Apol1 inhibitors and methods of use

Abstract

Provided herein are compounds of formula (I'): or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein X1, X2, X3, X4, R1, R2, Y1, Y2, Y3, m,p, r, s, t, and ring A are as defined herein. Also provided are methods of preparing compounds of formula (I), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing. Also provided are methods of inhibiting AP0L1 and methods of treating an AP0L1 -mediated disease, disorder, or condition, such as kidney disease or diabetic retinopathy, in an individual.

Description

Docket No.: 79275-20027.40 APOL1 INHIBITORS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 527,216 filed on July 17, 2023, which is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] The disclosure generally relates to APOL1 inhibitors and methods of preparing the same. The disclosure also generally relates to methods of inhibiting APOL1 and methods of treating an APOL1-mediated disease, disorder, or condition in an individual. BACKGROUND OF THE INVENTION

[0003] Apolipoprotein L1 (APOL1) is a pore forming innate immunity factor, protecting individuals from trypanosome parasites (Vanhamme, L. et al. Nature (2003) 422, 83–87). The secreted form of APOL1 circulates in blood as part of distinct high-density lipoprotein (HDL) complexes, known as trypanosome lytic factors (TLFs) (Rifkin, M. R. Proc. Natl. Acad. Sci. USA. (1978) 75, 3450–3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910–1916). TLFs are internalized by the parasites through endocytosis (Hager, K. M. et al. J. Cell Biol. (1994) 126, 155–167). Within trypanosomes, APOL1 forms cation pores, causing ion flux, swelling, and eventual lysis (Rifkin, M. R. Exp. Parasitol. (1984) 58, 81–93; Molina-Portela, M. P. et al. Mol. Biochem. Parasitol. (2005) 144, 218–226; Pérez-Morga, D. et al. Science. (2005) 309, 469–472; Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA. (2015) 112, 2894–2899). APOL1 is secreted from the liver as part of an HDL particle that is taken up by T. brucei where it forms a pore that results in lysis of the parasite (Rifkin, M. R. Proc. Natl. Acad. Sci. USA. (1978) 75, 3450-3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910-1916). APOL1 is also expressed in other cell types throughout the body, including endothelial cells and podocytes, where it can be induced by various inflammatory cytokines (Nystrom et al. JAK inhibitor blocks COVID-19 cytokine-induced JAK / STAT / APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022 Jun 8;7(11): e157432). APOL1 expressed in cell types outside of liver is thought to be largely intracellular (Cheng et al, J Lipid Res. 2015 1sf-5953625Docket No.: 79275-20027.40 Aug;56(8):1583-93. doi: 10.1194 / jlr.M059733; Shukha et al, J Am Soc Nephrol. 2017 Apr; 28(4): 1079–1083).

[0004] Several Trypanosoma brucei subspecies (T.b. rhodesiense and T.b. gambiense) developed resistance mechanisms to APOL1-dependent killing (Pays, E. et al. Nat. Rev. Microbiol. (2014) 12, 575–584). Positive selection resulted in APOL1 variants, G1 (S342G, I384M) and G2 (N388∆, Y389∆), capable of interfering with these resistance mechanisms (Genovese, G. et al. Science. (2010) 329, 841–845). However, individuals with any binary combination of these variants (G1 / G1, G2 / G2, or G1 / G2), have a greater risk of developing a variety of chronic kidney diseases, including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN) (Genovese, G. et al. Science. (2010) 329, 841–845; Tzur, S. et al. Hum. Genet. (2010) 128, 345-350; Kopp, J. B. et al. J. Am. Soc. Nephrol. (2011) 22, 2129–2137), sickle cell nephropathy (Ashley-Koch, A. E. et al. Br. J. Haematol. (2011) 155, 386–394), lupus nephritis (Freedman, B. I. et al. Arthritis Rheumatol. (2014) 66, 390–396), and an increased rate of Glomerular Filtration Rate (GFR) decline in diabetic kidney disease (Parsa, A. et al. N. Engl. J. Med. (2013) 369, 2183–2196). The APOL1 high-risk genotype has also been associated with COVID-19 associated nephropathy and other viral nephropathies (Shetty, A. et al. J. Am. Soc. Nephrol. (2021) 32, 33–40; Chang, J. H. et al. Am. J. Kidney Dis. (2019) 73, 134–139). Moreover, decreased renal allograft survival has been observed after deceased-donor kidney transplantations from APOL1 high-risk genotype donors (Freedman, B. I. et al. Transplantation. (2016) 100, 194–202). In addition, having two APOL1 risk alleles increases risk for preeclampsia (Reidy, K. J. et al. Am. J. Hum. Genet. (2018) 103, 367–376) and sepsis (Chaudhary, N. S. et al. Clin. J. Am. Soc. Nephrol. (2019) 14, 1733–1740). These variants are predominantly found in individuals of West African descent and partially explain the substantially increased risk of end-stage kidney disease in this population (Genovese, G. et al. Science. (2010) 329, 841-845; Tzur, S. et al. Hum. Genet. (2010) 128, 345-350). These data provided the first evidence that dysregulation of APOL1 activity may cause disease. APOL1 induced kidney disease is thought to be due to pathological effects of intracellular APOL1, likely converging on APOL1 pore formation inside the cell. There are no approved therapies for APOL1-associated nephropathy, and patients are treated based on the standard of care for their 2sf-5953625Docket No.: 79275-20027.40 underlying form of chronic kidney disease. This presents a clear unmet need for therapies targeted to people with the APOL1 high-risk genotype.

[0005] Numerous studies have shown that APOL1 risk variants are toxic when overexpressed in human cells (Wan, G. et al. J. Biol. Chem. (2008) 283, 21540–21549; Lan, X. et al. Am. J. Physiol. Renal Physiol. (2014) 307, F326–F336; Olabisi, O. A. et al. Proc. Natl. Acad. Sci. USA. (2016) 113, 830–837; Ma, L. et al. J. Am. Soc. Nephrol. (2017) 28, 1093–1105; Lannon, H. et al. Kidney Int. (2019) 96, 1303–1307). Recent findings suggest that this toxicity is associated with APOL1 pore function (Giovinazzo, J. A. et al. eLife. (2020) 9, e51185). Thus, there is a need to develop compounds suitable for inhibiting APOL1 activity and methods for inhibiting the activity of APOL1 using such compounds.

[0006] Diabetic retinopathy (DR) is a common complication of diabetes and a frequent cause of blindness in this population. Approximately 35% of diabetic patients have some form of retinopathy, which is characterized by retinal microaneurysms, occlusions and neovascularization with attendant loss in visual acuity. Approximately 20% of patients with DR have macular edema (DME) which is a result of fluid leak from the capillary beds into the retina and is associated with more advanced eye disease, including severe vision loss or blindness (Yau, J.W. et al, Meta-Analysis for Eye Disease Study G: Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556-564). The pathophysiology of retinal microvascular disease in the context of diabetes is complex, but has been associated with higher levels of inflammation, and inflammatory cytokines in the eye (Mason, R.H. et al, Changes in aqueous and vitreous inflammatory cytokine levels in proliferative diabetic retinopathy: a systematic review and meta-analysis. Eye 2022 Jun 7, doi: https: / / doi.org / 10.1038 / s41433-022- 02127-x). A locus containing the gene for APOL1 has been reported as a risk factor for DME based on a genetic analysis that provided evidence that an APOL1 missense variant is associated with increased risk for DME (Stockwell, A.D. et al, Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights APOL1 as a high-risk locus in patients with diabetic macular edema. PLoS Genetics 19(8) (2023): e1010609).

[0007] There are currently no APOL1-targeted therapies for treating eye diseases such as DR and DME. There remains a need for therapies to treat these conditions. 3sf-5953625Docket No.: 79275-20027.40 BRIEF SUMMARY OF THE INVENTION

[0008] This disclosure describes compounds and compositions that may be useful for the treatment of APOL1-mediated diseases, including a variety of chronic kidney diseases such as FSGS, hypertension-attributed kidney disease, HIVAN, sickle cell nephropathy, lupus nephritis, diabetic kidney disease, viral nephropathy, COVID-19 associated nephropathy, and APOL1- associated nephropathy. The compounds and compositions may treat other APOL1-mediated disorders such as preeclampsia and sepsis. Additionally, for individuals with the APOL1 high- risk genotype, the disclosed compounds and may prevent the onset of non-diabetic renal disease and / or delaying the progression of any form of chronic kidney disease. The disclosed chemical matter may also prevent and / or delay progressive renal allograft loss in patients who have received a kidney transplant from a high-risk APOL1 genotype donor.

[0009] In some embodiments, the APOL1 mediated disease, disorder, or condition is selected from the group consisting of chronic kidney disease (including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle cell nephropathy, lupus nephritis, diabetic kidney disease, viral nephropathy, COVID-19 associated nephropathy, and APOL1-associated nephropathy), preeclampsia, sepsis, non-diabetic renal disease, progressive renal allograft loss in a kidney transplant recipient, diabetic retinopathies (including non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema), proteinuria, albuminuria, and kidney failure.

[0010] This disclosure also describes methods for treating diabetic retinopathies including non- proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema comprising administration of an APOL1 inhibitor or composition comprising an APOL1 inhibitor. Additionally, the disclosed methods may prevent the onset of diabetic retinopathies and / or delay the progression of diabetic retinopathies. The APOL1 inhibitor may be administered as a single agent or in combination with other agents including, e.g., anti-VEGF agents, Angiopoietin 2 blocking agents, dual VEGF-Angiopoietin 2 blocking agents, corticosteroids, and / or laser therapy.

[0011] A genetic link between a missense variant in APOL1 and DME has been established (Stockwell, A.D. et al, Multi-ancestry GWAS analysis identifies two novel loci associated with 4sf-5953625Docket No.: 79275-20027.40 diabetic eye disease and highlights APOL1 as a high-risk locus in patients with diabetic macular edema. PLoS Genetics 19(8) (2023): e1010609; herein incorporated by reference in its entirety). This variant contains glutamic acid instead of lysine at position 150 (E150 APOL1). E150 APOL1 has been shown to enhance the cytotoxic effects of APOL1 when overexpressed (Lannon et al, Apolipoprotein L1 (APOL1) risk variant toxicity depends on the haplotype background. Kidney International (2019) 96, 1303–1307; herein incorporated by reference in its entirety) and may explain the association of this APOL1 variant with diseases of the eye. APOL1 has been shown to be expressed in various cell types in the eye including endothelial cells and fibroblasts (Gautam et al. Multi-species single-cell transcriptomic analysis of ocular compartment regulons. Nat Commun. 2021 Sep 28;12(1):5675; herein incorporated by reference in its entirety).

[0012] DME and DR are associated with higher levels of inflammation and inflammatory cytokines in the eye (Mason, R.H. et al, Changes in aqueous and vitreous inflammatory cytokine levels in proliferative diabetic retinopathy: a systematic review and meta-analysis. Eye 2022 Jun 7, doi: https: / / doi.org / 10.1038 / s41433-022-02127-x; herein incorporated by reference in its entirety). Inflammatory cytokines like interferons, IL-1β and TNF-α are known inducers of APOL1 in endothelial cells (Nichols et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015 Feb;87(2):332-42; Nystrom et al. JAK inhibitor blocks COVID-19 cytokine-induced JAK / STAT / APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022 Jun 8;7(11):e157432; each herein incorporated by reference in its entirety). Interferon therapy can lead to retinopathy and macular edema, through mechanisms that remain unclear (Tokai et al. Interferon-associated retinopathy and cystoid macular edema. Arch Ophthalmol. 2001 Jul;119(7):1077-9; Zubir et al. Interferon-α- induced retinopathy in chronic hepatitis C treatment: summary, considerations, and recommendations. Graefes Arch Clin Exp Ophthalmol. 2019 Mar;257(3):447-452; each herein incorporated by reference in its entirety). Since interferon is a potent inducer of APOL1, it is plausible that these ocular effects could be driven through interferon mediated induction of APOL1 in eye tissues. In support of this concept, endothelial specific APOL1 expression has been reported to cause vascular leak in mouse models, consistent with the vascular leak seen in DR and DME (Wu et al, APOL1 risk variants in individuals of African genetic ancestry drivesf-5953625Docket No.: 79275-20027.40 endothelial cell defects that exacerbate sepsis. Immunity. 2021 Nov 9; 54(11): 2632–2649.e6; herein incorporated by reference in its entirety).

[0013] A cytotoxic APOL1 variant (E150 APOL1) is genetically associated with diabetic eye disease, and the overexpression of this variant drives toxicity in cellular models. APOL1 is expressed in the eye in cell types known to be relevant to the pathophysiology of diabetic eye disease including endothelial cells. Therapeutic use of interferon, which induces APOL1 expression in endothelial cells, is also associated with ocular side effects including retinopathy and macular edema. APOL1 induction in mouse models results in vascular leak, consistent with the role of vascular leak in diabetic eye diseases. APOL1 pore blockers have been shown to protect cells from cytotoxicity associated with kidney disease associated variants. Therefore, APOL1 inhibitors as disclosed herein may be therapeutically beneficial in patients with or at risk of developing DME or DR. Moreover, the APOL1 inhibitors as disclosed herein may be administered by a variety of routes including, e.g., oral administration.

[0014] In one aspect, provided provided is a compound of formula (I’):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: either: (1) Y1is CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; 6sf-5953625Docket No.: 79275-20027.40 Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule; and s and t are both 0 or 1, wherein when r is 1, both s and t are 1; or (2) Y1is a bond; Y2is -C(O)-; Y3is -NH-; and s and t are each 1; X1, X2, X3, and X4are each independently -CH- or -N-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2-, -O-, or ###-CH2O- ####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; p is an integer from 0 to 8;L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy;sf-5953625Docket No.: 79275-20027.40 L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0015] In one aspect, provided is a compound of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, or -O-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond; 8sf-5953625Docket No.: 79275-20027.40 R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; p is an integer from 0 to 8; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0016] In one aspect, provided herein is a compound of formula (I-A1):9sf-5953625Docket No.: 79275-20027.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, L2, and Ring A are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0017] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A1a):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, and L2are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0018] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A2):10sf-5953625Docket No.: 79275-20027.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, L2, and Ring A are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0019] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A2a):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, and L2are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0020] In some embodiments, the compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I’-A3):11sf-5953625Docket No.: 79275-20027.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1, X2, X3, X4, R1, m, L1, L2, and Ring A are as defined elsewhere herein.

[0021] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A3a):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, and L2are as defined elsewhere herein.

[0022] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, L2, and Ring A are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. 12sf-5953625Docket No.: 79275-20027.40

[0023] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A3a):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, and L2are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0024] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A4):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, L2, and Ring A are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.sf-5953625Docket No.: 79275-20027.40

[0025] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A4a):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, and L2are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0026] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A5):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, L2, and Ring A are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. 14sf-5953625Docket No.: 79275-20027.40

[0027] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A5a):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, and L2are as defined elsewhere herein. In another variation, m, R1, L1, L2, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0028] In some embodiments, the compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I’-A6):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, L2, and Ring A are as defined elsewhere herein.sf-5953625Docket No.: 79275-20027.40

[0029] In some embodiments, the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A6a):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, m, L1, and L2are as defined elsewhere herein.

[0030] In one aspect, provided herein is a compound of formula (I'-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1, X2, X3, X4, R1, R2, Y1, Y2, Y3, m, p, r, s, and t are as defined elsewhere herein, and Ring A is a 9-10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0031] In one aspect, provided herein is a compound of formula (I-B): 16sf-5953625Docket No.: 79275-20027.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, R2, Y1, Y2, Y3, m, p, and r are as defined elsewhere herein, and Ring A is a 9-10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3- 5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or - OH.

[0032] In one aspect, provided herein is a compound of formula (I’-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, wherein X1, X2, X3, X4, R1, R2, Y1, Y2, Y3, m, p, r, s, and t are as defined elsewhereherein.

[0033] In one aspect, provided herein is a compound of formula (I-C):sf-5953625Docket No.: 79275-20027.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, R2, Y1, Y2, Y3, m, p, and r are as defined elsewhere herein. In another variation, R1, R2, Y1, Y2, Y3, m, p, and r are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0034] In one aspect, provided herein is a pharmaceutical composition, comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I- A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’- B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0035] In one aspect, provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I- A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I- A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I- A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 18sf-5953625Docket No.: 79275-20027.40

[0036] In one aspect, provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’- A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients.

[0037] In one aspect, provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I- A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I- A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I- A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0038] In one aspect, provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’- A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I’), or any embodiment or variation thereof, such as a compound of 19sf-5953625Docket No.: 79275-20027.40 formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients.

[0039] In one aspect, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0040] In one aspect, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I- A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’- B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients.sf-5953625Docket No.: 79275-20027.40

[0041] In one aspect, provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I- A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’- A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0042] In one aspect, provided herein is a method of treating diabetic retinopathy in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, such as a compound of formula (I-A1), (I-A1a), (I- A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I- A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I- A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0043] In one aspect, provided herein is a method of preventing and / or delaying the development of diabetic retinopathy in an individual in need thereof, comprising administeringsf-5953625Docket No.: 79275-20027.40 to the individual a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I- A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a method of delaying the development of diabetic retinopathy in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I- A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0044] In one aspect, provided herein is a kit, comprising (1) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I- A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I- A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-5953625Docket No.: 79275-20027.40

[0045] In some aspect, provided herein are methods of preparing a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I- A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0046] All pharmaceutical compositions, methods, kits, uses, or other aspects described herein with reference to formula (I) or (I’), or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein such as formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I- A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), the same as if each and every embodiment were specifically and individually listed. BRIEF DESCRIPTION OF THE FIGURES

[0047] FIG. 1 shows the results of an APOL1 E150 G2 mouse transgenic model to validate acute effects of interferon on APOL1 expression in eye retinal tissue.

[0048] FIG. 2 shows the results of an APOL1 E150 G2 mouse transgenic model to validate chronic effects of interferon on APOL1 expression in eye tissue. DETAILED DESCRIPTION OF THE INVENTION

[0049] Unless clearly indicated otherwise, the terms “a,” “an,” and the like, refer to one or more.

[0050] As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

[0051] “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, some primates and humans. In some embodiments, individual refers to a human.sf-5953625Docket No.: 79275-20027.40

[0052] As used herein, an “at risk” individual is an individual who is at risk of developing a disease or condition. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).

[0053] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0054] As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and / or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

[0055] As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.sf-5953625Docket No.: 79275-20027.40

[0056] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.

[0057] As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

[0058] The term “alkyl”, as used herein, refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C1-20alkyl), 1-16 carbons (i.e., C1-16alkyl), 1-12 carbons (i.e., C1-12alkyl), 1-10 carbons (i.e., C1-10alkyl), 1-8 carbons (i.e., C1-8alkyl), 1-6 carbons (i.e., C1-6alkyl), 1-4 carbons (i.e., C1-4alkyl), or 1-3 carbons (i.e., C1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n- butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3- hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso-propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”.

