2021213758   13 Oct 2026 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o  C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (vi)   each R5 is independently chosen from • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and 2021213758   13 Oct 2026 •  C1-C6 linear and branched alkyl groups.

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

[0069] In some embodiments, wherein R3 is hydrogen.

[0070] In some embodiments, each R1 is independently chosen from halogen groups.

[0071] In some embodiments, each R1 is fluoro.

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

[0073] In some embodiments, each R2 is independently chosen from halogen groups.

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

[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, the at least one entity is chosen from compounds of Formula (II): (II), pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 is independently chosen from: • halogen groups, • hydroxy, • thiol, • amino, 2021213758   13 Oct 2026 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 groups, -C(O)NHaryl groups, -NHC(O)heteroaryl groups, -C(O)NHheteroaryl groups, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2aryl groups, -S(O)2NHaryl groups, -NHS(O)2heteroaryl groups, -S(O)2NHheteroaryl groups, -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, -NHC(O)NHaryl groups, -NHC(O)NHheteroaryl groups, 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, benzylamino, or benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocycloalkyl groups, and 5- and 6-membered heteroaryl groups; or 2021213758   13 Oct 2026 two R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group; (ii) each R2 is independently chosen from •  halogen groups, •  hydroxy, •   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 groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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 2021213758   13 Oct 2026 •  C1-C4 linear, branched, and cyclic haloalkoxy groups; (iii) m is chosen from 0, 1, 2, 3, and 4; (iv) n is chosen from 0, 1, 2, 3, 4, and 5; (v)    R3 and R4 are independently chosen from • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, 2021213758   13 Oct 2026 o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, or R3 and R4, 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 chosen from: o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, 2021213758   13 Oct 2026 o  C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (vi) each R5 is independently chosen from • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and •  C1-C6 linear and branched alkyl groups.

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

[0085] In some embodiments, each R1 is independently chosen from halogen groups, and methyl; each R2 is independently chosen from halogen groups, and methyl; m is 0, 1 or 2; and n is 1 or 2.

[0086] In some embodiments, each R1 is fluoro.

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

[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. 2021213758   13 Oct 2026

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

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

[0095] In some embodiments, R5 is hydrogen.

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

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

[0098] In some embodiments, R4 is chosen from: •  C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups.

[0099] In some embodiments, R4 is chosen from: •  C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o hydroxy, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, and o 5- or 6-membered heteroaryl groups optionally substituted with one or two groups chosen from C1-C6 linear and branched alkyl groups 2021213758   13 Oct 2026 optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups.

[00100] In some embodiments, R4 is chosen from •  C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o hydroxy, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear alkyl groups, and o 5- or 6-membered heteroaryl groups optionally substituted with one or two groups chosen from C1-C6 linear alkyl groups.

[00101] In some embodiments, R3 and R4, 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 chosen from: o hydroxy, o  C1-C6 linear alkyl groups, and o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups.

[00102] In some embodiments, the at least one entity of the disclosure is chosen from compounds of Formula (IIIa) (IIIa), compounds of Formula (IIIb): 2021213758   13 Oct 2026 pharmaceutically acceptable salts of any of the foregoing, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 is independently chosen from: • halogen groups, • hydroxy, • 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 groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, -NHC(O)NHheteroaryl groups, 2021213758   13 Oct 2026 •  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, benzylamino, or benzylthio groups, •  3- to 6-membered heterocycloalkenyl groups, •  3- to 6-membered heterocycloalkyl groups, and •  5- and 6-membered heteroaryl groups; or two R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group; (ii)    each R2 is independently chosen from: • halogen groups, • hydroxy, • 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 groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, 2021213758   13 Oct 2026 •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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 chosen from 0, 1, 2, 3, and 4; (iv) n is chosen from 0, 1, 2, 3, 4, and 5; (v)    R3 and R4 are independently chosen from: • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, 2021213758   13 Oct 2026 • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, 2021213758   13 Oct 2026 or R3 and R4, 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 chosen from: o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o  C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (vi) each R5 is independently chosen from • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and •  C1-C6 linear and branched alkyl groups.

[00103] In some embodiments, each R1 is independently chosen from halogen groups, and C1-C6 linear and branched alkyl groups; each R2 is independently chosen from halogen 60 2021213758   13 Oct 2026 groups, and C1-C6 linear and branched alkyl groups; m is chosen from 0, 1, 2, and 3; and n is 1 or 2.

[00104] In some embodiments, each R1 is independently chosen from halogen groups, and methyl; each R2 is independently chosen from halogen groups, and methyl; m is 0, 1 or 2; and n is 1 or 2.

[00105] In some embodiments, each R1 is fluoro.

[00106] In some embodiments, each R2 is fluoro.

[00107] In some embodiments, m is 0, 1 or 2.

[00108] In some embodiments, m is 2.

[00109] In some embodiments, m is 0.

[00110] In some embodiments, n is 1 or 2.

[00111] In some embodiments, n is 1.

[00112] In some embodiments, R5 is chosen from hydrogen, amino, alkyl, and halo.

[00113] In some embodiments, R5 is chosen from hydrogen and C1-C6 linear alkyl groups.

[00114] In some embodiments, R5 is hydrogen.

[00115] In some embodiments, R3 is chosen from hydrogen and C1-C6 linear and branched alkyl groups.

[00116] In some embodiments, R3 is chosen from hydrogen and methyl.

[00117] In some embodiments, R4 is chosen from C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl 2021213758   13 Oct 2026 groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups.

[00118] In some embodiments, R4 is chosen from C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o hydroxy, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, and o 5- or 6-membered heteroaryl groups optionally substituted with one or two groups chosen from C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups.

[00119] In some embodiments, R4 is chosen from C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o hydroxy, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear alkyl groups, and o 5- or 6-membered heteroaryl groups optionally substituted with one or two groups chosen from C1-C6 linear alkyl groups.

[00120] In some embodiments, R3 and R4, 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 chosen from: o hydroxy, o  C1-C6 linear alkyl groups, and o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups.

[00121] In some embodiments, the at least one entity of the disclosure is chosen from compounds of Formula (IV): 2021213758   13 Oct 2026 (IV) pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 and R2 is independently chosen from: • fluoro, • chloro, • bromo, • cyano, • methyl, • cyclopropyl, • ethyl, • hydroxypropyl, • isopropyl, • propen-2-yl, • dihydrofuran, • furan, and • methoxy; (ii)    R3 and R4 are independently chosen from: • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, 2021213758   13 Oct 2026 • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), 2021213758   13 Oct 2026 o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (iii) each R5 is independently chosen from: 2021213758   13 Oct 2026 • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and •  C1-C6 linear and branched alkyl groups.

[00122] In some embodiments, R3 is hydrogen and R4 is independently chosen from: •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, 2021213758   13 Oct 2026 o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups.

[00123] In some embodiments, R4 is independently chosen from C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups; and R3 is independently chosen from: • C1-C6 linear and branched alkylsulfonyl groups, • C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups 2021213758   13 Oct 2026 optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and 2021213758   13 Oct 2026 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups.

[00124] In some embodiments, R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o  C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups.

[00125] In some embodiments, in the at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of 2021213758   13 Oct 2026 any of the foregoing, each R1 and R2 is independently chosen from fluoro, chloro, bromo, cyano, and methyl.

[00126] In some embodiments, the at least one entity of the disclosure is chosen from Compounds 1 to 286 depicted in Table 1 and pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. A wavy line in a compound in Table 1 (i.e., ^) depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. Table 1. Compounds 1 to 286 3 00 V-nh 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 117 N OH OH F F 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 263 265 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026

[00127] In some embodiments, the at least one entity of the disclosure is chosen from Compounds 287 to 465 depicted in Table 2 and pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. A wavy line in a compound in Table 2 (i.e.,   ) depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. Table 2. Compounds 287 to 465 2021213758   13 Oct 2026 2021213758   13 Oct 2026 308 309 310 F F 311 312 313 F 0 F 314 315 316 O F 317 320 323 318 321 324 319 F 322 O F 325 2021213758   13 Oct 2026 326 327 328 0 F 329 F 332 335 338 341 344 0 F 330 331 333 334 0 F 336 O F 339 F 342 O F 345 F F 337 O F 340 343 2021213758   13 Oct 2026 2021213758   13 Oct 2026 359 F 362 F 365 360 361 0 0 NH F F_____ 363 HO F F 366 F 364 367 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026 425 426 427 2021213758   13 Oct 2026 2021213758   13 Oct 2026 2021213758   13 Oct 2026

[00128] Another aspect of the disclosure provides pharmaceutical compositions comprising at least one compound according to any one formula chosen from Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), Compounds 1 to 286 (Table 1) and Compounds 287 to 465 (Table 2), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, the pharmaceutical composition comprising at least one compound chosen from Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV) (Va), and (Vb), Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing is administered to a patient in need thereof.

[00129] A pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants. 2021213758   13 Oct 2026

[00130] It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb) , (IV) , (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound chosen from Compounds 1 to 286 (Table 1) and Compounds 287 to 465 (Table 2), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent.

[00131] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and 2021213758   13 Oct 2026 potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[00132] In some embodiments of the disclosure, the compounds and the pharmaceutical compositions described herein are used to treat APOL1 mediated kidney disease. In some embodiments, the APOL1 mediated kidney disease is chosen from ESKD, FSGS, HIV-associated nephropathy, NDKD, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1 mediated kidney disease treated with the compound, deuterated derivative, pharmaceutically acceptable salt, and / or composition of the invention is FSGS. In some embodiments, the APOL1 mediated kidney disease treated with the compound, deuterated derivative, pharmaceutically acceptable salt, and / or composition of the invention is NDKD. In some embodiments, the APOL1 mediated kidney disease treated with the compound, deuterated derivative, and pharmaceutically acceptable salt and / or composition of the invention is ESKD. In some embodiments, the patient with APOL1 mediated kidney disease to be treated with the compound, deuterated derivative, pharmaceutically acceptable salt, and / or composition of the invention has two APOL1 risk alleles. In some embodiments, the patient with APOL1 mediated kidney disease is homozygous for APOL1 genetic risk alleles G1: S342G:I384M. In some embodiments, the patient with APOL1 mediated kidney disease is homozygous for APOL1 genetic risk alleles G2: N388del:Y389del. In some 2021213758   13 Oct 2026 embodiments, the patient with APOL1 mediated kidney disease is heterozygous for APOL1 genetic risk alleles G1: S342G:I384M and G2: N388del:Y389del.

[00133] In some embodiments, the methods of the disclosure comprise administering to a patient in need thereof at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, the compound of Formula I is chosen from Compounds 1 to 286 (Table 1) and Compounds 287 to 465 (Table 2), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, said patient in need thereof possesses APOL1 genetic variants, i.e., G1: S342G:I384M and G2: N388del:Y389del.

[00134] Another aspect of the disclosure provides methods of inhibiting APOL1 activity comprising contacting said APOL1 with at least one entity chosen from compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IVa), (Va), and (Vb),pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, the methods of inhibiting APOL1 activity comprise contacting said APOL1 with at least one entity chosen from Compounds 1 to 286 (Table 1) and Compounds 287 to 465 (Table 2), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. Non-limiting Exemplary Embodiments 1.    A compound chosen from compounds of Formula (I): (I) pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)    Ring A is a 3- to 7-membered ring, wherein the ring is a cyclic alkyl or a heterocycle; 2021213758   13 Oct 2026 (ii) Q is N or CR5; (iii) each R1 is independently chosen from • halogen groups, • hydroxy, • 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 groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, • -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, •  -NHC(O)NHheteroaryl groups, •  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, 2021213758   13 Oct 2026 •  C1-C6 linear, branched, and cyclic halothioalkyl groups, •  C1-C6 linear, branched, and cyclic haloalkoxy groups, • benzyloxy, benzylamino, or benzylthio groups, •  3- to 6-membered heterocycloalkenyl groups, •  3- to 6-membered heterocycloalkyl groups, and •  5- and 6-membered heteroaryl groups; or two R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group; (iv) each R2 is independently chosen from •  halogen groups, •  hydroxy, •   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 groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  C1-C4 linear, branched, and cyclic alkyl groups, •  C2-C4 linear, branched, and cyclic alkenyl groups, 2021213758   13 Oct 2026 •  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; (v) m is chosen from 0, 1, 2, 3, and 4; (vi) n is chosen from 0, 1, 2, 3, 4, and 5; (vii) X is chosen from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with one to four groups independently chosen from: o      C1-C6 alkyl groups, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino; (viii) Y is chosen 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, wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with one to three groups independently chosen from o     C1-C6 alkyl groups optionally substituted with hydroxy, o      C3-C6 cyclic alkyl, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and 2021213758   13 Oct 2026 o     amino, or wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally fused to a C3-C6 cyclic alkyl; (ix)    o is chosen from 0, 1, 2, 3, and 4; (x)    p is chosen from 0, 1, 2, 3, and 4; (xi)   R3 and R4 are independently chosen from: • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 linear and branched alkoxy groups optionally substituted with a C3- C6 cyclic alkyl group or a 3- to 6-membered heterocycle; •  C1-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from: o halogen groups, o  hydroxy, o oxo, o  C1-C6 linear and branched alkoxy groups, o  C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o amido groups, • heterocyclic groups optionally substituted with one to four groups independently chosen from: o halogen groups, o oxo, o hydroxy, and o  C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl 2021213758   13 Oct 2026 groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and •  C1-C7 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy, o oxo, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and branched alkoxy groups, C1-C6 linear and branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy, o  C2-C6 linear and branched alkynyl groups, o  C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups optionally substituted with one or two 2021213758   13 Oct 2026 groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkyl groups, o amide groups optionally substituted with one to four groups indepedently chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with one to four groups indepedently chosen 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 chosen from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and 2021213758   13 Oct 2026 o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (xii)   R5 is absent or is chosen from: • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and •  C1-C6 linear and branched alkyl groups, wherein when R5 is absent, Q is a bridgehead atom. 2.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1, wherein Ring A is a 4- to 6-membered ring. 3.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 2, wherein Ring A is a 4-membered ring. 4.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 2, wherein Ring A is a cyclobutyl. 5.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 2, wherein Ring A is chosen from: , and 6.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-4, wherein Q is CR5. 7.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-6, wherein each R1 is independently chosen from: • halogen groups, • hydroxy, • thiol, 2021213758   13 Oct 2026 •  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, and •  C1-C6 linear, branched, and cyclic haloalkoxy groups. 8.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-7, wherein each R1 is independently chosen from halogen groups and C1-C6 linear, branched, and cyclic haloalkyl groups. 9.     The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-8, wherein each R1 is independently chosen from fluoro and CF3. 10. The compound, salt, or deuterated derivative according to any one of embodiments 1-9, wherein each R1 is fluoro. 11. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-10, wherein each R2 is independently chosen from: • halogen groups, • hydroxy, • 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, 2021213758   13 Oct 2026 •  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. 12. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-11, wherein each R2 is independently chosen from halogen groups. 13. The compound, salt, or deuterated derivative according to any one of embodiments 1-12, wherein each R2 is fluoro. 14. The compound, salt, or deuterated derivative according to any one of embodiments 1-13, wherein m is 2. 15. The compound, salt, or deuterated derivative according to any one of embodiments 1-14, wherein n is 1. 16. The compound, salt, or deuterated derivative according to any one of embodiments 1-15, wherein X is chosen from divalent C1-C8 linear, branched, and cyclic alkyl groups, wherein the divalent alkyl groups are optionally substituted with one to four groups chosen from: o      C1-C6 alkyl groups, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino. 17. The compound, salt, or deuterated derivative according to any one of embodiments 1-16, wherein X is chosen from -CH2- and -CH2-CH2-. 18. The compound, salt, or deuterated derivative according to any one of embodiments 1-17, wherein Y is chosen from divalent amino, divalent oxygen, divalent C1-C8 linear, branched, and cyclic alkyl groups, and divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, wherein the divalent alkyl groups and divalent aminoalkyl groups are optionally substituted with one to three groups independently chosen from o     C1-C6 alkyl groups optionally substituted with hydroxy, 2021213758   13 Oct 2026 o      C3-C6 cyclic alkyl, o     oxo, and o     hydroxy, or wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally fused to a C3-C6 cyclic alkyl. 19. The compound, salt, or deuterated derivative according to any one of embodiments 1-18, wherein Y is chosen from 0           O              0 Y^ n        n ■'^Y^   Y^ n H       / H A , and ' H        . 20. The compound, salt, or deuterated derivative according to any one of embodiments 1-19, wherein o is 0. 21. The compound, salt, or deuterated derivative according to any one of embodiments 1-19, wherein o is 1. 22. The compound, salt, or deuterated derivative according to any one of embodiments 1-21, wherein p is 0. 23. The compound, salt, or deuterated derivative according to any one of embodiments 1-21, wherein p is 1. 24. The compound, salt, or deuterated derivative according to any one of embodiments 1-23, wherein R3 is hydrogen, and and R4 is chosen from: • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 linear and branched alkoxy groups optionally substituted with a C3- C6 cyclic alkyl group or a 3- to 6-membered heterocycle; 2021213758   13 Oct 2026 •  C1-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from: o halogen groups, o hydroxy, o oxo, o  C1-C6 linear and branched alkoxy groups, o  C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o amido groups, • heterocyclic groups optionally substituted with one to four groups independently chosen from: o halogen groups, o oxo, o hydroxy, and o  C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and •  C1-C7 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy, o oxo, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, 2021213758   13 Oct 2026 o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and branched alkoxy groups, C1-C6 linear and branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy, o  C2-C6 linear and branched alkynyl groups, o  C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and branched alkoxy groups. 25. The compound, salt, or deuterated derivative according to any one of embodiments 1-23, wherein R3 and R4, 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 chosen from: o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkyl groups, 2021213758   13 Oct 2026 o amide groups optionally substituted with one to four groups indepedently chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with one to four groups indepedently chosen 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 chosen from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups. 26. The compound, salt, or deuterated derivative according to any one of embodiments 1-25, wherein R5 is independently chosen from hydrogen, halogen groups, and C1-C6 linear and branched alkyl groups. 27. The compound, salt, or deuterated derivative according to any one of embodiments 1-26, wherein R5 is independently chosen from hydrogen, fluoro, and methyl. 28. The compound, salt, or deuterated derivative according to embodiment 1, wherein the compound is selected from compounds of Formula (V-a) and (V-b): 2021213758   13 Oct 2026 (V-b), pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein R1, R2, R3, R4, Y, and p are as defined in embodiment 1. 29. The compound, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 28, wherein each R1 is independently chosen from: •  halogen groups, •  hydroxy, •   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, and •  C1-C6 linear, branched, and cyclic haloalkoxy groups. 30.    The compound, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 28 or 29, wherein each R1 is independently chosen from halogen groups and C1-C6 linear, branched, and cyclic haloalkyl groups. 31. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 28-30, wherein each R1 is independently chosen from fluoro and CF3. 2021213758   13 Oct 2026 32. The compound, salt, or deuterated derivative according to any one of embodiments 28-31, wherein each R1 is fluoro. 33. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 28-32, wherein R2 is chosen from: •  halogen groups, •  hydroxy, •   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, and •  C1-C4 linear, branched, and cyclic haloalkoxy groups. 34.    The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 28-33, wherein R2 is chosen from halogen groups. 35. The compound, salt, or deuterated derivative according to any one of embodiments 28-34, wherein R2 is fluoro. 36. The compound, salt, or deuterated derivative according to any one of embodiments 28-35, wherein Y is chosen from divalent amino, divalent oxygen, divalent C1-C8 linear, branched, and cyclic alkyl groups, and divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, wherein the divalent alkyl groups and divalent aminoalkyl groups are optionally substituted with one to three groups independently chosen from o     C1-C6 alkyl groups optionally substituted with hydroxy, o      C3-C6 cyclic alkyl, o     oxo, and o     hydroxy, 2021213758   13 Oct 2026 or wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally fused to a C3-C6 cyclic alkyl. 37. The compound, salt, or deuterated derivative according to any one of embodiments 28-36, wherein Y is chosen from , and 38. The compound, salt, or deuterated derivative according to any one of embodiments 28-37, wherein p is 0. 39. The compound, salt, or deuterated derivative according to any one of embodiments 28-37, wherein p is 1. 40. The compound, salt, or deuterated derivative according to any one of embodiments 28-39, wherein R3 is hydrogen and R4 is chosen from: • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 linear and branched alkoxy groups optionally substituted with a C3- C6 cyclic alkyl group or a 3- to 6-membered heterocycle; •  C1-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from: o halogen groups, o  hydroxy, o oxo, o  C1-C6 linear and branched alkoxy groups, 2021213758   13 Oct 2026 o C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o amido groups, • heterocyclic groups optionally substituted with one to four groups independently chosen from: o halogen groups, o oxo, o hydroxy, and o C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and •  C1-C7 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy, o oxo, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and branched alkoxy groups, C1-C6 linear and branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy, o  C2-C6 linear and branched alkynyl groups, o  C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, 2021213758   13 Oct 2026 o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and branched alkoxy groups. 41. The compound, salt, or deuterated derivative according to any one of embodiments 28-39, wherein R3 and R4, 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 chosen from: o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkyl groups, o amide groups optionally substituted with one to four groups indepedently chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with one to four groups indepedently chosen from C1-C6 linear, branched, and cyclic alkyl groups, 2021213758   13 Oct 2026 o  C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups. 42. A compound chosen from compounds of Formula (Ia): R3 (Ia), pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 is independently chosen from • halogen groups, • hydroxy, • 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, 2021213758   13 Oct 2026 •  -NHC(O)aryl groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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, benzylamino, or benzylthio groups, •  3- to 6-membered heterocycloalkenyl groups, •  3- to 6-membered heterocycloalkyl groups, and •  5- and 6-membered heteroaryl groups; or two R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group; (ii)    each R2 is independently chosen from • halogen groups, • hydroxy, 2021213758   13 Oct 2026 •   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 groups, •  -C(O)NHaryl groups, •  -NHC(O)heteroaryl groups, •  -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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 chosen from 0, 1, 2, 3, and 4; (iv) n is chosen from 0, 1, 2,3 4, and 5; (v) X is chosen from divalent C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl 141 2021213758   13 Oct 2026 groups and divalent thioalkyl groups are optionally substituted with at least one group chosen from o      C1-C6 alkyl groups, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino; (vi) Y is chosen 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 chosen from o      C1-C6 alkyl groups, o      aryl groups, o     heteroaryl groups, o     halogen groups, o     hydroxy, and o     amino; (vii)   o is chosen from 0, 1, 2, 3, and 4; (viii)  p is chosen from 0, 1, 2, 3, and 4; (ix) R3 and R4 are independently chosen from • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, 2021213758   13 Oct 2026 • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), 2021213758   13 Oct 2026 o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o  C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (vi)   each R5 is independently chosen from 2021213758   13 Oct 2026 • hydrogen, • halogen groups, • hydroxy, • thiol, • amino, and •  C1-C6 linear and branched alkyl groups. 43. The compound, salt, or deuterated derivative of embodiment 42, wherein R3 is hydrogen or methyl. 44. The compound, salt, or deuterated derivative of embodiment 42 or 43, wherein R3 is hydrogen. 45. The compound, salt, or deuterated derivative of any one of embodiments 42-44, wherein each R1 is independently chosen from halogen groups. 46. The compound, salt, or deuterated derivative of any one of embodiments 42-45, wherein each R1 is fluoro. 47. The compound, salt, or deuterated derivative of any one of embodiments 42-46, wherein each R2 is independently chosen from halogen groups and methyl. 48. The compound, salt, or deuterated derivative of any one of embodiments 42-47, wherein each R2 is independently chosen from halogen groups. 49. The compound, salt, or deuterated derivative of any one of embodiments 42-48, wherein each R2 is fluoro. 50. The compound, salt, or deuterated derivative of any one of embodiments 42-49, wherein m is 1 or 2. 51. The compound, salt, or deuterated derivative of any one of embodiments 42-50, wherein m is 2. 52. The compound, salt, or deuterated derivative of any one of embodiments 42-51, wherein n is 1 or 2. 53. The compound, salt, or deuterated derivative of any one of embodiments 42-52, wherein o is 1. 54. The compound, salt, or deuterated derivative of any one of embodiments 42-53, wherein p is 1. 55. The compound, salt, or deuterated derivative of any one of embodiments 42-52 or 54, wherein o is 0. 2021213758   13 Oct 2026 56. The compound, salt, or deuterated derivative of any one of embodiments 42-51 or 53, wherein p is 0. 57. The compound, salt, or deuterated derivative of any one of embodiments 42-56, wherein R5 is hydrogen. 58. A compound chosen from compounds of Formula (II): (II) pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i)     each R1 is independently chosen from halogen groups, hydroxy, 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 groups, -C(O)NHaryl groups, -NHC(O)heteroaryl groups, -C(O)NHheteroaryl groups, -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, -NHS(O)2aryl groups, -S(O)2NHaryl groups, 2021213758   13 Oct 2026 •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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, benzylamino, or benzylthio groups, •  3- to 6-membered heterocycloalkenyl groups, •  3- to 6-membered heterocycloalkyl groups, and •  5- and 6-membered heteroaryl groups; or two R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group; (ii)    each R2 is independently chosen from • halogen groups, • hydroxy, • 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 groups, •  -C(O)NHaryl groups, • -NHC(O)heteroaryl groups, 2021213758   13 Oct 2026 • -C(O)NHheteroaryl groups, •  -NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups, •  -S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups, •  -NHS(O)2aryl groups, •  -S(O)2NHaryl groups, •  -NHS(O)2heteroaryl groups, •  -S(O)2NHheteroaryl groups, •  -NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups, • -NHC(O)NHaryl groups, • -NHC(O)NHheteroaryl groups, •  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 chosen from 0, 1, 2, 3, and 4; (iv) n is chosen from 0, 1, 2, 3, 4, and 5; (v)    R3 and R4 are independently chosen from • hydrogen, •  C1-C6 linear and branched alkylsulfonyl groups, •  C1-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and amido groups, • heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups 2021213758   13 Oct 2026 optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, • heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and •  C1-C6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano, o  carboxylic acid, o  halogen groups, o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o  C3-C6 cyclic alkyl groups optionally substituted with one or two groups chosen from halogen groups and hydroxy, o  C1-C6 linear and branched alkynyl groups, o  C1-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy, o  C1-C6 linear and branched alkylsulfonyl groups, o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, o carbonyl-(4-methylpiperazin-1-yl), o carbonyl-(N-morpholino), o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and 2021213758   13 Oct 2026 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, or R3 and R4, 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 chosen from o hydroxy, o oxo, o  C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, o amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups, o  C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and (vi)   each R5 is independently chosen from • hydrogen, • halogen groups, 2021213758   13 Oct 2026 • hydroxy, • thiol, • amino, and •  C1-C6 linear and branched alkyl groups. 59. The compound, salt, or deuterated derivative of embodiment 58, wherein (i)     each R1 is independently chosen from • halogen groups, and •  C1-C6 linear and branched alkyl groups; (ii) each R2 is independently chosen from • halogen groups, and •  C1-C6 linear and branched alkyl groups; (iii) m is chosen from 0, 1, 2, and 3; and (iv) n is 1 or 2. 60. The compound, salt, or deuterated derivative embodiment 58 or 59, wherein: (i)     each R1 is independently chosen from • halogen groups, and • methyl; (ii) each R2 is independently chosen from • halogen groups, and • methyl; (iii) m is 0, 1 or 2; and (iv) n is 1 or 2. 61. The compound, salt, or deuterated derivative of any one of embodiments 58-60, wherein each R1 is fluoro. 62. The compound, salt, or deuterated derivative of any one of embodiments 58-61, wherein each R2 is fluoro. 63. The compound, salt, or deuterated derivative of any one of embodiments 58-62, wherein m is 0, 1 or 2. 64. The compound, salt, or deuterated derivative of any one of embodiments 58-63, wherein m is 2. 65. The compound, salt, or deuterated derivative of any one of embodiments 58-63, wherein m is 0. 2021213758   13 Oct 2026 66. The compound, salt, or deuterated derivative of any one of embodiments 58-65, wherein n is 1 or 2. 67. The compound, salt, or deuterated derivative of any one of embodiments 58-65, wherein n is 1. 68. The compound, salt, or deuterated derivative of any one of embodiments 58-67, wherein R5 is chosen from hydrogen, amino, alkyl, and halo. 69. The compound, salt, or deuterated derivative of any one of embodiments 58-67, wherein R5 is chosen from hydrogen and C1-C6 linear alkyl groups. 70. The compound, salt, or deuterated derivative of any one of embodiments 58-69, wherein R5 is hydrogen. 71. The compound, salt, or deuterated derivative of any one of embodiments 58-70, wherein R3 is chosen from hydrogen and C1-C6 linear and branched alkyl groups. 72. The compound, salt, or deuterated derivative of any one of embodiments 58-71, wherein R3 is chosen from hydrogen and methyl. 73. The compound, salt, or deuterated derivative of any one of embodiments 58-72, wherein R4 is chosen from: •      C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o     amino groups, o     hydroxy, o     cyano, o     amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, o     4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and o     4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups. 2021213758   13 Oct 2026 74. The compound, salt, or deuterated derivative of any one of embodiments 58-73, wherein R4 is chosen from: •      C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o     hydroxy, o     amido groups optionally substituted with one or two groups chosen from C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups, and o     5- or 6-membered heteroaryl groups optionally substituted with one or two groups chosen from C1-C6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and branched alkoxy groups. 75. The compound, salt, or deuterated derivative of any one of embodiments 58-74, wherein R4 is chosen from •      C1-C6 linear and branched alkyl groups optionally substituted with at least one group chosen from: o     hydroxy, o     amido groups optionally substituted with one or two groups chosen from C1-C6 linear alkyl groups, and o     5- or 6-membered heteroaryl groups optionally substituted with one or two groups chosen from C1-C6 linear alkyl groups. 76. The compound, salt, or deuterated derivative of any one of embodiments 58-70, wherein R3 and R4, 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 chosen from: o     hydroxy, o      C1-C6 linear alkyl groups, and o     amide groups optionally substituted with at least one group chosen from C1-C6 linear, branched, and cyclic alkyl groups. 77. A compound chosen from Compounds 1 to 286 (Table 1), pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. 2021213758   13 Oct 2026 78. A compound chosen from Compouds 287 to 465 (Table 2), pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. 79. A pharmaceutical composition comprising the compound, salt, or deuterated derivative according to any one of embodiments 1-78 and a pharmaceutically acceptable carrier. 80. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, salt, or deuterated derivative according to any one of embodiments 1-78 or a pharmaceutical composition according to embodiment 79. 81. The method according to embodiment 80, wherein the APOL1 mediated kidney disease is chosen from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. 82. The method according to embodiment 80, wherein the APOL1 mediated kidney disease is FSGS. 83. The method according to embodiment 80, wherein the APOL1 mediated kidney disease is NDKD. 84. The method according to embodiment 80, wherein the APOL1 mediated kidney disease is ESKD. 85. The method according to any one of embodiments 80-84, wherein the APOL1 mediated kidney disease is associated with APOL1 genetic alleles chosen from homozygous G1: S342G:I384M and homozygous G2: N388del:Y389del. 86. The method according to any one of embodiments 80-84, wherein the APOL1 mediated kidney disease is associated with compound heterozygous G1: S342G:I384M and G2: N388del:Y389del APOL1 genetic alleles. 87. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, salt, or deuterated derivative according to any one of embodiments 1-78 or a pharmaceutical composition according to embodiment 79. 88. The method according to embodiment 87, wherein the APOL1 is associated with APOL1 genetic alleles chosen from homozygous G1: S342G:I384M and homozygous G2: N388del:Y389del. 2021213758   13 Oct 2026 89. The method according to embodiment 87, wherein the APOL1 is associated with compound heterozygous G1: S342G:I384M and G2: N388del:Y389del APOL1 genetic alleles. General Synthetic Schemes

