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WO2025015104A2 - Inhibiteurs d'apol1 et procédés d'utilisation - Google Patents

Inhibiteurs d'apol1 et procédés d'utilisation Download PDF

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Publication number
WO2025015104A2
WO2025015104A2 PCT/US2024/037470 US2024037470W WO2025015104A2 WO 2025015104 A2 WO2025015104 A2 WO 2025015104A2 US 2024037470 W US2024037470 W US 2024037470W WO 2025015104 A2 WO2025015104 A2 WO 2025015104A2
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Prior art keywords
optionally substituted
6alkyl
alkyl
compound
pharmaceutically acceptable
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WO2025015104A3 (fr
Inventor
Christopher Joseph Sinz
Birong Zhang
Sarah M. BRONNER
David John Morgans Jr.
Maarten HOEK
Victoria Anne ASSIMON
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Maze Therapeutics Inc
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Maze Therapeutics Inc
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Publication of WO2025015104A2 publication Critical patent/WO2025015104A2/fr
Publication of WO2025015104A3 publication Critical patent/WO2025015104A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems

Definitions

  • 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.
  • Apolipoprotein L1 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).
  • 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.
  • 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 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).
  • 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.
  • FGS focal segmental glomerulosclerosis
  • HAVAN human immunodeficiency virus-associated nephropathy
  • Diabetic retinopathy is a common complication of diabetes and a frequent cause of blindness in this population.
  • retinopathy 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).
  • DME macular edema
  • 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.
  • 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.
  • 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.
  • the disclosed compounds may prevent the onset of non-diabetic renal disease and/or delay 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.
  • 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.
  • 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.
  • anti-VEGF agents e.g., Angiopoietin 2 blocking agents, dual VEGF-Angiopoietin 2 blocking agents, corticosteroids, and/or laser therapy.
  • a genetic link between a missense variant in APOL1 and DME has been established (Stockwell, A.D.
  • 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.
  • 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.
  • 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).
  • DME and DR are associated with higher levels of inflammation, and inflammatory cytokines in the eye (Mason, R.H.
  • 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- ⁇ -induced retinopathy in chronic hepatitis C treatment: summary, considerations, and recommendations.
  • 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 DME or DR. Moreover, the APOL1 inhibitors as disclosed herein may be administered by a variety of routes including, e.g., oral administration.
  • R 1 is C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R 2 is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R 2 is optionally substituted with one or more -OH;
  • R 3 if present, is C1-6alkyl;
  • L 1 is C1-6alkylene, wherein the C1-6alkylene of L 1 is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C 1-6 alkyl is further optionally substituted with one or more -OH or C 1-6 alkoxy;
  • L 2 is O or N(R x ), wherein R
  • n is 1 or 2; and m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 1 , X 2 , X 5 , X 6 , X 7 , X 8 , R 6 , and R 7 of formula (II-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.
  • m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , R 5 , R 6 , and R 7 of formula (II-B) 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.
  • m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , and R 5 of formula (II-C) 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.
  • m, p ⁇ R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , and X 8 of formula (II-D) 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.
  • m, p, R 1 , R 2 , R 3 , L 1 , X 2 , R 6 , R 7 , ring A, X 5 , X 6 , X 7 , X 8 , and X 9 are as defined elsewhere herein.
  • m, p, R 1 , R 2 , R 3 , L 1 , X 2 , R 6 , R 7 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (II-E) 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.
  • m, p, R 1 , R 2 , R 3 , L 1 , R 5 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (II-F) 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.
  • m, p, R 1 , R 2 , R 3 , L 1 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (II-G) 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.
  • m, R 1 , X 2 , X 3 , X 4 , ring A, X 5 , X 6 , X 7 , and X 8 are as defined elsewhere herein.
  • m, R 1 , X 2 , X 3 , X 4 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (II-H) 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.
  • 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 (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 1 , X 2 , X 5 , X 6 , X 7 , X 8 , R 6 , and R 7 of formula (I-A) are as defined for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , R 5 , R 6 , and R 7 of formula (I-B) are as defined for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , and R 5 of formula (I-C) are as defined for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, p ⁇ R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , and X 8 of formula (I-D) are as defined for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, p, R 1 , R 2 , R 3 , L 1 , X 2 , R 6 , R 7 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (I-E) are as defined for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, p, R 1 , R 2 , R 3 , L 1 , R 5 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (I-F) are as defined 25 for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, p, R 1 , R 2 , R 3 , L 1 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (I-G) are as defined for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m, R 1 , X 2 , X 3 , X 4 , ring A, X 5 , X 6 , X 7 , and X 8 are as defined elsewhere herein.
  • m, R 1 , X 2 , X 3 , X 4 , ring A, X 5 , X 6 , X 7 , and X 8 of formula (I-H) are as defined for a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • each embodiment provided herein of a compound of formula (I) or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing such as embodiments related to m, n, p, R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , R 4 , X 1 , X 2 , X 5 , X 6 , X 7 , X 8 , R 6 , and R 7 apply to formula (II), (I), (I- A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II- H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt
  • a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a compound of formula (I) such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising (i) a compound of formula (II), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a compound of formula (I) such as a
  • This aspect in some embodiments may employ a compound of any of formulas (II), (I), (I-B), (I-C), (I-D), (I-E), (I- F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a compound of formula (I) such as a
  • a method of inhibiting APOL1 in a cell comprising exposing the cell to an effective amount of (i) a compound of formula (II), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (II), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excip
  • This aspect may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the individual is a human.
  • 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-A) (I-B), (I- C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a compound of formula (I), or any variation or embodiment thereof such
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • This aspect may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II- G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the individual is a human.
  • 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-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a compound of formula (I), or any variation or embodiment thereof such as a
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • This aspect may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I- C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the individual is a human.
  • a method of preventing and/or delaying the development of diabetic retinopathy in a subject in need thereof comprising administering to the subject a compound of formula (I) , or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a compound of formula (I) or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a method of delaying the development of diabetic retinopathy in a subject in need thereof comprising administering to the subject a compound of formula (I) , or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • a compound of formula (I) or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II- E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • kits comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I- F), (I-G), or (I-H), 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.
  • a compound of formula (I) such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I- F), (I-G), or (I-H), 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.
  • kits comprising an effective amount of (i) a compound of formula (II), or any variation or embodiment thereof, 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 (II), or any variation or embodiment thereof, 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 APOL-1-mediated disease, disorder, or condition in an individual in need thereof.
  • This aspect may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II- E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the individual is a human.
  • kits comprising (i) a compound of formula (II), or any variation or embodiment thereof, 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 (II), or any variation or embodiment thereof, 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 APOL-1-mediated disease, disorder, or condition in an individual in need thereof.
  • the kit comprises a therapeutically effective amount of the compound or pharmaceutical composition.
  • This aspect may employ a compound of any of formulas (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the individual is a human.
  • a compound of formula (I) or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a compound of formula (II), or any embodiment or variation thereof such as a compound of formula (II), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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.
  • 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.
  • FIG.3A shows a schematic highlighting the administration of IFN ⁇ -AAV and urine/tissue collections.
  • FIG.3B shows terminal serum levels of IFN ⁇ from mice.
  • FIG.3C shows quantified western blots of normalized APOL1 levels from mouse kidneys.
  • FIG.3D shows serum levels of APOL1 from mice dosed with IFN ⁇ -AAV or vehicle (PBS).
  • FIG.3E shows urine albumin/creatinine ratio (uACR) in APOL1 G1/G2 HET mice.
  • FIG.3F shows the fold change for kidney injury markers, KIM-1 and NGAL, evaluated by qPCR from mouse kidney tissue homogenates.
  • FIG.3G shows PAS staining of mouse kidneys. DETAILED DESCRIPTION OF THE INVENTION
  • the terms “a,” “an,” and the like refer to one or more.
  • “about” a parameter or value includes and describes that parameter or value per se.
  • “about X” includes and describes X per se.
  • “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.
  • 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).
  • “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).
  • “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.
  • 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.
  • 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.
  • 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.
  • 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.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain.
  • alkyl has 1-20 carbons (i.e., C1-20alkyl), 1-16 carbons (i.e., C1- 16 alkyl), 1-12 carbons (i.e., C 1-12 alkyl), 1-10 carbons (i.e., C 1-10 alkyl), 1-8 carbons (i.e., C 1-8 alkyl), 1- 6 carbons (i.e., C 1-6 alkyl), 1-4 carbons (i.e., C 1-4 alkyl), or 1-3 carbons (i.e., C 1-3 alkyl).
  • 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.
  • alkyl residue having a specific number of carbons 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”.
  • alkynyl refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond.
  • alkynyl has 2-20 carbons (i.e., C 2-20 alkynyl), 2-16 carbons (i.e., C 2-16 alkynyl), 2-12 carbons (i.e., C 2-12 alkynyl), 2-10 carbons (i.e., C2-10alkynyl), 2-8 carbons (i.e., C2-8alkynyl), 2-6 carbons (i.e., C2-6alkynyl), 2-4 carbons (i.e., C2-4alkynyl), or 2-3 carbons (i.e., C2-3alkynyl).
  • alkynyl examples include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl.
  • alkynyl 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, “propynyl” includes prop-1-ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art.
  • alkoxy refers to an -O-alkyl moiety.
  • alkoxy has, for example, 1-6 carbons (i.e., C 1-6 alkoxy), or 1-3 carbons (i.e., C 1-3 alkoxy).
  • 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.
  • aryl refers to a fully unsaturated carbocyclic ring moiety.
  • aryl encompasses monocyclic and polycyclic fused-ring moieties.
  • 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., C 6-16 aryl), 6 to 12 annular carbon atoms (i.e., C 6-12 aryl), or 6 to 10 annular carbon atoms (i.e., C 6-10 aryl).
  • aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.
  • cycloalkyl refers to a saturated or partially unsaturated carbocyclic ring moiety.
  • 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.
  • cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C 3- 20 cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C 3-16 cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C 3-12 cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C 3-10 cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C 3-8 cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C 3-6 cycloalkyl), 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.
  • cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.
  • halo refers to atoms occupying group VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).
  • heteroaryl refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • heteroaryl includes both monocyclic and polycyclic fused-ring moieties.
  • a heteroaryl comprises, 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 comprising 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 the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety).
  • heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzindolyl, benzofuranyl, benzonaphthofuranyl, benzoxazolyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, furanyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl,
  • fused-heteroaryl rings include, but are not limited to, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.
  • heterocyclyl refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • 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 comprising 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).
  • heterocyclyl is intended to encompass any polycyclic ring moiety comprising 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.
  • a heterocyclyl comprises, 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 15 annular atoms (i.e., a 3-15 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
  • heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl,
  • spiro heterocyclyl rings include, but are not limited to, 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, and 6-oxa-1-azaspiro[3.3]heptanyl.
  • fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3- c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • 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.
  • the phrase “methyl optionally substituted with one or more chloro” encompasses -CH 3 , -CH 2 Cl, -CHCl 2 , and -CCl 3 moieties.
  • 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.
  • the free base can be obtained by basifying a solution of the acid salt.
  • 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.
  • 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.
  • 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.
  • 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.
  • Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • a compound of formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium.
  • Tautomers are in equilibrium with one another.
  • 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. [0076] 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.
  • the compounds of the present disclosure 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, 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).
  • 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 generally 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 other. [0079] 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., [0080] Where a given structure has the potential for enantiomeric and/or diastereomeric forms, flat bonds indicate that all stereoisomeric forms may be present, e.g.,
  • composition is made up of at least 90%, by weight, an asterisk indicates a single enantiomer or diastereomer with unknown relative or absolute stereochemistry, e.g., .
  • 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, 75 th Ed, hereby incorporated herein by reference in its entirety. The following examples are intended to be illustrative only and not limiting in any way.
  • n is an integer from 0 to 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 2 is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R 2 is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R 2 is optionally substituted with one or more -OH.
  • R 2 is H, C 1-3 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the C 1-3 alkyl of R 2 is optionally substituted with one or more deuterium, halo, -OH, -NH 2 , or C 1-3 alkoxy, and the C 3-6 cycloalkyl of R 2 is optionally substituted with one or more -OH.
  • R 2 is H.
  • R 2 is C1-6alkyl. In some embodiments, R 2 is C1-3alkyl. In some embodiments, R 2 is methyl or ethyl. In some embodiments, R 2 is methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 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 (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 1 is halo, -CN, C 1-6 alkoxy or -C 1-6 alkyl, wherein the C 1-6 alkoxy or R 1 is optionally substituted with one or more halo, and wherein the C1-6alkyl of R 1 is optionally substituted with one or more halo.
  • R 1 is halo, -CN, C1-3alkoxy, or -C1-3alkyl, wherein the C1-3alkoxy of R 1 is optionally substituted with one or more halo, and wherein the C1-3alkyl of R 1 is optionally substituted with one or more halo.
  • R 1 is selected from the group consisting of Cl and .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • p is an integer from 0 to 10. 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 (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 3 is C1-6alkyl. In some embodiments, R 3 is C1-3alkyl. In some embodiments, R 3 is methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the ring system bearing (R 1 )m and R 2 is a 2-dihydropyrrolopyridinone optionally substituted at one or more of positions 1, 5, and 7.
  • the 2-dihydropyrrolopyridinone is a 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2- one.
  • the 2-dihydropyrrolopyridinone is a 1,3-dihydro-2H-pyrrolo[2,3- c]pyridin-2-one.
  • the 2-dihydropyrrolopyridinone is a 1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2-one. In some embodiments, the 2-dihydropyrrolopyridinone is a 1,3- dihydro-2H-pyrrolo[3,2-c]pyridin-2-one. In some embodiments, the 2-dihydropyrrolopyridinone ring system is unsubstituted. In some embodiments, the 2-dihydropyrrolopyridinone ring system is substituted at position 1. In some embodiments, the 2-dihydropyrrolopyridinone ring system is substituted at position 5.
  • the 2-dihydropyrrolopyridinone ring system is substituted at position 7. In some embodiments, the 2-dihydropyrrolopyridinone ring system is substituted at positions 1, and 5. In some embodiments, the 2-dihydropyrrolopyridinone ring system is substituted at positions 5 and 7. In some embodiments, the 2-dihydropyrrolopyridinone ring system is substituted at positions 1, 5, and 7. In some embodiments, positions 1, 5 and 7 are defined as indicated in the structure, .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the ring system bearing (R 1 )m and R 2 is selected from the group consisting of , , , wherein ## represents the point of attachment to the remainder of the molecule.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the ring bearing (R 3 ) p is wherein ## represents the point of attachment to the remainder of the molecule.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the ring system bearing (R 1 ) m , R 2 , and (R 3 ) p is selected from the group consisting .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 is C 1-6 alkylene optionally substituted with one or more deuterium, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with -OH or C1-6alkoxy.
  • L 1 is C1-3alkylene optionally substituted with one or more deuterium, or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with -OH or C1-3alkoxy.
  • L 1 is methylene.
  • L 1 is ethylene.
  • L 1 is ethylene optionally substituted with one or more deuterium, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more -OH or C 1-3 alkoxy.
  • L 1 is , wherein # denotes the point of attachment to L 2 and ## denotes the point of attachment to the remainder of the molecule.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 2 is O or N(R x ), wherein R x is H or C 1-6 alkyl. In some embodiments, L 2 is O or N(R x ), wherein R x is H or C 1-3 alkyl.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 2 is O.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 3 is absent or is O, C3- 10 cycloalkyl, 3-10 membered heterocyclyl, or C 1-6 alkylene, wherein the C 1-6 alkylene of L 3 is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH, the C3-10cycloalkylof L 3 is optionally substituted with one or more –OH, and the 3-10 membered heterocyclyl of L 3 is optionally substituted with one or more –OH.
  • L 3 absent.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -S(O) 2 -R a , 5-20 membered heteroaryl, -N(R d ) 2 , -NS(O)-(C 1-6 alkyl) 2 , -C(O)-N(R e ) 2 , 3-10 membered heterocyclyl, - S(O)(N-C 1-6 alkyl)-(C 1-6 alkyl), or -CN.
  • R 4 is S(O) 2 -R a , 5-10 membered heteroaryl, -N(R d ) 2 , -NS(O)-(C 1-3 alkyl) 2 , -C(O)-N(R e ) 2 , 3-6 membered heterocyclyl, -S(O)(N-C 1- 3alkyl)-(C1-3alkyl), or -CN.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -S(O)2-R a , wherein R a is C3-10cycloalkyl.
  • R 4 is -S(O)2-R a , wherein R a is C3-10cycloalkyl optionally substituted with one or more -OH, C(O) 2 -C 1-6 alkyl, -C(O)-NH(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl) 2, – C(O)-C 3-10 heterocyclyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O) 2 -R a , wherein R a is C 3-6 cycloalkyl optionally substituted with one or more -OH, C(O) 2 -C 1-6 alkyl, -C(O)-NH(C 1-6 alkyl), -C(O)-N(C 1-6 alkyl) 2 , –C(O)-C 3- 10heterocyclyl, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O)2-R a , wherein R a is C3-6cycloalkyl optionally substituted with one or more -OH, C(O)2-C1-3alkyl, -C(O)-NH(C1-3alkyl), -C(O)-N(C1-3alkyl)2, –C(O)-C3-6heterocyclyl, or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more -OH.
  • R 4 is 5-20 membered heteroaryl. In some embodiments, R 4 is 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl. In some embodiments, R 4 is 5-6 membered heteroaryl optionally substituted with one or more C1-6alkyl.
  • R 4 is 5-6 membered heteroaryl optionally substituted with one or more C1-3alkyl. In some embodiments, R 4 is 5-6 membered heteroaryl optionally substituted with one or more methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -N(R d ) 2 , wherein each of R d is independently H, C1-6 alkyl, or -S(O)2-R a , wherein the C1-6alkyl of R d is optionally substituted with one or more –OH, and wherein R a is C1-6alkyl.
  • R 4 is -N(R d )2, wherein each of R d is independently H, C1-3 alkyl, or -S(O)2-R a , wherein the C1-3alkyl of R d is optionally substituted with one or more –OH, and wherein R a is C1-3alkyl.
  • R 4 is -N(R d )2, wherein each of R d is independently H, C1-6 alkyl, or -S(O)2-R a , wherein the C1-3alkyl of R d is optionally substituted with one or more –OH, and wherein R a is methyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein each of R e is independently H or C1-6 alkyl. In some embodiments, R 4 is –C(O)-N(R e )2, wherein each of R e is independently H or C1-3 alkyl.