[0059] The term “alkoxy”, as used herein, refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert- butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0060] The term “aryl”, as used herein, refers to an aromatic carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C6-20aryl), 6 to 16 annular carbon atoms (i.e., C6-16aryl), 6 to 12 annular carbon atoms (i.e., C6-12aryl), or 6 to 10 annular carbon atoms (i.e., C6-10aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.sf-5953625Docket No.: 79275-20027.40

[0061] The term “cycloalkyl”, as used herein, refers to a non-aromatic carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C3-8cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C3-6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7- dimethyl -bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.

[0062] The term “halo”, as used herein, refers to atoms occupying group VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-C4 haloalkyl” is mean to include trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[0063] The term “heteroaryl”, as used herein, refers to an aromatic ring moiety having one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl may have, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety having one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of thesf-5953625Docket No.: 79275-20027.40 molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, benzo[d][1,2,3]triazolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of the fused- heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5- a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring (whether a single or multiple fused rings) containing at least one heteroatom is considered a heteroaryl regardless of the attachment to the remainder of the molecule (including through any one of the fused rings). “Heteroaryl” does not encompass or overlap with “aryl” as defined above.

[0064] The term “heterocyclyl”, as used herein, refers to a non-aromatic cyclic moiety that has one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non- aromatic monocyclic or polycyclic ring moiety having at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety having at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the aromatic moiety or through any annular carbon or any annularsf-5953625Docket No.: 79275-20027.40 heteroatom of the non-aromatic moiety). As used herein, a heterocyclyl may have, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, and thiamorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl, and 6- azaspiro[2.5]octanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, isoindolinyl, and azabicyclo[3.1.0]hexanyl, where the heterocyclyl can be bound via either ring of the fused system.

[0065] The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses -CH3, -CH2Cl, - CHCl2, and -CCl3 moieties.sf-5953625Docket No.: 79275-20027.40

[0066] It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.

[0067] The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Such compositions are well known in the pharmaceutical art. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl), amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0068] Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atomssf-5953625Docket No.: 79275-20027.40 are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. In some embodiments, a compound of formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

[0069] Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.

[0070] Also provided herein are prodrugs of the compounds depicted herein, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vivo to release the parent drug compound. The development of prodrug compounds is well known in the pharmaceutical art. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat. Rev. Drug. Discov. 7, 255–270 (2008), which is incorporated herein by reference.

[0071] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example,sf-5953625Docket No.: 79275-20027.40 chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

[0072] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each othemr.

[0073] Where a given structure has potential for cis and trans configuration, and the composition is made up of at least 90%, by weight, dashes or wedges indicate known cis or trans configuration, e.g.,.

[0074] Where enantiomeric and / or diastereomeric forms exist of a given structure, and the composition is made up of at least 90%, by weight, flat bonds and the presence of an astrisk (*) indicates a single stereogenic center with unknown stereochemistry, e.g.,sf-5953625Docket No.: 79275-20027.40.

[0075] Where a given structure has the potential for enantiomeric forms and / or diastereomeric forms, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,

[0076] Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd, hereby incorporated herein by reference in its entirety. The following examples are intended to be illustrative only and not limiting in any way. °C degrees Celsius DME dimethoxyethane μL microliter DMF N,N-dimethylformamide [M+XX]+observed mass DMSO dimethylsulfoxide AC50 half-maximal activity DPPF 1,1'- concentration bis(diphenylphosphino)ferro BF3·Et2O borontrifluoride diethyl cene etherate EC50half-maximal effective Calc’d calculated concentration CO carbon monoxide EtOAc ethyl acetate CO2 carbon dioxide EtOH Ethanol Cs2CO3cesium carbonate Fe iron d deuterated (NMR solvents) g grams d doublet (NMR) h hours dd doublet of doublets (NMR) H hydrogen DAST diethylaminosulfur H2O water trifluoride H2O2hydrogen peroxide DDQ 2,3-dichloro-5,6-dicyano- H2SO4sulfuric acid 1,4-benzoquinone HCl hydrochloric acid DCE 1,2-dichloroethane HPLC high-performance liquid DCM dichloromethane chromatography DIEA N,N-diisopropylethylamine I2iodine DMA dimethylacetamide In vacuo in a vacuumsf-5953625Docket No.: 79275-20027.40 i-PrOH isopropanol NH4HCO3 ammonium bicarbonate IUPAC International Union of Pure Na2CO3 sodium carbonate and Applied Chemistry Na2SO3 sodium sulfite J-coupling value (NMR) Na2SO4sodium sulfate potassium carbonate NaHCO3sodium bicarbonate potassium acetate NMR nuclear magnetic resonance potassium osmate (VI) NaIO4 sodium periodate dihydrate NaOH sodium hydroxidelithium Pd(dppf)Cl2[1,1′- bis(trimethylsilyl)amide bis(diphenylphosphino)ferro MeOH methanol cene]dichloropalladium(II) MeCN acetonitrile Pd(OAc)2 palladium (II) acetate MHz megahertz s singlet (NMR) m multiplet (NMR) SFC super fluid chromatography mg milligrams SiO2Silica dioxide min minutes t triplet (NMR) mL milliliter TBAF tetrabutylammonium mmol millimole fluoride mM millimolar TEA triethylamine M molarity or molar TFA trifluoroacetic acid MS mass spectrometry THF tetrahydrofuran MTBE methyl tert-butyl ether TMSCN trimethylsilyl cyanide n / a not applicable TLC thin layer chromatography NaH sodium hydride TsOH•H2O p-toluenesulfonic acid NBS N-bromosuccinimide monohydrate NCS N-chlorosuccinimide Zn zinc NH4Cl Ammonium chloride Zn(CN)2 zinc cyanide COMPOUNDS

[0077] Provided herein is a compound of formula (I’):sf-5953625Docket No.: 79275-20027.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: either: (1) Y1is CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule; and s and t are both 0 or 1, wherein when r is 1, both s and t are 1; or (2) Y1is a bond; Y2is -C(O)-; Y3is -NH-; and s and t are each 1; X1, X2, X3, and X4are each independently -CH- or -N-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2-, -O-, or ###-CH2O- ####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl;sf-5953625Docket No.: 79275-20027.40 m is an integer from 0 to 4; p is an integer from 0 to 8; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0078] Provided herein is a compound of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-;sf-5953625Docket No.: 79275-20027.40 Y3is a bond, -CH2-, or -O-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; p is an integer from 0 to 8; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0079] Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. Any embodiments provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound ofsf-5953625Docket No.: 79275-20027.40 formula formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0080] Any embodiments provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. Thus, it is understood and described that each embodiment provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to X1, X2, X3, X4, R1, R2, Y1, Y2,r, s, t, and ring A apply to formula (I’), the same as if each and every embodiment were specifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein. And, each embodiment provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to X1, X2, X3, X4, R1, R2, Y1, Y2,r, s, t, and ring A also apply to formula formula (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula

[0081] In some embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing: Y1is CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule; and s and t are both 0 or 1, wherein when r is 1, both s and t are 1.sf-5953625Docket No.: 79275-20027.40

[0082] In some embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing: Y1is a bond; Y2is -C(O)-; Y3is -NH-; and s and t are each 1.

[0083] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -CH2-. In some embodiments, Y1is -N(Ry)-. In some embodiments, Y1is -N(Ry)-, wherein Ryis H. In some embodiments, Y1is -N(Ry)-, wherein Ryis C1-6alkyl optionally substituted with one or more D, halo, or -OH. In some embodiments, Y1is -N(Ry)-, wherein Ryis C2-6alkynyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis C3-10cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis C3-6cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis C6-10cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis 3-6 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis 6-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-sf-5953625Docket No.: 79275-20027.40 A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0084] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y2is -CH(OH)-, -C(O)-, -S(O)2-, or - O-. In some embodiments, Y2is -CH(OH)-. In some embodiments, Y2is -C(O)-. Y2is -S(O)2-. In some embodiments, Y2is -O-. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I- A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0085] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y3is a bond, -CH2-, or -O-. In some embodiments, Y3is a bond. In some embodiments, Y3is -CH2-. In some embodiments, Y3is - O-. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I- A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’- B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0086] In some embodiments of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule. In some embodiments, Y3is a bond. In some embodiments, Y3is -CH2-. In some embodiments, Y3is -O-. In some embodiments, Y3is ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule.sf-5953625Docket No.: 79275-20027.40

[0087] In some embodiments of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, s and t are both 0 or 1, wherein when r is 1, both s and t are 1. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, s and t are both 0. In some embodiments, s and t are both 1. In some embodiments, r is 1 and both s and t are 1.

[0088] In some embodiments of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is a bond. In some embodiments, Y1is a bond, Y2is - C(O)-, Y3is -NH-, and s and t are each 1.

[0089] In some embodiments of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X1, X2, X3, and X4are each independently -CH- or -N-. In some embodiments, one of X1, X2, X3, and X4is -N- and the others of X1, X2, X3, and X4are each -CH-. In some embodiments, X1is -N- and X2, X3, and X4are each -CH-.

[0090] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, r is 0 or 1, provided that (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond. In some embodiments, r is 0. In some embodiments, r is 1. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I- A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0091] In some embodiments of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), 40sf-5953625Docket No.: 79275-20027.40 (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, r is 0 or 1, provided that (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule and (2) when r is 1, then Y3is a bond. In some embodiments, r is 0. In some embodiments, r is 1.

[0092] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo halo. In some embodiments, R1is, independently at each occurrence, halo. In some embodiments, R1is, independently at each occurrence, chloro. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0093] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is C1-6alkyl. In some embodiments, R2is C1-3alkyl. In some embodiments, R2is methyl or ethyl. In some embodiments, R2is methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I- A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’- B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0094] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a 41sf-5953625Docket No.: 79275-20027.40 pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments m is 1. In some embodiments, m is 2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing..

[0095] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is an integer from 0 to 8. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’- A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0096] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is C1-3alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is methylene or ethylene, each independently optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is methylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is ethylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is unsubstituted C1- 42sf-5953625Docket No.: 79275-20027.40 6alkylene. In some embodiments, L1is unsubstituted C1-6alkylene. In some embodiments, L1is unsubstituted C1-3alkylene. In some embodimemts, L1is unsubstituted ethylene. In some embodiments, L1is unsubstituted methylene. In some embodiments, L1is , wherein # denotes the point of attachment to L2and ## denotes the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I- A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’- A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0097] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L2is -O- or -NH-. In some embodiments, L2is -O-. In some embodiments, L2is -NH-. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I- A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0098] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety is, wherein & denotes the point of attachment to Ring A and & denotes the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I- A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-5953625Docket No.: 79275-20027.40

[0099] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1H- spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2- dioxide moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1H- spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety substitiuted with two chloro. In some embodiments, the ring system bearingsome embodiments, the ring system bearing (R1)mand (R2)pisthe ring system bearing (R1)m and (R2)p is 44sf-5953625Docket No.: 79275-20027.40 . In some embodiments, the ring system bearing (R1)m and (R2)p is. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I- A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’- A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0100] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A2), (I-A2a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 1',4'-dihydro-2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1',4'-dihydro-2'H- spiro[piperidine-4,3'-quinolin]-2'-one moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is an unsubstituted 1',4'-dihydro- 2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1',4'-dihydro-2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)pis a 1',4'-dihydro-2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1',4'-dihydro- 2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1',4'-dihydro-2'H-spiro[piperidine- 4,3'-quinolin]-2'-one moiety substitiuted with two chloro. In some embodiments, the ringsf-5953625Docket No.: 79275-20027.40embodiments, the ring system bearingsome embodiments,provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I- A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing..

[0101] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A3), (I-A3a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 3H-spiro[isobenzofuran-1,4'-piperidine] moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some 46sf-5953625Docket No.: 79275-20027.40 embodiments, the ring system bearing (R1)m and (R2)p is a 3H-spiro[isobenzofuran-1,4'- piperidine] moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted 3H-spiro[isobenzofuran-1,4'-piperidine] moiety. In some embodiments, the ring system bearing (R1)mand (R2)pis a 3H- spiro[isobenzofuran-1,4'-piperidine] moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 3H-spiro[isobenzofuran-1,4'- piperidine] moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a 3H-spiro[isobenzofuran-1,4'-piperidine] moiety substitiuted with one chloro. In some embodiments, the ring system bearingsome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’- A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0102] In some embodiments of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A3), (I-A3a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)m and (R2)p is a 3'-bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 3'-bromo-5'H-1l2- spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted 3'-bromo-5'H- 1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a 3'-bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)p is a 3'-bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety substitiuted with one or more bromo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 3'-sf-5953625Docket No.: 79275-20027.40 bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety substitiuted with one bromo. In some embodiments, the ring system bearing

[0103] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A4), (I-A4a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety. In some embodiments, the ring system bearing (R1)mand (R2)pis a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'- piperidin]-2(1H)-one moiety substitiuted with one or more fluoro. In some embodiments, the ring system bearing (R1)mand (R2)pis a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one fluoro. In some embodiments, the ring system bearing (R1)m andsome embodiments, the ring system bearing 48sf-5953625Docket No.: 79275-20027.40any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0104] In some embodiments of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A4), (I-A4a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 1H-spiro[benzo[e][1,4]oxazepine-5,4'-piperidin]-2(3H)-one moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1H- spiro[benzo[e][1,4]oxazepine-5,4'-piperidin]-2(3H)-one moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is an unsubstituted 1H-spiro[benzo[e][1,4]oxazepine-5,4'-piperidin]-2(3H)-one moiety. In some embodiments, the ring system bearing

[0105] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or 49sf-5953625Docket No.: 79275-20027.40 tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)m and (R2)p is a 2,3-dihydrospiro[indene-1,4'-piperidin]-2-ol moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 2,3-dihydrospiro[indene-1,4'- piperidin]-2-ol moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted 2,3-dihydrospiro[indene-1,4'-piperidin]- 2-ol moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a 2,3- dihydrospiro[indene-1,4'-piperidin]-2-ol moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 2,3-dihydrospiro[indene-1,4'- piperidin]-2-ol moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a 2,3-dihydrospiro[indene-1,4'-piperidin]-2-ol moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis . In some embodiments, the ring system bearing (R1)m and (R2)p is . In some embodiments, the ring system bearing (R1)m and (R2)p is. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A1), (I- A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-5953625Docket No.: 79275-20027.40

[0106] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -NH-, Y2is -S(O)2-, Y3is a bond, p is 0, and r is 0, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formulasf-5953625Docket No.: 79275-20027.40 detailed herein, such as a compound of formula (I’), (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0107] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -NH-, Y2is -C(O)-, Y3is a bond, p is 0, and r is 1, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, selected from the group consistingsf-5953625Docket No.: 79275-20027.40stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0108] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -CH2-, Y2is -O-, Y3is a bond, p is 0, and r is 0, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,sf-5953625Docket No.: 79275-20027.40 wherein the compoundstereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0109] In some embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X1, X2, X3, and X4are each independently -CH- or -N-; Y1is -CH2-, Y2is -O-, Y3is a bond, p is 0, and r is 0, such that the compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I’-A3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,sf-5953625Docket No.: 79275-20027.40stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0110] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -NH-, Y2is -C(O)-, Y3is -O-, p is 0, and r is 0, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A4):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, selected from the group consistingsf-5953625Docket No.: 79275-20027.40stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0111] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -CH2-, Y2is - CH(OH)-, Y3is a bond, p is 0, and r is 0, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A5):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, selected from the group consistingsf-5953625Docket No.: 79275-20027.40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0112] In some embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -NH-, Y2is -C(O)-, Y3is ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule, p is 0, and r is 0, such that the compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I’-A6):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a compound of formula (I’-A6), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,selected from the group consisting of , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-5953625Docket No.: 79275-20027.40

[0113] In some embodiments, of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), or (I-A5a), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A), (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I’-A3), (I’-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), or (I’-A6a), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0114] In some embodiments, Ring A is C9-10aryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, Ring A is C9aryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, Ring A is C10aryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0115] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), or (I-A5a),, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is 9-10 membered heterocyclyl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, Ring A is a 9- membered heterocyclyl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, Ring A is a 10-membered heterocyclyl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A), (I-A1),sf-5953625Docket No.: 79275-20027.40 (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I’-A3), (I’-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’- A6), or (I’-A6a), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0116] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), or (I-A5a),, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is 9-10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, provided herein is a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-B), wherein Ring A is a 9-membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3- 5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or - OH. In some embodiments, Ring A is a 10-membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, Ring A is a 1H-benzo[d]imidazole moiety optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, Ring A is a 1H-benzo[d]imidazole moiety substituted with one or more C1-3haloalkyl and one or more C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodients, Ringsome embodiments, Ring Asome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A), (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I’-A3), (I’-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), or (I’-A6a), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 59sf-5953625Docket No.: 79275-20027.40

[0117] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), or (I-A5a), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L1is unsubstituted ethylene, L2is -O-, and Ring A is 9- 10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments of formula (I), (I-A1), (I-A2), (I-A3), (I-A4), or (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L1is unsubstituted ethylene, L2is -O-, and Ringsome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I-A), (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I’-A3), (I’-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), or (I’-A6a), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0118] In some embodiments, provided herein is a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1, X2, X3, and X4are each independently -CH- or -N ; L1is unsubstituted ethylene; and L2is -O-, such that the compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I’-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is 9-10 membered heteroaryl optionally substituted with one or more 60sf-5953625Docket No.: 79275-20027.40 C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0119] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted ethylene and L2is -O-, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is 9-10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I’-B), or (I- B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0120] In some embodiments, provided herein is a compound of formula (I’) or formula (I’-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted ethylene, L2is -O-, and Ringthat the compound of formula (I’) or formula (I’-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I’-C): 61sf-5953625Docket No.: 79275-20027.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0121] In some embodiments, provided herein is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted ethylene, L2is -O-, and Ringcompound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 62sf-5953625Docket No.: 79275-20027.40