[00135] Another aspect of the disclosure provides methods for making compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), Compounds 1 to 286 and Compounds 287 to 465, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, and intermediates for making any of the foregoing. Throughout the synthetic schemes and descriptions for preparing compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), (IV), (Va), and (Vb), Compounds 1 to 286 (Table 1) and Compound 287 to 465 (Table 2), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, the following abbreviations are used: Abbreviations 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-propan-2-amine DMAP = dimethylamino pyridine DMA = dimethyl acetamide DME = dimethoxyethane DMEM = Dulbecco’s modified Eagle’s medium DMF = dimethylformamide DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide EtOAc = Ethyl Acetate EtOH = ethanol FBS = fetal bovine serum FLU = fluorescent values 2021213758   13 Oct 2026 HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (Phosphorus Hexafluoride Ion) HDMC = N-[(5-Chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HBSS = Hank’s balanced salt solution IPA = isopropyl alcohol LDA = lithium diisopropyl amide LED = light emitting diode MeOH = methanol MTBE = Methyl tert-butyl ether NMM = N-methyl morpholine NMP = N-methyl pyrrolidine PBS = phosphate-buffered saline Pd(dppf)2Cl2 = [1,1‘-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride PP = polypropylene PTSA = p-Toluenesulfonic acid monohydrate T3P = 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TEA = triethylamine Tet = tetracycline TFA = trifluoroacetic acid THF = tetrahydrofuran THP = tetrahydropyran TMSS = Tris(trimethylsilyl)silane

[00136] Scheme 1 provides processes suitable for the preparation of indoles of Formula 1-4. In some embodiments, X1 is a halogen. In some embodiments, the halogen is Cl, I, or Br. R1, R2, m and n are as defined above. Any suitable conditions for coupling an alkyne can be used to convert aryl halides of Formula 1-1 and alkynes of formula 1-2 to afford an amino aryl alkyne of Formula 1-3. For example, in some embodiments, the coupling is performed in the presence of a CuI and Pd(PPh3)2Cl2 catalyst system. In some embodiments, the reaction is performed in the presence of at least one base. In some embodiments, the at least one base is DIPEA or NEt3. In some embodiments, conversion 2021213758   13 Oct 2026 of compounds of formula 1-3 to indoles of Formula 1-4 is accomplished by treatment with CuI or PdCl2 in at least one polar solvent in the presence of added heat. In some embodiments, the at least one polar solvent is chosen from DMF and MeCN. In some embodiments, the added heat is greater than 100 oC. Scheme 1 1-4

[00137] Scheme 2 describes processes for the preparation of formula I. Indoles of formula 1-4 may react with carbonyl compounds of formula 2-1, to afford compounds of formula 2-2. Compound 2-1 are any ketones or aldehydes which are suitable to form a compound of formula 2-2 upon reductive coupling with a compound of formula 1-4. For example, X’ may be CH, or X’ may be absent (o = 0). In some embodiments, the reaction is performed in the presence of at least one acid and at least one reducing agent. In some embodiments, the acid is chosen from trifluoroacetic acid and methanesulfonic acid. In some embodiments, the reducing agent is Et3SiH. The reaction may be performed in a solvent such as dichloromethane. Processes for the preparation of a compound of formula I involve coupling of a carboxylic acid of formula 2-2 and amines 1-5 using any suitable method for the formation of an amide bond. 2021213758   13 Oct 2026 Scheme 2

[00138] Scheme 3 describes processes for preparation of compounds of Formulae (II), In some embodiments, compounds of formula 3-2 are prepared from indoles of formula 14 and ketones of formula 3-1. In some embodiments, the reaction is performed in the presence of at least one acid and at least one reducing agent. In some embodiments, the acid is chosen from trifluoroacetic acid and methanesulfonic acid. In some embodiments, the reducing agent is Et3SiH. In some embodiments, the reaction is performed in the at least one solvent. In some embodiments, the one solvent is dichloromethane. In some embodiments, processes for preparing compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), and (IVa), comprise reacting a 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), as depicted in Scheme 3. In some embodiments, the amide coupling agent is chosen from HATU, CDMT, HDMC, and T3P. In some embodiments, a suitable base is chosen from DIPEA and TEA. In some embodiments, HATU and triethylamine in at least one solvent is used. In some embodiments, the solvent is DMF. Other suitable conditions for amide bond formation may be used to prepare compounds of Formulae (I), (Ia), (II), (IIIa), (IIIb), and (IVa) from compounds of Formula 1-5 and 3-2. 2021213758   13 Oct 2026 Scheme 3 II

[00139] Processes for the preparation of compounds of formula 4-3 and 4-5 are shown in Scheme 4. LG1 is any suitable leaving group, for example, p-nitrophenol. In some embodiments, where LG1 is a p-nitrophenol group, amines of formula 4-1 may be converted to an 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 performed in the presence of p-nitrophenol carbonate or (4-nitrophenyl) carbonochloridate. The reaction may be performed in a basic solvent such as pyridine. In alternative conditions, compounds of formula 4-2 may be prepared by treatment with p-nitrophenol carbonate in the presence of a base such as DIPEA, in a solvent such as DMF. Addition of an amine of formula 1-5 to a solution of an intermediate of formula 4-2 affords compounds of formula 4-3. In some embodiments, the reaction may be performed in the presence of a base such as triethylamine and a solvent such as DMF. The reaction may be performed at room temperature or with added heat. 2021213758   13 Oct 2026 Scheme 4 4-3

[00140] Scheme 5 shows a process for the preparation of compounds of formula 5-2. An amine of formula 4-1 may react with an alkyl halide if formula 5-1 in the presence of a base and solvent. In some embodiments, the base may be triethylamine. In some embodiments, the solvent may be DMF. In some embodiments, the reaction may be performed at room temperature. Scheme 5 2021213758   13 Oct 2026

[00141] Scheme 6 depicts processes for the preparation of amines of formula 6-3 and 66. Amines of formula 6-3 and 6-6 may be used as compounds of formula 4-1 in scheme 4 and scheme 5. PG1 is any suitable nitrogen protecting group, for example, CBz or Boc. Compounds of formula 6-2 may be prepared from indoles of formula 1-4 and ketones of formula 6-2 using any condition suitable for performing a reductive alkylation. An acid and a reducing agent may be used in the reductive alkylation step. In some embodiments, the acid used is trifluoroacetic acid or methanesulfonic acid. In some embodiments, the reducing agent may be triethylsilane. A compound of formula 6-3 may be prepared from 6-2 using any suitable condition for removal of a nitrogen protecting group. For example, where PG1 is CBz, hydrogenolysis using hydrogen gas and a palladium on carbon catalyst affords compounds of formula 6-3. In some embodiments, the reaction is performed in a solvent mixture such as THF and Methanol. Compounds of formula 6-6 may be prepared from indoles of formula 1-4 and aldehydes of formula 6-5 using processes described for the preparation of compounds of formula 6-3. 2021213758   13 Oct 2026 Scheme 6

[00142] Scheme 7 shows processes for the preparation of compounds of formula 7-3. Compounds of formula 7-2 may be prepared from 1-4 and 7-1 using any suitable conditions for reductive alkylation. Compounds of formula 7-3 may be prepared using any suitable method for the reduction of a nitrile group to an amine. In some embodiments, hydrogenation using a catalyst such as Raney Nickel may be used. The reaction may be performed in a solvent such as a solution of ammonia in methanol. The reaction may be performed at elevated pressure, for example 60 psi hydrogen atmosphere. In some alterative embodiments, reduction with LiAlH4 may be used. The reaction may be performed in a solvent such as THF. The reaction may be performed in the presence of 2021213758   13 Oct 2026 added heat (e.g. 60 oC). Compounds of formula 7-3 may be used as compounds of formula 4-1. Scheme 7 7-3

[00143] Scheme 8 shows processes for the preparation of compounds of formula 8-3 from alcohols of formula 8-1. LG2 is any suitable activated alcohol which forms a carbonate. Compound of formula 8-2 may be prepared from alcohols of formula 8-1 using any suitable reagent for the preparation of a carbamate. For example, where LG2 is a p-nitrophenol, compounds of formula 8-2 may be prepared by treatment of 8-1 with p-nitrophenol carbonate or (4-nitrophenyl) carbonochloridate. The reaction is performed in the presence of a suitable base, for example, triethylamine or pyridine. A solvent such as dichloromethane may be used. A compound of formula 8-3 may be prepared from carbamates of formula 8-2 and amines of formula 1-5 in the presence of base and solvent. In some embodiments, a base such as pyridine and a solvent such as DMF may be use. The reaction may be performed in the presence of added heat. For example, the reaction may be performed at 80oC. 2021213758   13 Oct 2026 Scheme 8 8-3

[00144] Scheme 9 shows processes for the preparation of alcohols of formula 9-3. Alcohols of formula 9-3 may be used as compound of formula 8-1. PG2 is any suitable alcohol protecting group. For example, PG2 may be an acetate group. Compounds of formula 9-2 may be prepared by reductive alkylation of compounds of formula 9-1 with indoles of formula 1-4. Any suitable conditions for reductive alkylation may be used. In some embodiments, a reducing agent such as Et3SiH may be used. An acid such as TFA may be used. The reaction may be performed in a solvent such as dichloromethane. A compound of formula 9-3 may be prepared from a compound of formula 9-2 using and suitable method for the removal of an alcohol protecting group. For example, where PG2 is an acetate group, treatment with a base such as K2CO3 in a solvent such as methanol may be used to afford compounds of formula 9-3. 2021213758   13 Oct 2026 Scheme 9 9-3

[00145] Scheme 10 shows processes for the preparation of compounds of formula 10-3. Ring A in compounds of formula 10-3 contains a nitrogen atom. A compound of formula 10-3 may be prepared from an amine 10-3 and an isocyanate of formula 10-2. In some embodiments, the reaction may be performed in the presence of a base such as DIPEA. In some embodiments, the reaction is performed in a solvent such as DMSO. Scheme 10 10-1 10-2 R3—N^=O Examples

[00146] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner. 2021213758   13 Oct 2026 Example 1. Synthesis of Compounds General Purification and Analysis Methods

[00147] Unless otherwise stated, all final products were purified, as necessary, by reversed-phase HPLC (Method: C18 Waters Sunfire column (30 x150 mm, 5 micron). Gradient: 10-100 % MeCN in H2O. Modifier: 0.2 % formic acid or 0.1 % Trifluoroacetic acid).

[00148] Products were analyzed by LCMS methods A, B, or C. LCMS m / z and retention times were collected.

[00149] LCMS Method A: HPLC Sunfire C18 column. Gradient: 2-98% MeCN / H2O over 3.8 minutes. TFA Modifier.

[00150] LCMS Method B: UPLC CSH C18 column. Gradient: 5-95% MeCN / H2O. TFA Modifier.

[00151] LCMS Method C: UPLC CSH C18 column. Gradient: 10-60% MeCN / H2O. TFA Modifier. 2021213758   13 Oct 2026 Preparations of S1-S3 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid (S1), 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid [TRANS] (S2) and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid [CIS] (S3) Step 1. Synthesis of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline (C2)

[00152] To a flask containing 2,4-difluoro-6-iodo-aniline C2 (134 g, 525.5 mmol) was added NEt3 (1.3 L), followed by DMF (250 mL), 1-ethynyl-4-fluoro-benzene (83.5 g, 695.1 mmol), CuI (20.5 g, 107.6 mmol), and PdCl2(PPh3)2 (25 g, 35.6 mmol). The mixture was allowed to stir at room temperature for 2 h. Solvent was removed under reduced pressure and water (500 mL) was added. The mixture was extracted with Ethyl acetate, filtered and concentrated in vacuo. The product mixture was filtered through a silica gel plug (Eluent: CH2Cl2), followed by a second silica plug filtration (Eluent: 30-40% EtOAc in Heptane). Silica gel chromatography (Gradient: 0-20% EtOAc in heptane) afforded the 2021213758   13 Oct 2026 product as a pale yellow solid. (87 g, 60%). 1H NMR (300 MHz, CDCI3) 8 7.58 - 7.45 (m, 2H), 7.14 - 7.02 (m, 2H), 6.92 (ddd, J = 8.8, 2.8, 1.7 Hz, 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)

[00153] To a solution of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline C2 (46 g, 167.5 mmol) in DMF (600 mL) was added CuI (1.9 g, 10.0 mmol) and the reaction was heated at reflux. Water (800 mL) was added and the mixture extracted with MTBE. The mixture was then washed with sat. NaCl solution, dried over Na2SO4 and then concentrated in vacuo to afford the product, which was used in subsequent steps without further purification (41 g, 87%). 1H NMR (300 MHz, CDCl3) 8 8.43 (s, 1H), 7.72 - 7.58 (m, 2H), 7.27 - 7.15 (m, 2H), 7.09 (dd, J = 9.0, 2.1 Hz, 1H), 6.85 - 6.63 (m, 2H) ppm. LCMS m / z 248.0 [M+H]+. Step 3. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid (S1)

[00154] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (100 mg, 0.4045 mmol) in CH2Cl2 (5 mL) and added 3-oxocyclobutanecarboxylic acid (47 mg, 0.4119 mmol), Et3SiH (235 mg, 2.021 mmol) and TFA (230 mg, 2.017 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated and re-dissolved in a water / ethyl acetate mixture. The organic layer was washed with NaHCO3 (aq), then dried with Na2SO4. 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid (Trifluoroacetate salt) (40 mg, 21%). 1H NMR (300 MHz, DMSO-d6) 812.20 (s, 1H), 11.72 (d, J = 3.9 Hz, 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), 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-indol-3-yl]cyclobutanecarboxylic acid [TRANS] (S2) and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid [CIS] (S3)

[00155] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (20 g, 80.90 mmol) and 3-oxocyclobutanecarboxylic acid (13.9 g, 121.8 mmol) in CH2Cl2 (160 mL) was added Et3SiH (65 mL, 407.0 mmol). TFA (31 mL, 402.4 mmol) was added slowly via an addition funnel while monitoring the temperature. A slight exotherm (2-3 oC) was observed during addition. After 1 h, the temperature rose to 24 oC. The mixture was 2021213758   13 Oct 2026 allowed to stir at room temperature overnight. The solvent was removed under reduced pressure, then quenched with saturated NaHCO3 to afford pH 7. The organic layer was separated and washed with brine. Solvent was removed under reduced pressure. Dichloromethane (25 mL) was added and the solids were triturated. The mixture was filtered and solvent removed under reduced pressure. The mixture contained the product as a mixture of cis and trans isomers. Silica gel chromatography (Gradient: 0-20% MeOH in dichloromethane) afforded the product.