  • R 4 is –C(O)-N(R e )2, wherein each of R e is independently H or methyl. In some embodiments, R is –C(O)-NH 2 . In some embodiments, R 4 is –C(O)-NH(CH 3 ). In some embodiments, R 4 is –C(O)-N(CH 3 ) 2 . In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is –C(O)-N(R e )2, wherein each of R e is independently H or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo.
  • R 4 is –C(O)- N(R e ) 2 , wherein each of R e is independently H or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is –C(O)-N(R e )2, wherein both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl.
  • R 4 is –C(O)-N(R e )2, wherein both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH2, -NH- S(O) 2 -R a , or -S(O) 2 -R a , wherein R a is C 1-6 alkyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH 2 , -NH-S(O) 2 -R a , or -S(O) 2 -R a , wherein R a is C 1-3 alkyl.
  • R 4 is –C(O)-N(R e )2, wherein both R e together with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH2, -NH-S(O)2-R a , or -S(O)2-R a , wherein R a is methyl.
  • R 4 is 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH, oxo or -S(O)2R a .
  • R 4 is 3-7 membered heterocyclyl optionally substituted with one or more C1-6alkyl, - OH, oxo or -S(O)2R a . In some embodiments, R 4 is 3-7 membered heterocyclyl optionally substituted with one or more C1-3alkyl, -OH, oxo or -S(O)2R a . In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -NS(O)-(C 1-6 alkyl) 2. In some embodiments, R 4 is -NS(O)-(C 1-3 alkyl) 2 . In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -S(O)(N-C1-6alkyl)-(C1- 6alkyl). In some embodiments, R 4 is -S(O)(N-C1-3alkyl)-(C1-3alkyl). In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -CN.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -(CH 2 ) q OH, wherein q is an integer from 0-6.
  • R 4 is -(CH 2 ) q OH, wherein q is an integer from 0-2.
  • R 4 is –OH.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -C(O)-C1-6alkyl. In some embodiments, R 4 is -C(O)-C1-3alkyl. In some embodiments, R 4 is -C(O)CH3. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 4 is -P(O)(C 1-6 alkyl) 2 . In some embodiments, R 4 is -P(O)(C 1-3 alkyl) 2 . In some embodiments, R 4 is -P(O)(CH 3 ) 2 . In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • each of X 1 and X 2 is independently N or C(R 5 ). In some embodiments, each of X 1 and X 2 is N. In some embodiments, each of X 1 and X 2 is C(R 5 ). In some embodiments, one of X 1 and X 2 is CR 5 , and the other of X 1 and X 2 is N.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing one of X 1 and X 2 is CR 5 , and the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-10 membered heterocyclyl optionally substituted with one or more of R b .
  • one of X 1 and X 2 is CR 5
  • the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-8 membered heterocyclyl optionally substituted with one or more of R b .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R b is, independently at each occurrence, selected from the group consisting of -OH, halo, oxo, C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)- NH2, -C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, -S(O)2-R a , C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of R b is optionally substituted with one or more halo, OH, - S(O)2-C1-6alkyl, or C3-10cycloalkyl, wherein the C3-10cycloalkyl of the C1-6alkyl of R b is further optionally substituted with one or more C
  • R b is, independently at each occurrence, selected from the group consisting of - OH, halo, oxo, C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)-NH 2 , -C(O)-NH(C 1-3 alkyl), -C(O)-N(C 1-3 alkyl) 2 , - S(O) 2 -R a , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, wherein the C 1-3 alkyl of R b is optionally substituted with one or more halo, OH, -S(O)2-C1-3alkyl, or C3-6cycloalkyl, wherein the C3- 6cycloalkyl of the C1-3alkyl of R b is further optionally substituted with one or more C1-3alkyl or -OH, and the C3-6cycloalkyl of R b is optionally substituted with one or more
  • R b is selected from the group consisting of - OH, oxo, -S(O) 2 CH 3 , and . In some embodiments, R b is selected from the group consisting of oxo and . In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. [0116] 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, R b is oxo.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing one of X 1 and X 2 is CR 5 , and the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-10 membered heteroaryl.
  • one of X 1 and X 2 is CR 5
  • the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-6 membered heteroaryl.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • one of X 1 and X 2 is CR 5
  • the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-10 membered heteroaryl optionally substituted with one or more R c .
  • one of X 1 and X 2 is CR 5
  • the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-6 membered heteroaryl optionally substituted with one or more R c .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R c is independently at each occurrence, selected from the group consisting of halo, C1-6alkyl, -C(O)-C1-6alkyl, -C(O)-NH2, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, -S(O)2-R a , C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C 1-6 alkyl of R c is optionally substituted with one or more OH or -S(O) 2 -C 1- 6 alkyl, the C 3-10 cycloalkyl of R c is optionally substituted with one or more –OH, C 1-6 alkoxy, or C 1- 6 alkyl, wherein the C 1-6 alkoxy of the C 3-10
  • R c is independently at each occurrence, selected from the group consisting of halo, C1-3alkyl, -C(O)-C1-3alkyl, -C(O)-NH2, -C(O)-NH(C 1-3 alkyl), -C(O)-N(C 1-3 alkyl) 2 , -S(O) 2 -R a , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, wherein the C 1-3 alkyl of R c is optionally substituted with one or more -S(O) 2 -C 1-3 alkyl, the C 3-6 cycloalkyl of R c is optionally substituted with one or more –OH, C 1-6 alkoxy, or C 1-3 alkyl, wherein the C 1-6 alkoxy of the C 3-10 cycloalkyl of R c is optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle, and where
  • R c is selected from the group consisting of methyl and in some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R c is independently at each occurrence, selected from the group consisting of -CN, halo, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, - C(O)-NH2, -C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, -S(O)2-R a , C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of R c is optionally substituted with one or more OH, - S(O)2-C1-6alkyl, or C1-6alkoxy, and wherein the C1-6alkoxy of the C1-6alkyl of R c is optionally substituted with one or more halo, the C3-10cyclo
  • R c is independently at each occurrence, selected from the group consisting of -CN, halo, C1-3alkyl, -C(O)-C1-3alkyl, -C(O)-NH2, -C(O)-NH(C1-3alkyl), -C(O)-N(C1- 3alkyl)2, -S(O)2-R a , C3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-3alkyl of R c is optionally substituted with one or more OH, -S(O) 2 -C 1-3 alkyl, or C 1-3 alkoxy, and wherein the C 1- 3 alkoxy of the C 1-3 alkyl of R c is optionally substituted with one or more halo, the C 3-6 cycloalkyl of R c is optionally substituted with one or more halo, –OH, -C(O)NH 2 , C 1-6 alkoxy, or C
  • R c is selected from the group consisting of methyl and [0121]
  • R 5 is independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1- 6alkyl of R 5 is optionally substituted with one or more halo, or -OH and wherein the C1-6alkoxy is optionally substituted with one or more halo.
  • R 5 is independently at each occurrence, H, halo, -CN, 3-6 membered heterocyclyl, C1-3alkyl, or C1-3alkoxy, wherein the C1- 3 alkyl of R 5 is optionally substituted with one or more halo, or -OH and wherein the C 1-3 alkoxy is optionally substituted with one or more halo.
  • R 5 is selected from the group consisting of F and .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 5 is H.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • X 3 is N or C(R 6 ).
  • X 4 is N or C(R 7 ).
  • X 5 , X 6 , X 7 , and X 8 are each independently N or -CH-, provided that at least one of X 5 , X 6 , X 7 , or X 8 is N.
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N. In some embodiments, X 5 and X 8 are each N. In some embodiments, X 6 and X 7 are each N. In some embodiments, X 5 and X 7 are each N. In some embodiments, X 6 and X 8 are each N. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • R 6 and R 7 are each independently H, halo, or C1-6alkyl, wherein C1-6alkyl is optionally substituted with one or more halo.
  • R 6 and R 7 are each independently H or fluoro.
  • each of R 6 and R 7 is H.
  • each of R 6 and R 7 is fluoro.
  • one of R 6 and R 7 is H and the other of R 6 and R 7 is fluoro.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a bi-substituted phenyl with one group bound at the para position relative to the phenyl’s attachment to L 2 .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a tri-substituted phenyl with two groups bound at a meta, and the para positions relative to the phenyl’s attachment to L 2 .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a tetra-substituted phenyl with three groups bound at the meta, and para positions relative to the phenyl’s attachment to L 2 .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a bi-substituted pyridine with one group bound at the para position relative to the pyridine’s attachment to L 2 .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a tri-substituted pyridine with two groups bound at the meta, and para positions relative to the pyridine’s attachment to L 2 .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a tri-substituted pyridine with two groups bound at the meta, and para positions relative to the pyridine’s attachment to L 2 .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a bi-substituted pyrimidine with two groups bound at the para position relative to the pyrimidine’s attachment to L 2 .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a heterocycle of the structure
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a heteroaryl selected from the group consisting of
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form a heteroaryl selected from the group consisting .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form some embodiments, L 1 , L 2 , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form .
  • L 1 , 2 L , and the ring bearing L 3 , R 4 , R 6 , and R 7 together form .
  • n is 1 or 2, and L 2 is O.
  • n is 2, and L 2 is O.
  • n is 1, and L 2 is O.
  • n is 1 or 2
  • L 2 is O and R 4 is S(O)2- R a .
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • n is 1, p is 0, L 2 is O and each of X 1 and X 2 is C(R 5 ), wherein each R 5 is independently H, halo, -CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl of R 5 is optionally substituted with one or more halo, or -OH, and wherein the C1-6alkoxy of R 5 is optionally substituted with one or more halo.
  • n 1, p is 0, L 2 is O and each of X 1 and X 2 is C(R 5 ), wherein each R 5 is independently H. In some embodiments, n is 1, p is 0, L 2 is O and each of X 1 and X 2 is C(R 5 ), wherein one of R 5 is H and the other of R 5 is halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R 5 is optionally substituted with one or more halo, or -OH, and wherein the C 1-6 alkoxy is optionally substituted with one or more halo.
  • n 1, p is 0, L 2 is O and each of X 1 and X 2 is C(R 5 ), wherein each R 5 is independently halo, -CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl of R 5 is optionally substituted with one or more halo, or -OH, and wherein the C1-6alkoxy is optionally substituted with one or more halo.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • n is 1, p is 0, L 2 is O, one of X 1 and X 2 is N, and the other of X 1 and X 2 is C(R 5 ), wherein R 5 is H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R 5 is optionally substituted with one or more halo, or -OH, and wherein the C1-6alkoxy of R 5 is optionally substituted with one or more halo.
  • n 1, p is 0, L 2 is O, one of X 1 and X 2 is N, and the other of X 1 and X 2 is C(R 5 ), wherein R 5 is H.
  • n 1, p is 0, L 2 is O, one of X 1 and X 2 is N, and the other of X 1 and X 2 is C(R 5 ), wherein R 5 is halo, -CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl of R 5 is optionally substituted with one or more halo, or -OH, and wherein the C 1-6 alkoxy of R 5 is optionally substituted with one or more halo.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • n is 1, L 2 is O, and each of X 1 and X 2 is N.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • n is 1, p is 0, L 2 is O, one of X 1 and X 2 is C(R 5 ), wherein R 5 is H, the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , and each of R 6 and R 7 is H.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • n is 1, L 2 is O, one of X 1 and X 2 is C(R 5 ), wherein R 5 is H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R 5 is optionally substituted with one or more halo, or -OH, and wherein the C1-6alkoxy of R 5 is optionally substituted with one or more halo, the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , or (ii) a 5-10 membered heteroaryl,
  • n is 1, L 2 is O, one of X 1 and X 2 is C(R 5 ), wherein R 5 is H, the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , and each of R 6 and R 7 is H.
  • n 1, L 2 is O, one of X 1 and X 2 is C(R 5 ), wherein R 5 is halo, -CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl of R 5 is optionally substituted with one or more halo, or -OH, and wherein the C 1-6 alkoxy of R 5 is optionally substituted with one or more halo, the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , and each of R 6 and R 7 is H.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • n is 1, p is 0, L 2 is O, one of X 1 and X 2 is N, the other of X 1 and X 2 is C that is taken together with R 4 , and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , and each of R 6 and R 7 is H.
  • the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • X 9 is -C-;
  • L 3 is absent or is O, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 1-6 alkylene, wherein the C 3-10 cycloalkyl of L 3 is optionally substituted with one or more –OH or C 1-6 alkyl, the C 1-6 alkylene of L 3 is optionally substituted with one or more –OH or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH, and the 3-10 membered heterocyclyl of L 3 is optionally substituted with one or more –OH or C1-6alkyl;
  • X 1 and X 2 are each independently N or C(R 5 ); and
  • R 4 is: (i) -S(O)2-R a ; (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R 4 is optionally substituted with one or
  • R b is, independently at each occurrence, selected from the group consisting of -OH, halo, oxo, C1-6alkyl, -C(O)-C1-6alkyl, -C(O)- NH2, -C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, -S(O)2-R a , C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of R b is optionally substituted with one or more halo, OH, - S(O)2-C1-6alkyl, or C3-10cycloalkyl, and wherein the C3-10cycloalkyl of the C1-6alkyl of R b is further optionally substituted with one or
  • X 9 is -C-;
  • L 3 is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L 3 is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L 3 is optionally substituted with one or more –OH or C1- 6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH, and the 3-10 membered heterocyclyl of L 3 is optionally substituted with one or more –OH or C 1-6 alkyl;
  • X 1 and X 2 are each independently N or C(R 5 ); and
  • R 4 is: (i) -S(O) 2 -R a ; (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R 4 is optionally substituted with one or more C 1-6 alkyl;
  • X 9 is -C-; L 3 is absent; and one of X 1 and X 2 is N or C(R 5 ); and the other of X 1 and X 2 is N or C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is, independently at each occurrence, selected from the group consisting of -OH, halo, oxo, C1-6alkyl, -C(O)-C1-6alkyl, -C(O)-NH2, -C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, -S(O)2-R a , C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the group consisting of -OH,
  • X 9 is -N-; L 3 is absent; and one of X 1 and X 2 is N or C(R 5 ); and the other of X 1 and X 2 is N or C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is optionally substituted with one or more R c , wherein R c is, independently at each occurrence, selected from the group consisting of -CN, halo, C1-6alkyl, C1-6alkoxy, -C(O)-C1-6alkyl, -C(O)-NH2, -C(O)-NH(C1- 6alkyl), -C(O)-N(C1-6alkyl)2, -S(O)2-R a , C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of R c is
  • n is 1 or 2; and wherein m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 1 , X 2 , X 5 , X 6 , X 7 , X 8 , R 6 , R 7 , and X 9 are as defined for formula (II).
  • a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein the compound is a compound of formula (II-B): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: wherein: m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , R 5 , R 6 , R 7 , and X 9 are as defined for formula (II).
  • a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein the compound is a compound of formula (II-C): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , R 5 , and X 9 are as defined for formula (II).
  • a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein the compound is a compound of formula (II-D): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p ⁇ R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as defined for formula (II).
  • a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein the compound is a compound of formula (II-E): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , X 2 , R 6 , R 7 , ring A, X 5 , X 6 , X 7 , X 8 , and X 9 are as defined for formula (II).
  • a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein the compound is a compound of formula (II-G): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , ring A, X 5 , X 6 , X 7 , and X 8 are as defined for formula (II).
  • a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein the compound is a compound of formula (II-H): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R 1 , X 2 , X 3 , X 4 , ring A, X 5 , X 6 , X 7 , and X 8 are as defined for formula (II).
  • R 2 is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, -OH, -NH 2
  • a compound of formula (I), 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-A): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is 1 or 2; and wherein m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 1 , X 2 , X 5 , X 6 , X 7 , X 8 , R 6 , and R 7 are as defined for formula (I).
  • X 5 is N.
  • X 6 is N.
  • X 7 is N. In some embodiments, X 8 is N. In some embodiments, X 5 and X 8 are each N. In some embodiments, X 6 and X 7 are each N. In some embodiments, X 5 and X 7 are each N. In some embodiments, X 6 and X 8 are each N. [0158] In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is H.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0. [0160] In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is an integer from 0 to 10. In some embodiments, p is 0 or 1. In some embodiments, p is 0.
  • L 1 is C 1-6 alkylene. In some embodiments, L 1 is C 1-3 alkylene. In some embodiments, L 1 is ethylene. In some 98 embodiments, L 1 is wherein, # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule.
  • L 3 is absent.
  • R 4 is -S(O) 2 -R a , wherein R a is C 1-6 alkyl. In some embodiments, R 4 is -S(O) 2 -R a , wherein R a is C 1-3 alkyl.
  • R 4 is -S(O) 2 -R a , wherein R a is methyl.
  • each of X 1 and X 2 is C(R 5 ).
  • R 5 is H.
  • each of R 6 and R 7 is H.
  • a compound of formula (I) or formula (I-A), 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):
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N. In some embodiments, X 5 and X 8 are each N. In some embodiments, X 6 and X 7 are each N. In some embodiments, X 5 and X 7 are each N. In some embodiments, X 6 and X 8 are each N. [0169] In some embodiments, provided herein is a compound of formula (I) or formula (I-A), 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):
  • n is 1 or 2; and wherein m, n, p, R 1 , R 2 , R 3 , L 1 , X 1 , X 2 , X 5 , X 6 , X 7 , X 8 , R 6 , R 7 , and R a are as defined for formula (I).
  • X 5 is N.
  • X 6 is N.
  • X 7 is N. In some embodiments, X 8 is N. In some embodiments, X 5 and X 8 are each N. In some embodiments, X 6 and X 7 are each N. In some embodiments, X 5 and X 7 are each N. In some embodiments, X 6 and X 8 are each N. [0171] In some embodiments, provided herein is a compound of formula (I), (I-A), or (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-B):
  • a compound of formula (I), (I-A), (I-A2), or (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof wherein the compound is a compound of formula (I-B1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, R 1 , R 2 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , R 6 , and R 7 are as defined for formula (I).
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 2 is H.
  • R 2 is C1-6alkyl. In some embodiments, R 2 is C1-3alkyl. In some embodiments, R 2 is methyl.
  • R 2 is C1-6alkyl optionally substituted with one or more halo, -OH, or C1-6alkoxy.
  • R 2 is C 1-3 alkyl optionally substituted with one or more halo, -OH, or C 1-3 alkoxy.
  • R 2 is ethyl optionally substituted with one or more halo, -OH, -NH 2 , or C 1-3 alkoxy.
  • R 2 is C 3-10 cycloalkyl optionally substituted with one or more -OH. In some embodiments, R 2 is C 3- 6 cycloalkyl optionally substituted with one or more -OH.
  • R 2 is 3-15 membered heterocyclyl. In some embodiments, R 2 is 3-6 membered heterocyclyl.
  • m is an integer from 0 to 4.