[0122] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y1is -CH2- or - N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or - OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -CH2-. In some embodiments, Y1is - N(Ry)-. In some embodiments, Y1is -N(Ry)-, wherein Ryis H. In some embodiments, Y1is - N(Ry)-, wherein Ryis C1-6alkyl optionally substituted with one or more D, halo, or -OH. In some embodiments, Y1is -N(Ry)-, wherein Ryis C2-6alkynyl. In some embodiments, Y1is - N(Ry)-, wherein Ryis C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some embodiments, Y1is -N(Ry)-, wherein Ryis 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0123] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-. In some embodiments, Y2is -CH(OH)-. In some embodiments, Y2is - C(O)-. Y2is -S(O)2-. In some embodiments, Y2is -O-. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0124] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y3is a bond, - CH2-, or -O-. In some embodiments, Y3is a bond. In some embodiments, Y3is -CH2-. In some embodiments, Y3is -O-. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0125] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, r is 0 or 1,sf-5953625Docket No.: 79275-20027.40 provided that (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond. In some embodiments, r is 0. In some embodiments, r is 1. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0126] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo halo. In some embodiments, R1is, independently at each occurrence, halo. In some embodiments, R1is, independently at each occurrence, chloro. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0127] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is C1-6alkyl. In some embodiments, R2is C1-3alkyl. In some embodiments, R2is methyl or ethyl. In some embodiments, R2is methyl. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0128] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments m is 1. In some embodiments, m is 2. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0129] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is an integer from 0 to 8. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. This aspect in some embodiments may employ a compound of any of 64sf-5953625Docket No.: 79275-20027.40 formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0130] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is C1-3alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is methylene or ethylene, each independently optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is methylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is ethylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy. In some embodiments, L1is unsubstituted C1-6alkylene. In some embodiments, L1is unsubstituted C1-6alkylene. In some embodiments, L1is unsubstituted C1-3alkylene. In some embodimemts, L1is unsubstituted ethylene. In some embodiments, L1is unsubstituted methylene. In some embodiments, L1is, wherein # denotes the point of attachment to L2and ## denotes the point of attachment to the remainder of the molecule. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0131] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L2is -O- or - NH-. In some embodiments, L2is -O-. In some embodiments, L2is -NH-. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0132] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, thesf-5953625Docket No.: 79275-20027.40, wherein & denotes the point of attachment to Ring A and & denotes the point of attachment to the remainder of the molecule. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0133] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)m and (R2)p is a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1H- spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2- dioxide moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)m and (R2)pis a 1H-spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1H- spiro[benzo[c]isothiazole-3,4'-piperidine] 2,2-dioxide moiety substitiuted with two chloro. In some embodiments, the ring system bearingsome embodiments, the ring system bearing (R1)mand (R2)pis 66sf-5953625Docket No.: 79275-20027.40 some embodiments, the ring system bearing (R1)m and (R2)p is . In some embodiments, the ring system bearing (R1)m and (R2)p is. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0134] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 1',4'-dihydro-2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1',4'-dihydro-2'H- spiro[piperidine-4,3'-quinolin]-2'-one moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is an unsubstituted 1',4'-dihydro- 2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1',4'-dihydro-2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1',4'-dihydro-2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis a 1',4'-dihydro- 2'H-spiro[piperidine-4,3'-quinolin]-2'-one moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a 1',4'-dihydro-2'H-spiro[piperidine-sf-5953625Docket No.: 79275-20027.40 4,3'-quinolin]-2'-one moiety substitiuted with two chloro. In some embodiments, the ringembodiments, the ring system bearingsome embodiments,some embodiments, the ring system bearingThis aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0135] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)m and (R2)p is a 3H-spiro[isobenzofuran-1,4'-piperidine] moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is a 3H-spiro[isobenzofuran-1,4'- piperidine] moiety optionally substitiuted with one or more halo. In some embodiments, the 68sf-5953625Docket No.: 79275-20027.40 ring system bearing (R1)m and (R2)p is an unsubstituted 3H-spiro[isobenzofuran-1,4'-piperidine] moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a 3H- spiro[isobenzofuran-1,4'-piperidine] moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 3H-spiro[isobenzofuran-1,4'- piperidine] moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis a 3H-spiro[isobenzofuran-1,4'-piperidine] moiety substitiuted with one chloro. In some embodiments, the ring system bearingThis aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0136] In some embodiments of a compound of formula (I’), (I), (I’-B), (I-B), or (I’-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 3'-bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4- b]pyridine] moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 3'-bromo- 5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)m and (R2)p is an unsubstituted 3'- bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety. In some embodiments, the ring system bearing (R1)mand (R2)pis a 3'-bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 3'-bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety substitiutedwith one or more chloro or bromo. In some embodiments, the ring system bearing (R1)mand (R2)p is a 3'-bromo-5'H-1l2-spiro[azetidine-3,7'-furo[3,4-b]pyridine] moiety substitiuted with 69sf-5953625Docket No.: 79275-20027.40 one chloro or bromo. In some embodiments, the ring system bearing (R1)m and (R2)p is.

[0137] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety optionally substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis a spiro[benzo[d][1,3]oxazine-4,4'- piperidin]-2(1H)-one moiety substitiuted with one or more fluoro. In some embodiments, the ring system bearing (R1)m and (R2)p is a spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one moiety substitiuted with one fluoro. In some embodiments, the ring system bearing (R1)mandsf-5953625Docket No.: 79275-20027.40of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0138] In some embodiments of a compound of formula (I’), (I), (I’-B), (I-B), or (I’-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 1H-spiro[benzo[e][1,4]oxazepine-5,4'-piperidin]- 2(3H)-one moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1- 6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis an unsubstituted 1H-spiro[benzo[e][1,4]oxazepine-5,4'-piperidin]-2(3H)-one moiety. In some embodiments, the ring system bearing

[0139] In some embodiments of a compound of formula (I), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring system bearing (R1)mand (R2)pis a 2,3-dihydrospiro[indene-1,4'-piperidin]-2-ol moiety optionally substitiuted with one or more (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 2,3-dihydrospiro[indene-1,4'- piperidin]-2-ol moiety optionally substitiuted with one or more halo. In some embodiments, thesf-5953625Docket No.: 79275-20027.40 ring system bearing (R1)m and (R2)p is an unsubstituted 2,3-dihydrospiro[indene-1,4'-piperidin]- 2-ol moiety. In some embodiments, the ring system bearing (R1)m and (R2)p is a 2,3- dihydrospiro[indene-1,4'-piperidin]-2-ol moiety substitiuted with one or more halo. In some embodiments, the ring system bearing (R1)mand (R2)pis a 2,3-dihydrospiro[indene-1,4'- piperidin]-2-ol moiety substitiuted with one or more chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis a 2,3-dihydrospiro[indene-1,4'-piperidin]-2-ol moiety substitiuted with one chloro. In some embodiments, the ring system bearing (R1)mand (R2)pis . In some embodiments, the ring system bearing (R1)m and (R2)p is . In some embodiments, the ring system bearing (R1)m and (R2)p is. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I’-B), (I-B), (I’-C), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0140] It is to be understood that any variation or embodiment of m, p, R1, R2, L1, L2, Y1, Y2, Y3, and Ring A provided herein can be combined with every other variation or embodiment of m, p, R1, R2, L1, L2, Y1, Y2, Y3, and Ring A, the same as if each and every combination had been individually and specifically described.

[0141] In some embodiments, provided herein is a compound of formula (I), or any variation of embodiment thereof, such a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I- A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of 72sf-5953625Docket No.: 79275-20027.40 the foregoing. In some embodiments of the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is selected from the compounds 1-11 of Table 1. In some embodiments, provided herein is a compound of formula (I’), or any variation of embodiment thereof, such a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is selected from the compounds 1-14 of Table 1. Table 1sf-5953625Docket No.: 79275-20027.40sf-5953625Docket No.: 79275-20027.4075sf-5953625Docket No.: 79275-20027.40

[0142] In some embodiments, the compound of formula (I’), or any variation of embodiment thereof, such a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I- A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consistingsf-5953625Docket No.: 79275-20027.40, , , , 77sf-5953625Docket No.: 79275-20027.40stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0143] In some embodiments, the compound of formula (I), or any variation of embodiment thereof, such a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I- A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of ,sf-5953625Docket No.: 79275-20027.40stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0144] In some embodiments, the compound of formula (I’), or any variation of embodiment thereof, such a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I- A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of: 5-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione, 1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione, 5,7-dichloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione, 6'-chloro-1-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one,sf-5953625Docket No.: 79275-20027.40 1-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one, 6',8'-dichloro-1-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one, (cis)-3-(5-{2-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidin]-1'-yl)ethoxy}-7- (trifluoromethyl)-1H-1,3-benzimidazol-1-yl)-1-methylcyclobutanol, 6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1H-spiro[3,1-benzoxazine-4,4'-piperidin]-2-one, 6-fluoro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1H-spiro[3,1-benzoxazine-4,4'-piperidin]-2-one, (R or S)-6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol, (S or R)-6-chloro-1'-(2-{1-[( cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol, (cis)-3-(5-{2-(5'-bromo-2'-oxa-1,7'-diazaspiro[azetidine-3,1'-indan]-1-yl)ethoxy}-7- (trifluoromethyl)-1H-1,3-benzimidazol-1-yl)-1-methylcyclobutanol; 1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)-1H,3H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one; and 6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[isoindoline-1,4'-piperidin]-3-one, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0145] In some embodiments, the compound of formula (I), or any variation of embodiment thereof, such a compound of formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I-A3), (I-A3a), (I-A4), (I- A4a), (I-A5), (I-A5a), (I-B), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of: 6'-chloro-1-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one, 5-fluoro-2-(4-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol- 5-yloxy]ethyl}-1-piperazinyl)phenol,sf-5953625Docket No.: 79275-20027.40 6',8'-dichloro-1-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy]ethyl}-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one, 6-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indan-1,4'-piperidin]-2-ol, 1-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one, 5,7-dichloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy]ethyl}-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione, 5-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione, 3-(5-{2-[4-(p-fluorophenyl)-1-piperazinyl]ethoxy}-7-(trifluoromethyl)-1H-1,3-benzimidazol-1- yl)-1-methylcyclobutanol, 3-(5-{2-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidin]-1'-yl)ethoxy}-7-(trifluoromethyl)-1H- 1,3-benzimidazol-1-yl)-1-methylcyclobutanol, 3-(5-{2-[4-(p-chlorophenyl)-4-fluoro-1-piperidyl]ethoxy}-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl)-1-methylcyclobutanol, 1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione, 3-(5-{2-[4-(p-chlorophenyl)-4-methyl-1-piperidyl]ethoxy}-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl)-1-methylcyclobutanol, 6-fluoro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}-1H-spiro[3,1-benzoxazine-4,4'-piperidin]-2-one, 6-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}-1H-spiro[3,1-benzoxazine-4,4'-piperidin]-2-one, 3-(5-{2-(5'-bromo-2'-oxa-1,7'-diazaspiro[azetidine-3,1'-indan]-1-yl)ethoxy}-7-(trifluoromethyl)- 1H-1,3-benzimidazol-1-yl)-1-methylcyclobutanol; 1'-(2-{1-[3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)-1H,3H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one; and 6-chloro-1'-(2-{1-[3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[isoindoline-1,4'-piperidin]-3-one, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-5953625Docket No.: 79275-20027.40

[0146] Isotopically labeled forms of any of the foregoing are also embraced, such as deuterated or tritiated forms (wherein at least one hydrogen is replaced by at least one deuterium or tritium) of any of the specific compounds detailed herein. Mixtures of any of the foregoing are also embraced and described. Prodrugs of any of the foregoing are also embraced herein.

[0147] As a non-limiting example, compounds of formula (I’) or (I), or any embodiment or variation thereof, are provided, wherein any one or more H atoms are replaced with deuterium. For example, compounds of formula (I’) or (I), or any embodiment or variation thereof, are provided wherein L1is C1-6alkylene, wherein one or more H atoms of the C1-6alkylene are replaced with deuterium. For example, compounds of formula (I’) or (I), or any embodiment or variation thereof, are provided wherein L1is -(CD2)1-6-. In some embodiments of formula (I), or any embodiment or variation thereof, L1is -(CD2)-(CD2)-.

[0148] In some embodiments, compounds of formula (I’) or (I) contain one or more hydrogen atoms that are replaced with deuterium, wherein deuterium is present in an amount that is greater than its natural abundance. Thus, as used herein, designation of an atom as deuterium at a position indicates that the abundance of deuterium is significantly greater than the natural abundance of deuterium. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its naturally abundant isotopic composition. Also unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is significantly greater than the natural abundance of deuterium, e.g., at least 3000 times greater than the natural abundance of deuterium, which is about 0.015% (i.e., the term “D” or “deuterium” indicates at least about 45% incorporation of deuterium).

[0149] Compound Names included in Table 1 and in the list in the paragraph above were generated using ChemDraw®software version 18.1.0.458, ChemDraw®software version 18.0.0.231, ChemDraw®software version 20.1.0.112, Collaborative Drug Discovery Inc. (CDD) CDD Vault Update (April 2023), or Collaborative Drug Discovery Inc. (CDD) CDD Vault update (June 2024). COMPOSITIONSsf-5953625Docket No.: 79275-20027.40

[0150] All compositions described herein with reference to formula (I), or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein such as formula (I’), the same as if each and every embodiment were specifically and individually listed. And, all compositions described herein with reference to a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to X1, X2, X3, X4, R1, R2, Y1, Y2, Y3, m, p, r, s, t, and ring A also apply to formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0151] Provided herein are pharmaceutical compositions comprising one or more compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a pharmaceutical composition comprising (i) a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0152] Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Examples of suitable excipients are well-known to those skilled in the art. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Academic Press, 23rded. (2020), which is incorporated herein by reference.sf-5953625Docket No.: 79275-20027.40

[0153] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, oral, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0154] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0155] The specific dose level of a compound as described herein will depend upon a variety of factors such as the age, body weight and sex of the individual as well as the route of administration and other factors. In some embodiments, a dosage is expressed as a number of milligrams of a compound described herein per kilogram of the individual’s body weight (mg / kg). Dosages of between about 0.1 mg / kg and 100-150 mg / kg may be appropriate.

[0156] The compound may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. METHODS OF TREATMENT

[0157] All methods described herein with reference to formula (I), or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein such as formula (I’), the same as if each and every embodiment were specifically and individually listed. And, all methods described herein with reference to a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or asf-5953625Docket No.: 79275-20027.40 pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to X1, X2, X3, X4, R1, R2, Y1, Y2, Y3, m, p, r, s, t, and ring A also apply to formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0158] Provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. Isotopically labeled forms of any of the foregoing are also embraced, including, but not limited to, deuterated or tritiated forms (wherein at least one hydrogen is replaced by at least one deuterium, or tritium) of any of the specific compounds detailed herein. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0159] Provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.sf-5953625Docket No.: 79275-20027.40

[0160] Provided herein is a method of inhibiting APOL1 in an individual, comprising administering to the individual an effective amount of a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of inhibiting APOL1 in an individual, comprising administering to the individual a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0161] In some embodiments, the compounds provided herein inhibit APOL1 at a concentration of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein inhibit APOL1 at a concentration of 1 to 10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

[0162] In some embodiments, the compounds provided herein reduce cell death caused by overexpression of APOL1. In some embodiments, the compounds provided herein reduce cell death caused by overexpression APOL1 at a concentration of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein reduce cell death caused by APOL1 overexpression at a concentration of 1 to 10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

[0163] In some embodiments, compounds provided herein have an EC50of less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein have an EC50of 1 to 10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

[0164] In some embodiments, compounds provided herein have an AC50of less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein have an AC50 of 1 to 10 μM, 0.01 to 1 μM, or 0.01 to 10 μM. In some embodiments, the AC50 value reflects the compound’s ability to prevent calcium influx by inhibiting APOL1.sf-5953625Docket No.: 79275-20027.40

[0165] In some embodiments, the compounds provided herein inhibit a cation channel. In some embodiments, the compounds of the present disclosure inhibit a calcium channel. In some embodiments, the compounds of the present disclosure reduce calcium transport.

[0166] Provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. Also provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered.

[0167] Provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. Also provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.sf-5953625Docket No.: 79275-20027.40

[0168] In some embodiments, the individual has a chronic kidney disease. In some embodiments, the individual has hypertension-attributed kidney disease. In some embodiments, the kidney disease, disorder, or condition is an APOL1-mediated kidney disease, disorder, or condition. In some embodiments, the kidney disease, disorder, or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, viral nephropathy, COVID-19 associated nephropathy, human immunodeficiency virus- associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, and diabetic kidney disease.

[0169] Also provided herein is a method of treating an APOL1-mediated disorder, such as preeclampsia and sepsis, comprising administering to an individual in need thereof a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the individual is genetically predisposed to developing the APOL1- mediated disorder. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0170] Also provided herein is a method of delaying development of progressive renal allograft loss in a kidney transplant recipient comprising administering to the kidney transplant recipient a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. In some embodiments, the kidney transplant recipient receives a kidney from a high-risk APOL1 genotype donor. In some embodiments, the kidney transplant recipient is administered the compound for a period of time before receiving the kidney transplant. In some embodiments, a therapeutically effective amount of the compound is administered. In some embodiments, the kidney transplant recipient is administered the compound subsequent to receiving the kidney transplant. In some embodiments, a therapeutically effective amount of the compound is administered. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or asf-5953625Docket No.: 79275-20027.40 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0171] Also provided herein is a method of treating diabetic retinopathy in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. In some embodiments, the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema. In some embodiments, the APOL1 inhibitor or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising an APOL1 inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is administered. In some embodiments, a therapeutically effective amount of an APOL1 inhibitor or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising an APOL1 inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is administered. In some embodiments, the administration comprises oral administration or intravitreal injection. In some embodiments, the administration comprises oral administration. In some embodiments, the administration comprises intravitreal injection. In some embodiments, the method further comprises administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0172] Provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein thesf-5953625Docket No.: 79275-20027.40 individual has an APOL1 mutation. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. Also provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, wherein the individual has an APOL1 mutation. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0173] The compounds provided herein may also be used in a method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition. In some embodiments, the APOL1-mediated disease, disorder, or condition is preeclampsia or sepsis and the individual has two APOL1 risk alleles. In some embodiments, the APOL1-mediated disease, disorder, or condition is a chronic kidney disease and the individual has any binary combination of G1 and G2 APOL1 risk alleles. In some embodiments, the chronic kidney disease is focal segmental glomerulosclerosis (FSGS), hypertension- attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), hypertension-attributed kidney disease, sickle cell nephropathy, viral nephropathy, COVID-19 associated nephropathy, lupus nephritis, diabetic kidney disease, or APOL1-associated nephropathy. The compounds as provided herein may also be used in a method of delaying the development of progressive renal allograft loss in an individual who has received a kidney transplantation from a high-risk APOL1 genotype donor. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.sf-5953625Docket No.: 79275-20027.40

[0174] In one aspect, provided herein is a method of preventing and / or delaying the development of diabetic retinopathy in an individual, comprising administering to the individual a compound of formula (I). In one aspect, provided herein is a method of delaying the development of diabetic retinopathy in an individual, comprising administering to the individual a compound of formula (I). In some embodiments of the compound of formula (I), or any variation of embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the diabetic retinopathy is selected from the group consisting of non- proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema. In some embodiments, the administration comprises oral administration or intravitreal injection. In some embodiments, the administration comprises oral administration. In some embodiments, the administration comprises intravitreal injection. In some embodiments, the method further comprises administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0175] In some embodiments of the methods described herein, the method comprises administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an APOL1 inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising an APOL1 inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is administered. In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered. In some embodiments of the compound of formula (I), or any variation of embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply tosf-5953625Docket No.: 79275-20027.40 any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0176] In some embodiments, the individual has a gain-of-function mutation in APOL1. In some embodiments, the individual has an APOL1 risk allele. In some embodiments, the APOL1 risk allele is a missense variant. In some embodiments, the APOL1 risk allele is a G1 variant. In some embodiments, the G1 variant is G1G(p.S342 G) or G1M(p.I384 M). In some embodiments, the APOL1 risk allele is the G2 variant. In some embodiments, the G2 variant is NYK388–389K. In some embodiments, the APOL1 risk variant is a mutation in the serum resistance-associated (SRA) binding domain of the APOL1 protein.