[00156] SFC Analysis was used to distinguish the cis and trans isomers by chromatography. Column: Daicel Chiralpak ® AD-H, 4.6 x 100 mm. Mobile Phase: 20% Methanol (containing 5 mM Ammonia), 80 % carbon dioxide. Flow: 5 mL / min.

[00157] Peak A (first eluting peak, retention time 0.86 minutes). Trans isomer.

[00158] Peak B (second eluting peak, retention time 0.98 minutes). Cis isomer.

[00159] 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid [TRANS] S2 (8.49 g, 30%). 1H NMR (300 MHz, Acetone- d6) 5 10.71 (s, 1H), 7.79 - 7.56 (m, 2H), 7.45 (dd, J = 9.8, 2.2 Hz, 1H), 7.39 - 7.21 (m, 2H), 6.85 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.14 (pd, J = 9.3, 1.3 Hz, 1H), 3.29 (dddd, J = 9.4, 7.3, 3.6, 1.3 Hz, 1H), 2.89 -2.56 (m, 4H) ppm. LCMS m / z 346.07 [M+H]+.

[00160] 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxylic acid [CIS] S3 (11.7 g, 42%). 1H NMR (400 MHz, Acetone-d6) 5 10.69 (s, 1H), 7.74 - 7.56 (m, 3H), 7.37 - 7.21 (m, 2H), 6.84 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 3.89 (tt, J = 10.2, 8.5 Hz, 1H), 3.19 (tt, J = 9.6, 8.4 Hz, 1H), 2.85 - 2.71 (m, 2H), 2.69 - 2.55 (m, 2H), 2.05 (m, J = 2.2 Hz, 2H) ppm. Preparation S4 1-Ethynyl-4-fluorobenzene-2,3,5,6-d4 (S4) S4 2021213758   13 Oct 2026 Step 1. Synthesis of 1-Bromo-4-fluorobenzene-2,3,5,6-d4 (C5)

[00161] A solution of bromine (34.8g, 218 mmol, 1.1 equiv) in CH2Cl2 (40 mL) was added dropwise to a solution of 1-fluorobenzene-2,3,4,5,6-d5 C4 (20 g, 200 mol, 1 equiv) and FeCl3 (0.6 g, 3.7 mmol, 0.02 equiv) in CH2Cl2 (40 mL) at 18-20 oC. After stirring at room temperature for 1.5 h, the mixture was washed with water (3 x 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. A small scale run of this reaction (5 g of 1-fluorobenzene-2,3,4,5,6-d5) which was processed in same manner was combined for distillation to remove solvent. The combined organic layers were evaporated under atmospheric distillation to remove dichloromethane and then distilled to afford the product (33.3 g, 75% yield, b.p. 150-152 oC) as a colorless oil. Step 2. Synthesis of ((4-Fluorophenyl-2,3,5,6-d4)ethynyl)trimethylsilane (C6)

[00162] (Trimethylsilyl) acetylene (32.9 mL, 232.5 mmol, 1.3 equiv), copper(I) iodide (3.5 g, 18.6 mmol, 0.1 equiv) and PdCl2(PPh3)2 (6.5 g, 9.3 mmol, 0.05 equiv) were added to a mixture of 1-Bromo-4-fluorobenzene-2,3,5,6-d4 C5 (33.3 g, 186.0 mmol, 1 equiv) in NEt3 (310 mL) at room temperature. The mixture was purged with nitrogen for 10 minutes, then stirred at 70-80 oC for 18 h. After cooling to room temperature, the mixture was diluted with EtOAc (300 mL), filtered through celite®, which was washed with EtOAc (2 x 100 mL). The filtrate was concentrated under reduced pressure at 30 oC to afford the product (45.3 g) as a dark-brown oil, which was used subsequently. Step 3. Synthesis of 1-Ethynyl-4-fluorobenzene-2,3,5,6-d4 (S4)

[00163] Potassium carbonate (128.5 g, 930 mmol, 5 equiv) was added to a mixture of ((4-Fluorophenyl-2,3,5,6-d4)ethynyl)trimethylsilane C6 (45.3 g, 186 mmol, 1 equiv) in MeOH (620 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was filtered through celite®, washing with MeOH (50 mL) and hexanes (3 x 50 mL). The filtrate was diluted with water (2000 mL) and separated. The aqueous layer was extracted with hexanes (3 x 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 oC) to give the product (30 g, theoretical yield 23.09 g) as a dark oil. (Note: 1-Ethynyl-4-fluorobenzene-2,3,5,6-d4 is volatile, and it was co-distilled with other solvents (MeOH, hexanes) under reduced pressure or under atmospheric distillation. The 2021213758   13 Oct 2026 crude 1-Ethynyl-4-fluorobenzene-2,3,5,6-d4 S4 was used in next step without column purification in order to minimize the loss during evaporation of solvents.) Compound 1 N-(2-amino-2-oxo-ethyl)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxamide (1) S2                                             1

[00164] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutane-carboxylic acid (130 g, 376.5 mmol) in DMF (920 mL) was added HATU (217 g, 570.7 mmol) and the mixture stirred for 10 min. The reaction was cooled to 5 oC on an ice bath. 2-aminoacetamide (Hydrochloride salt) (48 g, 434.2 mmol) and DIPEA (197 mL, 1.131 mol) were added slowly via an addition funnel maintaining the temperature below 30 oC. The ice bath was removed and stirred for 1 h at room temperature. The mixture was quenched with sat NaHCO3 (2 L) and EtOAc (1 L) was added. The product crystallized out during the quench. The solids were filtered off and washed with water (1 L). The filtrate layers were separated and washed with EtOAc (1 L), then combined organic layers were washed with water (2 L) and brine (2 L). The product precipitated out of the organic layer and the solids were filtered off. The filtrate was concentrated by 90 % of the original volume under reduced pressure (no additional product). The combined solid was slurried in 4:1 water / acetone (500 mL) for 12 h. The solids were filtered, washed with water (400 mL) and dried overnight in vacuum oven at 55 oC. N-(2-amino-2-oxo-ethyl)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxamide (109.75 g, 72%). 1H NMR (300 MHz, Methanol-d4) 5 7.56 - 7.44 (m, 2H), 7.32 (dd, J = 9.7, 2.2 Hz, 1H), 7.20 (t, J = 8.8 Hz, 2H), 6.74 (ddd, J = 11.0, 9.6, 2.2 Hz, 1H), 4.18 - 4.02 (m, 1H), 3.88 (s, 2H), 3.25 (dtd, J = 9.2, 4.9, 2.3 Hz, 1H), 2.75 - 2.56 (m, 4H) ppm. LCMS m / z 402.24 [M+H]+. SFC analysis indicates 99:1 trans / cis ratio (Column: Daicel Chiralpak ® AD-H, 10 x 250 2021213758   13 Oct 2026 mm; Mobile Phase: 40% MeOH (containing 5 mM Ammonia), 70% carbon dioxide. Flow: 75 mL / min).

[00165] Trans stereochemistry was confirmed by single crystal X-ray structure. Compounds 2-45

[00166] Compounds 2-45 (Table 3) were prepared from S2 and a commercially available amine by HATU coupling as described in standard procedure A. Standard procedure A. HATU Coupling of amines

[00167] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutane-carboxylic acid S2 (25 mg, 0.07 mmol) in DMF (2 mL) and amine (0.07 mmol), HATU (~ 36 mg, 0.09 mmol) and EtaN (approximately 7.3 mg, 10.1 ^L, 0.07 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and purified by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid. Table 3. Structure, physicochemical properties, and LCMS analysis for compounds 2-45 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 2 H J o. f V-nh / =\ Y TVa ^f N 1 H F LCMS m / z 428.16 [M+H]+ A; 3.32 3 nh2 Vnh 0H T   —YY-f V-^7 1 H F LCMS m / z 418.16 [M+H]+ A; 2.66 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 4 Ox H V-N J X \_-nh2 T TXa / / f 1 H F LCMS m / z 402.2 [M+H]+ A; 2.7 5 OH % / V-nh F\ / ^^   / =x T TyA # F 1 H F LCMS m / z 415.19 [M+H]+ A; 3.41 6 HO 1 | 0? / V-nh / =x T XVa # f 1 H F LCMS m / z 429.17 [M+H]+ A; 3.8 7 \ 0^ J oK V-NH Fx^^^X 7=\ T X Va # f 1 H F LCMS m / z 442.17 [M+H]+ A; 3.46 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 8 OH / OH Ox / V-nh Fx / X^   / =\ T X Va # f N I H F LCMS m / z 419.17 [M+H]+ A; 3.14 9 0. H HN-" V-n T / =\ 1 H F LCMS m / z 430.18 [M+H]+ A; 3.44 10 0 Vnh 0H T XVa / / f N 1 H F LCMS m / z 403.14 [M+H]+ A; 3.42 11 \ ° hVoNH2 F^^j /   / =x T TrA / ^F \^'N 1 H F LCMS m / z 430.18 [M+H]+ A; 3.42 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 12 vNc°Me _ X JX3—F 1 H F LCMS m / z 403.17 [M+H]+ A; 3.8 13 OH V HN\_0 / =. X x vx y 1 H F LCMS m / z 403.17 [M+H]+ A; 3.5 14 OH oK y^oH V-NH F'vxX„ / =\ i tx-x y \Xn 1 H F LCMS m / z 419.17 [M+H]+ A; 3.16 15 ^0 0. f X-NH / =\ X vyx y \Xn X 1 H F LCMS m / z 415.16 [M+H]+ A; 3.72 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 16 OH HN^O T TrA # F 1 H F LCMS m / z 433.18 [M+H]+ A; 3.24 17 Ox / V-NH F\-" / vX   / -\ T X >X Xf N   \= / 1 H F LCMS m / z 426.14 [M+H]+ A; 4.12 18 / p^O HN F\ / ^X / =\ T XXX Xf 1 H F LCMS m / z 415.16 [M+H]+ A; 3.84 19 V-NH F-^^X / =\ T XXX XF N 1 H F LCMS m / z 415.16 [M+H]+ A; 3.72 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 20 ^OH HNA0 F^ / ^A / =x T FH # F 1 H F LCMS m / z 415.19 [M+H]+ A; 3.38 21 HN F\x-^A / =\ T Fm 1 H F LCMS m / z 415.19 [M+H]+ A; 3.67 22 \ । V^N ox / V-nh T TaA # F 1 H F LCMS m / z 425.19 [M+H]+ A; 3.81 23 HN-'X oAA 0. f V-NH f\^^A / =\ T jT / A / ^f 1 H F LCMS m / z 442.17 [M+H]+ A; 3.42 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 24 / V v° ox / V-nh F\^x7   / =\ T A Ya # f 1 H F LCMS m / z 426.17 [M+H]+ A; 3.18 25 nA^ v° Ox ' V-nh F\ / ^xA / =x T AAA # F N 1 H F LCMS m / z 433.18 [M+H]+ A; 3.24 26 0 A NH hn^o° Fx^xV / = T A AA # F 1 H F LCMS m / z 456.14 [M+H]+ A; 3.46 27 vA°h Fx / xJ / =x T A Va ^f 1 H F LCMS m / z 403.17 [M+H]+ A; 3.48 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 28 0 O. '' NHo V-NH    2 if XVa # f 1 H F LCMS m / z 416.04 [M+H]+ A; 3.32 29 / OH ox V-nh F\ / ^_7   / =\ T XVa #f 1 H F LCMS m / z 431.19 [M+H]+ A; 3.8 30 0 x)^0NH2 / =\ If XVX Xf \^~N x-' 1 H F LCMS m / z 458.32 [M+H]+ A; 3.74 31 V™ 0H F.^_7   / =\ T TrA XF 1 H F LCMS m / z 417.18 [M+H]+ A; 3.84 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 32 0 H2N \ , VnV°h Y TrA # F 1 H F LCMS m / z 432.13 [M+H]+ A; 3.07 33 F ^f 0.    ' F V-nh F^^^A / =\ T PM XF 1 H F LCMS m / z 427.21 [M+H]+ A; 4.09 34 o c\ V-nh f^ / ^A / =x Y A Va # f 1 H F LCMS m / z 438.16 [M+H]+ A; 4.05 35 Ox H V-N / A    \-N \ \         / A__ Fx^-^A / = T XVa Xf 1 H F LCMS m / z 453.21 [M+H]+ A; 3.48 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) N^, VN 36 Ox V-nh LCMS m / z 440.15 A; 3.25 / =\ [M+H]+ t yvy #F 1 H F 37 O-N ox / V-nh LCMS m / z 440.15 A; 3.82 [M+H]+ 1 X VY Yf 1 H F / =N HN 38 LCMS m / z 439.17 A; 3.53 / =\ [M+H]+ T TYA / / f 1 H F oN 39 ox r^ V-nh LCMS m / z 440.15 A; 2.87 [M+H]+ T X VY Yf 1 H F 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 40 °^SC ox / V-nh T XVa Xf 1 H F LCMS m / z 451.26 [M+H]+ B ; 0.81 41 / \ / F r-"\ / F ox / ^7 V-nh / =\ T XVa Xf 1 H F LCMS m / z 449.14 [M+H]+ A; 4.12 42 / ” x0 Ox V-nh / = Y JM Xf 1 H F LCMS m / z 443.18 [M+H]+ A; 3.82 43 O / NF V-NH T TrA Xf 1 H F LCMS m / z 440.02 [M+H]+ A; 3.74 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 44 H o N^U ox V-nh / ----\ T X'Xf Xf \= / 1 H F LCMS m / z 428.29 [M+H]+ A; 3.23 45 Ox H o V-N zT / NH / -----v L X / Xf 1 H F 1H NMR (300 MHz, Methanol-d4) 8 7.56 - 7.40 (m, 2H), 7.32 (dd, J = 9.8, 2.2 Hz, 1H), 7.27 - 7.07 (m, 2H), 6.74 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.52 (dd, J = 10.3, 8.8 Hz, 1H), 4.11 (m, 1H), 3.41 - 3.32 (m, 2H), 3.24 - 3.13 (m, 1H), 2.79 - 2.61 (m, 3H), 2.58 - 2.38 (m, 1H), 2.04 - 1.87 (m, 1H). LCMS m / z 428.16 [M+H]+ A; 3.32 Compound 46 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)cyclobutanecarboxamide (46) OH 2021213758   13 Oct 2026

[00168] A 250 mL round bottom flask was charged with a magnetic stir bar, 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-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 was allowed to stir at room temperature. The mixture was diluted with water (~250 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with water (200 mL), brine (~200 mL), and dried with MgSO4. The mixture was filtered and concentrated in vacuo to a volume of ~ 50 mL. The product formed a white precipitate which was collected via vacuum filtration using a Buchner funnel. The filter cake was washed with EtOAc, collected and dried under vacuum to afford 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)cyclobutanecarboxamide (4.86 g, 77%). 1H NMR (300 MHz, Acetone) 8 10.69 (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, 0.7 Hz, 1H), 3.60 (q, J = 5.5 Hz, 2H), 3.34 (q, J = 5.6 Hz, 2H), 3.29 - 3.11 (m, 1H), 2.71 -2.46 (m, 4H) ppm. LCMS m / z 389.29 [M+H]+. Compounds 47-48

[00169] Compounds 47-48 (Table 4) were prepared by coupling of S2 and the appropriate commercially available amine according to standard procedure A. Table 4. Structure, physicochemical properties, and LCMS analysis for compounds 4748 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 47(1) Ox H V OH / =x T XVa Xf 1 H F 1H NMR (300 MHz, Acetone-d6) 8 10.69 (s, 1H), 7.69 - 7.57 (m, 2H), 7.38 (dd, J = 9.8, 2.2 Hz, 1H), 7.35 - 7.21 (m, 2H), 6.85 (ddd, J = 11.1, 9.7, 2.2 Hz, 1H), 4.21 -4.03 (m, 1H), 3.54 (s, 1H), 3.27 (s, 2H), 3.24 - 3.08 (m, 1H), 2.61 (ddd, J = 9.7, 6.7, 3.0 Hz, 3H), 0.90 - 0.65 (m, 3H). A; 2.195 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) LCMS m / z 415.2 [M+H]+ 48 o. / V-NH Fx / xJ / =\ T TyF / / f N 1 H F 1H NMR (300 MHz, Acetone) 8 8.80 (s, 1H), 7.77 - 7.54 (m, 2H), 7.54 - 7.36 (m, 2H), 7.39 - 7.15 (m, 2H), 6.84 (ddd, J = 11.5, 9.7, 2.2 Hz, 1H), 4.52 (d, J = 4.1 Hz, 2H), 4.27 - 4.08 (m, 1H), 4.04 (s, 3H), 3.29 - 2.81 (m, 2H), 2.84 - 2.43 (m, 3H). LCMS m / z 439.185 [M+H]+ A; 1.73 (1) Purification by reversed-phase chromatography (Column: C18. Gradient: 0-100% MeCN in water with 0.1 % trifluoroacetic acid) afforded the product. DIPEA was used as the base in the coupling reaction. Compounds 49-82