  • m is an integer from 0 to 2. In some embodiments, m is 0. In some embodiments m is 1. In some embodiments, m is 2. [0180] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is halo. In some embodiments R 1 is Cl. In some embodiments, R 1 is Br.
  • R 1 is C1-6alkyl. In some embodiments, R 1 is methyl.
  • R 1 is C1-6alkyl, wherein the C1-6alkyl of R 1 is optionally substituted with one or more halo.
  • R 1 is C1-3alkyl, wherein the C1-3alkyl of R 1 is optionally substituted with one or more halo. In some embodiments, R 1 is methyl, wherein the methyl of R 1 is optionally substituted with one or more F. In some embodiemtns. R 1 is . [0183] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is -CN.
  • p is an integer from 0 to 10. In some embodiments, p is 0.
  • L 1 is C1-6alkylene, wherein the C1-6alkylene of L 1 is optionally substituted with one or more C1-6alkyl.
  • L 1 is C 1-3 alkylene optionally substituted with one or more C 1-3 alkyl. In some embodiments, L 1 is ethylene optionally substituted with one or more C 1-6 alkyl. In some embodiments, L 1 is wherein # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule. [0186] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L 3 is absent.
  • L 3 is C 1-6 alkylene. In some embodiments, L 3 C 1-3 alkylene.
  • L 3 is C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl of L 3 is optionally substituted with one or more -OH. In some embodiments, L 3 is C3-8cycloalkyl, wherein the C3-8cycloalkyl of L 3 is optionally substituted with one or more -OH.
  • L 3 is 3-10 membered heterocyclyl. In some embodiments, L 3 is 3-6 membered heterocyclyl.
  • R 4 is -S(O)2-R a , wherein R a is C1-6alkyl.
  • R 4 is -S(O)2-R a , wherein R a is C1-6alkyl, wherein the C1-6alkyl of R a is optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or -N(C 1-6 alkyl)-C(O)-C 1-6 alkyl.
  • R 4 is -S(O) 2 -R a , wherein R a is C 1-3 alkyl, wherein the C 1-3 alkyl of R a is optionally substituted with one or more halo, -OH, -S(O) 2 -C 1-3 alkyl, or -N(C 1-3 alkyl)-C(O)-C 1-3 alkyl.
  • R 4 is -S(O) 2 -R a , wherein R a is C 3-10 cycloalkyl.
  • R 4 is -S(O) 2 -R a , wherein R a is C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl of R a is optionally substituted with one or more -OH, C(O) 2 -C 1-6 alkyl, -C(O)-NH(C 1- 6alkyl), -C(O)-N(C1-6alkyl)2, –C(O)-C3-10heterocyclyl or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O)2-R a , wherein R a is C3- 6cycloalkyl, wherein the C3-6cycloalkyl of R a is optionally substituted with one or more -OH, C(O)2- C1-6alkyl, -C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, –C(O)-C3-10heterocyclyl, or C1-6alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O) 2 -R a , wherein R a is C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl of R a is optionally substituted with one or more -OH, C(O) 2 -C 1-3 alkyl, -C(O)-NH(C 1-3 alkyl), -C(O)-N(C 1-3 alkyl) 2 , –C(O)-C 3-6 heterocyclyl, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O) 2 -R a , wherein R a is 3-10 membered heterocyclyl.
  • R 4 is -S(O) 2 -R a , wherein R a is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of R a is optionally substituted with one or more C1-6alkyl.
  • R 4 is -S(O)2-R a , wherein R a is 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R a is optionally substituted with one or more C1-6alkyl. In some embodiments, wherein R 4 is -S(O)2-R a , wherein R a is 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R a is optionally substituted with one or more C 1-3 alkyl.
  • R 4 is 5-20 membered heteroaryl. In some embodiments, R 4 is 5-20 membered heteroaryl optionally substituted with one or more C 1-6 alkyl. In some embodiments, R 4 is 5-6 membered heteroaryl optionally substituted with one or more C 1-6 alkyl. In some embodiments, R 4 is 5-6 membered heteroaryl optionally substituted with one or more C1-3alkyl.
  • R 4 is 5-6 membered heteroaryl optionally substituted with one or more methyl.
  • R 4 is -N(R d ) 2 , wherein each of R d is independently H, or C 1 - 6 alkyl, wherein the C 1-6 alkyl of R d is optionally substituted with one or more –OH or -S(O) 2 -R a , wherein R a is C 1-6 alkyl.
  • R 4 is -N(R d )2, wherein each of R d is independently H, or C1-3 alkyl, wherein the C1- 3alkyl of R d is optionally substituted with one or more –OH, or -S(O)2-R a , wherein R a is C1-3alkyl.
  • R 4 is -N(R d )2, wherein each of R d is independently H, or C1-3alkyl, wherein the C1-3alkyl of R d is optionally substituted with one or more –OH or -S(O)2-R a , wherein R a is methyl.
  • R 4 is –C(O)-N(R e )2, wherein each of R e is independently H or C1-6 alkyl. In some embodiments, R 4 is – C(O)-N(R e ) 2 , wherein each of R e is independently H or C 1-3 alkyl. In some embodiments, R 4 is – C(O)-N(R e ) 2 , wherein each of R e is independently H or methyl.
  • R 4 is –C(O)- NH 2 . In some embodiments, R 4 is –C(O)-NH(CH 3 ). In some embodiments, R 4 is –C(O)-N(CH 3 ) 2 . [0196] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl.
  • R 4 is –C(O)-N(R e )2, wherein both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH2, -NH-S(O)2-R a , or -S(O)2-R a , wherein R a is C1-6alkyl.
  • R 4 is –C(O)-N(R e )2, wherein both R e together with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH 2 , -NH-S(O) 2 -R a , or -S(O) 2 -R a , wherein R a is C 1- 3 alkyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH2, -NH-S(O)2-R a , or - S(O)2-R a , wherein R a is methyl.
  • R 4 is 3-10 membered heterocyclyl optionally substituted with one or more oxo. In some embodiments, R is 3-7 membered heterocyclyl optionally substituted with one or more oxo.
  • R 4 is -NS(O)-(C 1-6 alkyl) 2. In some embodiments, R 4 is -NS(O)-(C 1-3 alkyl) 2 .
  • R 4 is -S(O)-N(C1-6alkyl)-(C1-6alkyl).
  • R 4 is -CN.
  • R 4 is -P(O)(C1-6alkyl)2. In some embodiments, R 4 is -P(O)(C1-3alkyl)2. In some embodiments, R 4 is - P(O)(CH3)2.
  • a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1) is selected from the group consisting
  • a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1) is selected from the group
  • a compound of formula (I), (I-A), (I-A2), or (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof wherein the compound is a compound of formula (I-B2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R 5 is halo, -CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1- 6alkyl of R 5 is optionally substituted with one or more halo, or -OH and wherein the C1-6alkoxy is optionally substituted with one or more halo; and m, R 1 , R 2 , L 1 , L 3 , R 4 , X 5
  • R 2 is H.
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more halo, -OH.
  • R 2 is C 1-3 alkyl, wherein the C 1-3 alkyl of R 2 is optionally substituted with one or more halo, -OH. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl, wherein the ethyl of R 2 is optionally substituted with one or more halo, -OH. [0207] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 1.
  • R 1 is halo. In some embodiments R 1 is Cl.
  • R 1 is -CN.
  • L 1 is C1-6alkylene optionally substituted with one or more C1-6alkyl, wherein the C1-6alkyl is optionally substituted with -OH or C1-6alkoxy.
  • L 1 is methylene.
  • L 1 is ethylene optionally substituted with one or more C1-6alkyl, wherein the C1-6alkyl is optionally 1 substituted with one or more -OH or C1-6alkoxy.
  • L is , wherein # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule. [0211] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L 3 is absent.
  • L 3 is 3-10 membered heterocyclyl. In some embodiments, L 3 is 3-6 membered heterocyclyl.
  • R 4 is -S(O) 2 -R a , wherein R a is C 1-6 alkyl. In some embodiments, R 4 is -S(O) 2 -R a , wherein R a is C 1-6 alkyl. In some embodiments, R 4 is -S(O) 2 -R a , wherein R a is C 1-3 alkyl.
  • R 4 is -N(R d ) 2 , wherein each of R d is independently H, C 1 - 6 alkyl, or -S(O) 2 -R a , wherein R a is C 1-6 alkyl.
  • R 4 is -N(R d )2, wherein each of R d is independently H, C1-3 alkyl, or -S(O)2-R a , wherein R a is C 1-3 alkyl.
  • R is -N(R d ) 2 , wherein each of R d is independently H, C 1 - 6 alkyl, or -S(O) 2 -R a , wherein R a is methyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein each of R e is independently H or C 1-6 alkyl. In some embodiments, R 4 is – C(O)-N(R e )2, wherein each of R e is independently H or C1-3 alkyl. In some embodiments, R 4 is – C(O)-N(R e )2, wherein each of R e is independently H or methyl.
  • R 4 is –C(O)- NH2. In some embodiments, R 4 is –C(O)-NH(CH3). In some embodiments, R 4 is –C(O)-N(CH3)2. [0216] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 4 is –C(O)-N(R e )2, wherein each of R e is independently H or 3-10 membered heterocycle, wherein the 3- 10 membered heterocycle is optionally substituted with one or more oxo.
  • R 4 is –C(O)-N(R e ) 2 , wherein each of R e is independently H or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo.
  • R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more oxo, -OH, -NH2, or -S(O)2-R a , wherein R a is C1-6alkyl.
  • R 4 is –C(O)-N(R e )2, wherein both R e together with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH 2 , -NH-S(O) 2 -R a , or -S(O) 2 -R a , wherein R a is C 1-3 alkyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, -NH2, -NH-S(O)2-R a , or -S(O)2-R a , wherein R a is methyl.
  • R 5 is halo. In some embodiments, R 5 is Cl, or F. [0219] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 5 is -CN.
  • R 5 is C1-6alkyl, wherein the C1-6alkyl of R 5 is optionally substituted with one or more halo, or -OH.
  • R 5 is C1-3alkyl, wherein the C1-3alkyl of R 5 is optionally substituted with one or more halo, or –OH.
  • R 5 is C1-3alkyl, wherein the C1-3alkyl of R 5 is optionally substituted with one or more fluoro, or -OH. In some embodiments, R 5 is selected from the group consisting of fluoro . [0221] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 5 is 3-10 membered heterocyclyl. In some embodiments, R 5 is 3-6 membered heterocyclyl.
  • R 5 is C1-6alkoxy, wherein the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments R 5 is C 1-3 alkoxy, wherein the C 1-3 alkoxy is optionally substituted with one or more halo. In some embodiments, R 5 is C 1-3 alkoxy, wherein the C 1-3 alkoxy is optionally substituted with one or more fluoro.
  • R 6 and R 7 are each independently H or halo. In some embodiments, R 6 and R 7 are each independently H or fluoro. In some embodiments, each of R 6 and R 7 is H. In some embodiments, one of R 6 and R 7 is H and the other of R 6 and R 7 is fluoro.
  • each R 5 is, independently at each occurrence, halo, -CN, 3-10 membered heterocyclyl, C1- 6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl of R 5 is optionally substituted with one or more halo, or - OH and wherein the C 1-6 alkoxy is optionally substituted with one or more halo; and m, R 1 , R 2 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , X 8 , R 6 ,
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 2 is H.
  • R 2 is C1-6alkyl. In some embodiments, R 2 is methyl.
  • m is an integer from 0 to 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments m is 1. [0229] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is halo.
  • R 1 is Cl.
  • R 1 is -CN.
  • L 1 is C1-6alkylene optionally substituted with one or more C1-6alkyl, wherein the C1-6alkyl is optionally substituted with -OH or C1-6alkoxy.
  • L 1 is methylene.
  • L 1 is ethylene optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally 1 -6 1 substituted with one or more -OH or C alkoxy.
  • L is , wherein # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule. [0232] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L 3 is absent.
  • L 3 is C1-6alkylene. In some embodiments, L 3 is C1-3alkylene.
  • L 3 is 3-10 membered heterocyclyl. In some embodiments, L 3 is 3-6 membered heterocyclyl.
  • R 4 is -S(O)2-R a , wherein R a is C1-6alkyl. In some embodiments, R 4 is -S(O)2-R a , wherein R a is C1-6alkyl. In some embodiments, R 4 is -S(O)2-R a , wherein R a is C1-3alkyl.
  • R 4 is -N(R d )2, wherein each of R d is independently C1-6 alkyl, or -S(O)2-R a , and wherein R a is C1-6alkyl.
  • R 4 is -N(R d )2, wherein each of R d is independently C1-3 alkyl, or -S(O)2-R a , wherein R a is C 1-3 alkyl.
  • R 4 is -N(R d ) 2 , wherein each of R d is methyl, or - S(O) 2 -R a , wherein R a is methyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more oxo.
  • R 4 is –C(O)-N(R e ) 2 , wherein both R e together with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more oxo.
  • R 5 is, independently at each occurrence selected from the group consisting of, halo and C1-6alkyl.
  • R 5 is, independently at each occurrence selected from the group consisting of halo and C1-3alkyl. In some embodiments, R 5 is, independently at each occurrence, selected from the group consisting of F and methyl. In some embodiments, each R 5 is F. In some embodiments, each R 5 is methyl. [0239] In some embodiments, a compound of formula (I-B) is selected from the group
  • a compound of formula (I-B) is selected from the group consisting of
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 2 is H.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments m is 1.
  • R 1 is halo. In some embodiments R 1 is Cl.
  • R 1 is -CN.
  • L 1 is C 1-6 alkylene. In some embodiments, L 1 is ethylene. In some embodiments, L 1 is wherein, # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule.
  • L 3 is absent.
  • L 3 is C1-6alkylene. In some embodiments, L 3 is C1-3alkylene.
  • R 4 is -S(O)2-R a , wherein R a is C1-6alkyl. In some embodiments, R 4 is -S(O)2-R a , wherein R a is C1-3alkyl.
  • R 4 is -S(O)2-R a , wherein R a is C3-10cycloalkyl.
  • R 4 is -S(O)2-R a , wherein R a is C3-10cycloalkyl, wherein the C3-10cycloalkyl of R a is optionally substituted with one or more C1-6alkyl, and wherein the C1-6alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O)2-R a , wherein R a is C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl of R a is optionally substituted with one or more C 1- 6 alkyl, and wherein the C 1-6 alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O) 2 -R a , wherein R a is C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl of R a is optionally substituted with one or more C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more -OH.
  • R 4 is -S(O)2-R a , wherein R a is 3-10 membered heterocyclyl.
  • R 4 is -S(O)2-R a , wherein R a is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of R a is optionally substituted with one or more C1-6alkyl.
  • R 4 is -S(O)2-R a , wherein R a is 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R a is optionally substituted with one or more C 1-6 alkyl. In some embodiments, wherein R 4 is -S(O) 2 -R a , wherein R a is 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R a is optionally substituted with one or more C 1-3 alkyl.
  • R 4 is –C(O)-N(R e ) 2 , wherein each of R e is independently H or C 1-6 alkyl. In some embodiments, R 4 is – C(O)-N(R e )2, wherein each of R e is independently H or C1-3 alkyl. In some embodiments, R 4 is – C(O)-N(R e )2, wherein each of R e is independently H or methyl.
  • R 4 is –C(O)- NH2. In some embodiments, R 4 is –C(O)-N(CH3)2. In some embodiments, R 4 is –C(O)-NH2. In some embodiments, R 4 is –C(O)-NH(CH3).
  • a compound of formula (I), (I-A), or (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof wherein the compound is a compound of formula (I-C2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R 5 is, halo, -CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1- 6alkyl of R 5 is optionally substituted with one or more halo, or -OH and wherein the C1-6alkoxy is optionally substituted with one or more halo; m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I).
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 2 is H.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments m is 1.
  • R 1 is halo. In some embodiments R 1 is Cl.
  • R 1 is -CN.
  • R 1 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 1 is optionally substituted with one or more halo. In some embodiments, R 1 is C 1-3 alkyl, wherein the C 1-3 alkyl of R 1 is optionally substituted with one or more halo. In some embodiments, R 1 is methyl, wherein the methyl of R 1 is optionally substituted with one or more F. In some embodiemtns. R 1 is .
  • L 1 is C1-6alkylene. In some embodiments, L 1 is ethylene. In some embodiments, L 1 is wherein, # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule.
  • L 3 is absent.
  • L 3 is C 1-6 alkylene, wherein the C 1-6 alkylene of L 3 is optionally substituted with one or more –OH, or C 1- 6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH.
  • L 3 is C 1-3 alkylene, wherein the C 1-6 alkylene of L 3 is optionally substituted with one or more –OH, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH.
  • L 3 is C3-10cycloalkyl, wherein the C3-10cycloalkyl of L 3 is optionally substituted with one or more -OH.
  • L 3 is C3-8cycloalkyl, wherein the C3-8cycloalkyl of L 3 is optionally substituted with one or more -OH.
  • R 4 is -S(O)2-R a , wherein R a is C1-6alkyl. In some embodiments, R 4 is -S(O)2-R a , wherein R a is C1-3alkyl.
  • R 4 is –(CH2)qOH, wherein q is an integer from 0-6.
  • R 4 is –(CH2)qOH, wherein q is an integer from 0-2.
  • R 4 is –OH.
  • R 4 is -C(O)-C1-6alkyl. In some embodiments, R 4 is -C(O)-C1-3alkyl. In some embodiments, R 4 is - C(O)CH3.
  • R 5 is C1-6alkyl. In some embodiments, R 5 is C1-3alkyl. In some embodiments, R 5 is methyl.
  • R 5 is C1-6alkyl, wherein the C1-6alkyl of R 5 is optionally substituted with one or more halo. In some embodiments, R 5 is C1-3alkyl, wherein the C1-3alkyl of R 5 is optionally substituted with one or more halo. In some embodiments, R 5 is C1-3alkyl, wherein the C1-3alkyl of R 5 is optionally substituted with one or more fluoro.
  • R 5 is [0272] In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 5 is halo. In some embodiments, R 5 is Cl, or F. [0273] In some embodiments, provided herein is a compound of formula (I), (I-A), or (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-D):
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N. In some embodiments, X 5 and X 8 are each N. In some embodiments, X 6 and X 7 are each N. In some embodiments, X 5 and X 7 are each N. In some embodiments, X 6 and X 8 are each N. [0275] In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is H.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments m is 1. [0277] In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is halo. In some embodiments R 1 is Cl.
  • R 1 is -CN.
  • R 1 is C1-6alkyl, wherein the C1-6alkyl of R 1 is optionally substituted with one or more halo.