[0177] Also provided herein is a method of inhibiting APOL1 in an individual comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0178] Also provided herein is method of preventing kidney failure in an individual comprising administering a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing to the individual. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. In some embodiments, the compound prevents tissue necrosis. In some embodiments, the compound prevents apoptosis. In some embodiments, the compound reduces inflammation. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.sf-5953625Docket No.: 79275-20027.40

[0179] Provided herein is a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in modulating APOL1 in a cell. Also provided herein is a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in modulating APOL1 in a cell.

[0180] Provided herein is a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in inhibiting APOL1 in a cell. Also provided herein is a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in inhibiting APOL1 in a cell.

[0181] Provided herein is a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein is a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

[0182] Provided herein is a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceuticallysf-5953625Docket No.: 79275-20027.40 acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in delaying the development of an APOL1-mediated disease, disorder, or condition. Also provided herein is a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in delaying the development of an APOL1-mediated disease, disorder, or condition.

[0183] Provided herein is use of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for use in modulating APOL1 in a cell. Also provided herein is use of a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture of a medicament for use in modulating APOL1 in a cell.

[0184] Provided herein is use of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for use in inhibiting APOL1 in a cell. Also provided herein is use of a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture of a medicament for use in inhibiting APOL1 in a cell.

[0185] Provided herein is use of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or asf-5953625Docket No.: 79275-20027.40 pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein is use of a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture of a medicament for use in treating an APOL1- mediated disease, disorder, or condition in an individual in need thereof.

[0186] Provided herein is use of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for use in delaying the development of an APOL1-mediated disease, disorder, or condition. Also provided herein is use of a pharmaceutical composition comprising an effective amount of a compound of formula (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture of a medicament for use in delaying the development of an APOL1-mediated disease, disorder, or condition

[0187] In some embodiments, the compounds provided herein reduce or eliminate one or more symptoms of a kidney disease. In some embodiments, the compounds reduce nausea, vomiting, loss of appetite, fatigue and weakness, sleep problems, urinary frequency issues, muscle twinges and cramps, swelling, itching, chest pain, shortness of breath, and / or high blood pressure.

[0188] In some embodiments, the compounds provided herein reduce the rate of kidney damage and / or progression of kidney damage. In some embodiments, the compounds provided herein reduce the rate of kidney failure. In some embodiments, the compounds provided herein reverse kidney damage. In some embodiments, the compounds reduce the need for dialysis. In some embodiments, the compounds provided herein delay the need for dialysis at least one month, at least two months, at least three months, or at least one year.sf-5953625Docket No.: 79275-20027.40

[0189] In some embodiments, the compounds reduce the rate of or delay the need for a kidney transplant. For example, in some embodiments, the compounds provided herein delay the need for a kidney transplant at least one month, at least two months, at least three months, at least six months, or at least one year. In some embodiments, the compounds provided herein eliminate the need for a kidney transplant.

[0190] In some embodiments, the individual has stage 1, stage 2, stage 3A, stage 3B, stage 4, or stage 5 chronic kidney disease. In some embodiments, kidney function is evaluated using an estimated glomerular filtration rate (eGFR) kidney function test.

[0191] The compounds and compositions comprising the compounds provided herein may also be used in a method of delaying or preventing proteinuria, the method comprising administering the compound, or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to an individual. In one aspect, the methods herein comprise preventing or reducing protein in the urine, e.g., proteinuria. In some embodiments, the methods provided herein prevent proteinuria. In some embodiments, the methods reduce proteinuria. In some embodiments, the methods provided herein prevent albuminuria. In some embodiments, the methods reduce albuminuria. In some embodiments, the methods reduce urine albumin. In some embodiments, urine albumin is reduced by at least about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine albumin is reduced by at least about 50%. In some embodiments, urine albumin is reduced by at least about 60%. In some embodiments, urine albumin is reduced by at least about 70%. In some embodiments, urine albumin is reduced by at least about 80%. In some embodiments, urine albumin is reduced by at least about 90%. In some embodiments, reduction of urine albumin is dose-dependent. In some embodiments, the methods provided herein reduce urine albumin / creatine ratio. In some embodiments, urine albumin / creatine ratio is reduced by at least about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine albumin / creatine ratio is reduced by at least about 50%. In some embodiments, urine albumin / creatine ratio is reduced by at least about 60%. In some embodiments, urine albumin / creatine ratio is reduced by at least about 70%. In some embodiments, urine albumin / creatine ratio is reduced by at least about 80%. In some embodiments, urine albumin / creatine ratio is reduced by at least about 90%. In some embodiments, reduction of urine albumin / creatine ratio is dose-dependent. In somesf-5953625Docket No.: 79275-20027.40 embodiments, the reduction and / or ratios are measured according to assays detailed herein. In any of the aforementioned methods, the individual is an individual in need thereof, such as an individual having an APOL1-mediated disease, disorder, or condition. In some embodiments, the APOL1-mediated disease, disorder, or condition is a kidney disease. In some embodiments, the APOL1-mediated disease, disorder, or condition is a chronic kidney disease. In some embodiments, the individual has hypertension-attributed kidney disease. In some embodiments, the kidney disease, disorder, or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, viral nephropathy, COVID-19 associated nephropathy, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, and diabetic kidney disease.

[0192] In some embodiments, the APOL1 mediated disease, disorder, or condition is selected from the group consisting of chronic kidney disease (including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle cell nephropathy, lupus nephritis, diabetic kidney disease, viral nephropathy, COVID-19 associated nephropathy, and APOL1-associated nephropathy), preeclampsia, sepsis, non-diabetic renal disease, progressive renal allograft loss in a kidney transplant recipient, diabetic retinopathies (including non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema), proteinuria, albuminuria, and kidney failure.

[0193] In some embodiments, the administration is oral administration.

[0194] In some embodiments, the APOL1 risk allele is a G0 variant. In some embodiments, the G0 variant is G0 E150 (p.K150E). KITS

[0195] All kits described herein with reference to formula (I), or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein such as formula (I’), the same as if each and every embodiment were specifically and individually listed. And, all kits described herein with reference to a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to X1, X2, X3, X4, R1, R2, Y1, Y2, Y3, m, p,sf-5953625Docket No.: 79275-20027.40 r, s, t, and ring A also apply to formula (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I- A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0196] The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound.

[0197] Provided herein are kits, comprising (i) a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0198] Also provided herein are kits, comprising (i) a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating diabetic retinopathy in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or moresf-5953625Docket No.: 79275-20027.40 pharmaceutically acceptable excipients; and (ii) instructions for use in treating diabetic retinopathy in an individual in need thereof. In some embodiments, the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema. In some embodiments, the administration comprises oral administration or intravitreal injection. In some embodiments, the administration comprises oral administration. In some embodiments, the administration comprises intravitreal injection. In some embodiments, the method further comprises administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0199] Provided herein are kits, comprising (i) a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in preventing and / or delaying the development of diabetic retinopathy in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in preventing and / or delaying the development of diabetic retinopathy in an individual in need thereof. Provided herein are kits, comprising (i) a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in delaying the development of diabetic retinopathy in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in delaying the development of diabetic retinopathy in an individual in need thereof. In some embodiments, the diabeticsf-5953625Docket No.: 79275-20027.40 retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema. In some embodiments, the administration comprises oral administration or intravitreal injection. In some embodiments, the administration comprises oral administration. In some embodiments, the administration comprises intravitreal injection. In some embodiments, the method further comprises administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0200] In some embodiments of the kits disclosed herein, the individual is a human.

[0201] Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0202] In some embodiments of the methods disclosed herein, the individual is a human. METHODS OF PREPARING

[0203] The present disclosure further provides methods for preparing the compounds of present invention. In some aspect, provided herein are methods of preparing a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’- 100sf-5953625Docket No.: 79275-20027.40 A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0204] In some aspects, provided is a method for preparing the compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising a step of reacting a compound of formula (I’-A’):wherein: either: (1) Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule; s and t are both 0 or 1, wherein when r is 1, both s and t are 1; or (2) Y1is a bond; Y2is -C(O)-; Y3is -NH-; and s and t are each 1; X1, X2, X3, and X4are each independently -CH- or -N-;r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2-, -O-, or ###-CH2O- ####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule, and (2) when r is 1, then Y3is a bond; 101sf-5953625Docket No.: 79275-20027.40 R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1- 6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; and p is an integer from 0 to 8 with a compound of formula (I’-B):wherein: the dashed line represents a single or double bond; Z is halo, oxo, or a sulfonate ester; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1- 3alkyl or -OH, to give a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 102sf-5953625Docket No.: 79275-20027.40

[0205] In some aspects, provided is a method for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising a step of reacting a compound of formula (I’-A):wherein: Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, or -O-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; and p is an integer from 0 to 8; 103sf-5953625Docket No.: 79275-20027.40 with a compound of formula (I’-B):wherein: represents a single or double bond; Z is halo, oxo, or a sulfonate ester; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH, to give a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0206] In some embodiments, the compound of formula (I) is prepared by a step comprising alkylation of an amine of formula (I’-A) with an alkyl halide, or sulfonate ester compound of formula (I’-B) in the presence of an inorganic base. In some embodiments, the inorganic base is selected from the group consisting of potassium carbonate and sodium bicarbonate. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a 104sf-5953625Docket No.: 79275-20027.40 pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0207] In some aspects, provided is a process according to Scheme P1, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, provided is a method of preparing a compound of formula S1-10. Scheme P1

[0208] In some aspects, provided is a process according to Scheme P2, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, provided is a method ofsf-5953625Docket No.: 79275-20027.40 preparing a compound of formula S2-3, comprising reacting a compound of formula S2-1 with a compound of formula S2-2 in the presence of a base. Scheme P2

[0209] In some aspects, provided is a process according to Scheme P3, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, provided is a method of preparing a compound of formula S3-4, comprising reacting a compound of formula S3-2 with a compound of formula S3-3 in the presence of a base at elevated temperature. Scheme P3

[0210] In some aspects, provided is a process according to Scheme P4 wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, provided is a method of 106sf-5953625Docket No.: 79275-20027.40 preparing a compound of formula S4-3, comprising reacting a compound of formula S4-1 with a compound of formula S4-2 in the presence of a base at elevated temperature. Scheme P4

[0211] In some aspects, provided is a process according to Scheme P5, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. In some embodiments, provided is a method of preparing a compound of formula S5-4, comprising reacting a compound of formula S5-2 with a compound of formula S5-3 in the presence of a base at elevated temperature. Scheme P5

[0212] In some aspects, provided is a process according to Scheme P6, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionallysf-5953625Docket No.: 79275-20027.40 substituted with one or more C1-3alkyl or -OH. Compounds of formula S6-4 may be prepared by reduction of S6-1 with a reagent such as sodium borohydride, followed by chorination with a reagent such as NCS and subsequent N-Boc deprotection under the action of an acid such as TFA. In some embodiments, provided is a method of preparing a compound of formula S6-6, comprising reacting a compound of formula S6-4 with a compound of formula S6-5 in the presence of a base at elevated temperature. Scheme P6

[0213] In further examples, the compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A1), (I-A1a), (I-A2), (I-A2a), (I’-A3), (I’-A3a), (I-A3), (I-A3a), (I-A4), (I-A4a), (I-A5), (I-A5a), (I’-A6), (I’-A6a), (I’-B), (I-B), (I’-C) or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.is prepared by methods shown in the examples below. ENUMERATED EMBODIMENTSsf-5953625Docket No.: 79275-20027.40

[0214] The following Enumerated Embodiments are representative of some embodiments of the invention.

[0215] Enumerated Embodiment 1. A compound of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, or -O-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; 109sf-5953625Docket No.: 79275-20027.40 R2, if present, is, independently at each occurrence, C1-6alkyl; m is 0, 1, 2, 3, or 4; p is an integer from 0 to 8; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0216] Enumerated Embodiment 2. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y1is -NH-, Y2is -S(O)2-, Y3is a bond, p is 0, and r is 0, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 110sf-5953625Docket No.: 79275-20027.40

[0217] Enumerated Embodiment 3. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y1is -NH-, Y2is -C(O)-, Y3is a bond, p is 0, and r is 1, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0218] Enumerated Embodiment 4. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y1is -CH2-, Y2is -O-, Y3is a bond, p is 0, and r is 0, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0219] Enumerated Embodiment 5. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y1is -NH-, Y2is -C(O)-, Y3is -O-, p is 0, and r is 0, such that the compound of formula 111sf-5953625Docket No.: 79275-20027.40 (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A4):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0220] Enumerated Embodiment 6. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y1is -CH2-, Y2is -CH(OH)-, Y3is a bond, p is 0, and r is 0, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-A4):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0221] Enumerated Embodiment 7. The compound of any of Enumerated Embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted C1-6alkylene. 112sf-5953625Docket No.: 79275-20027.40

[0222] Enumerated Embodiment 8. The compound of any of Enumerated Embodiments 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted ethylene.

[0223] Enumerated Embodiment 9. The compound of any of Enumerated Embodiments 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L2is -O-.

[0224] Enumerated Embodiment 10. The compound of any of Enumerated Embodiments 1-9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is 9-10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

[0225] Enumerated Embodiment 11. The compound of any of Enumerated Embodiments 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring

[0226] Enumerated Embodiment 12. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted ethylene; L2is -O-; and Ring A is 9-10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH, such that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-B): 113sf-5953625Docket No.: 79275-20027.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0227] Enumerated Embodiment 13. The compound of Enumerated Embodiment 1 or Enumerated Embodiment 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted ethylene; L2is -O-; andsuch that the compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is a compound of formula (I-C):114sf-5953625Docket No.: 79275-20027.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0228] Enumerated Embodiment 14. The compound of any of Enumerated Embodiments 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the compounds of Table 1.

[0229] Enumerated Embodiment 15. A method for preparing the compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising a step of reacting a compound of formula (I’-A):wherein: Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, or -O-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl;sf-5953625Docket No.: 79275-20027.40 m is 0, 1, 2, 3, or 4; p is an integer from 0 to 8 with a compound of formula (I’-B):wherein: the dashed line represents a single or double bond; Z is halo, oxo, or a sulfonate ester; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1- 6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3- 5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1- 3alkyl or -OH, to give a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0230] Enumerated Embodiment 16. The method of Enumerated Embodiment 15, wherein the compound of Enumerated Embodiment 1 is prepared by a step comprising alkylation of an amine of formula (I’-A) with an alkyl halide or sulfonate ester compound of formula (I’-B) in the presence of an inorganic base.

[0231] Enumerated Embodiment 17. The method of Enumerated Embodiment 16, wherein the inorganic base is potassium carbonate or sodium bicarbonate. 116sf-5953625Docket No.: 79275-20027.40

[0232] Enumerated Embodiment 18. A pharmaceutical composition, comprising (1) a compound of any of Enumerated Embodiments 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients.

[0233] Enumerated Embodiment 19. A method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any or Enumerated Embodiments 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 18.

[0234] Enumerated Embodiment 20. A method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any of Enumerated Embodiments 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 18.

[0235] Enumerated Embodiment 21. A method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of any of Enumerated Embodiments 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 18.

[0236] Enumerated Embodiment 22. The method of Enumerated Embodiment 21, wherein the disease, disorder, or condition is a kidney disease or diabetic retinopathy.

[0237] Enumerated Embodiment 23. The method of Enumerated Embodiment 22, wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID- 19 associated nephropathy, preeclampsia, and sepsis.

[0238] Enumerated Embodiment 24. The method of any of Enumerated Embodiments 21-23, wherein the disease, disorder, or condition is a kidney disease. 117sf-5953625Docket No.: 79275-20027.40

[0239] Enumerated Embodiment 25. The method of any of Enumerated Embodiments 21-24, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

[0240] Enumerated Embodiment 26. The method of Enumerated Embodiment 21 or Enumerated Embodiment 22, wherein the disease, disorder, or condition is diabetic retinopathy.

[0241] Enumerated Embodiment 27. The method of Enumerated Embodiment 26, wherein the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema.

[0242] Enumerated Embodiment 28. The method of Enumerated Embodiment 26 or Enumerated Embodiment 27, wherein the administration comprises oral administration or intravitreal injection.

[0243] Enumerated Embodiment 29. The method of Enumerated Embodiment 28, wherein the administration comprises oral administration.

[0244] Enumerated Embodiment 30. The method of Enumerated Embodiment 28, wherein the administration comprises intravitreal injection.

[0245] Enumerated Embodiment 31. The method of any of Enumerated Embodiments 26-30, further comprising administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual.

[0246] Enumerated Embodiment 32. A method of delaying the development of an APOL1- mediated disease, disorder, or condition, comprising administering a compound of any of Enumerated Embodiments 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 18, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.

[0247] Enumerated Embodiment 33. The method of Enumerated Embodiment 32, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease or diabetic retinopathy.sf-5953625Docket No.: 79275-20027.40

[0248] Enumerated Embodiment 34. The method of Enumerated Embodiment 32 or Enumerated Embodiment 33, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease.

[0249] Enumerated Embodiment 35. The method of any of Enumerated Embodiments 32-34, wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.

[0250] Enumerated Embodiment 36. The method of Enumerated Embodiment 32, wherein the APOL1-mediated disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

[0251] Enumerated Embodiment 37. The method of Enumerated Embodiment 32 or Enumerated Embodiment 33, wherein the APOL-1 mediated disease, disorder, or condition is diabetic retinopathy.

[0252] Enumerated Embodiment 38. The method of Enumerated Embodiment 37, wherein the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema.

[0253] Enumerated Embodiment 39. The method of Enumerated Embodiment 37 or Enumerated Embodiment 38, wherein the administration comprises oral administration or intravitreal injection.

[0254] Enumerated Embodiment 40. The method of Enumerated Embodiment 39, wherein the administration comprises oral administration.

[0255] Enumerated Embodiment 41. The method of Enumerated Embodiment 39, wherein the administration comprises intravitreal injection. 119sf-5953625Docket No.: 79275-20027.40

[0256] Enumerated Embodiment 42. The method of any of Enumerated Embodiments 37-41, further comprising administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual.

[0257] Enumerated Embodiment 43. The method of any of Enumerated Embodiments 39-42, wherein the individual has an APOL1 mutation.