[00170] Compounds 49-82 (Table 5) were prepared from S2 and the appropriate commercially available amine by HATU coupling according to standard procedure A. Table 5. Structure, physicochemical properties, and LCMS analysis for compounds 49- 82 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 49 O. / y-N Jr O J Fx^xT   / = 1 H F LCMS m / z 443.18 [M+H]+ A; 4.02 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 50 0 0   1 NH y-NH ) J 4 T JM # F N 1 H F LCMS m / z 442.17 [M+H]+ A; 3.49 51 0 NH2 / == If FH ^f 1 H F LCMS m / z 416.17 [M+H]+ A; 3.3 52 0^ y-N <\ 0H F\^^_5   / == T TyF # f 1 H F LCMS m / z 429.17 [M+H]+ A; 3.85 53 Ox H    . V"N jF o % F\X^X / == 1 T TyF yF 1 H F LCMS m / z 443.31 [M+H]+ A; 4.07 54 0. H 0^ ■y-N 1 T TrA # F 1 H F LCMS m / z 429.17 [M+H]+ A; 3.88 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 55 OK H VN Jz V> / =\ L XVX Xf 1 H F 1H NMR (300 MHz, Acetone-d 6) 5 10.71 (s, 1H), 7.62 (td, J = 8.9, 5.5 Hz, 2H), 7.41 (dd, J = 9.8, 2.2 Hz, 1H), 7.35 -7.21 (m, 2H), 7.14 (s, 1H), 6.92 -6.77 (m, 1H), 4.22 - 4.04 (m, 1H), 3.40 - 3.33 (m, 1H), 3.38 - 3.27 (m, 2H), 3.32 -3.10 (m, 1H), 2.94 - 2.76 (m, 1H), 2.75 - 2.57 (m, 3H), 2.48 (qd, J = 8.5, 2.7 Hz, 1H), 1.83 - 1.69 (m, 2H), 1.75 - 1.51 (m, 5H). LCMS m / z 457.21 [M+H]+ A; 4.25 56 z o 0     / \ V-NH NH2 F\           '' BifZ F H LCMS m / z 428.16 [M+H]+ A; 3.34 57 H _ i / ^OH T zlM X 1 H F LCMS m / z 471.32 [M+H]+ A; 3.7 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 58 0H Ox ' I XVX Xf 1 H F LCMS m / z 429.2 [M+H]+ A; 3.77 59 ox / \ V-nh Voh T XXX Xf 1 H F LCMS m / z 429.17 [M+H]+ A; 3.68 60 E F O H \^F F\ / ^^(   / = T XXX Xf 1 H F LCMS m / z 484.12 [M+H]+ A; 3.68 61 z ^^-nX^° F\zz^_y   / =\ 1 X'X< XF I H F LCMS m / z 444.19 [M+H]+ A; 3.66 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 62 I X'Mx >-f T H F 1H NMR (300 MHz, Acetone-d6) 8 7.70 - 7.37 (m, 3H), 7.34 - 7.18 (m, 2H), 6.85 (dddd, J = 11.1, 9.6, 3.6, 2.2 Hz, 1H), 4.35 - 3.75 (m, 4H), 3.68 -3.26 (m, 1H), 3.15 - 2.93 (m, 5H), 2.93 - 2.85 (m, 3H), 2.82 - 2.61 (m, 4H). LCMS m / z 444.02 [M+H]+ A; 3.66 63 Ox / XN"\ 3'-^ Fx^^^C / =\ |f JM N 1 H F LCMS m / z 470.18 [M+H]+ A; 3.82 64 < NH O=( Ox /   \ V"N F^^^^   / _\ Y JLV\ \= / 1 H F LCMS m / z 470.3 [M+H]+ A; 3.83 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 65 / =\ T XVX Xf V^N 1 H F LCMS m / z 444.3 [M+H]+ A; 3.74 66 . O Oy '    N'-'X >"" Q F=^_X   / =\ Y XXX Xf 1 H F LCMS m / z 500.32 [M+H]+ A; 3.65 67 0. H O y-N^_ o n F=^X / = ^"N\ Y XXX Xf 1 H F LCMS m / z 485.34 [M+H]+ A; 2.86 68 0 M NH NH2 F= / ^^(   / = Y XXX Xf 1 H F 1H NMR (300 MHz, Acetone-d 6) 8 10.69 (s, 1H), 8.05 (dd, J = 10.1, 2.2 Hz, 1H), 7.77 -7.52 (m, 2H), 7.52 - 7.15 (m, 3H), 6.84 (ddt, J = 12.6, 9.6, 2.6 Hz, 1H), 4.63 - 4.41 (m, A; 3.45 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 1H), 4.12 (t, J = 9.0 Hz, 1H), 3.82 (p, J = 9.3, 8.9 Hz, 1H), 3.42 - 3.08 (m, 1H), 2.82 (dt, J = 16.4, 7.7 Hz, 1H), 2.65 (dd, J = 9.3, 6.4 Hz, 2H), 2.55 - 2.36 (m, 1H), 1.33 (dd, J = 6.9, 3.7 Hz, 3H). LCMS m / z 416.29 [M+H]+ 69 HO . ox / VJ y-NH F^^^A   / =x T TyA # F 1 H F 1H NMR (300 MHz, Acetone-de) 5 10.71 (s, 1H), 8.06 (dd, J = 10.2, 2.2 Hz, 1H), 7.68 -7.55 (m, 2H), 7.41 (dd, J = 9.8, 2.2 Hz, 1H), 7.35 -7.21 (m, 2H), 7.14 (s, 1H), 6.84 (ddt, J = 11.2, 9.6, 2.5 Hz, 1H), 4.22 -4.04 (m, 1H), 3.40 - 3.33 (m, 1H), 3.38 - 3.23 (m, 2H), 2.94 - 2.76 (m, 1H), 2.75 -2.57 (m, 3H), 2.48 (qd, J = 8.6, 2.7 Hz, 1H), 1.81 -1.69 (m, 1H), 1.69 - 1.51 (m, 2H), 1.59 (s, 4H). LCMS m / z 443.33 [M+H]+ A; 3.93 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 70 r-N7 Ox y-NH T TM # F 1 H F LCMS m / z 456.33 [M+H]+ A; 3.55 71 ’? 6 IZ LL LCMS m / z 456.33 [M+H]+ A; 3.68 72 / o < 6 °^O"^ZT LCMS m / z 456.33 [M+H]+ A; 3.49 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 73 0. / N y-NH if TrA Xf 1 H F 1H  NMR  (300 MHz, Acetone-d6) 5  10.71  (s,  1H), 7.69 - 7.54 (m, 2H), 7.40 (dd, J = 9.8, 2.2 Hz, 1H), 7.35 - 7.23  (m, 2H), 6.84 (ddt, J = 10.9, 9.6, 1.6 Hz, 1H), 6.17 (s, 1H), 4.41 (dd, J = 5.5, 3.1 Hz, 1H), 4.11 (q, J = 8.8 Hz, 1H), 3.84 (d, J = 1.8 Hz, 3H), 3.28 (t, J = 5.5 Hz, 1H), 3.28 - 3.11 (m, 1H), 2.84 (q, J = 9.6, 8.0 Hz, 1H), 2.75 - 2.59 (m, 3H), 2.49 (dd, J =  11.1,  8.3 Hz, 1H), 2.33 (d, J = 2.2    Hz,   3H). LCMS m / z 456.33 [M+H]+ A; 3.58 74 Ox / X / OH y-N^\ Y X>X Xf 1 H F 1H  NMR  (300 MHz, Acetone-d6) 5  10.70  (s,  1H), 7.73  -  7.55  (m, 2H), 7.44 (dd, J = 9.8, 2.2 Hz, 1H), 7.37  -  7.09  (m, 2H), 6.85 (dddd, J = 11.1, 9.6, 3.8, 2.2 Hz, 1H), 4.20  - 3.66 (m, 5H), 3.43 -  3.05  (m,  1H), 2.95  -  2.30  (m, 4H), 1.48 (s, 3H). LCMS m / z 456.33 [M+H]+ A; 3.65 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 75 0. / N y-NH T XrA Xf 1 H F LCMS m / z 456.33 [M+H]+ A; 3.83 76 Ox H X / =x 11 XVa Xf 1 H F LCMS m / z 456.33 [M+H]+ A; 3.81 77 HO 0,   /  \> y-NH / = T JX X 1 H F LCMS m / z 456.33 [M+H]+ A; 3.81 78 OH o y-NH r / =\ T XVa Xf 1 H F LCMS m / z 456.33 [M+H]+ A; 3.63 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 79 OH Ox V-N\ 1 H F LCMS m / z 456.33 [M+H]+ A; 3.68 80 ox H r"\ y-N A / H0 F\^x^   / =x Y JTYa I H F LCMS m / z 456.33 [M+H]+ A; 4.11 81 HN-n ox / y-NH / =\ Y TyY / XF 1 H F 1H  NMR  (300 MHz, Acetone-d6) 5  10.71  (s,  1H), 7.84 (dd, J = 3.7, 2.3 Hz, 1H), 7.70 -7.53 (m, 2H), 7.43 - 7.20 (m, 3H), 6.84 (dddd, J = 11.1, 9.6, 3.3, 2.2 Hz, 1H), 6.63 (s, 2H), 6.48 - 6.41 (m, 1H), 5.30 (p, J = 7.1 Hz, 1H), 4.21 - 4.03  (m,  1H), 3.37 - 3.09 (m, 1H), 2.65 (dddd, J = 10.9, 9.3, 6.4, 1.3 Hz, 4H), 1.54 (dd, J = 7.0, 2.8 Hz, 3H). LCMS m / z 456.33 [M+H]+. A; 3.49 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 82 VnH^" / =x T FH # F N 1 H F 1H NMR (300 MHz, Acetone-d6) 8 10.69 (s, 1H), 7.60 (ddd, J = 8.9, 4.5, 1.7 Hz, 2H), 7.41 (dd, J = 9.8, 2.2 Hz, 1H), 7.36 -7.22 (m, 2H), 6.85 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.22 -3.99 (m, 1H), 3.90 - 3.74 (m, 1H), 3.37 - 3.20 (m, 2H), 3.14 (ddd, J = 13.5, 6.9, 5.4 Hz, 1H), 2.69 - 2.57 (m, 3H), 1.10 (dd, J = 6.2, 1.4 Hz, 3H). LCMS m / z 456.33 [M+H]+. A; 3.47 Compounds 83-161

[00171] Compounds 83-161 (Table 6) were prepared from S2 and the appropriate commercially available amine by HATU coupling according to standard procedure A. Table 6. Structure, physicochemical properties, and LCMS analysis for compounds for compounds 83-161 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 83 OH Ox / y-nh / ---\ T JH VF 1 H F LCMS m / z 445.1 [M+H]+ A; 2.835 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 84 H . O=< J Ox ' y-NH Fx / X^   / -< L X / \ / F N   \= / 1 H F LCMS m / z 442.29 [M+H]+ A; 3.215 85 0   0 I H F LCMS m / z 513.17 [M+H]+ A; 3.95 86 OH Ox F\^x^   / =\ Y TyY # f 1 H F LCMS m / z 443.17 [M+H]+ A; 3.72 87 r—\ zOH 0.    ' ^N / \ /        OH Fx_^x5   / -V T Tr^ VF 1 H F LCMS m / z 459.17 [M+H]+ A; 3.29 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 88 0 V-N F\z^^ /   .-. T T'M Vf \A^N \= / 1 H F LCMS m / z 442.16 [M+H]+ A; 3.44 89 HO 0.     / \ A---N XXA - T JW Vf V^N  \= / 1 H F LCMS m / z 429.16 [M+H]+ A; 3.55 90 4 oH C^^F 1 H F LCMS m / z 417.18 [M+H]+ A; 3.71 91 O ™A °x V-N / F.^j(  >-K L X / \ MA \= / 1 H F LCMS m / z 470.18 [M+H]+ A; 3.62 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 92 nh2 F^^^A   / -\ T 1H VF 1 H F LCMS m / z 456.23 [M+H]+ A; 3.74 93 aa1 T TVa # F I H F LCMS m / z 431.09 [M+H]+ A; 3.87 94 c\ / ~A VN A F\ / ^A / =. T PH # F A^ N 1 H F LCMS m / z 457.21 [M+H]+ A; 4.08 95 "-0 %” A^^Ia^f 1 H F LCMS m / z 429.16 [M+H]+ A; 3.97 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 96 0. / X-N J MV 'M I X VX Vf 1 H F LCMS m / z 451.15 [M+H]+ A; 3.83 97 H / H0 N H \-O F^^^M   / -< Y X / \ / F 1 H F LCMS m / z 455.03 [M+H]+ A; 4.09 98 H hoXY / -- Y X / \ / F 1 H F LCMS m / z 441.05 [M+H]+ A; 3.64 99 H ? >H CXn JPX X     0H F^^^X  .-< Y Th Vf \= / 1 H F LCMS m / z 440.96 [M+H]+ A; 3.57 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 100 HO H HOU / H^N^o F\ / x7   / —\ T XVX Xf 1 H F LCMS m / z 459.17 [M+H]+ A; 3.33 101 >'r ho X X XX xx \^N     F 1 H F LCMS m / z 443.07 [M+H]+ A; 3.97 102 V-N X J 1 XXX XF 1 H F LCMS m / z 443.17 [M+H]+ A; 3.82 103 X XXX Xf X?^N \= / 1 H F LCMS m / z 441.15 [M+H]+ A; 3.78 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 104 Ox H y-N I ^^X^OH / =\ T XVx\ / / F T H F LCMS m / z 403.17 [M+H]+ A; 3.44 105 OH 0. XN / F\ / x7   / -\ T X Vx Xf I H F LCMS m / z 429.16 [M+H]+ A; 3.7 106 OH Ox 1 C V-N X / \ / o T JX Xf 1 H F LCMS m / z 500.21 [M+H]+ A; 2.72 107 X'-OH X-N Fx^i^X / =^ T TrA Xf 1 H F LCMS m / z 443.17 [M+H]+ A; 3.92 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 108 HO Oy VN j\ !        OH f-x / ^A / —\ Y rw Vf 1 H F LCMS m / z 473.17 [M+H]+ A; 3.35 109 ^OH \_-N Fx / ^x7 / -\ Y X X\ Xf 1 H F LCMS m / z 443.17 [M+H]+ A; 3.81 110 XH ox / V^\ vuh n- Fx / xJ ,=. Y XXY Xf 1 H F LCMS m / z 486.2 [M+H]+ A; 2.77 111 hoaX Fx / ^x?  r=\ L XVa Xf 1 H F LCMS m / z 431.18 [M+H]+ A; 3.88 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 112 V'n\ / 'oh Fx^=^   / -\ L X / \ / F 1 H F LCMS m / z 429.16 [M+H]+ A; 3.72 113 HO Y Fx=^X^(   ,=. T XYY Xf 1 H F LCMS m / z 459.17 [M+H]+ A; 3.66 114 "v x—N Fx / ^7   / -< T TyY X \= / 1 H F LCMS m / z 457.18 [M+H]+ A; 3.87 115 OH 0^ Xn Fx^^J / = T XVY XF \f?^N 1 H F LCMS m / z 431.12 [M+H]+ A; 3.52 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) H \ 'H 116 P'OH LCMS m / z 443.14 A; 3.73 F\ J [M+H]+ I X Va7 n \= 1 H F V- F OH 117 o. LCMS m / z 447.15 A; 3.29 F\ J / - OH [M+H]+ IXVX I H F / 7 F HO H \ oA^ 118 Xn LCMS m / z 445.08 A, A; 3.5 F\ J [M+H]+ I TVa V^'N 1 H F / 7 F ^-OH 119 Ox H ■y-N Loh LCMS m / z 475.19 A; 3.44 F \   J   f=\ [M+H]+ I TVa / N 1 H F ^F 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 120 O^ H / / / V-N rx HO"^ V"0 T XVa Xf 1 H F LCMS m / z 487.18 [M+H]+ A; 3.97 121 OH o-^ oK X I PH XF T H F LCMS m / z 487.05 [M+H]+ A; 4.03 122 ^OH o.       N'A. F^^^X   / -\ T XVa H N \= / 1 H F LCMS m / z 472.2 [M+H]+ A; 2.75 123 OH p y-N j pyp Hf 1 H F LCMS m / z 431.15 [M+H]+ A; 3.93 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 124 OH 0 s V-N T TYX XF 1 H F LCMS m / z 417.14 [M+H]+ A; 3.74 125 / —OH O. H O^ V-N __ / Mo 1 H F LCMS m / z 433.17 [M+H]+ A; 3.36 126 / —OH O.       N"^ y-N x__ / T yyy Vf N 1 H F LCMS m / z 458.19 [M+H]+ A; 2.7 127 r--\ OH ox / V y-\__ / OH T TVy Xf N   \= / 1 H F LCMS m / z 445.22 [M+H]+ A; 3.8 128 ox 1 \ V-N / 4 < F       _>(           0H YxV^^f \= / 1 H F LCMS m / z 457.18 [M+H]+ A; 3.91 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 129 OH °VNCj d 0H T TVa # f 1 H F LCMS m / z 447.05 [M+H]+ A; 3.39 130 H 0      N"%. Fx^x^ V^^F 1 H F LCMS m / z 554.25 [M+H]+ A; 3.65 131 xyoH H ^-N^O Fx^Xx>(    / --v T JTW Vf 1 H F LCMS m / z 457.18 [M+H]+ A; 3.9 132 OH d c? Fx_ / Xx^4 / = T JM ^F I H F LCMS m / z 467.15 [M+H]+ A; 3.7 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 133 0 oK / yX yN^y nh2 T X yy Xf N \= / 1 H F LCMS m / z 456.17 [M+H]+ A; 3.39 134 ,--OH F\^^y / —\ I XVy Vf \= / 1 H F LCMS m / z 457.02 [M+H]+ A; 3.79 135 O Ox / \ V'N T XVy Xf 1 H F LCMS m / z 442.13 [M+H]+ A; 3.32 136 o. / \-o FXX^F F LCMS m / z 485.16 [M+H]+ A; 3.99 137 o / WOH y-Ny^v F^-^y  >—K J XXy Vf \y^N \= / 1 H F LCMS m / z 441.25 [M+H]+ A; 3.52 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 138 OH Ox / f OH / =\ T TrA XF N 1 H F LCMS m / z 445.13 [M+H]+ A; 3.15 139 0 0 XH4^ y-NH Fx^^^   / -\ T X V\ Vf \= / 1 H F LCMS m / z 427.14 [M+H]+ A; 3.7 140 / OH 0 / ---\ t xxy Xf 1 H F LCMS m / z 429.16 [M+H]+ A; 3.55 141 __ / H •,-—N / yo HO^ I F^^^^  r=\ t xvy Xf N v^ / 1 H F LCMS m / z 431.18 [M+H]+ A; 3.77 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 142 z    0H Ox v-n A X XX Xf 1 H F LCMS m / z 417.18 [M+H]+ A; 3.69 143 HO ox r\J> 'y-NH F^xx^   / =\ A XXX Xf 1 H F LCMS m / z 429.16 [M+H]+ A; 3.75 144 nh2 oA H U V-N r y^0 HO^ X f\ / 5^\  f=\ A XXX Xf 1 H F LCMS m / z 432.13 [M+H]+ A; 3.07 145 oK / \ XN J ^OH F\zZ<^^   / =\ A XXA Xf 1 H F LCMS m / z 443.14 [M+H]+ A; 3.92 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 146 / --V^OH V-N F\ / ^^ / = T X Va / / f I H F LCMS m / z 443.17 [M+H]+ A; 3.92 147 °x V-N / / ----\ a xaa / f N   \= / 1 H F LCMS m / z 443.33 [M+H]+ A; 3.82 148 OH v() f^^^A .—< if XV \ Xf 1 H F LCMS m / z 445.13 [M+H]+ A; 3.5 149 OH o. ^A V-N / T XVa Xf \= / 1 H F LCMS m / z 429.16 [M+H]+ A; 3.71 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 150 ho^C2n^o Fx^xJ / —\ t X yy y 1 H F LCMS m / z 429.16 [M+H]+ A; 3.7 151 -OH vO Fx / ^x7   / -\ t yyy Vf \= / 1 H F LCMS m / z 445.16 [M+H]+ A; 3.5 152 OH vO Fx. / x7 / -y T x yy Xf 1 H F LCMS m / z 445.16 [M+H]+ A; 3.5 153 0 / \ ,.A < 7 nh2 V-n F'x / ^^^ /    / --\ j xyy Vf 1 H F LCMS m / z 442.13 [M+H]+ A; 3.44 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) P3 z "NH2 154 F. F "N H F LCMS m / z 442.13 [M+H]+ A; 3.32 ho^7 Ok ' y-NH *OH 155 Fx r F H —F LCMS m / z 433.14 [M+H]+ A; 3.22 HO ox V-N 156 F^ iQ F \= / H —F LCMS m / z 457.18 [M+H]+ A; 4.13 0 A 157 F-. r F O H'P 'y-NH \= / H —F LCMS m / z 427.14 [M+H]+ A; 3.7 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 158 —-OH ^-nAh Y T / —{ 1 H F LCMS m / z 433.17 [M+H]+ A; 3.33 159 X) Ox * V-nh F\^_7 / -. t rw Vf \= / 1 H F LCMS m / z 427.14 [M+H]+ A; 3.7 160 1 xOH hA H h Vn Ah >° ho^ f=\ Y Y VY Xf 1 H F LCMS m / z 433.17 [M+H]+ A; 3.24 161 OH VA F\ / ^V ,—< T X AA / F N \= / 1 H F LCMS m / z 444.18 [M+H]+ A; 0.27 2021213758   13 Oct 2026 Compounds 162-234