  • R 1 is C1-3alkyl, wherein the C1-3alkyl of R 1 is optionally substituted with one or more halo. In some embodiments, R 1 is C1-3alkyl, wherein the C1-3alkyl of R 1 is optionally substituted with one or more F. In some embodiments, R 1 is methyl, wherein the methyl of R 1 is optionally substituted with one or more F. In some embodiments, R 1 is .
  • L 1 is C1-6alkylene optionally substituted with one or more C1-6alkyl. In some embodiments, L 1 is ethylene optionally substituted with one or more C1-6alkyl. In some embodiments, L 1 is selected from the group consisting of 1 wherein, for each L , # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule.
  • L 3 is absent.
  • L 3 is -O-.
  • L 3 is C1-6alkylene. In some embodiments, L 3 is C1-3alkylene.
  • L 3 is C1-6alkylene, wherein the C1-6alkylene of L 3 is optionally substituted with one or more –OH, or C1- 6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH.
  • L 3 is C1-3alkylene, wherein the C1-3alkylene of L 3 is optionally substituted with one or more –OH, or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more -OH.
  • L 3 is C 3-10 cycloalkyl. In some embodiments, L 3 is C 3-8 cycloalkyl.
  • L 3 is C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl of L 3 is optionally substituted with one or more -OH.
  • L 3 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl of L 3 is optionally substituted with one or more -OH.
  • L3 is 3-10 membered heterocyclyl. In some embodiments, L 3 is 3-6 membered heterocyclyl.
  • R 4 is -S(O) 2 -R a , wherein R a is C 1-6 alkyl.
  • R 4 is -S(O) 2 -R a , wherein R a is C 1-3 alkyl.
  • R 4 is —C(O)-N(R e )2, wherein each of R e is H.
  • R 4 is –C(O)-NH2.
  • R 4 is 3-10 membered heterocyclyl optionally substituted with one or more C1-6 alkyl. In some embodiments, R 4 is 3-6 membered heterocyclyl optionally substituted with one or more C1-6 alkyl. In some embodiments, R 4 is 3-6 membered heterocyclyl optionally substituted with one or more C1-3 alkyl. In some embodiments, R 4 is 3-6 membered heterocyclyl optionally substituted with one or more methyl.
  • R 4 is 3-10 membered heterocyclyl optionally substituted with one or more C 1-6 alkyl. In some embodiments, R 4 is 3-6 membered heterocyclyl optionally substituted with one or more C 1-6 alkyl. In some embodiments, R 4 is 3-6 membered heterocyclyl optionally substituted with one or more C 1-3 alkyl. In some embodiments, R 4 is 3-6 membered heterocyclyl optionally substituted with one or more methyl.
  • R 4 is –(CH2)qOH, wherein q is an integer from 0-6.
  • R 4 is –(CH2)qOH, wherein q is an integer from 0-2.
  • R 4 is –OH.
  • R 4 is -N(R d )2, wherein each of R d is independently H. In some embodiments, R 4 is -NH2.
  • R 4 is -P(O)(C 1-6 alkyl) 2 .
  • R 4 is -P(O)(C 1-3 alkyl) 2 . In some embodiments, R is - P(O)(CH 3 ) 2 .
  • a compound of formula (I), (I-A) or (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof wherein the compound is a compound of formula (I-E): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R b , and wherein the 5- 10 membered heteroaryl of ring A is optionally substituted with one or more R c ; and m, p, R 1 , R 2 , R 3 L 1
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • a compound of formula (I), (I-A) or (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof wherein the compound is a compound of formula (I-E1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R b , and wherein the 5- 10 membered heteroaryl of ring A is optionally substituted with one or more R c ; and m, p, R 1 , R 2 , R 3 , L 1 , X 1 , R b , R c , R 6 , R 7 , X 5 , X 6 , X 7 , and X 8 are
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • r is an integer from 0-1; Y 1 and Y 2 are each independently C or N, optionally substituted by one or more H or R b ; and m, R 1 , R 2 , L 1 , X 2 , R b , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I); and wherein the dashed line represents a single or double bond.
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • r is an integer from 0-1; Y 1 and Y 2 are each independently C or N, optionally substituted by one or more H or R b ; R b1 is OH; R b2 is H, C 1-6 alkyl, or C 3-10 cycloalkyl, wherein the C 1-6 alkyl of R b2 is optionally substituted with one or more OH; and m, R 1 , R 2 , L 1 , X 2 , R b , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I); and wherein the dashed line represents a single or double bond.
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • r is an integer from 0-1; Y 2 , Y 3 and Y 4 are each independently C or N, optionally substituted by one or more H or R c ; and m, R 1 , R 2 , L 1 , X 2 , R c , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I); and wherein the dashed line represents a single or double bond.
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • r is an integer from 0-1; Y 3 , Y 4 and Y 5 are each independently C or N, optionally substituted by one or more H or R c ; R c1 is OH; R c2 is H, C 1-6 alkyl, or C 3-10 cycloalkyl, wherein the C 1-6 alkyl of R c2 is optionally substituted with one or more OH; and m, R 1 , R 2 , L 1 , X 2 , R c , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I); and wherein the dashed line represents a single or double bond.
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • a compound of formula (I-E) is selected from the group
  • a compound of formula (I-E) is selected from the group consisting of
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R b , and wherein the 5- 10 membered heteroaryl of ring A is optionally substituted with one or more R c ; and m, R 1 , R 2 , L 1 , R b , R c , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I).
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 2 is H.
  • R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more - OH, -NH 2 , or C 1-6 alkoxy. In some embodiments, R 2 is methyl.
  • R 2 is C3-10cycloalkyl, wherein the C3-10cycloalkyl of R 2 is optionally substituted with one or more -OH. In some embodiments, R 2 is C3-6cycloalkyl, wherein the C3-6cycloalkyl of R 2 is optionally substituted with one or more -OH.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments m is 1.
  • R 1 is halo. In some embodiments R 1 is Cl.
  • R 1 is -CN.
  • L 1 is C 1-6 alkylene, wherein the C 1-6 alkylene of L 1 is optionally substituted with one or more C 1-6 alkyl.
  • L 1 is ethylene, wherein the ethylene of L 1 is optionally substituted with one or more C 1-6 alkyl.
  • L 1 is , wherein # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , wherein R b is oxo.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , wherein R b is oxo.
  • R b is oxo.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C1-6alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more more halo, OH , or - S(O) 2 -C 1-6 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein wherein each R b is independently oxo, or C 1-3 alkyl, wherein the C 1-3 alkyl of R b is optionally substituted with one or more more halo, OH, or -S(O)2-C1-3alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -C(O)-NH(C1-6alkyl).
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -C(O)- NH(C 1-3 alkyl).
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -C(O)-C 1-6 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -C(O)-C1-3alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -S(O) 2 -R a , wherein R a is C1-6alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is - S(O)2-R a , wherein R a is C1-3alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -S(O) 2 -R a , wherein R a is methyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C 3-10 cycloalkyl, wherein the C 3- 10 cycloalkyl of R b is optionally substituted with one or more –OH.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C3-6cycloalkyl, wherein the C3-6cycloalkyl of R b is optionally substituted with one or more –OH.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C3-10cycloalkyl, wherein the C3- 10cycloalkyl of R b is optionally substituted with one or more –OH or C1-6alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl of R b is optionally substituted with one or more –OH or C 1-3 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more .
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is 3-10 membered heterocyclyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is 3-6 membered heterocyclyl.
  • R b is 3-6 membered heterocyclyl.
  • ring A is a 5-10 membered heteroaryl. In some embodiments, ring A is a 5-6 membered heteroaryl.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C1-6alkyl.
  • ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C1-3alkyl.
  • ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is methyl. In some embodiments, ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is isopropyl.
  • ring A is , wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C 1-6 alkyl, wherein the C 1-6 alkyl of R c is optionally substituted with one or more -OH or –S(O) 2 -R a , wherein R a is C 1-6 alkyl.
  • ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C1-3alkyl, wherein the C1- 3alkyl of R c is optionally substituted with one or more -OH or –S(O)2-R a , wherein R a is C1-3alkyl.
  • ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C 1-3 alkyl, wherein the C 1- 3 alkyl of R c is optionally substituted with one or more –S(O) 2 -R a , wherein R a is methyl.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C 3-10 cycloalkyl, wherein the C3-10cycloalkyl of R c is optionally substituted with one or more –OH.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C3-6cycloalkyl, wherein the C3-6cycloalkyl of R c is optionally substituted with one or more –OH.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl of R c is optionally substituted with one or more –OH, or C 1-6 alkyl.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C3-6cycloalkyl, wherein the C3-6cycloalkyl of R c is optionally substituted with one or more –OH, or C1-3alkyl.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more .
  • ring A is , wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R b , wherein R b is 3-10 membered heterocyclyl.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R b , wherein R b is 3-6 membered heterocyclyl.
  • R b is 3-6 membered heterocyclyl.
  • provided herein is a compound of formula (I), (I-A) or (I-A2), (I- E), (I-E1), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-F2):
  • R 5 is halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1- 6alkyl of R 5 is optionally substituted with one or more halo, or -OH and wherein the C1-6alkoxy is optionally substituted with one or more halo;
  • ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R b , and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R c ; and m, R 1 , R 2 , L 1 , R b , R c , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 2 is H.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2.
  • m is 1. [0339] In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is halo. In some embodiments R 1 is Cl.
  • R 1 is -CN.
  • L 1 is C1-6alkylene. In some embodiments, L 1 is ethylene.
  • L 1 is , wherein, for each L 1 , # denotes the point of attachment to L 2 and ## denotes the point of attachment to the remainder of the molecule.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , wherein one or more R b is oxo.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R b , wherein one or more R b is oxo.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C 1-6 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C1-6alkyl, wherein the C1-6alkyl of R b is optionally substituted with one or more more halo, OH , or - S(O)2-C1-6alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C1-3alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C 3-10 cycloalkyl, wherein the C 3- 10 cycloalkyl of R b is optionally substituted with one or more –OH or C 1-6 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl of R b is optionally substituted with one or more –OH or C1-3alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more .
  • ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C 3-10 cycloalkyl, wherein the C3-10cycloalkyl of R c is optionally substituted with one or more –OH, or C1-6alkyl.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more R c is C3-6cycloalkyl, wherein the C3-6cycloalkyl of R c is optionally substituted with one or more –OH, or C1-3alkyl.
  • ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R c , wherein one or more .
  • ring A is , wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.
  • R 5 is halo. In some embodiments, R 5 is fluoro.
  • R 5 is C1-6alkyl. In some embodiments, R 5 is C1-3alkyl. In some embodiments, R 5 is methyl.
  • R 5 is C1- 6alkyl, wherein the C1-6alkyl of R 5 is optionally substituted with one or more halo. In some embodiments, R 5 is C1-3alkyl, wherein the C1-3alkyl of R 5 is optionally substituted with one or more halo. In some embodiments, R 5 is C 1-3 alkyl, wherein the C 1-3 alkyl of R 5 is optionally substituted 5 with one or more fluoro. In some embodiments, R is . [0351] In some embodiments, a compound of formula (I-F) is selected from the group
  • a compound of formula (I-F) is selected from the group consisting of
  • ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R b , and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R c ; and m, p, R 1 , R 2 , R 3 , L 1 , ring A, X 5 , X 6 , X 7 , and X 8 are as defined for formula (I).
  • R 2 is H.
  • m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0 or 1.
  • m is 1.
  • R 1 is halo.
  • R 1 is Cl.
  • R 1 is -CN.
  • R 1 is C1-6alkyl, wherein the C1-6alkyl of R 1 is optionally substituted with one or more halo. In some embodiments, R 1 is C1-3alkyl, wherein the C1-3alkyl of R 1 is optionally substituted with one or more halo. In some embodiments, R 1 is C1-3alkyl, wherein the C1-3alkyl of R 1 is optionally substituted with one or more F.
  • R 1 is methyl, wherein the methyl of R 1 is optionally substituted with one or more F. In some embodiments, R 1 is methyl. In some embodiments, . [0358] In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I- G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L 1 is C1-6alkylene. In some embodiments, L 1 is C1-3alkylene. In some embodiments, L 1 is thylene.
  • L 1 e is , wherein, for each L 1 , # denotes the point of attachment to -O- and ## denotes the point of attachment to the remainder of the molecule.
  • # denotes the point of attachment to -O-
  • ## denotes the point of attachment to the remainder of the molecule.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C 1-6 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more -OH.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein wherein each R b is independently oxo, or C1- 3alkyl, wherein the C1-3alkyl of R b is optionally substituted with one or more -OH.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C 1-6 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo, or C1-6alkyl.
  • the C1-6alkyl of R b is optionally substituted with one or more halo, OH, -S(O)2-C1-6alkyl, or C3-10cycloalkyl, wherein the C3-10cycloalkyl of the C1-6alkyl of R b is further optionally substituted with one or more C 1-6 alkyl or -OH.
  • each R b is independently oxo, or C 1-3 alkyl.
  • the C 1-3 alkyl of R b is optionally substituted with one or more halo, OH, -S(O) 2 -C 1-3 alkyl, or C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl of the C 1- 3 alkyl of R b is further optionally substituted with one or more C 1-3 alkyl or -OH.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein each R b is independently oxo.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -C(O)-C1-6alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein one or more of R b is -C(O)-C 1-3 alkyl.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C 3-10 cycloalkyl, wherein the C 3- 10 cycloalkyl of R b is optionally substituted with one or more –OH.
  • ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is C3-6cycloalkyl, wherein the C3-6cycloalkyl of R b is optionally substituted with one or more –OH.
  • R b is C 3-10 cycloalkyl optionally substituted with one or more -OH, C 3-10 cycloalkyl, or C 1- 6 alkyl, wherein the C 1-6 alkyl is further optionally substituted with one or more –OH.
  • R b is C3-6cycloalkyl optionally substituted with one or more -OH, C3-6cycloalkyl, or C1-3alkyl, wherein the C1-3alkyl is further optionally substituted with one or more –OH. In some embodiments, . [0364] In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I- G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.
  • R c is independently at each occurrence, selected from the group consisting of halo, C1-6alkyl, -C(O)-C1-6alkyl, -C(O)-NH2, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, -S(O)2-R a , C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of R c is optionally substituted with one or more -OH or -S(O)2- C 1-6 alkyl, the C 3-10 cycloalkyl of R c is optionally substituted with one or more –OH, C 1-6 alkoxy, or C 1-6 alkyl, wherein the C 1-6 alkoxy of the C 3-10 cycl
  • R c is independently at each occurrence, selected from the group consisting of halo, C1-3alkyl, -C(O)-C1-3alkyl, -C(O)-NH2, -C(O)-NH(C1- 3alkyl), -C(O)-N(C1-3alkyl)2, -S(O)2-R a , C3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C 1-3 alkyl of R c is optionally substituted with one or more -OH or -S(O) 2 -C 1-3 alkyl, the C 3-6 cycloalkyl of R c is optionally substituted with one or more –OH, C 1-6 alkoxy, or C 1-3 alkyl, wherein the C 1- 6 alkoxy of the C 3-10 cycloalkyl of R c is optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is
  • R c is selected from the group consisting of methyl .
  • R c is selected from the group consisting of methyl .
  • a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I- G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing ring , wherein ## represents a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.
  • a compound of formula (I-G) is selected from the group consisting stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a compound of formula (I), 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-H): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R b , and wherein the 5- 10 membered heteroaryl of ring A is optionally substituted with one or more R c ; and m, R 1 , R 5 , R b , R c , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are as defined for formula (I).
  • X 5 is N.
  • X 6 is N.
  • X 7 is N.
  • X 8 is N.
  • X 5 and X 8 are each N.
  • X 6 and X 7 are each N.
  • X 5 and X 7 are each N.
  • X 6 and X 8 are each N.
  • R 1 is halo. In some embodiments, R 1 is chloro. In some embodiments, R 1 is C1-6alkyl substituted with one or more halo. In some embodiments, R 1 is methyl substituted with one or more fluoro. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, X 3 and X 4 are each CH. In some embodiments, X 2 is N. In some embodiments, X 2 is C(R 5 ). In some embodiments, R 5 is H.
  • R 5 is is C 1-6 alkyl optionally substituted with one or more halo.
  • R b is methyl substituted with one or more fluoro.
  • ring A is piperidinyl optionally substituted with one or more R b or pyrazolyl optionally substituted with one or more R c .
  • ring A is piperidinyl optionally substituted with one or more R b .
  • R b is oxo.
  • R b is C 3-10 cycloalkyl optionally substituted with one or more -OH or C3-10cycloalkyl. In some embodiments, R b is cyclobutyl substituted with -OH and methyl. In some embodiments, ring A is pyrazolyl optionally substituted with one or more R c . In some embodiments, R c is C3-10cycloalkyl optionally substituted with one or more -OH or C3-10- cycloalkyl. In some embodiments, R c is cyclobutyl substituted with -OH and methyl. [0372] In some embodiments, a compound of formula (I) or (I-H) is selected from the group consisting
  • a compound of formula (I) or (I-H) is selected from the group consisting of
  • R 1 is CHCF 2 , R 2 is H, L 1 is ethylene, L 2 is O, L 3 is absent, X 2 is C(R 5 ), R 5 is CF 3 , X 1 is taken together with R 4 and the atoms to which they are attached to form pyrazolyl, R c is cyclobutyl substituted with -OH and methyl, X 5 is CH, X 6 is CH, X 7 is CH, X 8 is N, X 3 is C(R 6 ), X 4 is C(R 7 ), R 6 is H, and R 7 is H, can be combined to give .
  • a 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 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.
  • a compound of formula (II), or any variation of embodiment thereof, 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. Table 1.
  • a compound of formula (II) is selected from the group consisting of 6-chloro-1'-(2- ⁇ 7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-diaza-3- naphthyloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 6-chloro-1'-(2- ⁇ 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 1'-(2- ⁇ 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-one;
  • a compound of formula (II) is selected from the group consisting of 6-chloro-1'-(2- ⁇ 7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-diaza-3- naphthyloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 6-chloro-1'-(2- ⁇ 1-[3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 1'-(2- ⁇ 1-[3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-yloxy ⁇ ethyl)- 1'
  • a compound of formula (I) is selected from the group consisting of 6-chloro-1'-(2- ⁇ 7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-diaza-3- naphthyloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 6-chloro-1'-(2- ⁇ 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 1'-(2- ⁇ 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-one;
  • a compound of formula (I) is selected from the group consisting of 6-(difluoromethyl)-1'- ⁇ 2-[7-fluoro-1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-1H-1,3- benzimidazol-5-yloxy]ethyl ⁇ -1',3,7-triazaspiro[indan-1,4'-piperidin]-2-one; 6-(difluoromethyl)-1'- ⁇ 2-[7-fluoro-1-(3-hydroxy-3-methylcyclobutyl)-1H-indazol-5-yloxy]ethyl ⁇ - 1',3,7-triazaspiro[indan-1,4'-piperidin]-2-one; 6-(difluoromethyl)-1'- ⁇ 2-[1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy]e
  • a compound of formula (I) is selected from the group consisting of 6-chloro-1'-(2- ⁇ 7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-diaza-3- naphthyloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 6-chloro-1'-(2- ⁇ 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy ⁇ ethyl)-1',3,4-triazaspiro[indan-1,4'-piperidin]-2-one; 1'-(2- ⁇ 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-one;
  • compounds of formula (I), or any embodiment or variation thereof are provided wherein L 1 is C 1- 6 alkylene, wherein one or more H atoms of the C 1-6 alkylene are replaced with deuterium.