[0258] Enumerated Embodiment 44. The method of Enumerated Embodiment 43, wherein the APOL1 mutation is a gain-of-function mutation.

[0259] Enumerated Embodiment 45. The method of any of Enumerated Embodiments 21-44, wherein a therapeutically effective amount of a compound of any of Enumerated Embodiments 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 18, is administered.

[0260] Enumerated Embodiment 46. A kit, comprising (1) a compound of any of Enumerated Embodiments 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 18, and (2) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

[0261] Enumerated Embodiment 47. The kit of Enumerated Embodiment 46, wherein the disease, disorder, or condition is a kidney disease or diabetic retinopathy.

[0262] Enumerated Embodiment 48. The kit of Enumerated Embodiment 46 or Enumerated Embodiment 47, wherein the disease, disorder, or condition is a kidney disease.

[0263] Enumerated Embodiment 49. The kit of any of Enumerated Embodiments 46-48, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

[0264] Enumerated Embodiment 50. The kit of any of Enumerated Embodiments 46-49, wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell 120sf-5953625Docket No.: 79275-20027.40 nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

[0265] Enumerated Embodiment 51. The kit of Enumerated Embodiment 46, wherein the disease, disorder, or condition is diabetic retinopathy.

[0266] Enumerated Embodiment 52. The kit of Enumerated Embodiment 51, wherein the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema.

[0267] Enumerated Embodiment 53. The kit of Enumerated Embodiment 51 or Enumerated Embodiment 52, wherein the administration comprises oral administration or intravitreal injection.

[0268] Enumerated Embodiment 54. The kit of Enumerated Embodiment 53, wherein the administration comprises oral administration.

[0269] Enumerated Embodiment 55. The kit of Enumerated Embodiment 53, wherein the administration comprises intravitreal injection.

[0270] Enumerated Embodiment 56. The kit of any of Enumerated Embodiments 51-55, further comprising instructions for administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual.

[0271] Enumerated Embodiment 57. The kit of any of Enumerated Embodiments 46-56, wherein the individual has an APOL1 mutation.

[0272] Enumerated Embodiment 58. The kit of Enumerated Embodiment 57, wherein the APOL1 mutation is a gain-of-function mutation. EXAMPLES

[0273] The following synthetic reaction schemes, which are detailed in the Schemes, General Procedures, and Examples, are merely illustrative of some of the methods by which the 121sf-5953625Docket No.: 79275-20027.40 compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art.

[0274] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0275] Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and / or by methods available to one of ordinary skill in the art. Synthetic Examples

[0276] As depicted in the Schemes, General Procedures, and Examples below, in certain exemplary embodiments, compounds of formula (I) or (I’), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein. Scheme S1 122sf-5953625Docket No.: 79275-20027.40

[0277] Compounds of formula S1-10 may be prepared according to Scheme S1, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. Bromination of a nitrobenzene derivative S1-1 with NBS, under acidic conditions, gives S1-2. SNAr reaction with an amine such as S1-3 in the presence of a tertiary amine base gives S1-4. S1-4 may be converted to phenylene diamine derivative S1-5 upon reaction with a reducing agent as such sodium dithiionite, followed by heating with a protic acid such as HCl. Heating S1-5 in the presence of an orthoester such as trimethyl orthoformate and an acid such as PTSA gives benzimidazole S1- 6. S1-6 may then undergo palladium-catalyzed borylation with diboron reagents such as S1-7 in the presence of a catalyst such as [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), potassium acetate as base, and an aprotic solvent such as 1,4-dioxane to give S1-8. Reaction with Oxone then provides S1-9, which may undergo selective alkylation with 1,2-dibromoethane 123sf-5953625Docket No.: 79275-20027.40 upon heating in IPA in the presence of a base such cesium carbonate to generate compounds of formula S1-10. Compound S1-10 may be further elaborated as depicted in the Schemes below. Scheme S2

[0278] Compounds of formula S2-3 may be prepared according to Scheme S2, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. Heating a mixture of S2-1 and S2-2 in the presence of a base such as triethylamine in an aprotic solvent such as DMF gives compounds of formula S2-3. Scheme S3

[0279] Compounds of formula S3-4 may be prepared according to Scheme S3, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. Sultam derivative S3-1 may be 124sf-5953625Docket No.: 79275-20027.40 functionalized with a reagent such as NCS in the presence of an acid such as TFA to give S3-2. Heating a mixture of S3-2 and alkyl bromide S3-3 in the presence of a base such as triethylamine in an aprotic solvent such as DMF gives compounds of formula S3-4. Scheme S4

[0280] Compounds of formula S4-3 may be prepared according to Scheme S4, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. Heating a mixture of spiropiperidine derivative S4-1 and alkyl bromide S4-2 in the presence of a base such as sodium bicarbonate in an aprotic solvent such as acetonitrile gives compounds of formula S4-3. Scheme S5

[0281] Compounds of formula S5-4 may be prepared according to Scheme S5, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl issf-5953625Docket No.: 79275-20027.40 optionally substituted with one or more C1-3alkyl or -OH. Spiropiperidine derivative S4-1 may be functionalized with a reagent such as NCS in the presence of an acid such as TFA to give S5- 2. Heating a mixture of spiropiperidine derivative S5-2 and alkyl bromide S5-3 in the presence of a base such as sodium bicarbonate in an aprotic solvent such as acetonitrile gives compounds of formula S5-4. Scheme S6

[0282] Compounds of formula S6-6 may be prepared according to Scheme S6, wherein R5, R6, and R7are each independently C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. Indanone derivative S6-1 may be converted to alcohol S6-2 upon reaction with sodium borohydride in EtOH. Reaction with NCS in the presence of acetic acid gives S6-3. Boc group removal occurs upon treatment with a protic acid such as HCl to give S6-4. Heating a mixture of spiropiperidine derivative S6-4 and alkyl bromide S6-5 in the presence of a base such as sodium bicarbonate in an aprotic solvent such as acetonitrile gives compounds of formula S6-6. General Procedure for Intermediate A-2 126sf-5953625Docket No.: 79275-20027.40Step 1: 5-bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene

[0283] To concentrated H2SO4 (15 mL) at 0 °C was added a solution of 2-fluoro-1-nitro-3- (trifluoromethyl)benzene (5.00 g, 23.0 mmol) in TFA (10 mL). NBS (5.11 g, 28.7 mol) was added to the 0 °C mixture in several portions. The mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature, and then poured into ice water (200 mL). The mixture was extracted with petroleum ether (2 x 80 mL). The combined organic layers were washed with saturated aqueous NaHCO3until pH = 8–9. The organic layer was separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 5- bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene.1H NMR (400 MHz, DMSO-d6): δ 8.70 (dd, J = 6.0 Hz, 2.4 Hz, 1H), 8.46 (dd, J = 5.6 Hz, 2.4 Hz, 1H). Step 2: (cis)-3-[4-bromo-2-nitro-6-(trifluoromethyl)phenylamino]-1-methylcyclobutanolsf-5953625Docket No.: 79275-20027.40

[0284] A mixture of 5-bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene (6.50 g, 22.6 mmol), DIEA (11.2 mL, 67.7 mmol) and (cis)-3-amino-1-methylcyclobutan-1-ol (3.42 g, 24.8 mmol, HCl salt) in THF (35 mL) in MeCN (35 mL) was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with H2O (150 mL) and extracted with MTBE (2 x 80 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated in vacuo to give (cis)-3-[4- bromo-2-nitro-6-(trifluoromethyl)phenylamino]-1-methylcyclobutanol, which was used in the subsequent step without further purification. MS = 368.9 / 370.9 [M+H]+. Step 3: (cis)-3-[2-amino-4-bromo-6-(trifluoromethyl)phenylamino]-1-methylcyclobutanol

[0285] To a three-neck round-bottom flask equipped with a magnetic stir bar and a thermometer was added H2O (170 mL) and sodium dithionite (32.1 g, 184 mmol). To the mixture was added a solution of (cis)-3-[4-bromo-2-nitro-6-(trifluoromethyl)phenylamino]-1-methylcyclobutanol (17.0 g, 46.1 mmol) in MeOH (170 mL) dropwise. The mixture was stirred at room temperature for 1 h, and then 12 M aqueous HCl (35 mL, 420 mmol) was added. The mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo to remove MeOH, and the residue was diluted with H2O (150 mL). The aqueous layer was adjusted to pH > 7 by addition of solid Na2CO3. The mixture was extracted with MTBE (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give (cis)-3-[2-amino-4-bromo-6-(trifluoromethyl)phenylamino]-1- methylcyclobutanol, which was used in the subsequent steps without further purification. MS = 339.0 / 341.0 [M+H]+. Step 4: (cis)-3-[5-bromo-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1- methylcyclobutanolsf-5953625Docket No.: 79275-20027.40

[0286] A mixture of (cis)-3-[2-amino-4-bromo-6-(trifluoromethyl)phenylamino]-1- methylcyclobutanol (13.0 g, 38.3 mmol), trimethoxymethane (6.10 g, 57.5 mmol), and TsOH•H2O (729 mg, 3.83 mmol) in THF (130 mL) was stirred at 50 °C for 1 h. The mixture was cooled to room temperature and concentrated in vacuo to remove most of the THF. The residual solution was diluted with saturated aqueous NaHCO3 solution (200 mL) and extracted with MTBE (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated in MTBE (20 mL) for 30 min. The mixture was filtered to collect the solid to afford (cis)-3-[5-bromo-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol. MS = 349.0 / 350.9 [M+H]+. Step 5: (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol

[0287] A mixture of (cis)-3-[5-bromo-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1- methylcyclobutanol (6.00 g, 17.2 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5- dimethyl-1,3,2-dioxaborinane (5.82 g, 25.8 mmol), KOAc (5.06 g, 51.6 mmol) and Pd(dppf)Cl2(130 mg, 0.172 mmol) in 1,4-dioxane (60 mL) was purged with N2 (3x) and then stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- (trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1-methylcyclobutanol, which was used in the subsequent step without further purification. Step 6: 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- ol129sf-5953625Docket No.: 79275-20027.40

[0288] To a 0 °C solution of (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- (trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1-methylcyclobutanol (9.00 g, 23.6 mmol) in THF (50 mL) and H2O (50 mL) was added Oxone (14.5 g, 23.6 mmol). The mixture was stirred at room temperature for 2 h. The mixture was cooled to 0 °C and quenched by addition of saturated aqueous Na2SO3 solution (60 mL). The mixture was adjusted to pH = 7 by addition of saturated aqueous NaHCO3solution and extracted with EtOAc (2 x 60 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with MTBE (20 mL) to give 1-[(cis)-3-hydroxy-3-methylcyclobutyl]- 7-(trifluoromethyl)-1H-1,3-benzimidazol-5-ol (Intermediate A-1), which was used in the subsequent step without further purification. MS = 287.1 [M+H]+.Step 7: (cis)-3-[5-(2-bromoethoxy)-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1- methylcyclobutanol

[0289] A solution of 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-ol (Intermediate A-1, 1.00 g, 3.49 mmol), 1,2-dibromoethane (5.27 mL, 69.9 mmol) and Cs2CO3 (2.85 g, 8.73 mmol) in i-PrOH (5 mL) was stirred at 60 °C for 16 h. After cooling to room temperature, solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage 20 g cartridge, 50–90% EtOAc / Petroleum ether) to give (cis)-3-[5-(2-bromoethoxy)-7-(trifluoromethyl)-1H- 1,3-benzimidazol-1-yl]-1-methylcyclobutanol (Intermediate A-2). MS = 393.0 / 394.9 [M+H]+. General Procedure for Intermediates B-1 & B-2 130sf-5953625Docket No.: 79275-20027.40

[0290] To a solution of 1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione (200 mg, 728 μmol, HCl salt) and TFA (54.1 μL, 728 μmol) in MeCN (5 mL) was added NCS (107 mg, 801 μmol). The mixture was stirred at room temperature for 3 h. MeCN was removed under reduced pressure. The filtrate was purified by reverse phase preparative HPLC (Waters Xbridge Prep BEH C18 column, 1–20% MeCN:10 mM NH4HCO3 in H2O) to give 5-chloro-1H,2H- spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione (Intermediate B-1, first eluting isomer) and 5,7-dichloro-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione (Intermediate B-2, second eluting isomer). 5-chloro-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2- dione (Intermediate B-1): MS = 273.0 [M+H]+.5,7-dichloro-1H,2H-spiro[2λ⁶,1- benzisothiazole-3,4'-piperidine]-2,2-dione (Intermediate B-2): MS = 307.0 [M+H]+. General Procedure for Intermediates B-3 & B-4

[0291] To a solution of 1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one (100 mg, 396 μmol, HCl salt) and TFA (29.4 μL, 396 μmol) in MeCN (2 mL) was added NCS (52.8 mg, 396 μmol). The mixture was stirred at room temperature for 3 h. MeCN was removed under reduced pressure. The residue was purified by reverse phase preparative HPLC (Phenomenex Luna C18column, 1– 30% MeCN:10 mM TFA in H2O) to give 6'-chloro-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'- one (Intermediate B-3, first eluting isomer) and 6',8'-dichloro-1'H,4'H-spiro[piperidine-4,3'- quinolin]-2'-one (Intermediate B-4, second eluting isomer). 6'-chloro-1'H,4'H-spiro[piperidine- 4,3'-quinolin]-2'-one (Intermediate B-3): MS = 251.2. 6',8'-dichloro-1'H,4'H-spiro[piperidine- 4,3'-quinolin]-2'-one (Intermediate B-4): MS = 285.2 [M+H]+. General Procedure for Intermediates B-5 131sf-5953625Docket No.: 79275-20027.40 ^^ Step 1: spiro[indan-1,4'-piperidin]-2-ol^

[0292] To a 0 °C mixture of tert-butyl 2-oxospiro[indan-1,4'-piperidine]-1'-carboxylate (2.30 g, 7.63 mmol) in EtOH (30 mL) was added NaBH4 (900 mg, 23.8 mmol) in portions. The mixture was warmed to room temperature and stirred for 5 h. The reaction mixture was quenched with ice water (20 mL), stirred at 0 °C for 10 min, then extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2-hydroxyspiro[indan-1,4'-piperidine]-1'-carboxylate. MS = 248.2 [M–C4H8+H]+. Step 2: tert-butyl 6-chloro-2-hydroxyspiro[indan-1,4'-piperidine]-1'-carboxylate

[0293] To a solution of tert-butyl 2-hydroxyspiro[indan-1,4'-piperidine]-1'-carboxylate (2.00 g, 6.59 mmol) in MeOH (21 mL) and AcOH (7 mL) was added NCS (2.64 g, 19.8 mmol). The mixture was heated to 50 °C and stirred for 5 h. After cooling to 0 °C, the reaction mixture was adjusted to pH = 8 by addition of saturated aqueous NaHCO3solution. The mixture was extracted with EtOAc (3 x 30 mL), the combined organic layers were dried over anhydrous 132sf-5953625Docket No.: 79275-20027.40 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Sepaflash 40 g cartridge, 0–50% EtOAc / Petroleum ether). The crude products were further purified by reverse phase preparative HPLC (Waters Xbridge Prep BEH C18column, 40–70% MeCN:10 mM NH4HCO3in H2O) to provide a crude mixture of tert-butyl 6-chloro-2-hydroxyspiro[indan-1,4'-piperidine]-1'-carboxylate and isomers, which was taken to the next step without further purification. MS = 281.8 [M–C4H8+H]+. Step 3: 6-chlorospiro[indan-1,4'-piperidin]-2-ol (Intermediate B-5)

[0294] A mixture of tert-butyl 6-chloro-2-hydroxyspiro[indan-1,4'-piperidine]-1'-carboxylate and isomers (270 mg, 799 μmol) in 4.0 M HCl in EtOAc (3.00 mL, 12.0 mmol) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude mixture of 6-chlorospiro[indan-1,4'-piperidin]-2-ol (Intermediate B-5, HCl salt) and isomers, which was used in subsequent steps without further purification. MS = 237.8 [M+H]+. Example 1 5-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione (Compound 1)

[0295] A mixture of 5-chloro-1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione (Intermediate B-1, 120 mg, 440 μmol), (cis)-3-[5-(2-bromoethoxy)-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol (Intermediate A-2, 173 mg, 440 μmol) and TEA (184 μL, 1.32 mmol) in DMF (2 mL) was warmed to 50 °C and stirred for 16 h. After cooling to 133sf-5953625Docket No.: 79275-20027.40 room temperature, the mixture was poured into H2O (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Waters Xbridge Prep OBD C18column, 20–50% MeCN:10 mM NH4HCO3in H2O) to give 5-chloro-1'-(2-{1- [(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-yloxy}ethyl)- 1H,2H-spiro[2λ⁶,1-benzisothiazole-3,4'-piperidine]-2,2-dione (Compound 1).1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.67 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.46 (s, 1H), 7.28 – 7.22 (m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 5.30 (s, 1H), 4..62 – 4.52 (m, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.02 – 2.94 (m, 2H), 2.86 – 2.78 (m, 2H), 2.65 – 2.54 (m, 6H), 2.20 – 2.07 (m, 4H), 1.33 (s, 3H). MS = 585.1 [M+H]+.

[0296] The following compounds in Table T1 were prepared according to procedures similar to steps described for Example 1 using the appropriate starting materials or common intermediates. Table T1134sf-5953625Docket No.: 79275-20027.40Example 2 6'-chloro-1-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one (Compound 4)

[0297] A mixture of 6'-chloro-1'H,4'H-spiro[piperidine-4,3'-quinolin]-2'-one (Intermediate B-5, 70.0 mg, 192 μmol, TFA salt), (cis)-3-[5-(2-bromoethoxy)-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol (Intermediate A-2, 75.5 mg, 192 μmol) and NaHCO3 (80.6 mg, 960 μmol) in MeCN (4 mL) was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Phenomenex Luna C18 column, 5–35% MeCN: 0.04% HCl in H2O) to give 6'-chloro-1-(2-{1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-yloxy}ethyl)-1'H,4'H- spiro[piperidine-4,3'-quinolin]-2'-one (Compound 4, HCl salt). 1H NMR (400 MHz, DMSO- d6): δ 10.86 (s, 0.5H), 10.60 (s, 0.5H), 10.42 – 10.39 (m, 1H), 9.17 – 9.15 (m, 1H), 7.71 – 7.64 (m, 1H), 7.44 – 7.43 (m, 1H), 7.36 – 7.22 (m, 2H), 7.00 – 6.88 (m, 1H), 6.41 (br s, 1H), 4.66 –sf-5953625Docket No.: 79275-20027.40 4.44 (m, 3H), 3.57 – 3.51 (m, 4H), 3.42 – 3.25 (m, 2H), 3.14 (s, 1H), 2.81 (s, 1H), 2.66 – 2.64 (m, 4H), 2.26 – 2.14 (m, 1H), 2.02 – 1.75 (m, 2H), 1.64 – 1.57 (m, 1H), 1.34 (s, 3H). MS = 563.1 [M+H]+.