[00172] Compounds 162-234 (Table 7) were prepared from S2 and the appropriate commercially available amine by HATU coupling according to standard procedure A. Table 7. Structure, physicochemical properties, and LCMS analysis for compounds 162234 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 162 ^-NH LX0 Y--nhh Fx / ^x5  - T X XX Xf 1 H F 1H NMR (300 MHz, Methanol-d4) 8 7.97 (s, 1H), 7.57 - 7.44 (m, 2H), 7.32 (dd, J = 9.8, 2.2 Hz, 1H), 7.29 - 7.09  (m,  2H),  6.73 (dddd, J = 11.0, 9.6, 5.4, 2.2 Hz, 1H), 4.51 (ddd, J = 10.3, 8.8, 3.2 Hz, 1H), 4.18 - 3.99 (m, 1H), 3.44 - 3.31 (m, 2H), 3.25 - 3.15 (m, 1H), 2.73 - 2.56 (m, 3h), 2.55 - 2.45 (m, 1H), 2.01 (ddt, J = 12.6, 10.4, 9.2 Hz, 1H). LCMS  m / z  428.2 [M+H]+ C; 0.97 163 H0^XX ^nX f Fxx<5x^4 / --\ T XXX XF \j^-N   ^= / I H F 1H NMR (300 MHz, Methanol-d4) 8 8.34 (d, J = 9.3 Hz, 1H), 7.56 -7.43 (m, 2H), 7.34 (dd, J = 9.7, 2.2 Hz, 1H), 7.27 - 7.12 (m, 2h), 6.75 (ddd, J = 11.1,9.6, 2.1 Hz, 1H), 4.81  - 4.56 (m, 1H), 4.10 (p, J = 9.1 Hz, 1H), 3.83 (dd, J = 11.7, 4.6 Hz, 1H), 3.71 (dd, J = 11.7, 6.9 Hz, 1H), 2.77 - 2.46 (m, 3H). LCMS m / z 457.12 [M+H]+ A; 3.81 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 164 c F HO" 0 H , H ' / to -NH F L-F F / F 1H NMR (300 MHz, Methanol-d 4) 8 8.34 (d, J = 9.3 Hz, 1H), 7.58 -7.44 (m, 2H), 7.34 (dd, J = 9.7, 2.2 Hz, 1H), 7.28 - 7.14 (m, 2H), 6.82 - 6.68 (m, 1H), 4.68 (s, 1H), 4.10 (p, J = 9.1 Hz, 1H), 3.89 -3.65 (m, 2H), 3.32 -3.08 (m, 1H), 2.80 -2.44 (m, 4H). LCMS m / z 457.21 [M+H]+ A; 3.81 165 c F 0 = 0 H H N-^ -NH ,0 / F LCMS  m / z  442.2 [M+H]+ A; 3.4 166 F. c F 0= 0 H H -NH ,0 / F LCMS  m / z  442.2 [M+H]+ A; 3.4 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 167 Vnh 0H T lVa #f I H F 1H NMR (300 MHz, Acetone-d6) 8 10.70 (s, 1H), 7.69 - 7.49 (m, 2H), 7.41 (dd, J = 9.8, 2.2 Hz, 1H), 7.36 - 7.21 (m, 2H), 7.12 (s, 1H), 6.85 (ddd, J = 11.1, 9.7, 2.2 Hz, 1H), 4.25 - 4.03 (m, 1h), 3.84 - 3.67 (m, 3h), 3.30 (ddt, J = 10.7, 8.9, 5.2 Hz, 2H), 3.20 - 3.01 (m, 1H), 2.71 - 2.58 (m, 3H), 1.11 (d, J = 6.3 Hz, 3H). LCMS m / z 403.21 [M+H]+ A; 3.48 168 Ox ' 'y-NH Y 1M Vf N   \= / 1 H F 1H NMR (300 MHz, Methanol-d^)  8  8.14 (dd, J = 4.2, 1.0 Hz, 1H), 7.81 (dq, J = 1.7, 1.0 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.32 (dd, J = 9.8, 2.2 Hz, 1H), 7.21 (ddt, J = 8.8, 6.6, 2.4 Hz, 2H),  6.74 (dddd, J = 13.9, 9.6, 4.3, 2.1 Hz, 1H), 4.34 (d, J = 1.0 Hz, 2H), 4.17 - 4.03 (m, 1h), 3.25 - 3.17 (m, 1h), 2.81 - 2.49 (m, 4h). LCMS  m / z  426.17 [M+H]+ A; 3.66 169 ox %—NH2 Y XV\ Vf N   \= / I H F LCMS  m / z  345.12 [M+H]+ A; 3.53 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 170 LL o cp '''!      ZI 1H NMR (300 MHz, Methanol-d4) 8 8.15 (d, J = 0.5 Hz, 1H), 7.58 -7.41 (m, 2H), 7.32 (dd, J = 9.7, 2.2 Hz, 1H), 7.26 - 7.14 (m, 2H), 7.03 (q, J = 0.8 Hz, 1H), 6.74 (ddd, J = 11.0, 9.6, 2.2 Hz, 1H), 4.48 (d, J = 1.0 Hz, 2H), 4.20 - 4.03 (m, 1H), 3.25 - 3.13 (m, 1H), 2.84 - 2.43 (m, 4H).   LCMS   m / z 426.17 [M+H]+ A; 3.63 171 O H N—N X X / \ Vf \A^N \= / 1 H F LCMS  m / z  427.15 [M+H]+ A; 3.63 172 o      rN 'y-NH X Jm / f 1 H F LCMS  m / z  441.16 [M+H]+ A; 3.52 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 173 0. d O-N y     n T TrA / f N \= / 1 H F LCMS  m / z  441.12 [M+H]+ A; 3.78 174 n^n"" OA y-NH T JLV\ VF N \= / 1 H F 1H NMR (300 MHz, Methanol-d4) 8 8.64 (s, 1H), 8.43 (d, J = 7.4 Hz, 2H), 8.24 (d, J = 9.6 Hz, 1H), 8.15 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.64 (d, J = 11.1 Hz, 1H), 5.36 (s, 2H), 5.01 (d, J = 9.0 Hz, 1H), 4.61 (s, 3H), 4.05 (d, J = 37.4 Hz, 1H), 3.73 - 3.26 (m, 4H). LCMS  m / z  439.17 [M+H]+ A; 2.76 o. A^*oh y-NH 175 Fx^x5   .-. T X / \ / F 1 H F LCMS  m / z  403.26 [M+H]+ A; 3 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 176 If X V \ XF I H F LCMS  m / z  457.23 [M+H]+ A; 3.36 177 Yf °^NH °H / rA IrnjF 1 H F LCMS  m / z  457.19 [M+H]+ A; 3.37 178 — o H’Hh ^NH OH F\^_^   / —\ If JLXa Xf 1 H F LCMS  m / z  415.28 [M+H]+ A; 3.06 179 H° \ J oK * y-NH / ---\ if XV \ XF I H F LCMS  m / z  429.29 [M+H]+ A; 3.22 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 180 Ox H v-n L X / \ / F 1 H F LCMS  m / z  429.29 [M+H]+ A; 3.06 181 V-oh Ox * Y-NH Y XXf Xf \y^N \= / 1 H F LCMS  m / z  415.25 [M+H]+ A; 3.13 182 HO" / J Ox * y-NH y vyx Xf 1 H F LCMS  m / z  429.29 [M+H]+ A; 3.21 183 / \-OH ox / ^NH --- T X / \ XF 1 H F LCMS  m / z  415.28 [M+H]+ A; 3.09 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 184 TV XXoh NHh F\x-^V / —\ T Th HF \Vn \= / 1 H F LCMS  m / z  431.27 [M+H]+ A; 2.91 185 HO ox / Vo ~y-NH / ----K L X / \ / F V^N \= / 1 H F LCMS  m / z  431.27 [M+H]+ A; 2.93 186 . OH HO-^N / V ox / y-NH F\^V / —\ If XV\ vF V^N \= / I H F LCMS  m / z  433.28 [M+H]+ A; 2.97 187 JDH ox * 'y-NH F\x-x^V / --\ L X / X / F V^N \= / 1 H F LCMS  m / z  429.29 [M+H]+ A; 3.01 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 188 0-^ O=\ J Ox 'y-NH T TW Vf N   ^=7 1 H F LCMS  m / z  429.25 [M+H]+ A; 3.16 189 HO^ \ 0 ox / y-NH T X Vf 1 H F LCMS  m / z  459.31 [M+H]+ A; 3.03 190 OH Xr / ----V 1 X / \ / F I H F LCMS  m / z  417.3 [M+H]+ A; 3.18 191 , OH ox ' 'y-NH T X V \ Xf 1 H F LCMS  m / z  428.24 [M+H]+ A; 3.15 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 192 HO^ ox / \ VN y / ---\ T TXy Xf \Tn \= / 1 H F 1H NMR (300 MHz, Methanol-d4) 8 7.55 -7.49  (m,  2H),  7.38 (ddd, J = 9.7, 5.7, 2.3 Hz, 1H), 7.27 - 7.07 (m, 2H), 6.77 (ddd, J = 11.4, 9.6, 2.1 Hz, 1H), 4.15 (d, J = 4.2 Hz, 2H), 3.74 - 3.62 (m, 2H), 3.44 (t, J = 6.6 Hz, 2H), 2.90 - 2.49 (m, 5H), 2.03 - 1.79 (m, 4H).   LCMS   m / z 429.29 [M+H]+ A; 3.33 193 OH . V F\ / ^T / -K T TTy XF \Tn \= / 1 H F LCMS  m / z  417.3 [M+H]+ A; 3.18 194 °x y-NH F\rT / —\ L XVy Xf \Tn \= / 1 H F LCMS  m / z  445.27 [M+H]+ A; 3.01 195 ox / r v-Ny y hoz Y XXy XF xTn \= / 1 H F LCMS  m / z  415.28 [M+H]+ A; 3.2 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 196 HQ-^X^X 0. y-NH Fx^^^X / -\ X IH Vf X^N \= / 1 H F LCMS  m / z  413.27 [M+H]+ A; 3.08 197 H N X / y-NH Fx^ / ^X   / -> T XV\ / F X^N \= / 1 H F LCMS  m / z  442.29 [M+H]+ A; 2.93 198 N-NZ o. X y-NH F\z%X / —\ X Xh / f XX^-N \= / 1 H F LCMS  m / z  440.27 [M+H]+ A; 3.2 199 Ox H y-N Fxx / —\ X X XX XF XX-N X / 1 H F LCMS  m / z  429.29 [M+H]+ A; 3.18 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 200 HO-A..... C\ ' y-NH 1 XV\ Xf 1 H F LCMS  m / z  403.26 [M+H]+ A; 3.01 201 Vn PH V w .      N F\^x^  >-y T Tyy Vf \= / I H F LCMS  m / z  414.28 [M+H]+ A; 3.09 202 F F V^-0H / —\ t y yy yp N \= / 1 H F LCMS  m / z  465.26 [M+H]+ A; 3.33 203 Ox / ^ y-NH 1 X V \ XF 1 H F LCMS  m / z  417.3 [M+H]+ A; 3.13 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 204 HO"\ ox / \ y-NH 1 XV\ Yf 1 H F LCMS  m / z  417.3 [M+H]+ A; 3.13 205 0.     1         i_। y-N / ’H / —\ T TYY Yf 1 H F LCMS  m / z  445.27 [M+H]+ A; 3.08 206 F\^^^ / -\ T TVY Yf N   ^=7 1 H F LCMS  m / z  415.28 [M+H]+ A; 3.2 207 \ Y° O /  ^0 y-NH F\^X^(   / -\ T XVY Yf \= / 1 H F LCMS  m / z  443.26 [M+H]+ A; 3.31 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 208 o r"OH T JH Vf N ^= / 1 H F LCMS  m / z  442.29 [M+H]+ A; 2.89 209 HO-. , / NH 0    / y-NH T X VX Vf 1 H F LCMS  m / z  458.27 [M+H]+ A; 2.67 210 HO—, ox / \ V-N^ / ---\ T rw Vf N 1 H F LCMS  m / z  429.29 [M+H]+ A; 3.32 211 H OH 3’ Y'NH T Tr^ Vf 1 H F LCMS  m / z  429.29 [M+H]+ A; 3.09 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 212 / ^NH H° \ J Ox '■ 'y-NH Y YYY Yf N ^=7 1 H F LCMS  m / z  430.41 [M+H]+ B ; 0.67 213 O O-S 0      / y-NH Y YYY Yf 1 H F 1H NMR (300 MHz, Methanol-d4) 8 7.59 -7.43 (m, 2H), 7.33 (dd, J = 9.8, 2.2 Hz, 1H), 7.30 - 7.18 (m, 2H), 6.77 (ddd, J = 11.1,9.6, 2.2 Hz, 1H), 4.17 - 3.98 (m, 1H), 3.29 (s, 3H), 3.29 - 3.17 (m, 1H), 2.81 - 2.60 (m, 4H).   LCMS   m / z 423.23 [M+H]+ A; 3.76 214 0. H nh, OH Y YYY Yf 1 H F LCMS  m / z  431.96 [M+H]+ A; 3.08 215 OH OK V-NH 0H Y L YY Yf 1 H F LCMS  m / z  447.15 [M+H]+ A; 3.37 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 216 ydOH YrS-O 1 H F LCMS  m / z  433.17 [M+H]+ A; 3.32 217 vO OH T T / \ VF 1 H F LCMS  m / z  445.13 [M+H]+ A; 3.53 218 Vn7 y A—oh Y JW / F 1 H F LCMS  m / z  429.16 [M+H]+ A; 3.9 219 yO XOH / —* T VW Vf \y^N \= / 1 H F LCMS  m / z  445.16 [M+H]+ A; 3.55 220 VnQ O ^°x Y X Vy VF y^-N \= / 1 H F LCMS  m / z  429.03 [M+H]+ A; 4.06 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 221 H NH2 o. / y-NH Fx / ^x^   / -\ T XV\ VF 1 H F LCMS  m / z  432.23 [M+H]+ A; 3.07 222 °T? X    <)Me t xyx Vf n \= / 1 H F LCMS  m / z  429.16 [M+H]+ A; 4.07 223 Ox ^V—\ ^Nx / ^OH / ----\ T TyX VF 1 H F LCMS  m / z  415.16 [M+H]+ A; 3.42 224 ^OH Vnh 0H T jT>—f n \=y 1 H F 1H NMR (300 MHz, DMSO-d6)  11.69 (s, 1H), 7.74 (t, J = 5.8 Hz, 1H), 7.52 (ddd, J = 8.6, 5.4, 2.6 Hz, 2H), 7.47 -7.23  (m,  3H),  7.00 (ddd, J = 11.7, 9.7, 2.2 Hz, 1H), 3.94 (p, J = 8.9 Hz, 1H), 3.58 - 3.36 (m, 2H), 3.36 -3.09 (m, 6H), 3.10 -2.91 (m, 2H). LCMS  m / z  419.13 [M+H]+ A; 3.17 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 225 ^-OH °H L TYY Yf 7=7 T H F 1H NMR (300 MHz, DMSO-d6) 11.67 (s, 1H), 7.72 (m, 1H), 7.63 - 7.42 (m, 2H), 7.42 -7.23  (m,  3H),  6.99 (ddd, J = 11.7, 9.7, 2.1 Hz, 2H), 3.93 (t, J = 9.0 Hz, 2H), 3.47 (m, 2H), 3.35 - 3.10 (m, 4h), 2.99 (m 1H). LCMS m / z 419.16 [M+H]+ A; 3.17 226 HO    OH < / OH ox y-NH if X YY / f 1 H F 1H NMR (300 MHz, DMSO-d6) 5 11.68 (s, 1H), 7.59 - 7.48 (m, 2h), 7.45 - 7.31 (m, 3h), 7.02 (s, 1H), 7.01 (ddd, J = 11.6, 9.7, 2.1 Hz, 1H), 4.76 (t, J = 5.8 Hz, 3H), 3.99 - 3.87 (m, 2H), 3.57 (d, J = 5.8 Hz, 6H), 2.50 -2.44 (m, 4H). LCMS m / z 448.88 [M+H]+ B , A; 1.95 227 OH ox 1 \ V-N )., J      'OH T £ YY Yf \= / 1 H F 1H NMR (300 MHz, CD3OD) 7.62 - 7.41 (m, 2H), 7.34 (dd, J = 9.7, 2.1 Hz, 1H), 7.29 -7.07  (m,  2H),  6.74 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.19 - 3.93 (m, 3H), 3.76 - 3.57 (m, 2H), 3.52-3.48 (m, 1H), 3.45 - 3.33 (m, 2H), 2.86 - 2.48 (m, 4H).   LCMS   m / z 431.15 [M+H]+ A; 3.14 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 228 yQ o 0 T   X 1 H F 1H NMR (300 MHz, CD3OD) 7.50 (dd, J = 8.8, 5.4 Hz, 2H), 7.36 (d, J = 9.8 Hz, 1H), 7.21 (t, J = 8.8 Hz, 2h), 6.74 (ddd, J = 11.3, 9.4, 2.3 Hz, 1H), 4.19-4.15 (m, 2H), 3.86-3.60 (m, 3H),  3.49-3.25  (m, 3H), 2.75 - 2.60 (m, 2h),  2.59-2.50  (m, 2h).   LCMS   m / z 427.99 [M+H]+ A; 3.36 229 H N> HN / =\ 1 H F 1H NMR (300 MHz, Methanol-d4) 8 7.57 -7.45 (m, 2H), 7.32 (dd, J = 9.8, 2.2 Hz, 1H), 7.24 -7.11 (m, 2H), 6.73 (dddd, J = 11.7, 8.9, 6.7, 2.1 Hz, 1H), 4.57 - 4.35 (m, 1h), 4.24 (dd, J = 7.8, 3.8 Hz, 1H), 4.20 - 4.03 (m, 1H), 3.60 (ddd, J = 9.9, 7.6, 3.8 Hz, 1H), 3.24 (q, J = 7.0 Hz, 1H), 3.12 (ddd, J = 9.9, 7.0, 4.0 Hz, 1H), 2.78 -2.51 (m, 4H). LCMS m / z 444.12 [M+H]+ A; 3.07 230 F / OH HN / =\ L X Va # f 1 H F 1H NMR (300 MHz, Methanol-d4) 8 7.61 -7.44 (m, 2H), 7.33 (dd, J = 9.7, 2.2 Hz, 1H), 7.25 - 7.03 (m, 2h), 6.89 - 6.66 (m, 1h), 5.98 (td, J = 55.6, 3.4 Hz, 1H), 4.32 (dddd, J = 14.0, 8.3, 5.8, 3.0 Hz, 1H), 4.12 (dt, J = 9.9, 8.6 Hz, 1H), 3.82 - 3.67 (m, 2H), 3.30 - 3.15 (m, 2H), 2.91 - A; 3.65 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 2.53 (m, 3H). LCMS m / z 439.1 [M+H]+ 231 ^OH HN"^ hX^° Fx^^>(   / =\ I T V4 XF T H F LCMS  m / z  445.97 [M+H]+ A; 3.11 232 HO HN"^ Fx^^y =, Y T>—{ Xf 1 H F LCMS  m / z  460.14 [M+H]+ A; 3.21 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 233 HO ,F J F HN^ Vnh 0 / =\ N   x— / 1 H F LCMS  m / z  514.38 [M+H]+ A; 3.54 234 HQ. J F HN^ XX^C^F 1 H F LCMS  m / z  514.31 [M+H]+ A; 3.54 2021213758   13 Oct 2026 Compound 235 N-(2-amino-2-oxo-ethyl)-3-[5,7-difluoro-2-(2,3,5,6-tetradeuterio-4-fluoro-phenyl)-1H- indol-3-yl]cyclobutanecarboxamide (235) 235 Step 1. 2,4-Difluoro-6-((4-fluorophenyl-2,3,5,6-d4)ethynyl)aniline (C8)

[00173] A mixture of crude 2,4-difluoro-6-iodoaniline C7 (59.7 g, 58% purity, 135.8 mmol, 1 equiv) and crude 1-Ethynyl-4-fluorobenzene-2,3,5,6-d4 C56 (28.1 g, 60% purity, 135.80 mmol, 1 equiv) in NEt3 (550 mL) was purged with nitrogen for 10 minutes. CuI (5.2 g, 27.2 mmol, 0.2 equiv) and Pd(PPh3)Cl2 (9.5 g, 13.6 mmol, 0.1 equiv) were added. The mixture was stirred at room temperature for 20 h, and then the mixture was concentrated under reduced pressure at 40 oC. The residue was purified twice over silica gel (800 g silica gel, dry-loading, eluting each time with a gradient of 0 to 10% 2021213758   13 Oct 2026 dichloromethane in heptanes) to give the product C8 (40.5 g) as a brown solid which was used in subsequent steps without further purification. (This material still contained some unreacted 2,4-difluoro-6-iodoaniline (40% based on LCMS)). Step 2. 5,7-Difluoro-2-(4-fluorophenyl-2,3,5,6-d4)-1H-indole (C9)

[00174] 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 equiv) in DMF (400 mL) was purged with nitrogen for 10 minutes. CuI (3.0 g, 15.7 mmol, 0.1 equiv) was added, and the mixture was purged with nitrogen for an additional 10 minutes. The mixture was heated at 145 oC for 20 h and cooled to room temperature. The mixture was concentrated under reduced pressure at 60 oC to remove most of DMF. The residue was diluted with water (500 mL) and t-butyl methyl ether (300 mL). The mixture was filtered through Celite®, which was washed with t-butyl methyl ether (100 mL). The layers of the filtrate were separated, and the aqueous layer was extracted with t-butyl methyl ether (2 x 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 oC. Purification by silica gel chromatography (Gradient: 0-10% EtOAc in heptanes) afforded 5,7-Difluoro-2-(4-fluorophenyl-2,3,5,6-d4)-1H-indole as an orange-brown solid (19 g, 80% yield). (1r,3r)-3-(5,7-Difluoro-2-(4-fluorophenyl-2,3,5,6-d4)-1H-indol-3-yl)cyclobutane-1-carboxylic acid (C10)

[00175] Trifluoroacetic acid (30.64 mL, 400.09 mmol, 6.02 equiv) was added dropwise to a solution of compound C9 (16.7 g, 66.47 mmol, 1 equiv), 3-oxocyclobutanecarboxylic acid (11.38 g, 99.71 mmol, 1.5 equiv) and triethylsilane (64.3 mL, 402.28 mmol, 6.05 equiv) in dichloromethane (200 mL) at room temperature. After stirring for 20 hours at room temperature, the reaction mixture was concentrated under reduced pressure to ~100 mL and the solid (cis isomer C11) was filtered and washed with dichloromethane (2 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified twice on an InterChim auto-chromatography system (330 g Sorbtech silica gel column), eluting each time with a gradient of 0 to 10% ethyl acetate in dichloromethane to give compound C10 (19.3 g, 83% yield) 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-indol-3-yl)cyclobutane-1-carboxamide (235)

[00176] HATU (24.0 g, 63.15 mmol, 1.5 equiv) was added to a solution of compound C10 (19.3 g, 42.1 mmol, 1 equiv) in DMF (200 mL) and the mixture was sparged with 238 2021213758   13 Oct 2026 nitrogen for 10 minutes. The mixture was cooled to 5 oC in an ice bath, and glycinamide hydrochloride (5.12 g, 46.31 mmol, 1.1 equiv) was added, followed by the dropwise addition of N,N-diisopropylethylamine (22.0 mL, 126.3 mmol, 3 equiv). 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 x 300 mL). The combined organic layers were washed with saturated brine (400 mL), filtered and concentrated under reduced pressure at 40 oC. The residue was purified on an InterChim auto-chromatography system (330 g SorbTech silica gel column), eluting with a gradient of 0 to 100% ethyl acetate in heptanes to give 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 give a pale yellow sticky solid (21 g), which was triturated twice in a 4 to 1 mixture of water and acetone (250 mL) to give compound 235 (13.9 g, 95% purity) as an off-white solid. This material was further purified by by SFC separation. Column: Daicel Chiralpak ® AD-H, 20 x 250 mm; Mobile Phase: 30% Methanol (containing 0.15% diethylamine), 70% carbon dioxide. Flow: 65 mL / min. The second eluting peak was the product compound 235 (7.5 g, 99.9% purity), obtained as a white solid. The cis isomer of compound 235 was isolated in the first eluting peak, obtained as a yellow solid (1.8 g, 95.8% purity).

[00177] Compound 235 was further purified by SFC an additional time. Column: achiral, 20 x 250 mm; Mobile Phase: 45 % Methanol, 65 % carbon dioxide. Flow: 75 mL / min. Compound 236-273