  • compounds of formula (I), or any embodiment or variation thereof are provided wherein L 1 is -(CD 2 ) 1-6 -.
  • L 1 is - (CD2)-(CD2)-.
  • compounds of formula (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.
  • designation of an atom as deuterium at a position indicates that the abundance of deuterium is significantly greater than the natural abundance of deuterium.
  • H hydrogen
  • D 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).
  • the aforementioned embodiments also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • Compound Names included in Table 1 and in the list in the paragraphs above were generated ChemDraw ® software version 18.1.0.458, ChemDraw ® software version 18.0.0.231, ChemDraw ® software version 20.1.0.112, or Collaborative Drug Discovery Inc. (CDD) CDD Vault Update (April 2023), or Collaborative Drug Discovery Inc. (CDD) CDD Vault update (June 2024).
  • 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.
  • 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.
  • compositions provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.
  • 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.
  • 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, 23 rd ed. (2020), which is incorporated herein by reference.
  • 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.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the methods of modulating APOL1 in a cell provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • 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.
  • the methods of inhibiting APOL1 in a cell also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • the methods of inhibiting APOL1 in an individual provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the compounds provided herein inhibit APOL1 at a concentration of less than 10 ⁇ M, less than 1 ⁇ M, less than 0.5 ⁇ M, or less than 0.1 ⁇ M. In some embodiments, the compounds provided herein inhibit APOL1 at a concentration of 1 to 10 ⁇ M, 0.01 to 1 ⁇ M, or 0.01 to 10 ⁇ M. [0395] 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 ⁇ M, less than 1 ⁇ M, less than 0.5 ⁇ M, or less than 0.1 ⁇ M.
  • the compounds provided herein reduce cell death caused by APOL1 overexpression at a concentration of 1 to 10 ⁇ M, 0.01 to 1 ⁇ M, or 0.01 to 10 ⁇ M.
  • compounds provided herein have an EC50 of less than 1 ⁇ M, less than 0.5 ⁇ M, or less than 0.1 ⁇ M.
  • the compounds provided herein have an EC 50 of 1 to 10 ⁇ M, 0.01 to 1 ⁇ M, or 0.01 to 10 ⁇ M.
  • compounds provided herein have an AC 50 of less than 1 ⁇ M, less than 0.5 ⁇ M, or less than 0.1 ⁇ M.
  • the compounds provided herein have an AC50 of 1 to 10 ⁇ M, 0.01 to 1 ⁇ M, or 0.01 to 10 ⁇ M. In some embodiments, the AC50 value reflects the compound’s ability to prevent calcium influx by inhibiting APOL1. [0398] 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.
  • 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.
  • 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.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • the methods of treating an APOL-1 mediated disease also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • 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.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • the methods of treating a kidney disease, disorder, or condition in an individual in need thereof provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the individual has a chronic kidney disease.
  • the individual has hypertension-attributed kidney disease.
  • the kidney disease, disorder, or condition is an APOL1-mediated kidney disease, disorder, or condition.
  • 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.
  • FGS focal segmental glomerulosclerosis
  • 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.
  • the individual is genetically predisposed to developing the APOL1-mediated disorder.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • the methods of treating an APOL1-mediated disorder such as preeclampsia and sepsis, provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • the kidney transplant recipient receives a kidney from a high- risk APOL1 genotype donor.
  • the kidney transplant recipient is administered the compound for a period of time before receiving the kidney transplant.
  • a therapeutically effective amount of the compound is administered.
  • the kidney transplant recipient is administered the compound subsequent to receiving the kidney transplant.
  • a therapeutically effective amount of the compound is administered.
  • the methods of delaying development of progressive renal allograft loss in a kidney transplant recipient also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • Also provided herein is a method of treating diabetic retinopathy in a subject in need thereof, comprising administering to the subject 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.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • 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.
  • 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.
  • 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.
  • 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 subject. In some embodiments, the methods of treating diabetic retinopathy in a subject in need thereof provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • any other formula detailed herein such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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 the individual has an APOL1 mutation.
  • 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 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.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • the methods of treating a kidney disease, disorder, or condition in an individual in need thereof provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • the APOL1-mediated disease, disorder, or condition is preeclampsia or sepsis and the individual has two APOL1 risk alleles.
  • 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.
  • 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.
  • the methods of delaying the development of an APOL1-mediated disease, disorder, or condition provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • chronic kidney disease including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunode
  • provided herein is a method of preventing and/or delaying the development of diabetic retinopathy in a subject, comprising administering to the subject a compound of formula (I). In one aspect, provided herein is a method of delaying the development of diabetic retinopathy in a subject, comprising administering to the subject 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.
  • 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.
  • the administration comprises oral administration or intravitreal injection.
  • the administration comprises oral administration.
  • the administration comprises intravitreal injection.
  • 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 subject.
  • the methods of preventing and/or delaying the development of diabetic retinopathy in a subject also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the method comprises administering to the subject 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.
  • 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.
  • a therapeutically effective amount of the compound of formula (I) is administered.
  • 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.
  • the methods provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • the individual has a gain-of-function mutation in APOL1.
  • the individual has an APOL1 risk allele.
  • the APOL1 risk allele is a missense variant.
  • the APOL1 risk allele is a G1 variant.
  • the G1 variant is G1 G (p.S342 G) or G1 M (p.I384 M).
  • the APOL1 risk allele is the G2 variant.
  • the G2 variant is NYK388–389K.
  • the APOL1 risk variant is a mutation in the serum resistance-associated (SRA) binding domain of the APOL1 protein.
  • SRA serum resistance-associated
  • 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.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • the methods of inhibiting APOL1 in an individual provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • a therapeutically effective amount of a compound of formula (I) is administered.
  • the compound prevents tissue necrosis.
  • the compound prevents apoptosis. In some embodiments, the compound reduces inflammation. In some embodiments, the methods of preventing kidney failure in an individual provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • 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. [0415] 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.
  • the compounds provided herein eliminate the need for a kidney transplant.
  • the individual has stage 1, stage 2, stage 3A, stage 3B, stage 4, or stage 5 chronic kidney disease.
  • kidney function is evaluated using an estimated glomerular filtration rate (eGFR) kidney function test.
  • eGFR estimated glomerular filtration rate
  • 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.
  • 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%.
  • 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%.
  • urine albumin/creatine ratio is reduced by at least about 90%. In some embodiments, reduction of urine albumin/creatine ratio is dose-dependent. In some embodiments, the reduction and/or ratios are measured according to assays detailed herein.
  • the individual is an individual in need thereof, such as an individual having an APOL1-mediated disease, disorder, or condition.
  • 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.
  • 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.
  • FSGS focal segmental glomerulosclerosis
  • HAVAN human immunodeficiency virus-associated nephropathy
  • the administration is oral administration.
  • the APOL1 risk allele is a G0 variant.
  • the G0 variant is G0 E150 (p.K150E).
  • KITS [0420]
  • the present disclosure further provides kits for carrying out the methods of the invention.
  • 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.
  • 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.
  • 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.
  • 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.
  • the individual is a human.
  • the kits provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • 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 diabetic retinopathy in an individual in need thereof.
  • 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.
  • the administration comprises oral administration or intravitreal injection.
  • the administration comprises oral administration.
  • the administration comprises intravitreal injection.
  • 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 subject.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the administration comprises oral administration or intravitreal injection.
  • 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 subject.
  • the kits provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • 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.
  • 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.
  • the articles of manufacture provided herein also apply to any other formula detailed herein, such as a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.
  • METHODS OF PREPARING [0425] The present disclosure further provides methods for preparing the compounds of present invention.
  • a compound of formula (II), or any embodiment or variation thereof such as a compound of formula (II-A) (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a compound of formula (I) or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a method for preparing a compound of formula (II), 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 (II’-A): wherein: m is an integer from 0 to 4; n is an integer from 0 to 2; p is an integer from 0 to 10; R 1 , if present is, independently at each occurrence selected from the group consisting of halo, -CN, C 1-6 alkoxy, and C 1-6 alkyl, wherein the C1-6alkoxy of R 1 is optionally substituted with one or more halo, and the C 1-6 alkyl of R 1 is optionally substituted with one or more halo; R 2 is H, C 1-6 alkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R
  • 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: m is an integer from 0 to 4; n is an integer from 0 to 2; p is an integer from 0 to 10; R 1 , if present is, independently at each occurrence selected from the group consisting of halo, -CN, C 1-6 alkoxy, and C 1-6 alkyl, wherein the C 1-6 alkoxy of R 1 is optionally substituted with one or more halo, and the C 1-6 alkyl of R 1 is optionally substituted with one or more halo; R 2 is H, C 1-6 alkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein the C 1-6 alkyl of R
  • 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.
  • the inorganic base is selected from the group consisting of potassium carbonate and sodium bicarbonate.
  • the compound of formula (II) is prepared by a step comprising alkylation of an amine of formula (II’-A) with an alkyl halide, or sulfonate ester compound of formula (II’-B) in the presence of an inorganic base.
  • provided is a process according to Scheme P1.
  • a method of preparing a compound of formula S1-12 comprising contacting a compound of formula S1-10 with a compound of formula S1-11 in the presence of a base.
  • the method further comprises contacting a compound of formula S1-4 with a compound of formula S1-5 in the presence of an acid.
  • Scheme P1 [0430] In some aspects, provided is a process according to Scheme P2. In some embodiments, provided is a method of preparing a compound of formula S2-10, comprising contacting a compound of formula S2-8 with a compound of formula S2-9 in the presence of a base. In some embodiments, the method further comprises contacting a compound of formula S2-7 with a dibromoalkane in the presence of a base.
  • Scheme P2 [0431] In some aspects, provided is a process according to Scheme P3. In some embodiments, provided is a method of preparing a compound of formula S3-9, comprising contacting a compound of formula S3-7 with a compound of formula S3-8 in the presence of a base.
  • the method further comprises contacting a compound of formula S3-6 with a dibromoalkane in the presence of a base.
  • Scheme P3 [0432] In some aspects, provided is a process according to Scheme P4. In some embodiments, provided is a method of preparing a compound of formula S4-5, comprising contacting a compound of formula S4-3 with a compound of formula S4-4 in the presence of a base. In some embodiments, the process further comprises contacting a compound of formula S4-2 with an acid.
  • Scheme P4 [0433] in some aspects, provided is a process according to Scheme P5.
  • a method of preparing a compound of formula S5-13 comprising contacting a compound of formula S5-11 with a compound of formula S5-12 in the presence of a base.
  • the method further comprises contacting a compound of formula S5-6 with a strong base.
  • Scheme P5 [0434] In some aspects, provided is a process according to Scheme P6. In some embodiments, provided is a method of preparing a compound of formula S6-11, comprising contacting a compound of formula S6-9 with a compound of formula S6-10 in the presence of a base. In some embodiments, the method further comprises contacting a compound of formula S6-4 with a base. Scheme P6 [0435] In some embodiments, provided is a process according to Scheme P7. In some embodiments, provided is a method of preparing a compound of formula S7-5, comprising contacting a compound of formula S7-4 with TFA. In some embodiments, the method further comprises contacting a compound of formula S7-2 with a compound of formula S7-3 in the presence of a base. Scheme P7
  • the compound of formula (I), or any embodiment or variation thereof such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.is prepared by methods shown in the examples.
  • ENUMERATED EMBODIMENTS [0437] Enumerated Embodiment 1.
  • R 2 is H, C 1-6 alkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more deuterium, halo, -OH, -NH 2 , or C 1- 6 alkoxy, and the C 3-10 cycloalkyl of
  • 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 X 5 is N, and X 6 , X 7 , and X 8 are CH.
  • 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 X 6 is N, and X 5 , X 7 , and X 8 are CH.
  • Enumerated Embodiment 9 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 R 1 is halo or -C1-3alkyl, wherein the C1-3alkyl of R 1 is optionally substituted with one or more halo.
  • Enumerated Embodiment 10 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 p is 0.
  • the compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Compounds 1-61 of Table 1. [0459] Enumerated Embodiment 23.
  • a method for preparing a compound of formula (I), as recited in Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing comprises a step of reacting a compound of formula (I’-A): wherein: m is an integer from 0 to 4; n is an integer from 0 to 2; p is an integer from 0 to 10; R 1 , if present is, independently at each occurrence selected from the group consisting of halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C 1-6 alkoxy of R 1 is optionally substituted with one or more halo, and the C1-6alkyl of R 1 is optionally substituted with one or more halo; R 2 is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C 1-6 alkyl of R 2 is optional
  • Enumerated Embodiment 24 The method of Enumerated Embodiment 23, 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.
  • Enumerated Embodiment 25 The method of Enumerated Embodiment 24, wherein the inorganic base is selected from the group consisting of potassium carbonate and sodium bicarbonate.
  • Enumerated Embodiment 26 The method of Enumerated Embodiment 23, 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.
  • a pharmaceutical composition comprising (i) a compound of any of Enumerated Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  • Enumerated Embodiment 27 A method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any of Enumerated Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 26.
  • Enumerated Embodiment 28 A pharmaceutical composition, comprising (i) a compound of any of Enumerated Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 26
  • 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 1-25 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 26. [0465] Enumerated Embodiment 29.
  • 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 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 26.
  • Enumerated Embodiment 30 The method of Enumerated Embodiment 29, wherein the disease, disorder, or condition is a kidney disease or diabetic retinopathy.
  • FGS focal segmental glomerulosclerosis
  • Enumerated Embodiment 33 The method of any of Enumerated Embodiments 27- 31, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).
  • Enumerated Embodiment 34 The method of Enumerated Embodiment 29, wherein the disease, disorder, or condition is diabetic retinopathy.
  • Enumerated Embodiment 35 The method of Enumerated Embodiment 34, 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.
  • Enumerated Embodiment 36 The method of Enumerated Embodiment 34 or 35, wherein the administration comprises oral administration or intravitreal injection.
  • Enumerated Embodiment 37 The method of Enumerated Embodiment 36, wherein the administration comprises oral administration.
  • Enumerated Embodiment 38 The method of Enumerated Embodiment 36, wherein the administration comprises intravitrael injection.
  • a method of delaying the development of an APOL1- mediated disease, disorder, or condition comprising administering a compound of any of Enumerated Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 26, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.
  • Enumerated Embodiment 41 The method of Enumerated Embodiment 40, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease or diabetic retinopathy.
  • Enumerated Embodiment 42 is a kidney disease or diabetic retinopathy.
  • Enumerated Embodiment 40 or 41 The method of Enumerated Embodiment 40 or 41, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease.
  • Enumerated Embodiment 43 The method of any of Enumerated Embodiments 40- 42, wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.
  • Enumerated Embodiment 44 The method of any of Enumerated Embodiments 40- 42, wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.
  • the method of Enumerated Embodiment 40 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.
  • FSGS focal segmental glomerulosclerosis
  • Enumerated Embodiments 40 or 41 wherein the APOL-1 mediated disease, disorder, or condition is diabetic retinopathy.
  • Enumerated Embodiment 46 The method of Enumerated Embodiment 45, 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.
  • Enumerated Embodiment 47 The method of Enumerated Embodiment 45 or 46, wherein the administration comprises oral administration or intravitreal injection.
  • Enumerated Embodiment 48 The method of Enumerated Embodiment 48.
  • Enumerated Embodiment 47 wherein the administration comprises oral administration.
  • Enumerated Embodiment 49 The method of Enumerated Embodiment 47, wherein the administration comprises intravitreal injection.
  • Enumerated Embodiment 50 The method of any of Enumerated Embodiments 45- 49, 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.
  • Enumerated Embodiment 51 The method of any of Enumerated Embodiments 27- 50, wherein the individual has an APOL1 mutation.
  • Enumerated Embodiment 52 The method of Enumerated Embodiment 51, wherein the APOL1 mutation is a gain-of-function mutation.
  • Enumerated Embodiment 53 The method of any of Enumerated Embodiments 29- 52, wherein a therapeutically effective amount of a compound of any of Enumerated Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 26, is administered.
  • Enumerated Embodiment 54 is administered.
  • a kit comprising (i) a compound of any of Enumerated Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 26, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.
  • Enumerated Embodiment 55 The kit of Enumerated Embodiment 54, wherein the disease, disorder, or condition is a kidney disease or diabetic retinopathy.
  • Enumerated Embodiment 56 The kit of Enumerated Embodiment 54 or 55, wherein the disease, disorder, or condition is a kidney disease.
  • Enumerated Embodiment 57 The kit of any of Enumerated Embodiments 54-56, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).
  • Enumerated Embodiment 58 The kit of any of Enumerated Embodiments 54-56, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).
  • kits of any of Enumerated Embodiments 54-57 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.
  • FSGS focal segmental glomerulosclerosis
  • HAVAN human immunodeficiency virus-associated nephropathy
  • HAVAN human immunodeficiency virus-associated nephropathy
  • APOL1-associated nephropathy viral nephropathy
  • COVID-19 associated nephropathy preeclampsia
  • sepsis secretorous glomerulosis
  • the kit of Enumerated Embodiment 54 wherein the disease, disorder, or condition is diabetic retinopathy.
  • Enumerated Embodiment 60 The kit of Enumerated Embodiment 59, 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.
  • Enumerated Embodiment 61 The kit of Enumerated Embodiments 59 or 60, wherein the administration comprises oral administration or intravitreal injection.
  • Enumerated Embodiment 62 The kit of Enumerated Embodiment 62.
  • Enumerated Embodiment 63 The kit of Enumerated Embodiment 61, wherein the administration comprises intravitreal injection.
  • Enumerated Embodiment 64 The kit of any of Enumerated Embodiments 59-62, 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.
  • Enumerated Embodiment 65 The kit of Enumerated Embodiment 65.
  • 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.
  • 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.