[0298] The following compounds in Table T2 were prepared according to procedures similar to steps described for Example 2 using the appropriate starting materials or common intermediates. Table T2136sf-5953625Docket No.: 79275-20027.40Example 3 (R or S)-6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol (Compounds 10 & 11)Step 1: 6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-olsf-5953625Docket No.: 79275-20027.40

[0299] To a mixture of 6-chlorospiro[indan-1,4'-piperidin]-2-ol (Intermediate B-5) and isomers (170 mg, 620 μmol, HCl salt) and (cis)-3-[5-(2-bromoethoxy)-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol (Intermediate A-2, 256 mg, 651 μmol) in MeCN (3 mL) was added NaHCO3 (260 mg, 3.10 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Phenomenex Gemini-NX C18column, 25–55% MeCN:10 mM NH4HCO3 in H2O) to give a crude mixture of 6-chloro-1'-(2-{1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol and isomers. MS = 550.1 [M+H]+. Step 2: (R or S)-6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)- 1H-1,3-benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol

[0300] A mixture of 6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3-benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol and isomers was separated by chiral preparative SFC (Daicel Chiralpak IG column, 45% MeOH with 0.1% NH4OH in CO2). The first eluting peak, a crude mixture of (S or R)-6-chloro-1'-(2-{1-[( cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol and isomers, was carried onto the next step for additional chiral purification. The second eluting peak, (R or S)-6-chloro-1'-(2-{1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- 138sf-5953625Docket No.: 79275-20027.40 yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol (Compound 10):1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.22 – 7.14 (m, 3H), 5.31 (s, 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.62 – 4.51 (m, 1H), 4.33 (t, J = 4.4 Hz, 1H), 4.21 (t, J = 5.6 Hz, 2H), 3.16 (dd, J = 16.8 Hz, 5.2 Hz, 1H), 2.85 – 2.74 (m, 4H), 2.67 – 2.56 (m, 5H), 2.42 – 2.34 (m, 2H), 2.01 – 1.94 (m, 1H), 1.82 – 1.74 (m, 1H), 1.51 – 1.43 (m, 2H), 1.33 (s, 3H). MS = 550.1 [M+H]+. The third eluting peak was an isomer of the title compound.

[0301] The position of the Cl in (R or S)-6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3- methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'- piperidin]-2-ol (Compound 10) was confirmed by 2D NMR (NOE interaction shown below):Step 3: (S or R)-6-chloro-1'-(2-{1-[( cis)-3-hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3-benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol

[0302] The first eluting peak from Step 2, a mixture of (S or R)-6-chloro-1'-(2-{1-[( cis)-3- hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol and isomers, was further purified by chiral preparative HPLC (Daicel Chiralcel Prep OJ column, 15% EtOH in Heptane, 0.1% isopropylamine modifier). The first eluting isomer of the title compound, (S or R)-6-chloro-1'- (2-{1-[( cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indan-1,4'-piperidin]-2-ol (Compound 11):1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.23 – 7.14 (m, 3H), 5.31 (s, 139sf-5953625Docket No.: 79275-20027.40 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.61 – 4.55 (m, 1H), 4.33 (t, J = 4.4 Hz, 1H), 4.21 (t, J = 5.6 Hz, 2H), 3.16 (dd, J = 16.4 Hz, J = 4.8 Hz, 1H), 2.86 – 2.73 (m, 4H), 2.69 – 2.56 (m, 5H), 2.42 – 2.32 (m, 2H), 2.01 – 1.93 (m, 1H), 1.84 – 1.73 (m, 1H), 1.51 – 1.42 (m, 2H), 1.33 (s, 3H). MS = 550.1 [M+H]+. The second and third eluting peaks were isomers of the title compound.

[0303] The position of the Cl in (S or R)-6-chloro-1'-(2-{1-[( cis)-3-hydroxy-3- methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-yloxy}ethyl)spiro[indan-1,4'- piperidin]-2-ol (Compound 11) was confirmed by 2D NMR (NOE interaction shown below):- -Step 1: 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]

[0304] To a solution of tert-butyl 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine]-1'- carboxylate (900 mg, 264 μmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine] TFA salt. MS = 241.0 / 243.0 [M+H]+^ 140sf-5953625Docket No.: 79275-20027.40 Step 2: (cis)-3-(5-(2-(3'-bromo-5'H-spiro[azetidine-3,7'-furo[3,4-b]pyridin]-1-yl)ethoxy)-7- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol

[0305] To a solution of 3-bromospiro[5H-furo[3,4-b]pyridine-7,3'-azetidine] (110 mg, 324 μmol, TFA salt) in MeCN (3 mL) were added NaHCO3(545 mg, 6.49 mmol) and (cis)-3-(5-(2- bromoethoxy)-7-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol (Intermediate A-2, 128 mg, 324 μmol). The reaction mixture was heated to 80°C and stirred for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (WePure Biotech XP tC18, 35-65% MeCN:10 mM NH4HCO3 in H2O) to give (cis)-3-(5-(2-(3'-bromo-5'H-spiro[azetidine-3,7'- furo[3,4-b]pyridin]-1-yl)ethoxy)-7-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1- methylcyclobutan-1-ol (Compound 12).1HNMR (400 MHz, DMSO-d6): δ 8.67 (s, 2H), 8.02 (s, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 5.31 (s, 1H), 5.03 (s, 2H), 4.60 – 4.52 (m, 1H), 4.10 (t, J = 5.2 Hz, 2H), 3.60 (dd, J = 21.6 Hz, 8.4 Hz, 4H), 2.90 (t, J = 5.2 Hz, 2H), 2.67 – 2.55 (m, 4H), 1.33 (s, 3H). MS = 553.1 / 555.1 [M+H]+. Example 5 1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)-1H,3H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one (Compound 13)Step 1: 1,3-dihydro-2H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one141sf-5953625Docket No.: 79275-20027.40

[0306] To a solution of tert-butyl 2-oxo-2,3-dihydro-1H-spiro[4,1-benzoxazepine-5,4'- piperidine]-1'-carboxylate (150 mg, 450 μmol) in 1,4-dioxane (1 mL) was added 4 M HCl in 1,4-dioxane (560 μL, 2.20 mmol) under N2atmosphere. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with 1,4-dioxane (5 mL) and filtered to give 1,3-dihydro-2H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one. MS = 233.2 [M+H]+. Step 2: 1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)-1H,3H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one

[0307] To a solution of 1,3-dihydro-2H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one (110 mg, 409 μmol, HCl salt) in ACN (0.7 mL) was added NaHCO3(86.0 mg, 1.02 mmol) and (cis)-3-(5- (2-bromoethoxy)-7-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol (Intermediated A-2, 134 mg, 341 μmol,). The reaction mixture was heated to 80 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Phenomenex KinetexC18 column, 5-50% MeCN / H2O with 0.1% formic acid modifier) to give 1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol- 5-yloxy}ethyl)-1H,3H-spiro[4,1-benzoxazepine-5,4'-piperidin]-2-one (Compound 13).1H NMR (500 MHz, DMSO-d6): δ 9.76 (s, 1H), 8.61 (s, 1H), 7.53 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.15 – 7.09 (m, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 5.25 (s, 1H), 4.50 (p, J = 8.4 Hz, 1H), 4.19 – 4.10 (m, 4H), 2.70 (q, J = 8.7 Hz, 4H), 2.63 – 2.48 (m, 4H), 2.33 (t, J = 2.6 Hz, 2H), 1.99 – 1.82 (m, 4H), 1.27 (s, 3H). MS = 545.3 [M+H]+. Example 6 6-chloro-1'-(2-((1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H- benzo[d]imidazol-5-yl)oxy)ethyl)spiro[isoindoline- piperidin]-3-one (Compound 14)Step 1: 2-(2-bromo-5-chlorophenyl)acetonitrile 142sf-5953625Docket No.: 79275-20027.40

[0308] To a 0 °C solution of 1-bromo-2-(bromomethyl)-4-chloro-benzene (3.00 g, 10.6 mmol) in MeCN (20 mL) was added TMSCN (1.36 g, 13.7 mmol) dropwise, followed by a solution of 1 M TBAF in THF (13.7 mL, 13.7 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was then cooled to 0 °C and quenched by addition of H2O (20 mL). The mixture was adjusted to pH = 9 with Na2CO3 solid. The precipitated solid was collected by filtration to give 2-(2-bromo-5-chlorophenyl)acetonitrile.1HNMR (400 MHz, CDCl3): δ 7.56 – 7.53 (m, 2H), 7.23 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 3.83 (s, 2H). Step 2: tert-butyl 4-(2-bromo-5-chlorophenyl)-4-cyanopiperidine-1-carboxylate

[0309] To a round-bottom flask equipped with a magnetic stir bar and thermometer was added 2-(2-bromo-5-chloro-phenyl)acetonitrile (1.00 g, 4.34 mmol) in DMA (10 mL). The mixture was degassed and purged with N2(3x) and cooled to 0 °C. Then NaH (60% in mineral oil, 382 mg, 9.54 mmol) was added in portions. The reaction mixture was stirred at 0 °C for 30 min. Then tert-butyl N,N-bis(2-chloroethyl)carbamate (1.58 g, 6.51 mmol) was added dropwise. The reaction mixture was heated to 60 °C and stirred for 6 h. The reaction mixture was then cooled to 0 °C and quenched by addition of H2O (15 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Sepaflash 20 g cartridge, 0-10% EtOAc / Petroleum ether). to give tert-butyl 4- (2-bromo-5-chlorophenyl)-4-cyanopiperidine-1-carboxylate濁澳MS = 299.0 / 301.0 [M- C5H8O2+H]+. Step 3: tert-butyl 4-(2-bromo-5-chlorophenyl)-4-carbamoylpiperidine-1-carboxylate 143sf-5953625Docket No.: 79275-20027.40

[0310] To a solution of tert-butyl 4-(2-bromo-5-chloro-phenyl)-4-cyano-piperidine-1- carboxylate (0.93 g, 2.33 mmol) in EtOH (10 mL) and H2O (5 mL) was added NaOH (372 mg, 9.31 mmol) in portions. The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was then cooled to 0 °C and diluted with H2O (10 mL). The mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-(2-bromo-5-chlorophenyl)-4-carbamoylpiperidine-1-carboxylate, which was taken to the next step without further purification. MS = 439.0 / 441.0 [M+Na]+. Step 4: tert-butyl 4-amino-4-(2-bromo-5-chlorophenyl)piperidine-1-carboxylate

[0311] To a solution of tert-butyl 4-(2-bromo-5-chloro-phenyl)-4-carbamoyl-piperidine-1- carboxylate (910 mg, 2.18 mmol) in MeCN (5 mL) and H2O (5 mL) was added [phenyl-(2,2,2- trifluoroacetyl)oxy-iodanyl] 2,2,2-trifluoroacetate (1.03 g, 2.40 mmol) in portions. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was cooled to 0 °C, quenched by addition of H2O (15 mL) and adjusted to pH = 8 with saturated aqueous Na2CO3 solution. The mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Sepaflash 20 g cartridge, 0-100% EtOAc / Petroleum ether) to give tert-butyl 4-amino-4-(2-bromo-5- chlorophenyl)piperidine-1-carboxylate. MS = 332.9 / 334.9 [M-C4H8+H]+. Step 5: tert-butyl 6-chloro-3-oxospiro[isoindoline-1,4'-piperidine]-1'-carboxylate 144sf-5953625Docket No.: 79275-20027.40

[0312] A mixture of tert-butyl 4-amino-4-(2-bromo-5-chloro-phenyl)piperidine-1-carboxylate (270 mg, 693 μmol), Pd(OAc)2 (15.6 mg, 69.3 μmol), TEA (289 μL, 2.08 mmol) and DPPF (38.4 mg, 69.3 μmol) in MeOH (5 mL) was degassed and purged with CO (3x). The mixture was then heated to 80 °C and stirred for 12 h under CO (50 psi) atmosphere. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Sepaflash 4 g cartridge, 0-100% EtOAc / Petroleum ether) to give tert-butyl 6-chloro-3-oxospiro[isoindoline-1,4'- piperidine]-1'-carboxylate. MS = 281.0 [M-C4H8+H]+. Step 6: 6-chlorospiro[isoindoline-1,4'-piperidin]-3-one

[0313] A mixture (75 mg, 222.68 μmol) of tert-butyl 6-chloro-3-oxo-spiro[isoindoline-1,4'- piperidine]-1'-carboxylate (75 mg, 222.68 μmol) in a solution of 4 M HCl in 1,4-dioxane (2.0 mL, 8.0 mmol) was stirred at room temperature for 1 h. The reaction mixture was filtered, and the filter cake was collected to give 6-chlorospiro[isoindoline-1,4'-piperidin]-3-one (HCl salt). MS = 237.0 [M+H]+. Step 7: 6-chloro-1'-(2-((1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H- benzo[d]imidazol-5-yl)oxy)ethyl)spiro[isoindoline-1,4'-piperidin]-3-one

[0314] To a solution of 6-chlorospiro[isoindoline-1,4'-piperidin]-3-one (30.0 mg, 126 μmol, HCl salt) in MeCN (2 mL) was added (cis)-3-(5-(2-bromoethoxy)-7-(trifluoromethyl)-1H-sf-5953625Docket No.: 79275-20027.40 benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol (Intermediate A-2, 45.0 mg, 114 μmol) and NaHCO3 (28.8 mg, 343 μmol). The reaction mixture was heated to 80 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Phenomenex Luna C18 column, 10-40% MeCN:10mM NH4HCO3 in H2O) to give 6- chloro-1'-(2-((1-((cis)-3-hydroxy-3-methylcyclobutyl) -7-(trifluoromethyl)-1H- benzo[d]imidazol-5-yl)oxy)ethyl)spiro [isoindoline-1,4'-piperidin]-3-one (Compound 14).1H NMR (400 MHz, DMSO-d6): δ 9.33 (s, 1H), 8.67 (s, 1H), 7.81 (s, 1H), 7.63 – 7.59 (m, 2H), 7.51 (dd, J = 9.6 Hz, 1.6 Hz, 1H), 7.25 (s, 1H), 5.31 (s, 1H), 4.59 – 4.55 (m, 1H), 4.23 (t, J = 5.2 Hz, 2H), 2.96 – 2.93 (m, 2H), 2.87 – 2.84 (m, 2H), 2.60 – 2.57 (m, 6H), 2.19 – 2.16 (m, 2H), 1.38 – 1.35 (m, 2H), 1.33 (s, 3H). MS = 549.2 [M+H]+. Biological Examples Example B1

[0315] This example shows that compounds of the present disclosure are able to inhibit calcium transport by APOL1 E150 G2.

[0316] A HEK293 clonal cell line was generated to stably express GCaMP6f, a genetically encoded calcium indicator, and inducibly express APOL1 E150 G2 (HEK T- REx / GCaMP6f / APOL1 G2 K6.3). Cells were maintained in the following standard complete medium: DMEM with 4.5 g / L glucose and sodium pyruvate (BioWhittaker, Lonza, BE12-614F), supplemented with 10% FBS Performance Plus (Gibco, 16000044), 1% penicillin-streptomycin (BioWhittaker, DE17-602E), 2 mM ultraglutamine-1 (BioWhittaker cat. BE 17-605 / U1), 50 μg / mL Zeocin (InvivoGen, ant-zn), 2.5 μg / mL Blasticidin (InvivoGen, ant-bl-5), and 25 μg / mL Hygromycin (InvivoGen, ant-hg). Standard propagation conditions consisted of plating 9x106, 4x106, 2x106cells in a T225 flasks to be processed after 2, 3, or 4 days, respectively.

[0317] A source plate was generated containing 20 serially diluted compounds in DMSO (duplicate 8-point dose response). Next, 0.8 μL of compounds were transferred from the source plate to a destination plate prefilled with 79.2 μL of Ca2+free Tyrode’s buffer (130 mM NaCl, 5 mM KCl, 1 mM MgCl2, 5 mM NaHCO3, 20 mM HEPES at pH 7.4). The destination plate was placed on a plate shaker (5 seconds at 2000 rpm) to mix. This process resulted in a destination 146sf-5953625Docket No.: 79275-20027.40 plate with 2X concentrated compound solutions. All transfer and mixing steps were conducted with an CyBi®-Well dispenser.

[0318] Cells were split by gently washing with DPBS (Euroclone, ECB4004L), followed by a 5- minute incubation (humidified, 37˚C with 5% CO2) with trypsin-EDTA solution (Euroclone, ECB3052D). Detached cells were diluted with standard complete medium without selective agents, counted, and plated in a 384 MTP microplate (GR4332CPL, Twin Helix) (10,000 cells / well in 25 μl / well) using a MATRIX WellMate dispenser. Plates were placed into a humidified incubator (37°C with 5% CO2) overnight. The following day, 20 μL of doxycycline (Sigma, D9891) at 20 ng / mL in standard complete medium was added to cells with a CyBi ®Drop dispenser to induce APOL1 E150 G2 expression. After a 6-hour incubation (humidified, 37˚C with 5% CO2), cells were washed 3 times with Ca2+free Tyrode’s Buffer (130 mM NaCl, 5 mM KCl, 1 mM MgCl2, 5 mM NaHCO3, 20 mM HEPES at pH 7.4) using a BIOTEK Microplate washer, such that 10 μL of buffer remained in each well after the final wash. Assay plates were then stored at room temperature for 10 minutes. Next, 10μL of diluted compounds were transferred to the assay plate from the 2X compound plate using a CyBi®-Well dispenser. Compound incubation was then carried out at room temperature for 10 minutes. The assay plate was transferred to the FLIPRTETRAand 20 μL of 10 mM Ca2+(final concentration = 5 mM) Tyrode’s buffer was injected.

[0319] AC50values reported in Table T3 below represent the half-maximal activity concentration for the inhibition of calcium transport by APOL1 E150 G2. Table T3† indicates data from one replicate

[0320] In the manner described above with regard to APOL1 E150 G2 (HEK T- REx / GCaMP6f / APOL1 G2 K6.3), a HEK293 clonal cell line can be generated to stably express GCaMP6f, a genetically encoded calcium indicator, and inducibly express APOL1 [G0] E150.sf-5953625Docket No.: 79275-20027.40 APOL1 dependent calcium entry into these cells can be monitored by the change in GCaMP6f fluorescence. The effect of APOL1 inhibitors on pore function can be determined by comparing the GCaMP6f dependent fluorescence signal in the absence and presence of compound. Example B2

[0321] This example shows that the compounds of the present disclosure are able to reduce cell death caused by overexpression of APOL1 E150 G2.