[00178] Compound 236-273 (Table 8) was prepared from S3 and the appropriate commercially available amine by HATU coupling according to standard procedure A. 2021213758   13 Oct 2026 Table 8. Structure, physicochemical properties, and LCMS analysis for compounds 236273 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 236 H V-nh / ---\ if XVX VF 1 H F LCMS m / z 428.16 [M+H]+ A; 3.33 237 0K H V"Nx, X Y X / #F N 1 H F 1H NMR (300 MHz, Acetone-d 6) 10.66 (s, 1H), 8.09 (dd, J = 10.2, 2.2 Hz, 1H), 7.77 - 7.51 (m, 2H), 7.37 -7.03 (m, 3H), 6.84 (ddd, J = 11.6, 9.6, 2.2 Hz, 1H), 3.97 - 3.68 (m, 1H), 3.59 (q, J = 5.6 Hz, 2H), 3.34 (q, J = 5.6 Hz, 2H), 3.24 -3.03 (m, 1H), 3.01 -2.74 (m, 2H), 2.45 (qd, J = 8.4, 2.6 Hz, 2H). LCMS m / z 389.155 [M+H]+. A; 2.085 238 Ox H N X F"T F-=^_5  =, T X / 4 # f 1 H F LCMS m / z 409.01 [M+H]+ A; 3.96 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 239 Ox H Y T / X # F 1 H F 1H NMR (300 MHz, Acetone-d6) 8 10.69 (s, 1H), 8.08 (dd, J = 10.2, 2.2 Hz, 1H), 7.73 - 7.47 (m, 2H), 7.38 -7.14 (m, 3H), 6.83 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.08 - 3.61 (m, 3H), 3.14 - 2.88 (m, 1H), 2.92 - 2.67 (m, 2H), 2.70 - 2.53 (m, 2H), 2.53 - 2.33 (m, 2H), 1.89 - 1.68 (m, 2H). LCMS m / z 415.16 [M+H]+ A; 3.43 240 V-nh f. / -^ / = Y TyY # F 1 H F LCMS m / z 429.2 [M+H]+ A; 3.83 241 O. H > Y OH "0 Y>h / =\ Y JL / < Yf Y^-n 1 H F LCMS m / z 419.17 [M+H]+ A; 3.17 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 242 Ox H 'V-N ^OMe T Tt~4 N 1 H F LCMS m / z 403.17 [M+H]+ A; 3.8 243 OH °V-NH y jL / A y~F 1 H F LCMS m / z 403.21 [M+H]+ A; 3.52 244 OH 0K H f V-N, A,. ?       OH TXVX # f N 1 H F 1H NMR (300 MHz, Acetone-d6) 8 10.67 (s, 1H), 8.03 (dd, J = 10.1, 2.2 Hz, 1H), 7.63 (ddt, J = 8.3, 5.3, 2.5 Hz, 2H), 7.40 - 7.13 (m, 3H), 6.84 (ddd, J = 11.3, 9.6, 2.2 Hz, 1H), 3.83 (tt, J = 10.4, 8.5 Hz, 1H), 3.67 (qd, J = 5.8, 4.7 Hz, 1H), 3.54 - 3.26 (m, 4H), 3.25 -3.09 (m, 1H), 2.84 (dtd, J = 11.9, 9.9, 2.1 Hz, 2H), 2.49 (ddddd, J = 10.3, 8.4, 6.1, 4.0, 2.3 Hz, 2H). LCMS m / z 419.2 [M+H]+ A; 3.18 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 245 HO—y / °V-NH OH Y T / 4 # f 1 H F 1H NMR (300 MHz, Acetone-d6) 8 10.68 (s, 1H), 8.12 - 8.02 (m, 1H), 7.70 - 7.53 (m, 2H), 7.35 - 7.21 (m, 2H), 6.93 - 6.77 (m, 2H), 4.09 (qd, J = 6.4, 2.9 Hz, 1H), 4.01 - 3.83 (m, 1H), 3.83 -3.73 (m, 1H), 3.72 -3.57 (m, 2H), 3.26 (tt, J = 9.4, 8.2 Hz, 1H), 2.98 - 2.76 (m, 2H), 2.74 - 2.58 (m, 1H), 2.58 - 2.39 (m, 2H), 2.12 - 2.04 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H). LCMS m / z 433.21 [M+H]+ A; 3.27 246 ^O^ °V--NH / =\ y T / Y # f 1 H F 1H NMR (300 MHz, Acetone-d^) 8 10.68 (s, 1H), 8.03 (dd, J = 10.1, 2.2 Hz, 1H), 7.75 - 7.52 (m, 2H), 7.49 -7.21 (m, 3H), 6.92 -6.70 (m, 2H), 4.69 -4.37 (m, 1H), 3.98 -3.70 (m, 1H), 3.40 (dd, J = 9.2, 4.2 Hz, 2H), 3.19 (p, J = 8.8 Hz, 1H), 2.84 (q, J = 10.2 Hz, 2H), 2.70 -2.35 (m, 3h), 2.03 -1.84 (m, 1H). LCMS m / z 415.29 [M+H]+ A; 3.73 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 247 Z-N °V-NH X / =\ 1 Ty-4 ^f 1 H F 1H NMR (300 MHz, Acetone-d6) 8 7.97 (dd, J = 10.1, 2.2 Hz, 1H), 7.69 - 7.56 (m, 2H), 7.36 - 7.22 (m, 2H), 6.85 (ddd, J = 11.1, 9.7, 2.2 Hz, 1H), 3.90 - 3.71 (m, 1H), 3.07 (p, J = 8.4 Hz, 1H), 2.80 (dt, J = 12.3, 9.6 Hz, 2H), 2.63 (s, 6H), 2.57 - 2.39 (m, 2H). LCMS m / z 425.16 [M+H]+ A; 3.67 248 o. / 0° V-NH / =\ T JL / —< )-f 1 H F LCMS m / z 415.16 [M+H]+ A; 2.77 249 VU o CNH / =\ T J¥ / a # f N ^7 1 H F LCMS m / z 442.17 [M+H]+ A; 3.42 250 NH, o. V-NH 0 F\ / ^^( / = T JIV¥ ^f 1 H F LCMS m / z 402.16 [M+H]+ A; 3.22 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 251 OH / OH Q V-nh I JL Va N 1 H F LCMS m / z 433.18 [M+H]+ A; 3.45 252 0 H 0 V'N II F_^'    ° ¥ ¥# F N 1 H F LCMS m / z 456.14 [M+H]+ A; 3.48 253 ^^0 H HN ¥ Ty¥ ^F 1 H F 1H NMR (300 MHz, Acetone-d¢) 8 7.92 (dd, J = 10.1, 2.2 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.36 - 7.22 (m, 2H), 6.85 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 3.92 - 3.74 (m, 1H), 3.60 (s, 2H), 3.17 (p, J = 8.5 Hz, 1H), 2.81 (qd, J = 9.6, 2.6 Hz, 2H), 2.49 (qd, J = 8.4, 2.6 Hz, 2H), 0.91 -0.74 (m, 4H). LCMS m / z 415.19 [M+H]+ A; 3.57 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 254 —( OH o V-NH TX / X#f 1 H F LCMS m / z 431.19 [M+H]+ A; 3.8 255 nh2 0=<^ —NH -- Y j / M z>-f 1 H F LCMS m / z 458.19 [M+H]+ A; 3.76 256 vY™ 7=\ Y YyY # f 1 H F LCMS m / z 417.18 [M+H]+ A; 3.85 257 ( OH 0    / ~7 V-NH / = T        / ^F 1 H F LCMS m / z 417.15 [M+H]+ A; 3.65 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 258 l,    OH 0, H z / =\ ¥ ¥m ¥f N 1 H F LCMS m / z 403.24 [M+H]+ A; 3.7 259 0 h2n¥ °'V-nh oh Fx^^^   / =\ ¥ ¥ ¥¥\ #~F N 1 H F LCMS m / z 432.13 [M+H]+ A; 3.08 260 °V-n¥ 3 Fx^^-Z  7=\ ¥ ¥ / 4 # F N 1 H F LCMS m / z 426.99 [M+H]+ A; 4.11 261 °v-n¥^'nx F\^xJ   / =\ ¥ ¥ / ¥ # F N 1 H F LCMS m / z 439.14 [M+H]+ A; 2.77 262 Ox H 'V-N.        / -. )    N^ Fx / Zx?   / = ¥ ¥ / )^F 1 H F LCMS m / z 438.16 [M+H]+ A; 4.1 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 263 n-n 0 V-NH Fx / ^7   / =\ ¥ j¥ / a 1 H F 1H NMR (300 MHz, Acetone-d6) 8 8.02 (dd, J = 10.3, 2.2 Hz, 1H), 7.81 - 7.51 (m, 3H), 7.49 - 7.12 (m, 2H), 6.85 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 6.06 (dd, J = 2.3, 0.6 Hz, 1H), 4.26 (dd, J = 6.5, 5.5 Hz, 2H), 3.89 - 3.69 (m, 1H), 3.69 -3.54 (m, 2H), 3.17 -2.96 (m, 1H), 2.80 (dt, J = 12.3, 9.5 Hz, 2H), 2.44 (qd, J = 8.4, 2.6 Hz, 2H), 2.21 (s, 2H). LCMS m / z 453.21 [M+H]+ A; 3.47 264 N"% F\ / ^5 = 1 Tm )—f 1 H F LCMS m / z 440.15 [M+H]+ A; 3.26 265 °^n¥^C^n F\ / ^^   / =. T JlVa #-f N 1 H F LCMS m / z 439.27 [M+H]+ A; 3.58 266 / \ZF Vnh^f T# f 1 H F LCMS m / z 449.14 [M+H]+ A; 4.13 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) OK H 267 11 h > V^N 1 H F 73 H —F LCMS m / z 415.16 [M+H]+ A; 3.42 H O^N' ? °V-NH 268 LCMS m / z 428.16 A; 3.33 [M+H]+ I TV / ) 1 H F >—F c 0    * V-NH 269 LCMS m / z 415.19 A; 3.74 / ___\ [M+H]+ I TTT ) N 1 H F >—F HoT / °H 270 o. / V-NH LCMS m / z 433.18 A; 3.26 F\^^-4 / _\ [M+H]+ I Ih ) 1 H F >—F 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 271 0V-NH~3H ¥ XV¥ Vf N X— 1 H F LCMS m / z 403.17 [M+H]+ A; 3.51 272 °V-n¥~Xdh ¥ Ty¥ # F 1 H F LCMS m / z 403.14 [M+H]+ A; 3.82 273 HO    OH V / OH ox V-nh F\^<5^4   / =\ ¥ T y¥ Vf 1 H F LCMS m / z 449.17 [M+H]+ A; 3.23 Compound 274-277

[00179] Compounds 274-277 (Table 9) were prepared from S3 and the appropriate commercially available amine by HATU coupling according to standard procedure A. 2021213758   13 Oct 2026 Table 9. Structure, physicochemical properties, and LCMS analysis for compounds 274277 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 274 oh VO J     OH FxVO / —\ Y jTM oF VO-N \= / 1 H F 1H NMR (300 MHz, CD3OD) 7.64 - 7.45 (m, 3H), 7.22 (t, J = 8.8 Hz, 2H),  6.72 (ddd, J = 11.6, 9.6, 2.1 Hz, 1H), 4.10 (dd, J = 12.3,  3.8 Hz, 2H), 3.91 - 3.67 (m, 2H), 3.62 (dd, J = 13.0, 4.2 Hz, 1H), 3.55 - 3.32 (m, 3H), 2.75 (m, 2H), 2.62 - 2.47 (m, 2H). LCMS m / z 431.12 [M+H]+ A; 3.14 275 5 / ° T C' 6 \\ / / --- LL 1H NMR (300 MHz, CD3OD) 7.59 - 7.39 (m, 3H), 7.22 (t, J = 8.7 Hz, 2H), 6.80 -6.65 (m, 1H), 4.15 (d, J = 11.3 Hz, 2H), 3.93 - 3.66 (m, 3H), 3.51 -3.31 (m, 3H), 2.72 (m, 2H), 2.55 (m, 2H). LCMS m / z 428.15 [M+H]+ A; 3.33 276 0. H F V-Nz__ / v\ y^ f oh / =. Y Tm o OV I H F LCMS  m / z  439.1 [M+H]+ A; 3.66 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 277 / ^NH HO" / 7 0   / ^0 y-NH T F'M 1 H F LCMS m / z 444.12 [M+H]+ A; 3.1 Compounds 278 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxamide (278) Step 1. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3- yl]cyclobutanecarbonitrile (C12)

[00180] 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (200 mg, 0.81 mmol) was taken in CH2Cl2 (10 mL) and added 3-oxocyclobutanecarbonitrile (100 mg, 1.1 mmol). Et3SiH (800 mg, 6.9 mmol) and TFA (600 mg, 5.3 mmol).The reaction mixture was stirred overnight. The reaction mixture was concentrated and diluted with saturated NaHCO3 / Ethyl acetate. The organic layer was dried with brine and Na2SO4 then concentrated to afford a solid. Purification by reversed-phase HPLC (Method: C18 Waters 2021213758   13 Oct 2026 Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid) afforded the product. 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarbonitrile (Trifluoroacetate salt) (220 mg, 55%). 1H NMR (300 MHz, DMSO-d6) 5 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]cyclobutanecarboxamide (278)

[00181] 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarbonitrile (C12) (50 mg, 0.1066 mmol) was dissolved in DMSO (2 mL) and added K2CO3 (15 mg, 0.11 mmol) and hydrogen peroxide (5 mg, 0.15 mmol). The frothy reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, filtered, and concentrated. Purification by reversed-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afforded the product). 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarboxamide (Trifluoroacetate salt) (4 mg, 7%). 1H NMR (300 MHz, Methanol-d4) 5 9.56 (s, 1H), 6.11 (dd, J = 9.9, 2.2 Hz, 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, 8.3 Hz, 1H), 1.72 - 1.42 (m, 1H), 1.31 -1.06 (m, 2H), 0.95 (qd, J = 8.3, 2.6 Hz, 2H) ppm. LCMS m / z 345.28 [M+1]+. Compounds 279-280

[00182] Compounds 279 and 280 (Table 10) were prepared from 3-[7-fluoro-2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-indol-3-yl]cyclobutanecarboxylic acid [CIS / TRANS mix] and the appropriate commercially available amine using standard method A. 3-[7-fluoro-2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-indol-3-yl]cyclobutanecarboxylic acid [CIS / TRANS mix] was prepared from 7-fluoro-2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-indole and 3-oxocyclobutanecarboxylic acid using the method described for the preparation of S1. 2021213758   13 Oct 2026 Table 10. Structure, physicochemical properties, and LCMS analysis for compounds 279-280 Compound Structure LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 279 Ox H V-N F^0H F 1 H F LCMS m / z 438.97 [M+H]+ A; 3.63 280 0 Ox / NHo V-NH INri2 ......f F HHV V^N \= / 1 H F LCMS m / z 452.14 [M+H]+ B; 0.82 Compounds 281-286

[00183] Compounds 281-286 (Table 11) were prepared from the appropriate acid and commercially available amine by coupling with HATU according to standard method A. Table 11. Structure, physicochemical properties, and LCMS analysis for compounds 281-286 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 281(1) OH < \ H F^ / ^7 / =^ T LH I H F LCMS m / z 429.2 [M+H]+ A; 3.63 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 282(1) 0 / \ > \1            N'" F^^^^ / = T LrA #F 1 H F LCMS m / z 453.21 [M+H]+ A; 2.82 283(1) 0 1 / N < \ H F^^^V  7=\ T £ W Yf 1 H F LCMS m / z 403.17 [M+H]+ A; 3.47 284(1) H N 0 L ? V^N'' \ \ H F\^\Y / —\ T 1YY Yf 1 H F LCMS m / z 442.17 [M+H]+ A; 3.41 285(2) HO 0 \ F \\ N \ \ H F\^\^ / —\ T 1YY Yf 1 H F 1H NMR (300 MHz, Acetone-d6) 8 10.77 (s, 1H), 8.08 (dd, J = 10.1, 2.2 Hz, 1H), 7.77 (s, 1H), 7.75 - 7.52 (m, 2H), 7.31 (s, 2H), 6.87 (d, J = 0.7 Hz, 1H), 4.19 (p, J = 9.5 Hz, 1H), 3.60 (s, 2H), 3.43 -3.14 (m, 2H), 3.13 - 2.86 (m, 1H), 2.70 - 2.47 (m, 2H), 0.98 -0.70 (m, 4H). LCMS m / z 433.14 [M+H]+. A; 3.78 2021213758   13 Oct 2026 Compound Structure 1H NMR (ppm); LCMS m / z [M+H]+ LCMS Method; LCMS retention time (min) 286(2) 0 / A H N=^ / = T 1H 1 H F LCMS m / z 457.15 [M+H]+ A; 2.87 (1) Prepared from 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1-methyl-cyclobutanecarboxylic acid. 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1-methyl-cyclobutanecarboxylic acid was prepared from C3 and 1-methyl-3-oxo-cyclobutanecarboxylic acid by reductive coupling with Et3SiH in the presence of TFA, as described for the preparation of S1. (2) Prepared from 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1-fluoro-cyclobutanecarboxylic acid.

[00184] All amines used in the preparation of compounds in Tables 3-11 are shown in Table 12. Amines in Table 12 were either purchased commercially or prepared by standard literature processes. Table 12. Amines used in the preparation of compounds in Tables 3-11 Compound Number Table Amine 2 3 3-aminopyrrolidin-2-one 3 3 1,3-diaminopropan-2-ol 4 3 propane-1,3-diamine 5 3 3-aminocyclobutanol 6 3 (1 -aminocyclobutyl)methanol 7 3 3-amino-1-methyl-pyrrolidin-2-one 8 3 2-aminopropane-1,3-diol 9 3 2-amino-N-methyl-propanamide 10 3 2-aminoacetic acid 11 3 2-amino-2 -methyl-propanamide 2021213758   13 Oct 2026 Compound Number Table Amine 12 3 2 -methoxyethanamine 13 3 2-aminopropan-1-ol 14 3 3-aminopropane-1,2-diol 15 3 tetrahydrofuran-3 -amine 16 3 (2S,3S)-2-aminobutane-1,3-diol 17 3 5 -methylisoxazol-3 -amine 18 3 2-methoxycyclopropanamine 19 3 (3 S)-tetrahydrofuran-3 -amine 20 3 3-aminocyclobutanol 21 3 (3R)-tetrahydrofuran-3-amine 22 3 1 -methylpyrazol-3-amine 23 3 3-aminopiperidin-2-one 24 3 5 -methyloxazo l-2 -amine 25 3 (2S)-2-aminobutane-1,3-diol 26 3 3-aminopiperidine-2,6-dione 27 3 (2R)-2-aminopropan-1-ol 28 31 (2R)-2-aminopropanamide 29 3 2-amino-3-methyl-butan-1-ol 30 3 2-amino-4-methyl-pentanamide 31 3 2-amino-2-methyl-propan-1-ol 32 3 2-amino-3-hydroxy-propanamide 33 3 2,2,2 -trifluoroethanamine 34 3 2-pyrrol-1-ylethanamine 35 3 2-(3 -methylpyrazol-1 -yl)ethanamine 36 3 2-(1,2,4-triazol-1-yl)ethanamine 37 3 (3-methylisoxazol-5-yl)methanamine 38 3 (1 -methylpyrazol-4-yl)methanamine 39 3 2-(1,2,4-triazol-4-yl)ethanamine 40 3 2-methylsulfonylethanamine 41 3 (3,3 -difluorocyclobutyl)methanamine 2021213758   13 Oct 2026 Compound Number Table Amine 42 3 tetrahydropyran-4-ylmethanamine 43 3 (5-methyloxazol-2-yl)methanamine 44 3 4-aminopyrrolidin-2-one 45 3 (3R)-3-aminopyrrolidin-2-one 47 4 (1 -aminocyclopropyl)methanol 48 4 (1 -methylimidazol-4-yl)methanamine 49 5 [1 -(methylaminomethyl)cyclopropyl]methanol 50 5 2-amino-N-cyclopropyl-acetamide 51 5 2-(methylamino)acetamide 52 5 2-(cyclopropylamino)ethanol 53 5 [1 -(methoxymethyl)cyclopropyl]methanamine 54 5 1-(methoxymethyl)cyclopropanamine 55 5 [1 -(ethoxymethyl)cyclopropyl]methanamine 56 5 1 -aminocyclopropanecarboxamide 57 5 [(6R)-7-oxa-4-azaspiro[2.5]octan-6-yl]methanol 58 5 [1 -(methylamino)cyclopropyl]methanol 59 5 2-(1-aminocyclopropyl)ethanol 60 5 2-amino-3,3,3-trifluoro-2-methyl-propanamide 61 5 (2R)-2-amino-N,N-dimethyl-propanamide 62 5 N,N-dimethyl-2 -(methylamino)acetamide 63 5 1 -isopropylpiperazin-2-one 64 5 (2S)-N-ethylpyrro lidine -2-c arboxamide 65 5 (2S)-2-amino-N,N-dimethyl-propanamide 66 5 2-amino-2 -methyl-1 -morpholino-propan-1 -one 67 5 2-amino-1-(4-methylpiperazin-1-yl)ethanone 68 5 2-aminopropanamide 69 5 1 -(aminomethyl)cyclopentanol 70 5 4-(aminomethyl)-1-methyl-pyrrolidin-2-one 71 5 (1 -methylpyrazol-3 -yl)methanamine 2021213758   13 Oct 2026 Compound Number Table Amine 72 5 [5-(methoxymethyl)- 1H-pyrazol-3-yl]methanamine 73 5 (1,5 -dimethylpyrazol-3 -yl)methanamine 74 5 3 -methylazetidin-3-ol 75 5 1-(1 -methylpyrazol-3 -yl)ethanamine 76 5 1-(2 -methylpyrazol-3 -yl)ethanamine 77 5 1 -(aminomethyl)cyclobutanol 78 5 2-amino-3 -fluoro-propan-1 -ol 79 5 2-(methylamino)ethanol 80 5 1 -(aminomethyl)cyclohexanol 81 5 1 -(1H-pyrazol-5-yl)ethanamine 82 5 (2S)-1-aminopropan-2-ol 83 6 [3-(aminomethyl)oxetan-3-yl]methanol 84 6 (3S)-3-amino-5-methyl-pyrrolidin-2-one 85 6 azetidin-3 -yl tetrahydropyran-4-carboxylate 86 6 2-(azetidin-3-yl)prop an-2-ol 87 6 4-(hydroxymethyl)piperidin-4-ol 88 6 (2S)-pyrrolidine-2-carboxamide 89 6 [(3R) -pyrro lidin-3-yl]methano l 90 6 1 -(methylamino)propan-2-ol 91 6 N-(3-piperidyl)acetamide 92 6 pip eridine-2 -c arb oxamide 93 6 2-methyl-1 -(methylamino)propan-2-ol 94 6 2-(2-piperidyl)ethanol 95 6 (3S)-3-methoxypyrrolidine 96 6 1 -(azetidin-3-yl)pyrazole 97 6 2-azabicyclo[2.2.1 ]heptan-3-ylmethanol 98 6 [(1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl]methanol 99 6 [(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]methanol 100 6 (3S,4R)-4-(hydroxymethyl)piperidin-3-ol 2021213758   13 Oct 2026 Compound Number Table Amine 101 6 2 -pyrro lidin-2 -ylethano l 102 6 4,4-dimethylpyrrolidin-3-ol 103 6 2-oxa-7-azaspiro[3.4]octane 104 6 3-aminopropan-1-ol 105 6 (3S)-piperidin-3-ol 106 6 4-morpholinopyrrolidin-3-ol 107 6 [(2R)-2-piperidyl]methanol 108 6 [4-(hydroxymethyl)-4-piperidyl]methanol 109 6 [(3R)-3-piperidyl]methanol 110 6 (3S,4S)-4-[(dimethylamino)methyl]piperidin-3-ol 111 6 2-(ethylamino)propan-1-ol 112 6 3-ethylazetidin-3-ol 113 6 2-morpholin-3-ylethanol 114 6 3,3-dimethylpiperidin-4-ol 115 6 morpholin-2-ol 116 6 (3S,4S)-3 -methylpiperidin-4 -ol 117 6 3-(2-hydroxyethylamino)propan-1 -ol 118 6 [(2S)-morpholin-2-yl]methanol 119 6 4-(aminomethyl)hexane-1,4-diol 120 6 [4-(methylaminomethyl)tetrahydropyran-4-yl]methanol 121 6 2-[2-(cyclobutylamino)ethoxy]ethanol 122 6 2-piperazin-1 -ylpropan-1 -ol 123 6 2-(isopropylamino)ethanol 124 6 2-(ethylamino)ethanol 125 6 2-(2-aminoethoxy)ethanol 126 6 2-piperazin-1 -ylethanol 127 6 piperidine-4,4-diol 128 6 2-(3-piperidyl)ethanol 129 6 1-(2-hydroxyethylamino)propan-2-ol 2021213758   13 Oct 2026 Compound Number Table Amine 130 6 (2,2-dimethylpiperazin-1-yl)-(3-hydroxy-3-methyl-cyclobutyl)methanone 131 6 1 -(3-piperidyl)ethanol 132 6 2-(pyrazin-2 -ylamino)ethanol 133 6 pip eridine-4 -c arb oxamide 134 6 2-(4-piperidyl)ethanol 135 6 (3R)-pyrrolidine-3-carboxamide 136 6 3 -(tetrahydro furan-2 -ylmethoxy)azetidine 137 6 2-azaspiro[3.3]heptan-6-ol 138 6 4-(hydroxymethyl)pyrrolidin-3-ol 139 6 (3R)-3-aminocyclopentanone 140 6 [(3S)-pyrrolidin-3-yl]methanol 141 6 (2S) -2-amino -3 -methyl-butan- 1-ol 142 6 (2R)-2-(methylamino)propan-1-ol 143 6 1 -(aminomethyl)cyclobutanol 144 6 (2S) -2-amino -3 -hydroxy-propanamide 145 6 2-piperidylmethanol 146 6 [(2S)-2 -pip eridyl]methano l 147 6 3 -piperidylmethanol 148 6 morpholin-2-ylmethanol 149 6 (3R)-piperidin-3-ol 150 6 piperidin-3-ol 151 6 morpholin-2-ylmethanol 152 6 morpholin-2-ylmethanol 153 6 (2R)-pyrrolidine-2-carboxamide 154 6 (3S)-pyrrolidine-3-carboxamide 155 6 (2S,3R)-2-aminobutane-1,3-diol 156 6 2-[(2R)-2 -pip eridyl]ethano l 157 6 (3S)-3-aminocyclopentanone 158 6 3 -(methylamino)propane-1,2 -diol 2021213758   13 Oct 2026 Compound Number Table Amine 159 6 3 -aminocyclopentanone 160 6 (2R,3R)-2-aminobutane-1,3-diol 161 6 [(2S)-piperazin-2-yl]methanol 162 7 (3S)-3-aminopyrrolidin-2-one 163 7 (2S)-2-amino-3,3,3 -trifluoro-propan-1 -ol 164 7 (2R)-2-amino-3,3,3 -trifluoro-propan-1 -ol 165 7 (3S)-3-aminopyrrolidine-2,5-dione 166 7 (3R)-3-aminopyrrolidine-2,5-dione 167 7 1 -aminopropan-2-ol 168 7 oxazol-4 -ylmethanamine 169 7 ammonia 170 7 oxazol-5 -ylmethanamine 171 7 1,3,4-oxadiazol-2-ylmethanamine 172 7 (5 -methyl-1,3,4-oxadiazol-2 -yl)methanamine 173 7 (3 -methyl-1,2,4-oxadiazol-5 -yl)methanamine 174 7 (3-methylimidazol-4-yl)methanamine 175 7 (2R)-1 -aminopropan-2-ol 176 7 (2S)-3-amino-1,1,1-trifluoro-propan-2-ol 177 7 (2R)-3-amino-1,1,1 -trifluoro-propan-2-ol 178 7 (1S,2S)-2-aminocyclobutanol 179 7 (1S,2R)-2-aminocyclopentanol 180 7 (1R,3S)-3 -aminocyclopentanol 181 7 (1 R,2 S)-2-aminocyclobutanol 182 7 (1R,2R)-2-aminocyclopentanol 183 7 1 -(aminomethyl)cyclopropanol 184 7 (3R,4S)-4-aminotetrahydrofuran-3-ol 185 7 3 -(aminomethyl)oxetan-3 -ol 186 7 2-amino-2 -methyl-propane-1,3 -diol 187 7 (1S,3S)-3 -aminocyclopentanol 188 7 (3S)-3-aminotetrahydrofuran-2-one 2021213758   13 Oct 2026 Compound Number Table Amine 189 7 [(2S,5R)-5-(aminomethyl)tetrahydrofuran-2-yl]methanol 190 7 (2R)-2-(methylamino)propan-1-ol 191 7 2-amino-3-hydroxy-2-methyl-propanenitrile 192 7 [(2 R) -pyrro lidin-2 -yl]methano l 193 7 2-(methylamino)propan-1-ol 194 7 (3 -aminotetrahydrofuran-3-yl)methanol 195 7 [(2 R) -azetidin-2 -yl]methano l 196 7 2-aminobut-3 -yn-1 -ol 197 7 3-amino-3-methyl-pyrrolidin-2-one 198 7 (2-methyltriazol-4-yl)methanamine 199 7 2-amino-2-cyclopropyl-ethanol 200 7 (2S)-2-aminopropan-1-ol 201 7 2-amino-3-hydroxy-propanenitrile 202 7 (1-amino-3,3-difluoro-cyclobutyl)methanol 203 7 (2R)-2-aminobutan-1-ol 204 7 (2S)-2-aminobutan-1-ol 205 7 4-(methylamino)tetrahydrofuran-3-ol 206 7 [(2S)-azetidin-2-yl]methanol 207 7 3 -amino-5 -methyl-tetrahydrofuran-2-one 208 7 3-(aminomethyl)pyrrolidin-2-one 209 7 (3S,5S)-3-amino-5-(hydroxymethyl)pyrrolidin-2-one 210 7 [(2S) -pyrro lidin-2 -yl]methanol 211 7 3 -amino-3 -methyl-cyclobutanol 212 7 (3S,4S)-4 -aminopyrro lidin-3 -ol 213 7 methanesulfonamide 214 7 (2S) -2-amino -3 -hydroxy-propanamide 215 7 1 -amino-3 -methyl-butane-2,3-diol 216 7 3 -amino-2 -methyl-propane-1,2 -diol 2021213758   13 Oct 2026 Compound Number Table Amine 217 7 [(3R)-morpholin-3-yl]methanol 218 7 (2-methylazetidin-2-yl)methanol 219 7 [(3S)-morpholin-3-yl]methanol 220 7 (2S)-2-(methoxymethyl)azetidine 221 7 (2R)-2-amino-3-hydroxy-propanamide 222 7 (2R)-2-(methoxymethyl)azetidine 223 7 azetidin-3 -ylmethanol 224 7 (2R)-3-aminopropane-1,2-diol 225 7 (2 S)-3-aminopropane-1,2 -diol 226 7 2-amino-2-(hydroxymethyl)propane-1,3-diol 227 7 (3R,4R)-pyrrolidine-3,4-diol 228 7 piperazin-2-one 229 7 (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one 230 7 (2S)-2-amino-3,3-difluoro-propan-1-ol 231 7 2-amino-N-(2 -hydroxyethyl)acetamide 232 7 2-amino-N-[(1R)-2-hydroxy-1 -methyl-ethyl]acetamide 233 7 2-amino-N-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]acetamide 234 7 2-amino-N-[(2S)-3,3,3-trifluoro-2-hydroxy-propyl]acetamide 236 8 (3R)-3-aminopyrrolidin-2-one 237 8 2-aminoethanol 238 8 2,2 -difluoro ethanamine 239 8 3-aminocyclobutanol 240 8 (1 -aminocyclobutyl)methanol 241 8 2-aminopropane-1,3-diol 242 8 2 -methoxyethanamine 243 8 2-aminopropan-1-ol 244 8 3-aminopropane-1,2-diol 2021213758   13 Oct 2026 Compound Number Table Amine 245 8 (2S,3S)-2-aminobutane-1,3-diol 246 8 (3 S)-tetrahydrofuran-3 -amine 247 8 2-methylpyrazol-3-amine 248 8 oxetan-3 -ylmethanamine 249 8 3-aminopiperidin-2-one 250 8 2-aminoacetamide 251 8 2-amino-2 -methyl-propane-1,3 -diol 252 8 3-aminopiperidine-2,6-dione 253 8 (1 -aminocyclopropyl)methanol 254 8 2-amino-3-methyl-butan-1-ol 255 8 2-amino-4-methyl-pentanamide 256 8 2-amino-2-methyl-propan-1-ol 257 8 (2S)-2-aminobutan-1-ol 258 8 (2R)-1 -aminopropan-2-ol 259 8 2-amino-3-hydroxy-propanamide 260 8 2,2,2 -trifluoroethanamine 261 8 (1 -methylimidazol-4-yl)methanamine 262 8 2-pyrrol-1-ylethanamine 263 8 2-(3 -methylpyrazol-1 -yl)ethanamine 264 8 2-(1,2,4-triazol-1-yl)ethanamine 265 8 (2-methylpyrazol-3-yl)methanamine 266 8 (3,3 -difluorocyclobutyl)methanamine 267 8 3-aminocyclobutanol 268 8 3-aminopyrrolidin-2-one 269 8 (3R)-tetrahydrofuran-3-amine 270 8 (2S)-2-aminobutane-1,3-diol 271 8 (2S)-2-aminopropan-1-ol 272 8 (2R)-2-aminopropan-1-ol 273 8 2-amino-2-(hydroxymethyl)propane-1,3-diol 274 9 (3R,4R)-pyrrolidine-3,4-diol 2021213758   13 Oct 2026 Compound Number Table Amine 275 9 piperazin-2-one 276 9 (2S)-2-amino-3,3-difluoro-propan-1-ol 277 9 (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one 279 10 2-aminoethanol 280 10 2-aminoacetamide 281 11 (1 -aminocyclopropyl)methanol 282 11 (1 -methylimidazol-4-yl)methanamine 283 11 2-aminoethanol 284 11 (3S)-3-aminopyrrolidin-2-one 285 11 (1 -aminocyclopropyl)methanol 286 11 (1 -methylimidazol-4-yl)methanamine 0 Preparation S5 F                                             F C13                                    S5 Step 1. Synthesis of [3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutyl] acetate (C12)