  • 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.
  • Scheme 1 Compounds of formula S1-12 may be prepared according to Scheme 1.
  • S N Ar reaction between S1-1 and amine S1-2 occurs upon heating with a tertiary amine base such as DIEA in solvent to give S1-3.
  • Nitro group reduction by heating with iron and ammonium chloride in a mixed solvent such as ethanol and water or by treatment with sodium dithionite in mixed solvent such as water and methanol followed by heating in aqueous HCl solution gives S1-4.
  • Heating of S1-4 and an acid such as TsOH in organic solvent such as THF in the presence of an orthoester S1-5 such as trimethyl orthoformate or 1,1,1-trimethoxyethane gives S1-6.
  • Palladium catalyzed borylation may be conducted in a solvent such as 1,4-dioxane by reaction with diboron reagent S1-7, potassium acetate as base, and a palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S1-8.
  • a palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S1-8.
  • Oxone in a mixed solvent such as THF and water gives S1-9.
  • Alkylation with 1,2-dibromoethane in the presence of an inorganic base such as cesium carbonate gives S1-10.
  • S1-10 may be coupled with amine S1-11 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give compounds of S1-12.
  • Scheme 2 [0508] Compounds of formula S2-10 may be prepared according to Scheme 2. Alkylation of S2-1 with an electrophile such as S2-2 occurs in the presence of an inorganic base such as potassium carbonate in warm DMF to give S2-3. Treatment with a Grignard reagent such as methylmagnesium bromide at 0 °C in a solvent such as THF gives tertiary alcohol S2-4.
  • a Grignard reagent such as methylmagnesium bromide at 0 °C in a solvent such as THF gives tertiary alcohol S2-4.
  • Palladium catalyzed borylation may be conducted in a solvent such as 1,4-dioxane by reaction with diboron reagent S2-5, potassium acetate as base, and a palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S2-6.
  • a palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S2-6.
  • Oxone in a mixed solvent such as THF and water gives S2-7.
  • Alkylation with 1,2-dibromoethane in the presence of an inorganic base such as cesium carbonate gives S2-8.
  • S2-8 may be coupled with amine S2-9 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give compounds of formula S2-10.
  • Scheme 3 [0509] Compounds of formula S3-9 may be prepared according to Scheme 3. Alkylation of S3- 1 with an electrophile such as S3-2 occurs in the presence of an inorganic base such as potassium carbonate in warm DMF to give S3-3. Treatment with a Grignard reagent such as methylmagnesium bromide at 0 °C in solvent such as THF and Et2O gives tertiary alcohol S3-4.
  • a Grignard reagent such as methylmagnesium bromide at 0 °C in solvent such as THF and Et2O gives tertiary alcohol S3-4.
  • Palladium catalyzed borylation may be conducted in a solvent such as 1,4-dioxane by reaction with bis(pinacolato)diboron, potassium acetate as base, and a palladium catalyst such as [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S3-5.
  • a palladium catalyst such as [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S3-5.
  • Oxone in a mixed solvent such as acetone and water gives S3-6.
  • Alkylation with 1,2-dibromoethane in the presence of an inorganic base such as potassium carbonate gives S3-7.
  • S3-7 may be coupled with amine S3-8 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give compounds of formula S3-9.
  • Compounds of formula S4-5 may be prepared according to Scheme 4. Chlorination of S4-1 proceeds upon treatment with NCS in an organic solvent such as DMF to give S4-2. Boc- deprotection of S4-2 under acidic conditions such as HCl in EtOAc gives S4-3. S4-3 may be coupled with alkyl bromide S4-4 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give S4-5.
  • Scheme 5 Compounds of formula S5-13 may be prepared according to Scheme 5.
  • S5-1 is transformed to diazonium salt S5-2 via treatment with tert-butyl nitrite and BF 3 •Et 2 O.
  • S5-3 is generated.
  • S N Ar substitution of S5-3 with S5-4 occurs upon treatment with a base such as LiHMDS in an organic solvent such as THF to give S5-5.
  • Conversion of nitrile S5-5 occurs in the presence of H2O2, a base such as K2CO3, and an organic solvent such as DMA to afford amide S5-6.
  • Treatment of S5-6 with a strong base such as sodium hydride in a solvent such as DMA leads to cyclized product S5-7.
  • Palladium catalyzed vinylation may be conducted in mixed solvent such as 1,4-dioxane and H2O by reaction with potassium vinyltrifluoroborate, potassium carbonate as base, and a palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S5-8.
  • a palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S5-8.
  • Oxidation of S5-8 with K 2 Os 2 O 4 and NaIO 4 in mixed solvent such as THF and H 2 O affords aldehyde S5-9.
  • Deoxyfluorination of aldehyde S5-9 with DAST and an organic solvent such as DCM provides difluoromethyl S5-10.
  • S5-11 Boc-deprotection of S5-10 under acidic conditions such as HCl in EtOAc gives S5-11.
  • S5-11 may be coupled with alkyl bromide S5-12 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give compounds of formula S5-13.
  • Scheme 6 Compounds of formula S6-11 may be prepared according to Scheme 6.
  • SNAr substitution of S6-1 with S6-2 occurs upon treatment with a base such as LiHMDS in an organic solvent such as THF to give S6-3.
  • Conversion of nitrile S6-3 occurs in the presence of H2O2, a base such as K 2 CO 3 , and an organic solvent such as DMA to afford amide S6-4.
  • Heating of S6-4 with a base such as potassium carbonate in a solvent such as DMA leads to cyclized product S6-5.
  • Palladium catalyzed vinylation may be conducted in mixed solvent such as 1,4-dioxane and H 2 O by reaction with potassium vinyltrifluoroborate, potassium carbonate as base, and a palladium catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S6-6.
  • a palladium catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S6-6.
  • Oxidation of S6- 6 with K 2 Os 2 O 4 and NaIO 4 in mixed solvent such as THF and H 2 O affords aldehyde S6-7.
  • Deoxyfluorination of aldehyde S6-7 with DAST and an organic solvent such as DCM provides difluoromethyl analogue S6-8.
  • S6-9 may be coupled with alkyl bromide S6-10 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give compounds of formula S6-11.
  • Scheme 7 [0513] Compounds of formula S7-5 may be prepared according to Scheme 7. Alkylation of benzimidazolone S7-1 with 1,2-dibromoethane with an inorganic base such as cesium carbonate in hot isopropanol gives S7-2.
  • Coupling of S7-2 with piperidine S7-3 occurs upon heating in the presence of a base such as sodium bicarbonate in an aprotic solvent such as acetonitrile to give S7- 4.
  • Cleavage of the SEM-protecting group occurs upon treatment with a protic acid such as TFA in a solvent such as DCM to give compounds of formula S7-5.
  • Step 2 6-bromo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1,2,3,4-tetrahydro-1,8-diaza-2- naphthalenone [0515] To a 0 °C solution of 6-bromo-1-(3-oxocyclobutyl)-1,2,3,4-tetrahydro-1,8-diaza-2- naphthalenone (1.00 g, 3.39 mmol) in THF (20 mL) was added 3.0 M MeMgBr in Et 2 O (1.24 mL, 3.72 mmol).
  • Step 3 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-dihydro-1,8-diaza-2(1H)-naphthalenone [0516] To a solution of 6-bromo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1,2,3,4-tetrahydro- 1,8-diaza-2-naphthalenone (1.00 g, 3.21 mmol) in 1,4-dioxane (20 mL) were added bis(pinacolato)diboron (1.06 g, 4.18 mmol), Pd(dppf)Cl 2 •CH 2 Cl 2 (210 mg, 257 ⁇ mol) and KOAc (788 mg, 8.03 mmol).
  • Step 4 6-hydroxy-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1,2,3,4-tetrahydro-1,8- naphthyridin-2-one [0517] To a solution of 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydro-1,8-diaza-2(1H)-naphthalenone (610 mg, 1.70 mmol) in acetone (10 mL) and H 2 O (5 mL) was added Oxone (1.57 g, 2.55 mmol).
  • Step 5 6-(2-bromoethoxy)-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1,2,3,4-tetrahydro-1,8- naphthyridin-2-one
  • 6-hydroxy-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-3,4-dihydro-1,8-diaza-2(1H)- naphthalenone 400 mg, 1.61 mmol
  • 1,2-dibromoethane (1.82 mL, 24.2 mmol)
  • MeCN 10 mL
  • K2CO3 1,2-dibromoethane
  • Step 2 (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol [0519] A mixture of (cis)-3-[5-bromo-2-methyl-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]- 1-methylcyclobutanol (2.00 g, 5.51 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl- 1,3,2-dioxaborinane (2.49 g, 11.0 mmol), Pd(dppf)Cl2 (403 mg, 551 mmol) and KOAc (1.62 g, 16.5 mmol) in 1,4-dioxane (30 mL) was degassed and
  • Step 4 (cis)-3-[5-(2-bromoethoxy)-2-methyl-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1- methylcyclobutanol [0521] To a mixture of 2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)- 1H-1,3-benzimidazol-5-ol (Intermediate A-3, 1.40 g, 4.66 mmol) and 1,2-dibromoethane (17.5 g, 93.2 mmol) in i-PrOH (10 mL) was added Cs 2 CO 3 (3.80 g, 11.7 mmol).
  • Step 2 (cis)-3-(2-amino-4-bromo-6-fluorophenylamino)-1-methylcyclobutanol [0523] To a solution of (cis)-3-(4-bromo-2-fluoro-6-nitrophenylamino)-1-methylcyclobutanol (2.00 g, 6.27 mmol) in EtOH (20 mL) and H 2 O (10 mL) was added Fe (1.05 g, 18.8 mmol) and NH 4 Cl (1.68 g, 31.3 mmol). The mixture was stirred at 80 °C for 2 h. After cooling to room temperature, solids were removed by filtration and the filtrate was extracted with EtOAc (3 x 20 mL).
  • Step 3 (cis)-3-(5-bromo-7-fluoro-1H-1,3-benzimidazol-1-yl)-1-methylcyclobutanol [0524] To a solution of trimethyl orthoformate (2.27 mL, 20.8 mmol) and (cis)-3-(2-amino-4- bromo-6-fluorophenylamino)-1-methylcyclobutanol (5.00 g, 17.3 mmol) in THF (50 mL) was added TsOH•H2O (329 mg, 1.73 mmol). After slowly warming to 50 °C, the mixture was stirred at 50 °C for 5 h.
  • Step 4 (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-1H-1,3-benzimidazol-1-yl]-1- methylcyclobutanol [0525] To a solution of (cis)-3-(5-bromo-7-fluoro-1H-1,3-benzimidazol-1-yl)-1- methylcyclobutanol (4.00 g, 13.4 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5- dimethyl-1,3,2-dioxaborinane (3.62 g, 16.1 mmol) in 1,4-dioxane (60 mL) under N 2 atmosphere was added KOAc (3.28 g, 33.4 mmol) and Pd(dppf)Cl2 (978 mg, 1.34 mmol).
  • Step 5 7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzimidazol-5-ol
  • (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol (3.00 g, 9.03 mmol) in THF (30 mL) and H 2 O (10 mL) was added Oxone (2.78 g, 4.52 mmol) portion wise, and then the mixture was stirred at room temperature for 2 h.
  • Step 2 (cis)-3-[4-bromo-2-nitro-6-(trifluoromethyl)phenylamino]-1-methylcyclobutanol
  • 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.
  • Step 3 (cis)-3-[2-amino-4-bromo-6-(trifluoromethyl)phenylamino]-1-methylcyclobutanol [0530] 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) 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).
  • Step 4 (cis)-3-[5-bromo-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1-methylcyclobutanol [0531] 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.
  • Step 5 (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol [0532] 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
  • Step 6 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-ol [0533] 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.
  • Step 1 (cis)-3-(5-bromo-7-fluoro-2-methyl-1H-1,3-benzimidazol-1-yl)-1-methylcyclobutanol [0534] To a solution of (cis)-3-(2-amino-4-bromo-6-fluorophenylamino)-1-methylcyclobutanol (Intermediate A-5, 340 mg, 1.18 mmol) in THF (7 mL) was added 1,1,1-trimethoxyethane (177 ⁇ L, 1.41 mmol) and TsOH•H2O (22.4 mg, 118 ⁇ mol). The mixture was stirred at 50 °C for 5 h.
  • Step 2 (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-2-methyl-1H-1,3- benzimidazol-1-yl]-1-methylcyclobutanol
  • a mixture of (cis)-3-(5-bromo-7-fluoro-2-methyl-1H-1,3-benzimidazol-1-yl)-1- methylcyclobutanol 250 mg, 798 ⁇ mol
  • 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl- 1,3,2-dioxaborinane 216 mg, 958 ⁇ mol
  • KOAc 157 mg, 1.60 mmol
  • Pd(dppf)Cl2 58.4 mg, 79.8 ⁇ mol
  • Step 3 7-fluoro-2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzimidazol-5-ol
  • (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-2- methyl-1H-1,3-benzimidazol-1-yl]-1-methylcyclobutanol 300 mg, 867 ⁇ mol
  • THF 4 mL
  • H 2 O (1 mL)
  • Oxone 266 mg, 433 ⁇ mol
  • Step 1 3-(5-bromo-7-fluoro-1H-indazol-1-yl)cyclobutanone [0537] To a mixture of 5-bromo-7-fluoro-1H-indazole (2.00 g, 9.30 mmol) and K2CO3 (3.86 g, 27.9 mmol) in DMF (30 mL) was added 3-bromocyclobutanone (1.52 g, 10.2 mmol). The mixture was heated to 50 °C and stirred for 2 h. After cooling to room temperature, the reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (3 x 30 mL).
  • Step 2 (cis)-3-(5-bromo-7-fluoro-1H-indazol-1-yl)-1-methylcyclobutanol
  • 3-(5-bromo-7-fluoro-1H-indazol-1-yl)cyclobutanone 900 mg, 3.18 mmol
  • the mixture was cooled to 0 C and then 3.0 M MeMgBr in 2-MeTHF (1.17 mL, 3.51 mmol) was added dropwise.
  • Step 3 (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-1H-indazol-1-yl]-1- methylcyclobutanol [0539] A mixture of (cis)-3-(5-bromo-7-fluoro-1H-indazol-1-yl)-1-methylcyclobutanol (300 mg, 1.00 mmol), KOAc (148 mg, 1.50 mmol), Pd(dppf)Cl2 (36.7 mg, 50.1 ⁇ mol) and 2-(5,5- dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (45 mg, 2.01 mmol) in 1,4- dioxane (4 mL) was degassed and purged with N 2 (3x), then the mixture was stirred at 80 °C for 12 h under N 2 atmosphere.
  • Step 4 7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-indazol-5-ol
  • (cis)-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-1H- indazol-1-yl]-1-methylcyclobutanol 330 mg, 993 ⁇ mol
  • Oxone 672 mg, 1.09 mmol
  • reaction mixture was cooled to 0 °C and quenched with saturated aqueous Na2SO3 solution (10 mL). The resulting solids were removed by filtration, and the filter cake was washed with EtOAc (3 x 3 mL). The mixture was separated, and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 3-[5-bromo-3-iodo-7-(trifluoromethyl)-1H-indazol-1-yl]cyclobutan-1-one [0542] To a solution of 5-bromo-3-iodo-7-(trifluoromethyl)-1H-indazole (3.40 g, 8.70 mmol) in acetone (30 mL) was added K 2 CO 3 (3.61 g, 26.1 mmol) and 3-bromocyclobutanone (3.89 g, 26.1 mmol). The mixture was stirred at 30 °C for 12 h. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 20 mL).
  • Step 3 (cis)-3-[5-bromo-3-iodo-7-(trifluoromethyl)-1H-indazol-1-yl]-1-methylcyclobutan-1-ol [0543] To a –10 °C solution of 3-(5-bromo-3-iodo-7-(trifluoromethyl)-1H-indazol-1- yl)cyclobutan-1-one (1.20 g, 2.62 mmol) in DCM (20 mL) under N 2 atmosphere was added 3.0 M MeMgBr in 2-MeTHF (871 ⁇ L, 2.62 mmol). The mixture was stirred at room temperature for 1 h under N 2 atmosphere.
  • Step 4 (cis)-3-[5-bromo-7-(trifluoromethyl)-1H-indazol-1-yl]-1-methylcyclobutan-1-ol [0544] To a 0 °C mixture of (cis)-3-(5-bromo-3-iodo-7-(trifluoromethyl)-1H-indazol-1-yl)-1- methylcyclobutan-1-ol (650 mg, 1.37 mmol) in HOAc (7 mL) and MeOH (7 mL) was added Zn (930 mg, 14.2 mmol) portion wise. The mixture was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for another 30 min.
  • Step 5 (cis)-1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)- 1H-indazol-1-yl]cyclobutan-1-ol [0545] A mixture of (cis)-3-[5-bromo-7-(trifluoromethyl)-1H-indazol-1-yl]-1- methylcyclobutan-1-ol (380 mg, 1.09 mmol), bis(pinacolato)diboron (553 mg, 2.18 mmol), Pd(dppf)Cl2 (79.6 mg, 109 ⁇ mol), and KOAc (320 mg, 3.27 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N2 (3x), and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere.
  • Step 6 1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5-ol A 0 °C mixture of (cis)-1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)-1H-indazol-1-yl]cyclobutan-1-ol (431 mg, 1.09 mmol) and Oxone (1.34 g, 2.18 mmol) in THF (10 mL) and H 2 O (10 mL) was stirred for 1 h.
  • Step 1 5-bromo-7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1,3-dihydro-1,3- benzimidazol-2-one [0546] To a solution of (cis)-3-(2-amino-4-bromo-6-fluorophenylamino)-1-methylcyclobutanol (Intermediate A-5, 5.00 g, 17.3 mmol) in THF (50 mL) under N2 atmosphere was added 1,1’- carbonyldiimidazole (4.23 g, 25.9 mmol). The mixture was stirred at room temperature for 16 h under N 2 atmosphere.
  • the reaction mixture was diluted with H 2 O (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was dissolved into THF (60 mL) and H 2 O (20 mL), and then LiOH•H 2 O (2.46 g, 58.7 mmol) was added. The mixture was heated to 50 °C and stirred for 2 h. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 2 6-bromo-4-fluoro-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -1,3-dihydro-1,3-benzimidazol-2-one [0547] To a 0 °C solution of 5-bromo-7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1,3- dihydro-1,3-benzimidazol-2-one (2.60 g, 8.25 mmol) in THF (30 mL) was added NaH (60% in mineral oil, 990 mg, 24.8 mmol) in portions.