[0322] A HEK293 clonal cell line overexpressing APOL1 E150 G2 (HEK293 / T-REx APOL1 G2 / clone #2) was maintained in 1x DMEM-GlutaMax (Gibco, 10569-010) media with 10% tetracycline-free FBS (Takara Bio USA, 631101), 5 μg / mL Blasticidin (Gibco, A1113903), and 100 μg / mL Zeocin (Invitrogen, R25001) in T75 flasks. In preparation for the assay, this media was aspirated and 2 mL of prewarmed TrypLE Express (Gibco, 12605-010) was added to a flask to detach cells. The flask was then incubated (humidified, 37˚C with 5% CO2) for 3-5 minutes. Afterwards, 8 mL of prewarmed cell assay media (1x DMEM-GlutaMax media with 10% tetracycline-free FBS) was added to the trypsinized cells. The suspension was gently mixed, and cells were counted using a Countess Cell Counting Chamber (Invitrogen). The suspension was diluted using cell assay media to generate a working stock solution (166,667 cells / mL). Using a MultiDrop Combi (Thermo Electron Corp), 30 μL (final cell density = 5,000 cells / well) of the working stock solution was dispensed into each well of white 384-well assay ready plates (Nunc™, 164610) containing 6 ng / mL doxycycline, to induce APOL1 expression, and compound. All compounds were plated in a duplicate 8-point dilution series that consisted of 3- fold stepwise dilutions (0.5% DMSO final). Assay plates were incubated (humidified, 37˚C with 5% CO2) for 17 hours. After the incubation, the plates were equilibrated at room temperature for 1 hour. Next, 15 μl of CellTiter-Glo® reagent (Promega, G7570) was added to each well using a MultiDrop Combi. Plates were placed on an orbital shaker (500 rpm) for 5 minutes to induce cell lysis and then incubated at room temperature for 10 minutes. Luminescence was measured on an Envision plate reader. Collaborative Drug Discovery software was utilized for graphing data. Plots were generated using a four-parameter logistic curve fit. 148sf-5953625Docket No.: 79275-20027.40

[0323] Table T4 below provides the results from this experiment. Unless otherwise specified, EC50 values are reported as the geometric mean of at least 2 assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. Compounds in Table T4 are referred to by the corresponding Compound Number in Table 1, which is also referred to in the synthetic examples.

[0324] Rescue EC50values reported in Table T4 below represent the half-maximal effective concentration for reversal of cell death caused by overexpression of APOL1 E150 G2. This example demonstrates that compounds of the present disclosure are able to reduce cell death caused by overexpression of APOL1 at sub micromolar concentration. Table T4† indicates data from one replicate

[0325] In the manner described above with regard to APOL1 E150 G2 (HEK / T-REx APOL1 G2 / clone #2), a HEK293 clonal cell line was generated to inducibly express APOL1 [G0] E150. APOL1 dependent cell death in these cells can be monitored using CellTiter-Glo after 24-48 h of induction. The effect of APOL1 inhibition on cell death can be determined by comparing the APOL1 dependent cell death in the absence and presence of compound. Example B3

[0326] This example shows that the compounds of the present disclosure are able to reduce cell death caused by overexpression of APOL1. 149sf-5953625Docket No.: 79275-20027.40

[0327] Compounds were also assayed in a HEK293 clonal cell line overexpressing APOL1 E150 G1 by a method similar to that shown in Example B2 above.

[0328] Table T5 below provides the results from this experiment. Unless otherwise specified, EC50 values are reported as the geometric mean of at least 2 assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. A superscript † symbol indicates a value from the average of a technical replicate from a single assay run, where each compound was assayed twice in the same plate. Compounds in Table T5 are referred to by the corresponding Compound Number in Table 1, which is also referred to in the synthetic examples.

[0329] Rescue EC50values reported in Table T5 below represent the half-maximal effective concentration for reversal of cell death caused by overexpression of APOL1 E150. This example demonstrates that compounds of the present disclosure are able to reduce cell death caused by overexpression of APOL1 at sub micromolar concentration. Table T5Example B4

[0330] APOL1 G2 human immortalized podocyte viability assay for measurement of cytotoxicity reversal by compound (APOL1 G2 podocyte cell rescue assay). This example shows that the compounds of the present disclosure are able to reverse cytotoxicity in human immortalized podocytes.sf-5953625Docket No.: 79275-20027.40

[0331] Cell Handling. The hTERT-immortalized kidney podocyte cell line was procured from the laboratory of Dr. Moin Saleem at the University of Bristol, UK (Nephrology 17 (2012) 525– 531; doi:10.1111 / j.1440-1797.2012.01619.x; herein incorporated by reference in its entirety). Parental and engineered cell lines were cultured in RPMI 1640 media (Gibco, 11875093) with 10% Tet System Approved FBS (Takara, 631101). The engineered cell line was maintained under selection (2.5 μg / mL puromycin). Cell lines were maintained and engineered at 33˚C. Cell cultures were transferred to 37˚C for 10 to 14 days to initiate differentiation (Nephrology 17 (2012) 525–531; doi:10.1111 / j.1440-1797.2012.01619.x; herein incorporated by reference in its entirety). During this time, media was refreshed every 3 days. After differentiation, cells engineered to inducibly express APOL1 G2 were used in the podocyte cell rescue assay.

[0332] Cell Line Engineering. The APOL1 G2 coding sequence was cloned into the pLVX- TetOne-Puro vector and verified by sequencing (Genscript Biotech). This construct was designed to have a C-terminal HiBiT tag. Lentiviral packaging of the vector was conducted using the Lenti-X Packaging Single Shots (VSVG) system according to manufacturer instructions (Takara Bio, 631275). A stable cell line was generated by transfecting the parental podocyte cell line with the concentrated virus in media with 5 μg / mL polybrene (Sigma, TR-1003-G). Media was changed the following day. 72 hours post transfection, 2.5 μg / mL puromycin (Gibco, A1113803) was added to the cells and cells were maintained in selection media thereafter. This APOL1 G2 stable cellular pool was subjected to a stringent limiting dilution to generate a pure stable clone (Podocyte / pLVX-TetOne APOL1 G2 / clone D10) capable of inducible expression of APOL1 G2.

[0333] Assay Setup. T175 flasks containing differentiated podocytes engineered to inducibly express APOL1 G2 (Podocyte / pLVX-TetOne APOL1 G2 / clone D10) were washed once with 15 mL of DPBS (Thermo Fisher, 14190-144). These flasks were each trypsinized with 3 mL of prewarmed TrypLE Express (Gibco, 12605-010) and incubated at 37°C with 5% CO2until cells detached and neutralized with 7 mL of prewarmed assay media (RPMI 1640 media with 10% Tet System Approved FBS, no selection agent). Cells were pooled and the resulting suspension was gently mixed. The cell suspension was counted using a Countess Cell Counting Chamber (Invitrogen) and the cell concentration was adjusted to 240,000 cells / mL using assay media. Next, 25μL of a 480 ng / mL working stock of doxycycline diluted in assay media was added to 151sf-5953625Docket No.: 79275-20027.40 an assay ready plate. All experiments were performed in 384-well, white, solid bottom, tissue culture treated plates (Greiner, 781080). The assay ready compound plates were generated with duplicate 8-point compound dilution series that consisted of 3-fold stepwise dilutions (0.4% DMSO final). The plates were centrifuged at 1000 rpm for 1 minute. 25μL of diluted cell suspension (final cell density = 6,000 cells / well) was added to each well. The plates were centrifuged again at 1000rpm for 1 minute and then incubated in a humidified incubator (37°C with 5% CO2). After 95 hours, the assay plates were removed from the incubator and allowed to equilibrate to room temperature for 1 hour. CellTiter-Glo® reagent (Promega, G7570) was prepared according to the manufacturer's instructions. 25 μL of CellTiter-Glo® reagent was added to each well. Assay plates were sealed with foil and mixed for 5 minutes on an orbital shaker (500 rpm) to induce cell lysis. Plates were centrifuged at 1000 rpm for 1 minute. 10 minutes after CellTiter-Glo® reagent addition, an Envision plate reader (Perkin Elmer) was used to measure the luminescent signal of each assay plate. Collaborative Drug Discovery software was utilized for graphing data.

[0334] Table T6 below provides the results from this experiment. Unless otherwise specified, EC50values are reported as the geometric mean of at least 2 assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. Compounds in Table T6 are referred to by the corresponding Compound Number in Table 1, which is also referred to in the synthetic examples.

[0335] Rescue EC50 values reported in Table T6 below represent the half-maximal effective concentration for reversal of cell death caused by overexpression of APOL1 E150 G2. This example demonstrates that compounds of the present disclosure are able to reduce cell death caused by overexpression of APOL1 E150 G2 at sub micromolar concentration. Table T6sf-5953625Docket No.: 79275-20027.40Example B5

[0336] APOL1 G0 / G1 / G2 viability assay for measurement of cytotoxicity reversal by compound in trypanosomes (APOL1 G0 / G1 / G2 trypanosome cell rescue assay). This example shows that the compounds of the present disclosure are able to reverse cytotoxicity in trypanosomes. Example B5-A

[0337] APOL1 protein expression and purification. The mature form of APOL1 proteins, residues 28-398, were expressed from a pET28a vector with an N-terminal His-tag and TEV cleavage site. Proteins were expressed in Escherichia coli BL21-CodonPlus (DE3)-RIPL cells. Liter cultures of terrific broth were grown at 37°C until an OD600of ~0.8 was reached and then induced with isopropyl β-D-1-thiogalactopyranoside (IPTG; final concentration of 500 μM). Afterwards, cultures were grown for 3 hours at 37°C. For protein purification, cell pellets were resuspended in lysis buffer (50 mM Tris, pH 8.5, 5 mM EDTA, 0.5 mM DTT, 0.5 mM PMSF) supplemented with a cocktail of protease inhibitors. Cells were lysed by sonication, centrifuged, and the resulting pellet was collected. The homogenized pellet was resuspended in wash buffer (50 mM Tris, pH 8.5, 0.5 M NaCl, 5 mM EDTA, 0.5 mM DTT, 0.5 mM PMSF, protease inhibitor cocktail) and collected by centrifugation. Inclusion body dissolution was then conducted as previously reported (PNAS 112(9) (2015) 2894-2899; www.pnas.org / cgi / doi / 10.1073 / pnas.1421953112; herein incorporated by reference in its entirety). The solubilized APOL1 protein was applied to a nickel column (HisTrap, GE Life Sciences) preequilibrated in buffer A (50 mM Tris, pH 8.5, 0.15 M NaCl, 1% zwittergent 3–14, protease inhibitor cocktail). The resin was washed with buffer B (50 mM Tris, pH 8.5, 0.15 M NaCl, 0.1% DDM) and TEV cleavage was conducted on column overnight. Afterwards, the column was washed with buffer B, followed by His-washing buffer (50 mM Tris, pH 8.5, 0.15 M NaCl, 0.1% DDM, 10 mM imidazole). The protein was then removed from the resin using His- 153sf-5953625Docket No.: 79275-20027.40 elution buffer (50 mM Tris, pH 8.5, 0.15 M NaCl, 0.1% DDM, 250 mM imidazole). The sample was further purified by size exclusion chromatography using a Superdex 200 Increase column (GE Life Sciences) in 50 mM Tris, pH 8.5, 0.15 M NaCl, and 0.1% DDM buffer. All APOL1 proteins (G0, G1, and G2) were generated at Viva Biotech (Shanghai) Ltd.

[0338] Modified HMI-9 media preparation (https: / / tryps.rockefeller.edu / trypsru2_culture_media_preparation.html; herein incorporated by reference in its entirety). Trypanosomes were cultured in modified HMI-9 media consisting of IMDM (ThermoFisher, 12440053), 10% heat-inactivated FBS (Gibco, 10082-147), 10% Serum Plus (Sigma-Aldrich, 14008C), 1x HMI-9 supplement stock, and 1% hypoxanthine stock. The 10x HMI-9 supplement stock was made by dissolving 280 mg bathocuproine disulfonic acid (Sigma-Aldrich, 146625), 1820 mg cysteine (add after bathocuproine) (Sigma-Aldrich, 30089), 1100 mg pyruvic acid (Sigma-Aldrich, 107360), 100 mg uracil (Sigma-Aldrich, U0750), 100 mg cytosine (Sigma-Aldrich, C3506) and 140 μL 2-mercaptoethanol (Sigma-Aldrich, M3148) in 1000 mL of water. The resulting solution was aliquoted and stored at -20˚C. The hypoxanthine stock was made by dissolving 4 g of NaOH into 1000 mL of water. Afterwards, 13.6 g hypoxanthine (Sigma-Aldrich, H9377) was added to this mixture. The resulting solution was aliquoted and stored at -20˚C.

[0339] Assay Setup. Trypanosoma brucei Lister 427 VSG221 (ATCC, PRA-382) cells were cultured in modified HMI-9 media. All experiments were performed in 384-well, white, solid bottom, tissue culture treated plates (Greiner, 781080). Assay ready plates were generated with duplicate 11-point compound dilution series that consisted of 2-fold stepwise dilutions (0.4% DMSO final). To each well, was added 20 μL of 2 μg / mL of APOL1 G0, G1, or G2 recombinant protein in modified HMI-9 media using a MultiDrop Combi (final APOL1 protein concentration = 1 μg / mL). Trypanosomes were counted using a hemacytometer and diluted in modified HMI-9 media to a concentration of 1.25 x 104cell / mL. 20 μL of this trypanosome suspension was added to each well to give a total assay volume of 40 μL and a final cell count of 250 trypanosomes / well. Plates were centrifuged at 1000 rpm for 1 minute and then incubated for 20 hours (humidified, 37˚C with 5% CO2). After incubation, the plates were equilibrated at room temperature for 1 hour. Next, 20 μL of CellTiter-Glo® reagent (Promega, G7570) was added to each well. Plates were sealed and placed on an orbital shaker (500 rpm) for 5 minutes to induce 154sf-5953625Docket No.: 79275-20027.40 cell lysis. The plates were centrifuged at 1000 rpm for 1 minute and then incubated at room temperature for an additional 10 minutes. Luminescence signal was measured on an Envision plate reader. Collaborative Drug Discovery software was utilized for graphing data.

[0340] Table T7 below provides the results from this experiment. Unless otherwise specified, EC50 values are reported as the geometric mean of at least 2 assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. Compounds in Table T7 are referred to by the corresponding Compound Number in Table 1, which is also referred to in the synthetic examples.

[0341] Rescue EC50values reported in Table T7 below represent the half-maximal effective concentration for reversal of cell death caused by overexpression of APOL1 E150. This example demonstrates that compounds of the present disclosure are able to reduce cell death caused by overexpression of APOL1 E150 at sub micromolar concentration. Example B5-B

[0342] Assay Setup: Trypanosoma brucei Lister 427 VSG221 (ATCC, PRA-382) cells were cultured in modified HMI-9 media. All experiments were performed in 384-well, white, solid bottom, tissue culture treated plates (Greiner, 781080). Assay ready plates were generated with duplicate 11-point compound dilution series that consisted of 2-fold stepwise dilutions (0.4% DMSO final). To each well, was added 20 μL of APOL1 (G0, G1, or G2) diluted in modified HMI-9 media. The final concentrations of APOL1 G0, APOL1 G1, and APOL1 G2 were 0.40, 0.10, and 1.0 μg / mL, respectively. These concentrations of APOL1 proteins were sufficient to cause 90% trypanosome cell death. Trypanosomes were counted using a hemacytometer and diluted in modified HMI-9 media to a concentration of 5.0 x 104cells / mL. 20 μL of the trypanosome suspension was added to each well to give a total assay volume of 40 μL and a final cell count of 1000 trypanosomes / well. Plates were centrifuged at 1000 rpm for 1 minute and then incubated for 20 hours (humidified, 37˚C with 5% CO2). After incubation, the plates were equilibrated at room temperature for 1 hour. Next, 20 μL of CellTiter-Glo® reagent (Promega, G7570) was added to each well. Plates were sealed and placed on an orbital shaker (500 rpm) for 5 minutes to induce cell lysis. The plates were centrifuged at 1000 rpm for 1 minute and thensf-5953625Docket No.: 79275-20027.40 incubated at room temperature for an additional 10 minutes. Luminescence signal was measured on an Envision plate reader. Collaborative Drug Discovery software was utilized for graphing data. Table T7:indicates that the protocol described in Example B5-A was used; other compounds were tested using the protocol described in Example B5-B Example B6

[0343] APOL1 E150 G2 mouse renal model for measurement of albuminuria prevention by compound. This example shows that the compounds of the present disclosure are able to prevent albuminuria.

[0344] APOL1 transgenic (Tg) mice with a bacterial artificial chromosome (BAC) containing APOL1 G2 and its upstream and downstream genomic regions (Taconic, Model # 13022) are bred to homozygosity. APOL1 G2 homozygous (G2 HOM) male mice, greater than 6 weeks of age are utilized in experiments. All studies are conducted under a protocol approved by the Institutional Animal Care and Use Committee (IACUC).

[0345] Baseline urine samples are collected over a 24-hour period 7 days prior to the start of the experiment. Urine volume is determined by weight and stored at -80˚C until use. Afterwards, baseline blood samples are collected via submandibular bleed into serum separate (SS) tubessf-5953625Docket No.: 79275-20027.40 (BD Microtainer). Serum samples are allowed to clot at room temperature for 30 minutes prior to centrifugation at 12000 rpm, 4˚C for 5 minutes. The concentration of APOL1 is determined in these samples using an APOL1 ELISA kit (Proteintech, KE00047) according to the manufacturer’s instructions.

[0346] On the day of the experiment (0 hour), mice are individually identified, weighed, and assigned to one of the treatment groups. Treatment groups have similar average levels of serum APOL1. Mice are administered with two doses of compound test article and one dose of recombinant mouse interferon gamma (mIFNγ) (MilliporeSigma, Catalog #IF005) per day for 2 days. Compound test article is administered via oral gavage at 10 mL / kg body weight dose volume at 0, approximately 10, 24, and 34 hours. mIFNγ (1.5 x 1011unit / kg body weight) is administered via intraperitoneal injection at 10 mL / kg body weigh dose volume at 0 and 24 hours. Urine collection is immediately initiated after the second dose of mIFNγ. Specifically, mice are individually placed in a metabolic cage (Lab Products) for 24 hours where urine and feces are collected into separate tubes. During this time, mice have access to an enrichment toy, gel diet (Bio-serve), and drinking water (Innovive). At the end of the experiment, mice were anesthetized under isoflurane and blood is collected via cardiac puncture followed with a cervical dislocation to ensure death.