[00185] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (5 g, 20 mmol) in dichloromethane (25 mL) was added (3-oxocyclobutyl) acetate (3.8 g, 0.030 mol) followed by Et3SiH (12 g, 100 mmol) and trifluoroacetic acid (12 g, 110 mmol). The 2021213758   13 Oct 2026 mixture was stirred at room temperature overnight. The mixture was then partitioned between ethyl acetate and aqueous sat. sodium bicarbonate solution. The organic phase was separated and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0-40 % EtOAc in heptane) to afford the product. [3-[5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutyl] acetate (7 g, 67 %). LCMS m / z 360.2 [M+H]+. Step 2. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanol (C13)

[00186] To a solution of [3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutyl] acetate C12 (7 g, 12 mmol) in methanol (60 mL) was added potassium carbonate (2.2 g, 16 mmol). The mixture was stirred at room temperature for 4 h. The mixture was then partitioned between ethyl acetate and brine. The organic phase was separated and dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc in heptane to afford the product. 3-[5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanol (4 g, 95 %). 1H NMR (300 MHz, DMSO-d6) 8 11.67 (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, 7.0 Hz, 1H), 2.57 (d, J = 8.5 Hz, 2H), 2.21 (p, J = 10.8, 10.2 Hz, 2H). LCMS m / z 318.2 [M+H]+. Step 3. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanone (S5)

[00187] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanol C13 (500 mg, 1.1 mmol) in dichloromethane (25 mL) was added 3-oxo-1,3-dihydro-1X5,2-benziodoxole-1,1,1-triyl triacetate (580 mg, 1.4 mmol). The mixture was stirred at room temperature for 3 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0-50 % EtOAc in heptane) to afford the product. 3-[5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanone (200 mg, 37%). 1H NMR (400 MHz, DMSO-d6) 8 11.83 (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]+. 2021213758   13 Oct 2026 Preparation S6 C3 H2 Pd / C S6 Step 1. Synthesis of benzyl (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)carbamate (C14)

[00188] 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 was added benzyl N-(3-oxocyclobutyl)carbamate (4.9 g, 22 mmol) followed by Et3SiH (20 mL, 130 mmol) and trifluoroacetic acid (9.5 mL, 120 mmol). The mixture was stirred at room temperature overnight. The mixture was then concentrated in vacuo and partitioned between ethyl acetate and aqueous sat. sodium bicarbonate solution. The organic phase was separated and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) to afford the isomeric mixture of product. The isomeric mixture (6.5 g, 14 mmol) was separated by chiral SFC separation (Column: Daicel Chiralpak® AD-H, 20 x 250 mm; Mobile Phase: 40 % methanol (containing 5 mM ammonia), 60 % carbon dioxide. Flow: 75 mL / min) into trans isomer. Benzyl (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)carbamate (1.1 g, 52 %). 1H NMR (300 MHz, Acetone-d6) 5 7.64 - 7.57 (m, 2H), 7.43 - 7.24 (m, 7H), 6.90 - 6.80 (m, 2H), 5.10 (2, 2H), 4.35 (d, J = 6.9 Hz, 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]+. 2021213758   13 Oct 2026 Step 2. Synthesis of (1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanamine (S6)

[00189] To a solution of benzyl N-[(1r,3r)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutyl]carbamate C14 (1.7 g, 3.8 mmol) in MeOH (20 mL) and THF (5 mL) was added 10 % palladium on carbon catalyst (1 g, 50 % water). The reaction mixture was placed on Parr shaker at 30 psi for 6 h. Then the mixture was filtered through Celite®. The filtrate was removed in vacuo, and the resulting mixture was triturated with DCM (10 mL) to provide the product. (1r,3r)-3-[5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanamine (948.2 mg, 75 %). 1H NMR (300 MHz, Methanol-d4) 8 7.51 (ddt, J = 8.3, 5.2, 2.5 Hz, 2H), 7.26 (dtd, J = 8.8, 6.8, 2.2 Hz, 3H), 6.78 (ddd, J = 11.1, 9.6, 2.1 Hz, 1H), 4.25 (p, J = 9.0 Hz, 1H), 3.96 (dddt, J = 8.2, 7.0, 3.5, 1.9 Hz, 1H), 2.97 - 2.80 (m, 2H), 2.50 (ddt, J = 12.5, 9.6, 3.3 Hz, 2H). LCMS m / z 317.13 [M+H]+. Preparation S7 Preparation of 4-nitrophenyl ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclo-butyl)carbamate (S7)

[00190] To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3- yl]cyclobutanamine S6 (600 mg, 1.9 mmol) in THF (20 mL) was added bis(4-nitrophenyl) carbonate (285 mg, 0.937 mmol), followed by Et3N (200 mg, 2.0 mmol). The reaction mixture was stirred for a few hours. The mixture was then concentrated in vacuo to provide the product. 4-Nitrophenyl ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)carbamate (600 mg, 12 %). LCMS m / z 482.27 [M+H]+. 2021213758   13 Oct 2026 Preparation S8 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]methyl]cyclobutanecarboxylic acid (S8) Step 1. Synthesis of ethyl 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]methyl]cyclobutanecarboxylate (C15)

[00191] 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (750 mg, 3.034 mmol) and ethyl 3-formylcyclobutanecarboxylate (2.4 g, 15.37 mmol) were dissolved in CH2Cl2 (8 mL) and added Et3SiH (1.8 g, 15.48 mmol) and TFA (1.7 g, 14.91 mmol). The reaction mixture was stirred at room temperature overnight. The organic solvent (including TFA) was removed under reduced pressure. The resulting crude material was quenched with aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, concentrated and purified by silica gel chromatography using hexane and EtOAc to provide the product. Ethyl 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]methyl]cyclobutanecarboxy-late (1.1 g, 90 %). 1H NMR (300 MHz, Acetone- d6) 8 10.70 (s, 1H), 7.74 (dddd, J = 8.4, 7.5, 5.2, 3.1 Hz, 2H), 7.39 - 7.15 (m, 3H), 6.82 (ddd, J = 11.1, 9.7, 2.2 Hz, 1H), 4.03 (qd, J = 7.1, 2.6 Hz, 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, 1.5 Hz, 3H). LCMS m / z 388.35 [M+H]+.

[00192] Step 2. Synthesis of 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]methyl]cyclobutanecarboxylic acid (S8)

[00193] Ethyl 3-[[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3- yl]methyl]cyclobutanecarboxy-late C15 (1 g, 1.862 mmol) was dissolved in THF (10 mL), 270 2021213758   13 Oct 2026 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, diluted with water and EtOAc. The organic layer was neutralized with 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The organic layer was then concentrated and purified by silica gel chromatography (Gradient 0-20 % MeOH in DCM) to provide the product. 3-[[5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]methyl]cyclobutanecarboxylic acid (800 mg, quantitative). 1H NMR (300 MHz, Acetone-d6) 5 10.71 (s, 1H), 7.88 - 7.64 (m, 2H), 7.43 - 7.08 (m, 3H), 6.82 (ddd, J = 11.0, 9.7, 2.2 Hz, 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, 2.4 Hz, 2H). LCMS m / z 360.31 [M+H]+. Preparation S9 (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl (4-nitrophenyl) carbonate (S9) C12                                       C16 no2 pyridine DCM S9 Step 1. Synthesis of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutan- 1-ol (C16) 2021213758   13 Oct 2026

[00194] To a solution of [3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutyl] acetate C12 (700 mg, 1.2 mmol) in MeOH (10 mL) was added K2CO3 (200 mg, 1.4 mmol) at room temperature. The mixture was then partitioned between EtOAc and aqueous saturated sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by chiral SFC separation (Column: Daicel Chiralpak® OJ-H, 20 x 250 mm; Mobile Phase: 20 % isopropanol (containing 5 mM Ammonia), 80 % carbon dioxide. Flow: 75 mL / min) to afford the trans isomer. (1r,3r)-3-(5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutan-1-ol (100 mg, 46 %). 1H NMR (300 MHz, Acetone-d6) 8 10.67 (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, 3.5 Hz, 1H), 4.13 (ttd, J = 9.2, 7.9, 1.1 Hz, 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-indol-3-yl)cyclobutyl (4-nitrophenyl) carbonate (S9)

[00195] To a solution of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutan-1-ol C16 (2000 mg, 6.30 mmol) in DCM (20 mL) was added (4-nitrophenyl) carbonochloridate (2 g, 10 mmol), followed by pyridine (750 mg, 9.5 mmol). The mixture was stirred for 5 h at room temperature. The mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed with 2 M aqueous NaOH (x 3) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product. (1r,3r)-3-(5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl (4-nitrophenyl) carbonate. LCMS m / z 483.26 [M+H]+. 2021213758   13 Oct 2026 Preparation of S10 and S11 ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (S10) and ((1s,3s)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (S11) S10 S11 Step 1. Synthesis of 3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutane-1-carbonitrile (C17)

[00196] A 250 mL round bottom flask was charged with a magnetic stir bar, 5,7-difluoro-2-(4-fluorophenyl)-1H-indole S1 (3.8 g, 13.8 mmol), 3-oxocyclobutanecarbonitrile (1.7 g, 17.8 mmol), DCM (100 mL), Et3SiH (9.6 g, 82.5 mmol), and then TFA (9.5 g, 83.3 mmol) was added drop wise via syringe. After 16 h 2021213758   13 Oct 2026 additional 3-oxocyclobutanecarbonitrile (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 allowed to stir for another 20 h. The reaction was then judged to be complete by LCMS and was then carefully inverse quenched onto a solution of saturated aqueous NaHCO3. Once a neutral pH was obtained the mixture was poured into a separatory funnel and extracted with DCM (2 x 500 mL). The organic extract was then combined, dried with MgSO4, filtered through a bed of Celite and conc. in vacuo to afford the title compound as a ~ 1:1 mixture of cis / trans.

[00197] Upon standing solids formed which were triturated with DCM (~50 mL). The resulting white solids were then collected via vacuum filtration using a Buchner funnel. The solids were determined to be the cis-product and the filtrate was mostly trans. The filtrate (trans) material was pre-absorbed onto Celite and further purifed via SiO2 chromatography (120 g) using heptanes / ethyl actetate (8:1) as eluent to afford pure trans-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarbonitrile C17 (1.7 g, 26%). LCMS m / z 327.28 [M+H]+ and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanecarbonitrile C18 (2.2 g, 45%). LCMS m / z 327.28 [M+H]+. Synthesis of ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (S10)

[00198] To a solution of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclo-butane-1-carbonitrile C17 (901 mg, 2.62 mmol) in anhydrous THF (29 mL) at 0 °C under a nitrogen atmosphere was added lithium aluminum hydride (5.7 mL of 2 M, 11 mmol) slowly. The reaction was stirred at 0 °C for additional 10 min, slowly warmed to room temperature, and heated to 60 °C for 1 h. The reaction was then cooled to room temperature and slowly added to a cold solution of 1 M aqueous Rochelle's 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 %). 1H NMR (300 MHz, Acetone-d6) 5 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]+. 2021213758   13 Oct 2026 Synthesis of ((1s,3s)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3- yl)cyclobutyl)methanamine (S11)

[00199] To a solution of (1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclo-butane-1-carbonitrile C18 (3 g, 9 mmol) in anhydrous THF (45 mL) at 0 °C under an argon atmosphere was added lithium aluminum hydride (1.8 g, 48 mmol) in portions. The reaction was stirred at 0 °C for additional 10 min, slowly warmed to room temperature, and heated to 60 °C for 1 h. The reaction was then cooled to room temperature and quenched with aqueous sodium sulfate solution slowly. The mixture was filtered through a pad of Celite®, washed with ethyl acetate, and concentrated in vacuo. The residue was triturated with DCM to afford the product. ((1s,3s)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (3 g, 95 %). 1H NMR (400 MHz, DMSO- d6) 8 11.62 (s, 1H), 7.57 (dd, J = 8.5, 5.5 Hz, 2H), 7.46 (dd, J = 10.0, 2.2 Hz, 1H), 7.34 (t, J = 8.7 Hz, 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 S10                                                    S12 Preparation of 4-nitrophenyl (((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclo-butyl)methyl)carbamate (S12)

[00200] To a solution of bis(4-nitrophenyl) carbonate (2.2 g, 7.3 mmol) in DCM (40 mL) was added DIPEA (2 mL, 10 mmol) followed by a solution of ((1r,3r)-3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine S10 (1.89 g, 5.72 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h then diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product. (((1r,3r)-3-(5,7-Difluoro-2-(4-275 2021213758   13 Oct 2026 fluorophenyl)-1H-indol-3-yl)cyclobutyl)-methyl)carbamate (2.3 g, 81 %). LCMS m / z 496.22 [M+H]+. Preparation S13 C22 S13 Step 1. Synthesis of 3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutane-1-carbonitrile (C19)

[00201] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (200 mg, 0.81 mmol) and 3-oxocyclobutanecarbonitrile (100 mg, 1.1 mmol) in DCM (10 mL) was added Et3SiH (800 mg, 6.9 mmol), followed by trifluoroacetic acid (600 mg, 5.3 mmol). The mixture was stirred overnight and partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product. 2021213758   13 Oct 2026 3-(5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutane-1-carbonitrile (220 mg, 55 %). 1H NMR (300 MHz, DMSO-d6) 5 11.81 (s, 1H), 7.73 - 7.47 (m, 2H), 747 - 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)

[00202] To a suspension of Raney Ni (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 ammonia solution (400 mL, 7 M in methanol). The mixture was stirred at room temperature for 2 days under hydrogen atmosphere (60 psi). The mixture was filtered, and the filtrate was concentrated in vacuo to afford the product. (3-(5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methanamine (1.2 g, 77 %). 1H NMR (300 MHz, Methanol-d4) 5 6.25 (ddd, J = 8.6, 5.4, 2.7 Hz, 2H), 6.01 - 5.85 (m, 3H), 5.46 (ddd, J = 11.4, 9.7, 2.1 Hz, 1H), 2.52 (dq, J = 10.2, 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)