  • Step 3 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-fluoro-3-[(cis)-3-hydroxy-3- methylcyclobutyl]-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -1,3-dihydro-1,3-benzimidazol-2-one [0548] A mixture of 6-bromo-4-fluoro-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -1,3-dihydro-1,3-benzimidazol-2-one (1.70 g, 3.82 mmol), 2-(5,5- dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (1.03 g, 4.58 mmol), KOAc (936 mg, 9.54 mmol) and Pd(dppf)Cl
  • Step 4 4-fluoro-6-hydroxy-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -1,3-dihydro-1,3-benzimidazol-2-one [0549] To a 0 °C solution of 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-fluoro-3-[(cis)-3- hydroxy-3-methylcyclobutyl]-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -1,3-dihydro-1,3-benzimidazol- 2-one (1.90 g, 3.97 mmol) in THF (20 mL) and H2O (10 mL) was added Oxone (3.66 g, 5.96 mmol).
  • the mixture was allowed to warm to room temperature and stirred for 2 h.
  • the reaction mixture was cooled to 0 °C, quenched by addition of saturated aqueous Na 2 SO 3 solution (20 mL), diluted with H 2 O (20 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • the crude product was triturated with MTBE (10 mL) for 1 h and filtered.
  • Step 1 2-[4-bromo-2-nitro-6-(trifluoromethyl)phenylamino]-2-methyl-1-propanol [0551] To a solution of 5-bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene (Intermediate A- 14, 32.5 g, 113 mmol) and 2-amino-2-methyl-propan-1-ol (21.5 mL, 226 mmol) in MeCN (300 mL) was added DIEA (39.3 mL, 226 mmol). The mixture was heated to 80 °C and stirred for 12 h.
  • Step 2 2-[2-amino-4-bromo-6-(trifluoromethyl)phenylamino]-2-methyl-1-propanol [0552] To a solution of 2-[4-bromo-2-nitro-6-(trifluoromethyl)phenylamino]-2-methyl-1- propanol (15.0 g, 42.0 mmol) in EtOH (75 mL) and H2O (75 mL) were added Fe (7.04 g, 126 mmol) and NH4Cl (6.74 g, 126 mmol). The mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was cooled to 60 °C and filtered through Celite.
  • Step 3 2-[5-bromo-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-2-methyl-1-propanol [0553] To a solution of 2-[2-amino-4-bromo-6-(trifluoromethyl)anilino]-2-methyl-propan-1-ol (8.50 g, 26.0 mmol) and trimethoxymethane (28.5 mL, 260 mmol) in THF (80 mL) was added TsOH•H2O (447 mg, 2.60 mmol). The mixture was heated to 40 °C and stirred for 1 h.
  • Step 4 2-methyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl]-1-propanol
  • a mixture of 2-[5-bromo-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-2-methyl-1- propanol (8.20 g, 24.3 mmol), bis(pinacolato)diboron (9.20 g, 36.5 mmol), KOAc (7.20 g, 73.0 mmol) and Pd(dppf)Cl 2 (1.80 g, 2.43 mmol) in 1,4-dioxane (90 mL) was degassed and purged with N2 (3x).
  • Step 5 1-(2-hydroxy-1,1-dimethylethyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-ol
  • 2-methyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1-propanol 5.00 g, 13.0 mmol
  • H 2 O 20 mL
  • Oxone (12.0 g, 19.5 mmol
  • Step 2 5-bromo-2-(3-thietanylamino)-3-(trifluoromethyl)aniline
  • 3-[4-bromo-2-nitro-6-(trifluoromethyl)phenylamino]thietane (1.00 g, 2.80 mmol) in EtOH (5 mL) and H2O (5 mL) were added Fe (625 mg, 11.2 mmol) and NH4Cl (599 mg, 11.2 mmol).
  • the mixture was heated to 80 C and stirred for 2 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was poured into H 2 O (10 mL) and extracted with EtOAc (3 x 10 mL).
  • Step 3 5-bromo-1-(3-thietanyl)-7-(trifluoromethyl)-1H-1,3-benzimidazole
  • Step 4 5,5-dimethyl-2-[1-(3-thietanyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5-yl]-1,3,2- dioxaborinane
  • 5-bromo-1-(3-thietanyl)-7-(trifluoromethyl)-1H-1,3-benzimidazole 620 mg, 1.84 mmol
  • 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5- dimethyl-1,3,2-dioxaborinane (2.08 g, 9.19 mmol)
  • Pd(dppf)Cl 2 (403 mg, 552 ⁇ mol)
  • KOAc 541 mg, 5.52 mmol
  • Step 5 3-[5-hydroxy-7-(trifluoromethyl)-1H-1,3-benzimidazol-1-yl]-1 ⁇ 6-1,1-thietanedione
  • a 0 °C solution of 5,5-dimethyl-2-[1-(3-thietanyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yl]-1,3,2-dioxaborinane 500 mg, 1.35 mmol
  • THF 4 mL
  • H 2 O 2 mL
  • Step 2 methyl 5-bromo-2-[(cis)-3-hydroxy-3-methylcyclobutylamino]-3- (trifluoromethyl)benzoate
  • methyl 5-bromo-2-fluoro-3-(trifluoromethyl)benzoate (40.2 g, 133 mmol) and cis-3-amino-1-methylcyclobutan-1-ol (22.1 g, 160 mmol, HCl salt) in DMF (150 mL) was added K 2 CO 3 (55.4 g, 401 mmol). The mixture was heated to 100 °C and stirred for 3 h.
  • Step 3 (cis)-3-[4-bromo-2-(hydroxymethyl)-6-(trifluoromethyl)phenylamino]-1- methylcyclobutanol [0561] To a 0 °C solution of methyl 5-bromo-2-[(cis)-3-hydroxy-3-methylcyclobutylamino]-3- (trifluoromethyl)benzoate (20.0 g, 52.3 mmol) in THF (200 mL) was added 2.5 M LiAlH4 in THF (20.9 mL, 52.3 mmol) dropwise. The mixture was stirred at 0 °C for 2 h.
  • Step 4 6-bromo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8-(trifluoromethyl)-1,4-dihydro-3,1- benzoxazin-2-one [0562] To a 0 °C solution of (cis)-3-[4-bromo-2-(hydroxymethyl)-6- (trifluoromethyl)phenylamino]-1-methylcyclobutanol (15.2 g, 42.9 mmol) in THF (400 mL) were added DIEA (22.4 mL, 129 mmol) and bis(trichloromethyl) carbonate (12.7 g, 42.9 mmol) in portions. The mixture was stirred at 0 °C for 0.5 h.
  • Step 5 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8- (trifluoromethyl)-1,4-dihydro-3,1-benzoxazin-2-one [0563] To a solution of 6-bromo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8-(trifluoromethyl)- 1,4-dihydro-3,1-benzoxazin-2-one (17.0 g, 44.7 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2- yl)-5,5-dimethyl-1,3,2-dioxaborinane (20.2 g, 89.4 mmol) in 1,4-dioxane (150 mL) were added KOAc (13.2 g, 134 mmol) and Pd(dppf)Cl2 (3.27
  • the mixture was degassed and purged with N2 (3x). The mixture was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was quenched by addition of H2O (400 mL), and then extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 6 6-hydroxy-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8-(trifluoromethyl)-1,4-dihydro-3,1- benzoxazin-2-one [0564] To a solution of 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-[(cis)-3-hydroxy-3- methylcyclobutyl]-8-(trifluoromethyl)-1,4-dihydro-3,1-benzoxazin-2-one (20.0 g, 48.4 mmol) in THF (100 mL) and H2O (100 mL) was added Oxone (29.8 g, 194 mmol).
  • Step 1 N-[2-amino-5-bromo-3-(trifluoromethyl)phenyl](cis)-3-hydroxy-3- methylcyclobutanecarboxamide
  • DCM dimethylcyclobutanecarboxylic acid
  • Step 2 (cis)-3-[6-bromo-4-(trifluoromethyl)-1H-1,3-benzimidazol-2-yl]-1-methylcyclobutanol
  • Step 3 trimethyl(2- ⁇ [(cis)-3-[6-bromo-4-(trifluoromethyl)-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -1H-1,3-benzimidazol-2-yl]-1- methylcyclobutoxy]methoxy ⁇ ethyl)silane [0568] To a 0 °C solution of (cis)-3-[6-bromo-4-(trifluoromethyl)-1H-1,3-benzimidazol-2-yl]-1- methylcyclobutanol (1.40 g, 4.01 mmol) in THF (20 mL) was added NaH (60% w/w in mineral oil, 722 mg, 18.0 mmol).
  • Step 4 trimethyl(2- ⁇ [(cis)-3-[6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-(trifluoromethyl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -1H-1,3-benzimidazol-2-yl]-1- methylcyclobutoxy]methoxy ⁇ ethyl)silane [0569] A mixture of trimethyl(2- ⁇ [(cis)-3-[6-bromo-4-(trifluoromethyl)-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -1H-1,3-benzimidazol-2-yl]-1- methylcyclobutoxy]methoxy ⁇ ethyl)silane (300 mg, 492 ⁇ mol), KOAc (72.4 mg, 738 ⁇ mol), Pd(dppf)Cl 2 (18.0 mg, 24.6 ⁇ mol), and 2-(5,5-dimethyl-1,3,2-dio
  • Step 2 5-bromo-2-[((cis)-3-hydroxy-3-methyl-cyclobutyl)amino]-3-(trifluoromethyl)benzoate ⁇
  • methyl 5-bromo-2-fluoro-3-(trifluoromethyl)benzoate (40.2 g, 133 mmol) and cis-3-amino-1-methyl-cyclobutanol (22.1 g, 160 mmol, HCl salt)
  • DMF 150 mL
  • K 2 CO 3 55.4 g, 401 mmo
  • reaction mixture was quenched by addition of Na2SO4•10H2O (20.2 g) at 0 °C and stirred at 0 °C for 30 min. Then the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was further triturated with DCM (100 mL) at room temperature for 30 min and filtered. The filter cake was dried in vacuo to give 3-[4-bromo-2-(hydroxymethyl)-6- (trifluoromethyl)anilino]- (cis)-1-methyl-cyclobutanol.
  • reaction mixture was quenched by addition of H 2 O (100 mL) and extracted with DCM (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-bromo-2-[((cis)-3-hydroxy-3-methyl-cyclobutyl) amino]-3- (trifluoromethyl)benzaldehyde, which was used in the subsequent step without further purification.
  • Step 8 6-hydroxy-1-((cis)-3-hydroxy-3-methyl-cyclobutyl)-8-(trifluoromethyl)-3,4- dihydroquinazolin-2-one [0579] To a solution of 1-((cis)-3-hydroxy-3-methyl-cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-one (2.00 g, 4.69 mmol) in THF (10 mL) and H2O (10 mL) was added NaBO3•4H2O (2.89 g, 18.8 mmol).
  • Step 1 5-bromo-1-chloro-2-fluoro-3-nitro-benzene
  • TFA 300 mL
  • H2SO4 200 mL
  • NBS 60.8 g, 342 mmol
  • Step 2 3-(4-bromo-2-chloro-6-nitro-anilino)-(cis)-1-methyl-cyclobutanol
  • 5-bromo-1-chloro-2-fluoro-3-nitro-benzene (20.0 g, 78.6 mmol) and cis-3-amino-1-methyl-cyclobutanol (13.0 g, 94.3 mmol, HCl)
  • MeCN 200 mL
  • NaHCO3 13.2 g, 157 mmol
  • Step 3 3-(2-amino-4-bromo-6-chloro-anilino)- (cis)-1-methyl-cyclobutanol
  • disodium hydrosulfite 72.6 g, 417 mmol
  • H 2 O 200 mL
  • 3-(4-bromo-2-chloro-6-nitro-anilino)-1-methyl-cyclobutanol 20.0 g, 59.6 mmol
  • MeOH 100 mL
  • Step 4 3-(5-bromo-7-chloro-2-methyl-benzimidazol-1-yl)-(cis)-1-methyl-cyclobutanol [0583] To a solution of 3-(2-amino-4-bromo-6-chloro-anilino)-(cis)-1-methyl-cyclobutanol (10.0 g, 32.7 mmol) in THF (100 mL) was added MeC(OEt) 3 (11.7 g, 72.0 mmol). The mixture was then stirred at 40°C for 16 hrs. After cooling to the room temperature, the reaction mixture was quenched by addition of H 2 O (200 mL), and extracted with EtOAc (3 x 200 mL).
  • Step 5 3-[7-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-benzimidazol-1-yl]- (cis)-1-methyl-cyclobutanol [0584]
  • a mixture of 3-(5-bromo-7-chloro-2-methyl-benzimidazol-1-yl)-(cis)-1-methyl- cyclobutanol (6.83 g, 20.7 mmol)
  • 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2- dioxaborinane (9.36 g, 41.4 mmol)
  • KOAc (6.10 g, 62.2 mmol)
  • Pd(dppf)Cl 2 (1.52 g, 2.07 mmol) in dioxane (150 mL) was degassed and purged with N 2 for 3 times, and
  • Step 6 7-chloro-1-(cis-3-hydroxy-3-methyl-cyclobutyl)-2-methyl-benzimidazol-5-ol
  • 3-[7-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl- benzimidazol-1-yl]-1-methyl-cyclobutanol (3.20 g, 8.82 mmol) in THF (15 mL) and H 2 O (15 mL) was added NaBO3•4H2O (5.43 g, 35.3 mmol). The mixture was stirred at room temperature for 1 h.
  • Step 2 (cis)-1-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)- 1H-benzo[d][1,2,3]triazol-1-yl)cyclobutan-1-ol [0587] A mixture of (cis)-3-(5-bromo-7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)-1- methylcyclobutan-1-ol (640 mg, 1.83 mmol), bis(pinacolato)diboron (557 mg, 2.19 mmol), KOAc (359 mg, 3.66 mmol) and Pd(dppf)Cl 2 (134 mg, 183 ⁇ mol) in 1,4-dioxane (8 mL) was degassed and purged with N 2 (3x), and then the mixture was stirred at 80 °C for 12 h under N 2 atmosphere
  • Step 3 1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-5- ol
  • Step 1 N-(5-bromo-2-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3- (trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide
  • 2-hydroxy-2-methyl-propanoic acid (663 mg, 6.37 mmol) and DIEA (2.06 g, 15.9 mmol) in THF (20 mL) was added PyAOP (5.53 g, 10.6 mmol). The reaction mixture was stirred at room temperature for 0.5 h.
  • Step 2 (cis)-3-(5-bromo-2-(2-hydroxypropan-2-yl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-1- yl)-1-methylcyclobutan-1-ol
  • Step 3 (cis)-3-(2-(2-hydroxypropan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol
  • a mixture of (cis)-3-(5-bromo-2-(2-hydroxypropan-2-yl)-7-(trifluoromethyl)-1H- benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol 150 mg, 368 ⁇ mol
  • KOAc (72.3 mg, 737 ⁇ mol)
  • bis(pinacolato)diboron (281 mg, 1.11 mmol)
  • Pd(dppf)Cl2 (27.0 mg, 36.8 ⁇ mol) in 1,4-dioxane (5 mL) was degassed and purged with N 2 (3x).
  • Step 4 1-((cis)-3-hydroxy-3-methylcyclobutyl)-2-(2-hydroxypropan-2-yl)-7-(trifluoromethyl)- 1H-benzo[d]imidazol-5-ol [0592] To a solution of (cis)-3-(2-(2-hydroxypropan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol (170 mg, 374 ⁇ mol) in THF (3 mL) and H2O (1 mL) was added Oxone (460 mg, 748 ⁇ mol).
  • Step 2 (cis)-3-((2-(difluoromethyl)-6-nitrophenyl)amino)-1-methylcyclobutan-1-ol
  • Step 3 (cis)-3-((4-bromo-2-(difluoromethyl)-6-nitrophenyl)amino)-1-methylcyclobutan-1-ol
  • NBS NBS
  • Step 4 (cis)-3-((2-amino-4-bromo-6-(difluoromethyl)phenyl)amino)-1-methylcyclobutan-1-ol [0597] To a mixture of (cis)-3-((4-bromo-2-(difluoromethyl)-6-nitrophenyl)amino)-1- methylcyclobutan-1-ol (2.00 g, 5.70 mmol) in MeOH (20 mL) and H2O (2 mL) were added NH4Cl (914 mg, 17.1 mmol) and Fe (1.59 g, 28.5 mmol). The reaction mixture was then stirred at 60 °C for 5 h.
  • Step 5 (cis)-3-(5-bromo-7-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclobutan-1- ol
  • Step 7 7-(difluoromethyl)-1-((cis)-3-hydroxy-3-methylcyclobutyl)-1H-benzo[d]imidazol-5-ol
  • (cis)-3-(7-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol 700 mg, 1.85 mmol
  • THF 15 mL
  • H 2 O 5 mL
  • Oxone (1.14 g, 1.85 mmol
  • Step 1 N-[4-bromo-2-nitro-6-(trifluoromethyl)phenyl]-1-methylsulfonyl-azetidin-3-amine [0601] To a solution of 5-bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene (4.00 g, 13.9 mmol) in CH3CN (20 mL) was added DIEA (5.39 g, 41.7 mmol) and 1-(methylsulfonyl)azetidin-3- amine (2.50 g, 16.7 mmol) at room temperature. The mixture was then stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.
  • Step 2 4-bromo-N 1 -(1-methylsulfonylazetidin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine
  • N-[4-bromo-2-nitro-6-(trifluoromethyl)phenyl]-1-methylsulfonyl- azetidin-3-amine (3.50 g, 8.37 mmol)
  • H2O 20 mL
  • EtOH 20 mL
  • Fe 1.40 g, 25.1 mmol
  • NH4Cl (2.24 g, 41.9 mmol
  • Step 4 1-(1-methylsulfonylazetidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)benzimidazole
  • Step 5 1-(1-methylsulfonylazetidin-3-yl)-7-(trifluoromethyl)benzimidazol-5-ol
  • 1-(1-methylsulfonylazetidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7-(trifluoromethyl)benzimidazole (1.00 g, 2.25 mmol) in THF (20 mL) and H 2 O (20 mL) was added NaBO 3 •4H 2 O (2.07 g, 13.5 mmol). The mixture was then stirred at room temperature for 1 h.
  • Step 2 4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3-nitro-5-(trifluoromethyl)phenol [0607] To a 0 °C solution of (cis)-1-methyl-3-((2-nitro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(trifluoromethyl)phenyl)amino)cyclobutan-1-ol (16.0 g, 38.4 mmol) in THF (100 mL) and H 2 O (50 mL) was added Oxone (23.6 g, 38.4 mmol) in portions. The reaction mixture was then stirred at room temperature for 2 h.