[0347] Urine samples are analyzed for urine albumin and urine creatinine levels. The concentration of urine albumin is determined using a mouse albumin immunoperoxidase assay kit (Immunology Consultants Laboratory, E-90AL) according to the manufacturer’s instructions. Urine creatinine is analyzed using LC-MS methodology at WuXi App Tec (DMPK, New Jersey, USA). Example B7

[0348] This example shows that compounds of the present disclosure can be assessed in transgenic mouse models (or other animal models) engineered to express the pathogenic APOL1 E150 variant. APOL1 E150 G0, G1, and G2 are detectible in retinal tissue and induced by interferon stimulation or other stimulation from another cytokine in a mouse model known to mirror APOL1 disease phenotypes such as retinopathies.sf-5953625Docket No.: 79275-20027.40

[0349] Transgenic mice are generated harboring a randomly integrated bacterial artificial chromosome (BAC) designed to express the DME associated E150 APOL1 variant from the native human promoter. APOL1 is induced in these mice via interferon stimulation or other stimulation from another cytokine (Yoshida et al, APOL1 kidney risk variants in glomerular diseases modeled in transgenic mice. bioRxiv [Preprint]. 2023 Mar 27:2023.03.27.534273. doi: 10.1101 / 2023.03.27.534273. PMID: 37090576; PMCID: PMC10120684; and McCarthy et al, Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease. Dis Model Mech. 2021 Aug 1;14(8):dmm048952. doi: 10.1242 / dmm.048952. Epub 2021 Aug 5. PMID: 34350953; PMCID: PMC8353097; each herein incorporated by reference in its entirety) and the effect on vascular function in the eye is evaluated using methods such as, but not limited to, fundus fluorescein angiography and optical coherence tomography (Comin et al, Quantification of retinal blood leakage in fundus fluorescein angiography in a retinal angiogenesis model. Sci Rep. 2021 Oct 6;11(1):19903. doi: 10.1038 / s41598-021-99434-2. PMID: 34615975; PMCID: PMC8494755; and Fischer at al, Phenotyping of mouse models with OCT. Methods Mol Biol. 2013;935:79-85. doi: 10.1007 / 978- 1-62703-080-9_5. PMID: 23150361; each herein incorporated by reference in its entirety). The effects of compounds can be assessed in this model after either oral or intravitreal administration.

[0350] APOL1 E150 G2 mouse transgenic model to validate acute effects of interferon on APOL1 expression in eye retinal tissue

[0351] APOL1 transgenic (Tg) mice with a bacterial artificial chromosome (BAC) containing APOL1 E150 G2 and its upstream and downstream genomic regions (Taconic, Model # 13022) were bred to homozygosity. APOL1 E150 G2 homozygous (G2 HOM) male mice, greater than 6 weeks of age were utilized in experiments. All studies were conducted under a protocol approved by the Institutional Animal Care and Use Committee (IACUC).

[0352] On the day of the experiment (0 hour), mice were individually identified, weighed, and assigned to one of the treatment groups. Treatment groups had similar average levels of serum APOL1. PBS or mIFNγ (1.5 x 107unit / kg body weight) was administered via intraperitoneal injection at 10 mL / kg body weigh dose volume at 0 and 24 hours. At the end of the experiment, mice were anesthetized under isoflurane and blood was collected via cardiac puncture followedsf-5953625Docket No.: 79275-20027.40 with a cervical dislocation to ensure death. Eyes were collected, rinsed with cold PBS solution, and retina samples were dissected, and snap frozen in liquid nitrogen.

[0353] Fresh frozen retinas were transferred to 0.5ml Precellys tubes containing 1.4 mm ceramic beads (Bertin technologies, PN CK14) in liquid nitrogen. Tissue was homogenized using a Precellys Evolution Homogenizer (Bertin technologies) using the soft tissue setting (5800 rpm, 3 x 15 secs). RNA was extracted using Qiagen RNeasy plus mini kit (Qiagen, PN 74136) according to the manufacturer’s protocol and quantified on a NanoDrop spectrophotometer (Thermo Fisher Scientific Inc.).

[0354] Gene expression analysis for APOL1 and PECAM1 were performed by RT-PCR using TaqMan™ RNA-to-CT™ 1-Step Kit (Applied Biosystems, PN 4392938) according to the manufacturer’s instruction. The assay was performed on the Quantstudio 6 FLEX Real-Time PCR system (Thermo Fisher Scientific Inc.) in 10μL reaction volume containing 5μL of 2x Taqman RT-PCT mix, 0.25μL of Taqman RT enzyme mix, 1μL of RNA (25 ng) and 0.5μL gene specific Taqman probe [mouse GAPDH (housekeeping gene)- Mm99999915-g1; human APOL1- Hs01066280-m1; mouse PECAM1- Mm01242576-m1] and 3.25μL of RNase / DNase free water. Standard PCR reaction conditions were used for all transcripts. Each of the PCR reactions were performed in duplicates. The CT values of APOL1 and PECAM1 were normalized to the housekeeping gene, GAPDH, to obtain DCT. The DDCT and fold changes were calculated using the following equations: ΔΔCt = ΔCtIFNg– ΔCtPBS ; Fold change = 2-(''CT).Statistical analysis was performed by two-way ANOVA.

[0355] APOL1 E150 G2 was significantly induced with 48 hours of interferon treatment. The results are shown in Table T8 and FIG. 1 which shows results of the mouse eye APOL1 acute mouse model (sample type: retina). Table T8159sf-5953625Docket No.: 79275-20027.40Example B8

[0356] APOL1 E150 G2 mouse transgenic model to validate chronic effects of interferon on APOL1 expression in eye tissue.

[0357] APOL1 transgenic (Tg) mice with a bacterial artificial chromosome (BAC) containing APOL1 E150 G2 and its upstream and downstream genomic regions (Taconic, Model # 13022) were bred to homozygosity. APOL1 E150 G2 homozygous (G2 HOM) male mice, greater than 6 weeks of age were utilized in experiments. All studies were conducted under a protocol approved by the Institutional Animal Care and Use Committee (IACUC).

[0358] On the day of the experiment (0 hour), mice were individually identified, weighed, and assigned to one of the treatment groups. Treatment groups had similar average levels of serum APOL1 E150 G2. PBS or AAV8-CAG-IFNγ vector to drive mouse interferon expression was administered via intravenous injection at 2.0x1011gc / mouse in 200 μL dose volume at 0 hour. After 37 days (~5 weeks), mice were anesthetized under isoflurane and blood was collected via cardiac puncture followed with a cervical dislocation to ensure death. Eyes were collected, rinsed with cold PBS solution, and retina / choroid samples were dissected, and snap frozen in liquid nitrogen.

[0359] Fresh frozen retina / choroid samples were transferred to 0.5ml Precellys tubes containing 1.4 mm ceramic beads (Bertin technologies, PN CK14) in liquid nitrogen. Tissue was homogenized using a Precellys Evolution Homogenizer (Bertin technologies) using the soft tissue setting (5800 rpm, 3 x 15 secs). RNA was extracted using Qiagen RNeasy plus mini kit (Qiagen, PN 74136) according to the manufacturer’s protocol and quantified on a NanoDrop spectrophotometer (Thermo Fisher Scientific Inc.).

[0360] Gene expression analysis for APOL1 and PECAM1 were performed by RT-PCR using TaqMan™ RNA-to-CT™ 1-Step Kit (Applied Biosystems, PN 4392938) according to the manufacturer’s instruction. The assay was performed on the Quantstudio 6 FLEX Real-Time PCR system (Thermo Fisher Scientific Inc.) in 10μL reaction volume containing 5μL of 2x 160sf-5953625Docket No.: 79275-20027.40 Taqman RT-PCT mix, 0.25μL of Taqman RT enzyme mix, 1μL of RNA (25 ng) and 0.5μL gene specific Taqman probe [mouse GAPDH (housekeeping gene)- Mm99999915-g1; human APOL1- Hs01066280-m1; mouse PECAM1- Mm01242576-m1] and 3.25μL of RNase / DNase free water. Standard PCR reaction conditions were used for all transcripts. Each of the PCR reactions were performed in duplicates. The CT values of APOL1 and PECAM1 were normalized to the housekeeping gene, GAPDH, to obtain DCT. The DDCT and fold changes were calculated using the following equations:

[0361] ΔΔCt = ΔCt AAV-CAG-IFng– ΔCtPBS ; Fold change = 2-(DDCT).Statistical analysis was performed by two-way ANOVA.

[0362] APOL1 E150 G2 was significantly induced with 5 weeks of interferon treatment. The results are shown in Table T9 and FIG. 2, which shows the results of the mouse eye APOL1 chronic mouse model (sample type: retina / choroid). Table T9Example B9

[0363] APOL1 induction via interferon is sufficient to induce renal damage and the compounds of the present disclosure are able to prevent albuminuria in APOL1 E150 G2 BAC transgenic model. Compounds in the current disclosure can also be tested for their ability to prevent retinal damage in response to APOL1 induction via acute interferon administration (or of another administration of cytokine), by examining vascular leak via fundus fluorescein angiography or optical coherence tomography (Comin et al, Quantification of retinal blood leakage in fundus fluorescein angiography in a retinal angiogenesis model. Sci Rep. 2021 Oct 6;11(1):19903. doi: 10.1038 / s41598-021-99434-2. PMID: 34615975; PMCID: PMC8494755; and Fischer at al, Phenotyping of mouse models with OCT. Methods Mol Biol. 2013;935:79-85. doi: 10.1007 / 978- 1-62703-080-9_5. PMID: 23150361; each herein incorporated by reference in its entirety). 161sf-5953625Docket No.: 79275-20027.40 Example B10

[0364] APOL1 induction via interferon is sufficient to induce renal damage and the compounds of the present disclosure are able to prevent albuminuria in APOL1 E150 G2 BAC transgenic model. Compounds in the current disclosure can also be tested for their ability to prevent retinal damage in response to APOL1 induction via chronic interferon administration, by examining vascular leak via fundus fluorescein angiography or optical coherence tomography (Comin et al, Quantification of retinal blood leakage in fundus fluorescein angiography in a retinal angiogenesis model. Sci Rep. 2021 Oct 6;11(1):19903. doi: 10.1038 / s41598-021-99434-2. PMID: 34615975; PMCID: PMC8494755; and Fischer at al, Phenotyping of mouse models with OCT. Methods Mol Biol. 2013;935:79-85. doi: 10.1007 / 978-1-62703-080-9_5. PMID: 23150361; each herein incorporated by reference in its entirety).

[0365] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entireties, to the same extent as if each were incorporated by reference individually.

[0366] It is to be understood that, while the disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages, and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains. 162sf-5953625

Claims

Docket No.: 79275-20027.40 CLAIMS WHAT IS CLAIMED IS:

1. A compound of formula (I’):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: either: (1) Y1is CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule; and s and t are both 0 or 1, wherein when r is 1, both s and t are 1; or (2) Y1is a bond; Y2is -C(O)-; Y3is -NH-; and 163sf-5953625Docket No.: 79275-20027.40 s and t are each 1; X1, X2, X3, and X4are each independently -CH- or -N-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2-, -O-, or ###-CH2O- ####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; p is an integer from 0 to 8; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: 164sf-5953625Docket No.: 79275-20027.40 Y1is CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule; and s and t are both 0 or 1, wherein when r is 1, both s and t are 1.

3. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y1is a bond; Y2is -C(O)-; Y3is -NH-; and s and t are each 1.

4. The compound of claims 1 or 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:sf-5953625Docket No.: 79275-20027.40 Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, or -O-; r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2- or -O-, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; p is an integer from 0 to 8; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH. 166sf-5953625Docket No.: 79275-20027.40 5. The compound of any one of claims 1, 2, or 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

6. The compound of any one of claims 1, 2, or 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

7. The compound of any one of claims 1, 2, or 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I’-A3):sf-5953625Docket No.: 79275-20027.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

8. The compound of any one of claims 1, 2, or 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A4):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

9. The compound of any one of claims 1, 2, or 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A4): 168sf-5953625Docket No.: 79275-20027.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. The compound of any one of claims 1, 2, or 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I’-A6):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

11. The compound of any of claims 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted C1-6alkylene.

12. The compound of any of claims 1-11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is unsubstituted ethylene. 169sf-5953625Docket No.: 79275-20027.40 13. The compound of any of claims 1-12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L2is -O-.

14. The compound of any of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is 9-10 membered heteroaryl optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1-3alkyl or -OH.

15. The compound of any of claims 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring16. The compound of claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I’-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-5953625Docket No.: 79275-20027.40 17. The compound of any one of claims 1, 2, or 16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

18. The compound of any of claims 1-17, wherein the compound is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

19. A method for preparing the compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising a step of reacting a compound of formula (I’-A’):wherein: either: (1) Y1is -CH2- or -N(Ry)-, wherein Ryis (i) H, (ii) C1-6alkyl optionally substituted with one or more D, halo, or -OH, (iii) C2-6alkynyl, (iv) C3-15cycloalkyl optionally substituted withsf-5953625Docket No.: 79275-20027.40 one or more C1-6alkyl or C1-6haloalkyl, or (v) 3-15 membered heterocyclyl optionally substituted with one or more C1-6alkyl or C1-6haloalkyl; Y2is -CH(OH)-, -C(O)-, -S(O)2-, or -O-; Y3is a bond, -CH2-, -O-, or ###-CH2O-####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule; s and t are both 0 or 1, wherein when r is 1, both s and t are 1; or (2) Y1is a bond; Y2is -C(O)-; Y3is -NH-; and s and t are each 1; X1, X2, X3, and X4are each independently -CH- or -N-;r is 0 or 1, provided that, (1) when r is 0, Y1is -N(Ry)-, and Y2is -C(O)-, then Y3is -CH2-, -O-, or ###-CH2O- ####, wherein ### denotes the point of attachment to Y2and #### denotes the point of attachment to the rest of the molecule, and (2) when r is 1, then Y3is a bond; R1, if present, is, independently at each occurrence, (i) halo, (ii) -CN, (iii) -OH, (iv) C1-6alkyl optionally substituted with one or more halo, or (v) C1-6alkoxy optionally substituted with one or more halo; R2, if present, is, independently at each occurrence, C1-6alkyl; m is an integer from 0 to 4; p is an integer from 0 to 8 with a compound of formula (I’-B):sf-5953625Docket No.: 79275-20027.40 wherein: the dashed line represents a single or double bond; Z is halo, oxo, or a sulfonate ester; L1is C1-6alkylene optionally substituted with one or more D or C1-6alkyl, wherein the C1- 6alkyl is optionally substituted with one or more -OH or C1-6alkoxy; L2is -O- or -NH-; and Ring A is (i) C9-10aryl, (ii) 9-10 membered heterocyclyl, or (iii) 9-10 membered heteroaryl, wherein the C9-10aryl, 9-10 membered heterocyclyl, and 9-10 membered heteroaryl are independently optionally substituted with one or more C1-3haloalkyl or C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one or more C1- 3alkyl or -OH, to give a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

20. The method of claim 19, wherein the compound of claim 1 is prepared by a step comprising alkylation of an amine of formula (I’-A’) with an alkyl halide or sulfonate ester compound of formula (I’-B) in the presence of an inorganic base.

21. The method of claim 20, wherein the inorganic base is potassium carbonate or sodium bicarbonate.

22. A pharmaceutical composition, comprising (1) a compound of any of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (2) one or more pharmaceutically acceptable excipients.

23. A method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any or claims 1-18, or a stereoisomer orsf-5953625Docket No.: 79275-20027.40 tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22.

24. A method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22.

25. A method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of any of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22.

26. The method of claim 25, wherein the disease, disorder, or condition is a kidney disease or diabetic retinopathy.

27. The method of claim 26, wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

28. The method of any of claims 25-27, wherein the disease, disorder, or condition is a kidney disease.

29. The method of any of claims 25-28, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

30. The method of claim 25 or claim 26, wherein the disease, disorder, or condition is diabetic retinopathy.sf-5953625Docket No.: 79275-20027.40 31. The method of claim 30, wherein the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema.

32. The method of claim 30 or claim 31, wherein the administration comprises oral administration or intravitreal injection.

33. The method of claim 32, wherein the administration comprises oral administration.

34. The method of claim 32, wherein the administration comprises intravitreal injection.

35. The method of any of claims 30-34, further comprising administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual.

36. A method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a compound of any of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.

37. The method of claim 36, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease or diabetic retinopathy.

38. The method of claim 36 or claim 37, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease.

39. The method of any of claims 36-38, wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.

40. The method of claim 36, wherein the APOL1-mediated disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosissf-5953625Docket No.: 79275-20027.40 (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

41. The method of claim 36 or claim 37, wherein the APOL-1 mediated disease, disorder, or condition is diabetic retinopathy.

42. The method of claim 40, wherein the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema.

43. The method of claim 41 or claim 42, wherein the administration comprises oral administration or intravitreal injection.

44. The method of claim 43, wherein the administration comprises oral administration.

45. The method of claim 43, wherein the administration comprises intravitreal injection.

46. The method of any of claims 41-45, further comprising administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual.

47. The method of any of claims 43-46, wherein the individual has an APOL1 mutation.

48. The method of claim 47, wherein the APOL1 mutation is a gain-of-function mutation.

49. The method of any of claims 25-48, wherein a therapeutically effective amount of a compound of any of claims 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 18, is administered.sf-5953625Docket No.: 79275-20027.40 50. The method of any of claim 23-49, wherein the individual is a human.

51. A kit, comprising (1) a compound of any of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, and (2) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

52. The kit of claim 51, wherein the disease, disorder, or condition is a kidney disease or diabetic retinopathy.

53. The kit of claim 51 or claim 52, wherein the disease, disorder, or condition is a kidney disease.

54. The kit of any of claims 51-53, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

55. The kit of any of claims 51-54, wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

56. The kit of claim 51, wherein the disease, disorder, or condition is diabetic retinopathy.

57. The kit of claim 56, wherein the diabetic retinopathy is selected from the group consisting of non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema.

58. The kit of claim 56 or claim 57, wherein the administration comprises oral administration or intravitreal injection.

59. The kit of claim 58, wherein the administration comprises oral administration.sf-5953625Docket No.: 79275-20027.40 60. The kit of claim 58, wherein the administration comprises intravitreal injection.

61. The kit of any of claims 56-60, further comprising instructions for administration of an anti-VEGF agent, an Angiopoietin 2 blocking agent, a dual VEGF-Angiopoietin 2 blocking agent, a corticosteroid, or laser therapy to the individual.

62. The kit of any of claims 51-61, wherein the individual has an APOL1 mutation.

63. The kit of claim 62, wherein the APOL1 mutation is a gain-of-function mutation.

64. The kit of any of claim 51-62, wherein the individual is a human.

65. A compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, for use in modulating APOL1 in a cell.

66. A compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, for use in inhibiting APOL1 in a cell.

67. A compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

68. A compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, for use in delaying the development of an APOL1-mediated disease, disorder, or condition.

69. Use of a compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition ofsf-5953625Docket No.: 79275-20027.40 claim 22, in the manufacture of a medicament for use in modulating APOL1 in a cell.

70. Use of a compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, in the manufacture of a medicament for use in inhibiting APOL1 in a cell.

71. Use of a compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, in the manufacture of a medicament for use in of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

72. Use of a compound of any one of claims 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 22, in the manufacture of a medicament for use in delaying the development of an APOL1- mediated disease, disorder, or condition.sf-5953625

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