[00203] To a solution of (3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)-methanamine C20 (423 mg, 1.06 mmol) and ethyl chloroformate (0.135 mL, 1.41 mmol) in DCM (6 mL) was added Et3N (0.450 mL, 3.23 mmol). The reaction mixture was stirred at room temperature for 2 h then diluted with water. The aqueous layer was extracted with DCM, then the combined organics were washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (Gradient: 0 - 100 % EtOAc in hexanes) to afford the product. Ethyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-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-indol-3-yl)cyclobutyl)-N-methylmethanamine (C22)

[00204] To a solution of ethyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methyl)carbamate C21 (309 mg, 0.73 mmol) in THF (4 mL) at 0 °C was added LiAlH4 (1.3 mL, 2.99 mmol, 2.3 M in 2-methyltetrahydrofuran). The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with an 2021213758   13 Oct 2026 aqueous solution of Rochelle’s salt and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product. 1-(3-(5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-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-indol-3- yl)cyclobutyl)methyl)(methyl)carbamate (S13)

[00205] To a solution of bis(4-nitrophenyl) carbonate (308 mg, 1.01 mmol) in DCM (5 mL) was added Et3N (295 pL, 2.12 mmol) followed by a solution of 1-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-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 h then partitioned between water and EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product. 4-Nitrophenyl ((3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)methyl)(methyl)carbamate (266 mg, 62 %). LCMS m / z 510.24 [M+H]+. Preparation S14 Preparation of 3-(3-(bromomethyl)cyclobutyl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (S14)

[00206] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (380 mg, 1.5 mmol) in DCM (5 mL) was added 3-(bromomethyl)cyclobutanone (250 mg, 1.5 mmol), Et3SiH (900 mg, 7.7 mmol), and TFA (525 mg, 4.60 mmol). The reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was then diluted with EtOAc (~100 mL) and then washed with saturated aqueous NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered through Celite®, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 2021213758   13 Oct 2026 0-40 % EtOAc in hexanes) to afford 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 S15 Step 1. Synthesis of methyl 2-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)acetate (C23)

[00207] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (460 mg, 1.9 mmol) and methyl 2-(3-oxocyclobutyl)acetate (291 mg, 2.05 mmol) in DCE (5 mL) was added triethylsilane (1.2 mL, 7.5 mmol) followed by methanesulfonic acid (365 ^L, 5.63 mmol) at 70 °C. The mixture was heated at 70 °C for 2 h, and additional methyl 2-(3-oxocyclobutyl)acetate (291 mg, 2.05 mmol) was added. The mixture was stirred at 70 °C for additional 2 h. After cooling to room temperature, the mixture was diluted with DCM (80 mL) and washed with saturated aqueous sodium carbonate solution and brine. The organic layer was separated and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0-10 % EtOAc in hexanes) to afford the product. Methyl 2-(3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-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-indol-3-yl)cyclobutyl)acetic acid (S15) 2021213758   13 Oct 2026

[00208] To a solution of methyl 2-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutyl]acetate C23 (488 mg, 1.30 mmol) in THF (10 mL) was added saturated aqueous LiOH (5 mL). The mixture was then warmed to 50 °C and allowed to stir overnight. The mixture was then allowed to cool to ambient temperature and concentrated in vacuo. The resulting residue was then diluted with DCM (~ 50 mL) and acidified to pH 3 with 10 % HCl, and the aqueous layer was extracted with DCM (3 x 25 mL). The combined organic phase was washed with brine, dried with anhydrous MgSO4, filtered, and concentrated in vacuo to afford the product. 2-(3-(5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)cyclobutyl)acetic acid (508 mg, quantitative). 1H NMR (300 MHz, Chloroform-d) 8 8.05 (s, 1H), 7.57 - 7.39 (m, 2H), 7.29 - 7.16 (m, 4H), 6.87 - 6.64 (m, 1H), 3.86 - 3.72 (m, 2H), 2.80 - 2.47 (m, 3H), 2.06 (q, J = 10.8, 9.2 Hz, 1H), 1.88 (td, J = 5.7, 4.9, 3.1 Hz, 2H). LCMS m / z 360.19 [M+H]+. Preparation S16 Step 1. Synthesis of ethyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclopentanecarboxylate (C24)

[00209] To a solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C3 (501 mg, 1.89 mmol) and ethyl 3-oxocyclopentanecarboxylate (390 mg, 2.5 mmol) in DCE (8 mL) at 70 °C was added methanesulfonic acid (201 ^L, 3.10 mmol), triethylsilane (1 mL, 6 mmol). The mixture was heated to180 °C for 1 h. Then, additional ethyl 3- oxocyclopentanecarboxylate (390 mg, 2.5 mmol), methanesulfonic acid (201 ^L, 3.10 2021213758   13 Oct 2026 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 x 70 mL). Purification by silica gel chromatography (Gradient: 0100 % EtOAc in heptane) afforded the product. Ethyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclopentanecarboxylate (300 mg, 40 %). 1H NMR (300 MHz, Chloroform-d) 5 8.13 (s, 1H), 7.61 - 7.42 (m, 2H), 7.36 - 7.01 (m, 3H), 6.76 (ddd, J = 10.8, 9.4, 2.1 Hz, 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. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclopentanecarboxylic acid (S16)

[00210] A solution of ethyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-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 to 50 °C overnight. The mixture was concentrated in vacuo. Water (30 mL) was added to the residue, followed by HCl to adjust the pH to 1. The mixture was extracted with DCM (3 x 30 mL), and the combined organic phase was washed with brine and concentrated in vacuo to afford the product. 3-[5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclopentanecarboxylic acid (264 mg, 99 %). 1H NMR (300 MHz, Chloroform-d) 5 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]+. 2021213758   13 Oct 2026 Preparation S17 Step 1. Synthesis of benzyl 3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)azetidine-1-carboxylate (C25)

[00211] 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) was added Et3SiH (470 mg, 4.0 mmol), and TFA (310 mg, 2.71 mmol). The reaction mixture was allowed to stir overnight at ambient temperature and then concentrated in vacuo. The residue was dissolved in EtOAc (~50 mL) and washed with saturated aqueous NaHCO3. The organic layer was separated, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) to afford the product. Benzyl 3-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)azetidine-1-carboxylate (536 mg, 84 %). LCMS m / z 524.04 [M+H]+. Step 2. Synthesis of 3-(azetidin-3-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (S17)

[00212] A mixture of 10 wt % Pd / C (20 mg) in MeOH (10 mL) and benzyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]azetidine-1-carboxylate C25 (500 mg, 1.1 mmol) in MeOH (20 mL) was placed under an atmosphere of hydrogen. The resulting mixture was stirred at ambient temperature for 3 h. The mixture was filtered through Celite® and concentrated in vacuo. The residue was purified by reversed-phase 2021213758   13 Oct 2026 chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid) to afford the product. 3-(Azetidin-3-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (380 mg, 81 %). 1H NMR (300 MHz, Methanol-d4) 5 7.63 - 7.48 (m, 2H), 7.41 (dd, J = 9.5, 2.1 Hz, 1H), 7.37 - 7.18 (m, 2H), 6.85 (ddd, J = 11.0, 9.6, 2.1 Hz, 1H), 4.70 - 4.52 (m, 1H), 4.45 (dd, J = 11.0, 9.1 Hz, 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-indol-3-yl]cyclobutyl]amino]propanamide (287) Preparation of 3-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutyl]amino]propan-amide (287)

[00213] To a solution of 3-aminopropanamide (14 mg, 0.11 mmol) and 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]cyclobutanone S5 (30 mg, 0.1 mmol) in DMF (2.5 mL) was added triacetoxy(sodio)boron (24 mg, 0.11 mmol) followed by acetic acid (4 mg, 0.01 mmol) The mixture was allowed to stir at room temperature overnight. The reaction mixture was then filtered, and the fi...

Claims

1. A compound chosen from compounds of Formula (I):pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:(i)     Ring A is a 4- to 6-membered ring wherein the ring is a cyclic alkyl or aheterocycle;(ii) Q is N or CR5;(iii) each R1 is independently chosen from• halogen groups,• hydroxy,• thiol,• amino,• cyano,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic thioalkyl groups, and•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic haloalkyl groups;(iv) each R2 is independently chosen from• halogen groups,• hydroxy,• thiol,• amino, and• cyano;(v) m is chosen from 1, 2, and 3;2021213758   13 Oct 2026(vi) n is chosen from 1, 2, and 3;(vii) X is chosen from divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, wherein the divalent alkyl groups are optionally substituted with one to four groups independently chosen from:o      C1-C6 alkyl groups,o     halogen groups,o     hydroxy, ando     amino;(viii) Y is chosen from divalent amino, divalent oxygen, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkoxy groups, and divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic aminoalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, and divalent aminoalkyl groups are optionally substituted with one to three groups independently chosen fromo     C1-C6 alkyl groups optionally substituted with hydroxy,o      C3-C6 cyclic alkyl,o     halogen groups,o     hydroxy, ando     amino;(ix)    o is 0 or 1;(x)     p is 0 or 1;(xi)   R3 is chosen from:• hydrogen,•  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,•  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted witha C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle;•  C3-C6 cyclic alkyl groups optionally substituted with one to four groupsindependently chosen from:o halogen groups,o hydroxy,o oxo,o  C1-C6 linear and C3-C6 branched alkoxy groups,2021213758   13 Oct 2026o  C1-C6 linear and C3-C6 branched alkyl groups optionally substitutedwith one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando amido groups,• heterocyclic groups optionally substituted with one to four groups independently chosen from:o halogen groups,o oxo,o hydroxy, ando  C1-C6 linear and C3-C6 branched alkyl groups optionally substitutedwith one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and•  C1-C7 linear and C3-C7 branched alkyl groups, wherein the alkyl groups areoptionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy,o oxo,o cyano,o  carboxylic acid,o  halogen groups,o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,2021213758   13 Oct 2026o  C3-C6 cyclic alkyl groups optionally substituted with one or two groupsindependently chosen from halogen groups, C1-C6 linear and C3-C6 branched alkoxy groups, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy,o  C2-C6 linear and C3-C6 branched alkynyl groups,o  C2-C6 linear and C3-C6 branched alkoxy groups optionally substitutedwith at least one hydroxy,o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,o carbonyl-(4-methylpiperazin-1-yl),o carbonyl-(N-morpholino),o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and C3-C6 branched alkoxy groups, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and C3-C6 branched alkoxy groups;(xii)   R4 is chosen from:• hydrogen,•  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,•  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted witha C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle;2021213758   13 Oct 2026•  C3-C6 cyclic alkyl groups optionally substituted with one to four groupsindependently chosen from: o halogen groups, o  hydroxy,o oxo,o  C1-C6 linear and C3-C6 branched alkoxy groups,o  C1-C6 linear and C3-C6 branched alkyl groups optionally substitutedwith one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando amido groups,• heterocyclic groups optionally substituted with one to four groups independently chosen from:o halogen groups,o oxo,o hydroxy, ando  C1-C6 linear and C3-C6 branched alkyl groups optionally substitutedwith one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and•  C1-C7 linear and C3-C7 branched alkyl groups, wherein the alkyl groups aresubstituted with one to five groups independently chosen from:o amino groups,o hydroxy,o oxo,o cyano,o carboxylic acid,2021213758   13 Oct 2026o halogen groups,o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,o  C3-C6 cyclic alkyl groups optionally substituted with one or two groupsindependently chosen from halogen groups, C1-C6 linear and C3-C6 branched alkoxy groups, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy,o  C2-C6 linear and C3-C6 branched alkynyl groups,o  C2-C6 linear and C3-C6 branched alkoxy groups optionally substitutedwith at least one hydroxy,o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,o carbonyl-(4-methylpiperazin-1-yl),o carbonyl-(N-morpholino),o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and C3-C6 branched alkoxy groups, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and C3-C6 branched alkoxy groups,2021213758   13 Oct 2026or R3 and R4, 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 chosen from o hydroxy, o oxo,o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionallysubstituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkyl groups,o amide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o carboxamide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groupsoptionally substituted with one to four groups independently chosen from oxo, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, and heterocyclic groups,o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and(xiii) R5 is absent or is chosen from:2021213758   13 Oct 2026• hydrogen,• halogen groups,• hydroxy,• thiol,• amino, and•  C1-C6 linear and C3-C6 branched alkyl groups,wherein when R5 is absent, Q is a bridgehead atom.

2. A compound chosen from compounds of Formula (I):pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein(i)    Ring A is chosen from:(ii) Q is N or CR5;(iii) each R1 is independently chosen from• halogen groups,• hydroxy,• thiol,• amino,• cyano,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups,2021213758   13 Oct 2026•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic thioalkyl groups, and•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic haloalkyl groups;(iv) each R2 is independently chosen from• halogen groups,•  hydroxy,•   thiol,•  amino, and•  cyano;(v)    m is chosen from 1, 2, and 3;(vi) n is chosen from 1, 2, and 3;(vii) X is chosen from divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, wherein the divalent alkyl groups are optionally substituted with one to four groups independently chosen from:o  C1-C6 alkyl groups,o halogen groups, o hydroxy, and o amino;(viii) Y is chosen from divalent amino, divalent oxygen, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkyl groups, divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic alkoxy groups, and divalent C1-C8 linear, C3-C8 branched, and C3-C8 cyclic aminoalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, and divalent aminoalkyl groups are optionally substituted with one to three groups independently chosen fromo C1-C6 alkyl groups optionally substituted with hydroxy,o  C3-C6 cyclic alkyl,o halogen groups, o hydroxy, and o amino;(ix)    o is 0 or 1;(x)     p is 0 or 1;(xi)   R3 and R4 are independently chosen from:• hydrogen,2021213758   13 Oct 2026•  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,•  C1-C6 linear and C3-C6 branched alkoxy groups optionally substituted witha C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle;•  C3-C6 cyclic alkyl groups optionally substituted with one to four groupsindependently chosen from:o halogen groups,o hydroxy,o oxo,o  C1-C6 linear and C3-C6 branched alkoxy groups,o  C1-C6 linear and C3-C6 branched alkyl groups optionally substitutedwith one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando amido groups,• heterocyclic groups optionally substituted with one to four groups independently chosen from:o halogen groups,o oxo,o hydroxy, ando  C1-C6 linear and C3-C6 branched alkyl groups optionally substitutedwith one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and•  C1-C7 linear and C3-C7 branched alkyl groups, wherein the alkyl groups areoptionally substituted with one to five groups independently chosen from: o amino groups, o hydroxy,2021213758   13 Oct 2026o oxo,o cyano,o  carboxylic acid,o  halogen groups,o amido groups optionally substituted with one or two groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,o  C3-C6 cyclic alkyl groups optionally substituted with one or two groupsindependently chosen from halogen groups, C1-C6 linear and C3-C6 branched alkoxy groups, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy,o  C2-C6 linear and C3-C6 branched alkynyl groups,o  C2-C6 linear and C3-C6 branched alkoxy groups optionally substitutedwith at least one hydroxy,o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,o aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,o carbonyl-(4-methylpiperazin-1-yl),o carbonyl-(N-morpholino),o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C1-C6 linear and C3-C6 branched alkoxy groups, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted2021213758   13 Oct 2026with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and C3-C6 branched alkoxy groups;or R3 and R4, 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 chosen from• hydroxy,•  oxo,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substitutedwith one to four groups independently chosen from hydroxy, amino groups, C 1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkyl groups,• amide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,• carboxamide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups optionallysubstituted with one to four groups independently chosen from oxo, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, and heterocyclic groups,•  4- to 10-membered heterocyclyl groups optionally substituted with one or twogroups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and•  4- to 10-membered heteroaryl groups optionally substituted with one or two groupsindependently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and(xii)   R5 is hydrogen.

3. The compound, salt, or deuterated derivative according to claim 1 or claim 2,wherein Q is CR5.2021213758   13 Oct 20264.     The compound, salt, or deuterated derivative according to any one of claims 1-3,wherein each R1 is independently chosen from fluoro and CF3.

5. The compound, salt, or deuterated derivative according to any one of claims 1-4,wherein each R2 is fluoro.

6. The compound, salt, or deuterated derivative according to any one of claims 1-5,wherein m is 2.

7. The compound, salt, or deuterated derivative according to any one of claims 1-6,wherein n is 1.

8. The compound, salt, or deuterated derivative according to any one of claims 1-7,wherein X is chosen from -CH2- and -CH2-CH2-.

9. The compound, salt, or deuterated derivative according to any one of claims 1-8,wherein Y is chosen from, and10. The compound, salt, or deuterated derivative according to any one of claims 1-9, wherein R3 and R4, 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 chosen from:2021213758   13 Oct 2026o hydroxy,o oxo,o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionallysubstituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkyl groups,o amide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o carboxamide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groupsoptionally substituted with one to four groups independently chosen from oxo, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, and heterocyclic groups,o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups.

11. The compound, salt, or deuterated derivative according to any one of claims 1-10, wherein R5 is independently chosen from hydrogen, fluoro, and methyl.2021213758   13 Oct 202612. The compound, salt, or deuterated derivative according to claim 2, wherein the compound is selected from compounds of Formula (V-a) and (V-b):(V-b),pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

13. A compound chosen from compounds of Formula (IIIa)compounds of Formula (IIIb):pharmaceutically acceptable salts of any of the foregoing, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:(i)     each R1 is independently chosen from:• halogen groups,2021213758   13 Oct 2026• hydroxy,• thiol,• amino,• cyano,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups,•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic thioalkyl groups, and•  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic haloalkyl groups,(ii)    each R2 is independently chosen from:• halogen groups,• hydroxy,• thiol,• amino, and• cyano,(iii) m is chosen from 0, 1, 2, and 3;(iv) n is chosen from 0, 1, 2, and 3;(v)    R3 and R4 are independently chosen from:• hydrogen,• C1-C6 linear and C3-C6 branched alkylsulfonyl groups,• C3-C6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and amido groups,• heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups2021213758   13 Oct 2026optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and•  C1-C6 linear and C3-C6 branched alkyl groups, wherein the alkyl groups areoptionally substituted with at least one group chosen from:o amino groups,o hydroxy,o cyano,o  carboxylic acid,o  halogen groups,o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,o  C3-C6 cyclic alkyl groups optionally substituted with one or two groupschosen from halogen groups and hydroxy,o  C1-C6 linear and C3-C6 branched alkynyl groups,o  C1-C6 linear and C3-C6 branched alkoxy groups optionally substitutedwith at least one hydroxy,o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,o carbonyl-(4-methylpiperazin-1-yl),o carbonyl-(N-morpholino),o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and2021213758   13 Oct 2026o 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,or R3 and R4, 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 chosen from:o hydroxy,o oxo,o C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups,o amide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and heterocyclic groups, o 4- to 10-membered heterocyclyl groups optionally substituted with oneor two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and(vi) each R5 is independently chosen from2021213758   13 Oct 2026• hydrogen,• halogen groups,• hydroxy,• thiol,• amino, and•  C1-C6 linear and C3-C6 branched alkyl groups.

14. A compound chosen from compounds of Formula (IV):(IV)pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:(i)     each R1 and R2 is independently chosen from:•  fluoro,•  chloro,•  bromo,•  cyano,•  methyl,•  cyclopropyl,•   ethyl,•  isopropyl,• propen-2-yl, and•  methoxy;(ii)    R3 and R4 are independently chosen from:• hydrogen,•  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,2021213758   13 Oct 2026•  C3-C6 cyclic alkyl groups optionally substituted with at least one groupchosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, and amido groups,• heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,• heteroaryl groups optionally substituted with at least one group chosen from C1-C6 linear alkyl groups, and•  C1-C6 linear and C3-C6 branched alkyl groups, wherein the alkyl groups areoptionally substituted with at least one group chosen from: o amino groups, o hydroxy, o cyano,o  carboxylic acid,o  halogen groups,o amido groups optionally substituted with one or two groups chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,o  C3-C6 cyclic alkyl groups optionally substituted with one or two groupschosen from halogen groups and hydroxy,o  C1-C6 linear and C3-C6 branched alkynyl groups,o  C1-C6 linear and C3-C6 branched alkoxy groups optionally substitutedwith at least one hydroxy,o  C1-C6 linear and C3-C6 branched alkylsulfonyl groups,2021213758   13 Oct 2026o aryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,o carbonyl-(4-methylpiperazin-1-yl),o carbonyl-(N-morpholino),o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups,or R3 and R4, 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 chosen fromo hydroxy,o oxo,o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionallysubstituted with at least one groups chosen from hydroxy, amino groups, C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groups,o amide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o carboxamide groups optionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,o  C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkoxy groupsoptionally substituted with at least one group chosen from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and heterocyclic groups,2021213758   13 Oct 2026o 4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups, ando 4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C1-C6 linear and C3-C6 branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C1-C6 linear and C3-C6 branched alkoxy groups; and(iii) each R5 is independently chosen from:• hydrogen,• halogen groups,• hydroxy,• thiol,• amino, and•  C1-C6 linear and C3-C6 branched alkyl groups.

15. A compound chosen from3922021213758   13 Oct 20263933943953963973983994004024032021213758   13 Oct 20264042021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 2026431                       432                       433434                       435                       436437                       438                       4392021213758   13 Oct 20262021213758   13 Oct 20262021213758   13 Oct 2026pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

16. A pharmaceutical composition comprising the compound, salt, or deuterated derivative according to any one of claims 1-15 and a pharmaceutically acceptable carrier.

17. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, salt, or deuterated derivative according to any one of claims 1-15 or the pharmaceutical composition according to claim 16.

18. The method according to claim 17, wherein the APOL1 mediated kidney disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

19. The method according to claim 17, wherein the APOL1 mediated kidney disease is associated with APOL1 genetic alleles chosen from homozygous G1: S342G:I384M and homozygous G2: N388del:Y389del.2021213758   13 Oct 202620. The method according to claim 17, wherein the APOL1 mediated kidney disease is associated with compound heterozygous G1: S342G:I384M and G2: N388del:Y389del APOL1 genetic alleles.

21. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, salt, or deuterated derivative according to any one of claims 1-15 or the pharmaceutical composition according to claim 16.

22. Use of the compound, salt, or deuterated derivative according to any one of claims 1-15 in the manufacture of a medicament for treating APOL1 mediated kidney disease.

23. The use according to claim 22, wherein the APOL1 mediated kidney disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

24. The use according to claim 22, wherein the APOL1 mediated kidney disease is associated with APOL1 genetic alleles chosen from homozygous G1: S342G:I384M and homozygous G2: N388del:Y389del.

25. The use according to claim 22, wherein the APOL1 mediated kidney disease is associated with compound heterozygous G1: S342G:I384M and G2: N388del:Y389del APOL1 genetic alleles.

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