  • the reaction mixture was cooled to 0 °C and quenched by addition of saturated aqueous Na 2 SO 3 solution (100 mL). The suspension was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was then diluted with H 2 O (50 mL) and extracted with EtOAc (150 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 3 (cis)-3-((4-(2-bromoethoxy)-2-nitro-6-(trifluoromethyl)phenyl)amino)-1- methylcyclobutan-1-ol
  • 4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3-nitro-5- (trifluoromethyl)phenol (11.8 g, 38.5 mmol,) and 1,2-dibromoethane (72.4 g, 385 mmol) in CH3CN (110 mL) was added K2CO3 (16.0 g, 116 mmol) at room temperature.
  • the reaction mixture was then stirred at 80 °C for 12 h.
  • Step 4 (cis)-3-((2-amino-4-(2-bromoethoxy)-6-(trifluoromethyl)phenyl)amino)-1- methylcyclobutan-1-ol [0609] To a solution of sodium hydrosulfite (674 mg, 3.87 mmol) in H 2 O (5 mL) was added dropwise a solution of (cis)-3-((4-(2-bromoethoxy)-2-nitro-6-(trifluoromethyl)phenyl)amino)-1- methylcyclobutan-1-ol (200 mg, 484 ⁇ mol) in MeOH (2 mL). The mixture was then stirred at room temperature for 3 h.
  • Step 5 N-(5-(2-bromoethoxy)-2-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3- (trifluoromethyl)phenyl)-2,2-difluoroacetamide
  • TEA TEA
  • Step 6 (cis)-3-(5-(2-bromoethoxy)-2-(difluoromethyl)-7-(trifluoromethyl)-1H- benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol [0611] A solution of N-(5-(2-bromoethoxy)-2-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3- (trifluoromethyl)phenyl)-2,2-difluoroacetamide (700 mg, 1.52 mmol) in AcOH (10 mL) was stirred at 90 °C for 2 h.
  • Step 2 (cis)-3-(5-(2-bromoethoxy)-2-cyclopropyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-1- yl)-1-methylcyclobutan-1-ol
  • Step 1 N-(5-(2-bromoethoxy)-2-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3- (trifluoromethyl)phenyl)-2-(tert-butoxy)acetamide
  • (cis)-3-((2-amino-4-(2-bromoethoxy)-6-(trifluoromethyl)phenyl)amino)-1- methylcyclobutan-1-ol (Intermediate A-29, 260 mg, 0.678 mmol), 2-(tert-butoxy)acetic acid (224 mg, 1.70 mmol), PyAOP (884 mg, 1.70 mmol) and DIEA (0.302 g, 0.407 mL) in THF (6 mL) was stirred at 50 °C for 3 h.
  • Step 2 (cis)-3-(5-(2-bromoethoxy)-2-(tert-butoxymethyl)-7-(trifluoromethyl)-1H- benzo[d]imidazol-1-yl)-1-methylcyclobutan-1-ol
  • Step 3 (cis)-3-(5-bromo-3-fluoro-7-(trifluoromethyl)-1H-indazol-1-yl)-1-methylcyclobutan-1- ol and trans-3-(5-bromo-3-fluoro-7-(trifluoromethyl)-1H-indazol-1-yl)-1-methylcyclobutan-1- ol
  • To a -10 °C solution of 3-[5-bromo-3-fluoro-7-(trifluoromethyl)indazol-1- yl]cyclobutanone (1.50 g, 4.27 mmol) in DCM (15 mL) was added 3 M MeMgBr in Et2O (1.42 mL, 4.26 mmol) under N2 atmosphere.
  • reaction mixture was warmed to room temperature and stirred for 2 h.
  • the reaction mixture was cooled to 0 °C and quenched by addition of saturated aqueous Na 2 SO 3 solution (20 mL), and then diluted with H 2 O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 ((cis))-3-[2-bromo-4-nitro-6-(trifluoromethyl)phenylamino]-1-methylcyclobutanol [0625] To a solution of 1-bromo-2-fluoro-5-nitro-3-(trifluoromethyl)benzene (20.0 g, 69.4 mmol) and (cis)-3-amino-1-methylcyclobutan-1-ol (10.5 g, 76.4 mmol) in DMF (30 mL) was added K2CO3 (28.8 g, 208 mmol) in portions. The mixture was heated to 100 °C and stirred for 2 h.
  • Step 3 ((cis))-1-methyl-3-[4-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- (trifluoromethyl)phenylamino]cyclobutanol [0626] To a solution of ((cis))-3-[2-bromo-4-nitro-6-(trifluoromethyl)phenylamino]-1- methylcyclobutanol (10.0 g, 27.1 mmol) and bis(pinacolato)diboron (34.4 g, 135 mmol) in 1,4- dioxane (100 mL) was added KOAc (5.32 g, 54.2 mmol) and Pd(PPh3)2Cl2 (951 mg, 1.35 mmol).
  • Step 4 5-nitro-2-[((cis))-3-hydroxy-3-methylcyclobutylamino]-3-(trifluoromethyl)phenol [0627]
  • Step 5 6-nitro-3-[((cis))-3-hydroxy-3-methylcyclobutyl]-4-(trifluoromethyl)-2,3-dihydro-1,3- benzoxazol-2-one [0628] To a solution of 5-nitro-2-[((cis))-3-hydroxy-3-methylcyclobutylamino]-3- (trifluoromethyl)phenol (2.00 g, 6.53 mmol) in THF (20 mL) was added CDI (1.16 g, 7.18 mmol) in portions. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (3 x 20 mL).
  • Step 6 6-amino-3-[((cis))-3-hydroxy-3-methylcyclobutyl]-4-(trifluoromethyl)-1,3-benzoxazol- 2(3H)-one [0629] To a 0 °C solution of 6-nitro-3-[((cis))-3-hydroxy-3-methylcyclobutyl]-4- (trifluoromethyl)-2,3-dihydro-1,3-benzoxazol-2-one (2.00 g, 6.02 mmol) in EtOH (20 mL) and H2O (5 mL) was added Fe (1.34 g, 24.1 mmol) and NH 4 Cl (1.29 g, 24.1 mmol) in portions.
  • Step 7 3-[((cis))-3-hydroxy-3-methylcyclobutyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-4-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one [0630] To a 0 °C solution of 6-amino-3-[((cis))-3-hydroxy-3-methylcyclobutyl]-4- (trifluoromethyl)-1,3-benzoxazol-2(3H)-one (800 mg, 2.65 mmol) in H2O (10 mL) was added 4.0 M HCl in H2O (2.65 mL, 10.6 mmol) dropwise.
  • Step 8 6-hydroxy-3-[((cis))-3-hydroxy-3-methylcyclobutyl]-4-(trifluoromethyl)-1,3- benzoxazol-2(3H)-one [0631] To a 0 °C solution of 3-[(cis)-3-hydroxy-3-methylcyclobutyl]-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one (600 mg, 1.45 mmol) in THF (10 mL) and H 2 O (3 mL) was added NaBO 3 •4H 2 O (894 mg, 5.81 mmol) in portions.
  • the reaction mixture was warmed to room temperature and stirred for 12 h.
  • the reaction mixture was poured into saturated aqueous NaHCO3 solution (50 mL) and extracted with EtOAc (3 x 50 mL).
  • the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure.
  • the residue was purified by flash silica gel chromatography (Sepaflash 40 g cartridge, 0–10% EtOAc/Petroleum ether) to give 1-[3-(benzyloxy)cyclobutyl]-2- bromo-1-ethanone.
  • Step 4 2-[3-(benzyloxy)cyclobutyl]-5-iodo-7-(trifluoromethyl)-1,3a-diazaindene [0635]
  • a mixture of 1-[3-(benzyloxy)cyclobutyl]-2-bromo-1-ethanone (5.90 g, 20.8 mmol) and 5-iodo-3-(trifluoromethyl)-2-pyridylamine (4.00 g, 13.9 mmol) in DMF (40 mL) was stirred at 90 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 50 mL).
  • Step 5 3-[5-iodo-7-(trifluoromethyl)-1,3a-diaza-2-indenyl]cyclobutanol
  • Step 6 3-[5-iodo-7-(trifluoromethyl)-1,3a-diaza-2-indenyl]cyclobutanone [0637] To a solution of 3-[6-iodo-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]cyclobutanol (1.6 g, 4.19 mmol) in DCM (16 mL) was added DMP (1.95 mL, 6.28 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and quenched by addition of saturated aqueous Na2SO3 solution (30 mL), and then extracted with DCM (3 x 20 mL).
  • Step 7 ((cis))-3-[5-iodo-7-(trifluoromethyl)-1,3a-diaza-2-indenyl]-1-methylcyclobutanol and (trans)-3-[5-iodo-7-(trifluoromethyl)-1,3a-diaza-2-indenyl]-1-methylcyclobutanol [0638] To a 0 °C solution of 3-[5-iodo-7-(trifluoromethyl)-1,3a-diaza-2-indenyl]cyclobutanone (1.60 g, 4.21 mmol) in DCM (20 mL) was added 3.0 M MeMgBr in Et2O (1.40 mL, 4.20 mmol) dropwise.
  • reaction mixture was stirred at room temperature for 1 h under N2 atmosphere.
  • the reaction mixture was cooled to 0 °C, quenched by addition of saturated aqueous NH 4 Cl solution (15 mL), and then extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 2-[((cis))-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1,3a-diaza-5-indenol [0640] To a 0 °C solution of ((cis))-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- (trifluoromethyl)-1,3a-diaza-2-indenyl]-1-methylcyclobutanol (320 mg, 837 ⁇ mol) in THF (4 mL) and H 2 O (2 mL) was added Oxone (515 mg, 837 ⁇ mol) in portions. The reaction mixture was warmed to room temperature and stirred for 1 h.
  • Step 2 4-methoxy-N-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)pyridin-2-amine
  • Step 3 4-methoxy-6-(trifluoromethyl)pyridin-2-amine [0644] To a solution of 4-methoxy-N-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)pyridin-2- amine (3.30 g, 10.6 mmol) in DCM (20 mL) was added TFA (20.0 mL, 269 mmol). The mixture was stirred at 30 °C for 12 h. The reaction mixture was diluted with H2O (50 mL) and adjusted to pH > 7 with Na2CO3 solid, then extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step 4 2-(3-benzyloxycyclobutyl)-7-methoxy-5-(trifluoromethyl)imidazo[1,2-a]pyridine
  • a mixture of 4-methoxy-6-(trifluoromethyl)pyridin-2-amine (1.50 g, 7.81 mmol) and 1- (3-benzyloxycyclobutyl)-2-bromo-ethanone (2.65 g, 9.37 mmol) in i-PrOH (15 mL) was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL x 3).
  • Step 5 3-[7-methoxy-5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]cyclobutanol
  • Step 6 3-[7-methoxy-5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]cyclobutanone [0647] To a solution of 3-[7-methoxy-5-(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl]cyclobutanol (900 mg, 3.14 mmol) in DCM (10 mL) was added DMP (2.00 g, 4.72 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was then cooled to 0 °C and quenched by addition saturated aqueous Na2SO3 (20 mL), then diluted with H2O (20 mL) and extracted with DCM (30 mL x 3).
  • Step 7 ((cis))-3-(7-methoxy-5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1- methylcyclobutan-1-ol
  • 3-[7-methoxy-5-(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl]cyclobutanone 600 mg, 2.11 mmol
  • DCM 6 mL
  • 3 M MeMgBr in THF 7.04 ⁇ L, 2.11 mmol
  • reaction mixture was cooled to 0 °C and quenched by addition of saturated aqueous NH 4 Cl solution (5 mL), and then diluted with H 2 O (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with H 2 O (5 mL) and basified with NaHCO 3 solid till pH>7, then extracted with EtOAc (5 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Sepaflash 4 g cartridge, 0-40% Methanol/EtOAc) to give 2-((cis)-3- hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridin-7-ol (Intermediate A-42).
  • Step 1 5-bromo-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one
  • (cis)-3-((2-amino-4-bromo-6-(trifluoromethyl)phenyl)amino)-1- methylcyclobutan-1-ol (Intermediate A-7, 2.00 g, 5.90 mmol) and CDI (1.43 g, 8.85 mmol) in THF (20 mL) was stirred at 50 °C for 16 h.
  • Step 2 6-bromo-3-((cis)-3-hydroxy-3-methylcyclobutyl)-4-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [0653] To a 0 °C mixture of 5-bromo-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7- (trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.70 g, 7.39 mmol) in THF (30 mL) was added 60% NaH in mineral oil (887 mg, 22.2 mmol) in portions.
  • Step 4 6-hydroxy-3-((cis)-3-hydroxy-3-methylcyclobutyl)-4-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [0655] To a solution of 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-((cis)-3-hydroxy-3- methylcyclobutyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one (2.30 g, 4.35 mmol) in THF (16 mL) and H2O (8 mL) was added Oxone (4.01 g, 6.53 mmol).
  • Step 5 6-(2-bromoethoxy)-3-((cis)-3-hydroxy-3-methylcyclobutyl)-4-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [0656] To a solution of 6-hydroxy-3-((cis)-3-hydroxy-3-methylcyclobutyl)-4-(trifluoromethyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.60 g, 3.70 mmol) and 1,2-dibromoethane (2.79 mL, 37.0 mmol) in i-PrOH (20 mL) was added Cs 2 CO 3 (3.62 g, 11.1 mmol).
  • Step 6 5-(2-bromoethoxy)-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1,3- dihydro-2H-benzo[d]imidazol-2-one [0657] To a solution of 6-(2-bromoethoxy)-3-((cis)-3-hydroxy-3-methylcyclobutyl)-4- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (280 mg, 519 ⁇ mol) in DCM (3 mL) was added TFA (2 mL, 26.9 mmol).
  • Step 7 6-(2-bromoethoxy)-3-((cis)-3-hydroxy-3-methylcyclobutyl)-1-methyl-4- (trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [0658] To a 0 °C solution of 5-(2-bromoethoxy)-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7- (trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (120 mg, 293 ⁇ mol) and MeI (208 mg, 1.47 mmol) in THF (1 mL) was added t-BuOK (65.8 mg, 587 ⁇ mol).
  • Step 1 1-((5-bromo-2-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3- (trifluoromethyl)phenyl)carbamoyl)cyclopropyl acetate
  • Step 2 1-(5-bromo-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1,3- benzodiazol-2-yl)cyclopropyl acetate
  • a solution of 1-((5-bromo-2-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-3- (trifluoromethyl)phenyl)carbamoyl)cyclopropyl acetate (440 mg, 0.946 mmol) in HOAc (10 mL) was stirred at 90 °C for 20 h. The mixture was cooled to room temperature and concentrated under reduced pressure.
  • Step 3 1-(1-((cis)-3-hydroxy-3-methylcyclobutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-7-(trifluoromethyl)-1,3-benzodiazol-2-yl)cyclopropyl acetate
  • Step 4 1-(5-hydroxy-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1,3- benzodiazol-2-yl)cyclopropyl acetate
  • 1-(1-((cis)-3-hydroxy-3-methylcyclobutyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)-1,3-benzodiazol-2-yl)cyclopropyl acetate (300 mg, 606 ⁇ mol) in THF (6 mL) was added a solution of Oxone (373 mg, 1.21 mmol) in H 2 O (6 mL).
  • Step 5 1-(5-(2-bromoethoxy)-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1,3- benzodiazol-2-yl]cyclopropyl acetate
  • Step 6 1-(5-(2-bromoethoxy)-1-((cis)-3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1,3- benzodiazol-2-yl)propan-1-one and (cis)-3-(5-(2-bromoethoxy)-2-(1-hydroxycyclopropyl)-7- (trifluoromethyl)-1,3-benzodiazol-1-yl)-1-methylcyclobutan-1-ol [0664] To a mixture of 1-(5-(2-bromoethoxy)-1-((cis)-3-hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1,3-benzodiazol-2-yl)cyclopropyl acetate (0.255 g, 0.520 mmol) in THF (5 mL) and MeOH (0.5 mL) was added 3 M aqueous LiOH solution (0.52 mL, 1.56 mmol).
  • Step 2 (cis)-3-(5-(2-bromoethoxy)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1- methylcyclobutan-1-ol
  • Step 3 (cis)-3-(5-(2-bromoethoxy)-1-methyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1- methylcyclobutan-1-ol and (cis)-3-(6-(2-bromoethoxy)-1-methyl-4-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-1-methylcyclobutan-1-ol [0667] To a solution of (cis)-3-(5-(2-bromoethoxy)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)-1-methylcyclobutan-1-ol (500 mg, 1.27 mmol) in DMF (15 mL) were added iodomethane (541 mg, 3.81 mmol) and K 2 CO 3 (879 mg, 6.36 mmol).
  • Step 1 tert-butyl 3-((4-bromo-2-nitro-6-(trifluoromethyl)phenyl)amino)azetidine-1- carboxylate
  • Step 2 tert-butyl 3-((2-amino-4-bromo-6-(trifluoromethyl)phenyl)amino)azetidine-1- carboxylate
  • Step 3 tert-butyl 3-[5-bromo-7-(trifluoromethyl)-1,3-benzodiazol-1-yl]azetidine-1-carboxylate
  • Step 4 tert-butyl 3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)-1,3- benzodiazol-1-yl]azetidine-1-carboxylate
  • Step 5 tert-butyl 3-(5-hydroxy-7-(trifluoromethyl)-1,3-benzodiazol-1-yl)azetidine-1- carboxylate [0672] To a solution of tert-butyl 3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)-1,3-benzodiazol-1-yl]azetidine-1-carboxylate (0.167 g, 0.357 mmol) in THF (3 mL) was added a solution of Oxone (0.165 g, 0.536 mmol) in H2O (3 mL). The mixture was then stirred at room temperature for 2 h.
  • Step 6 tert-butyl 3-(5-(2-bromoethoxy)-7-(trifluoromethyl)-1,3-benzodiazol-1-yl)azetidine-1- carboxylate
  • a mixture of tert-butyl 3-(5-hydroxy-7-(trifluoromethyl)-1,3-benzodiazol-1- yl)azetidine-1-carboxylate (118 mg, 330 ⁇ mol), dibromoethane (1.24 g, 6.60 mmol) and Cs 2 CO 3 (215 mg, 660 ⁇ mol) in i-PrOH (2 mL) was stirred at 60 °C for 18 h.
  • Step 7 1-(azetidin-3-yl)-5-(2-bromoethoxy)-7-(trifluoromethyl)-1,3-benzodiazole [0674] To a solution of tert-butyl 3-(5-(2-bromoethoxy)-7-(trifluoromethyl)-1,3-benzodiazol-1- yl)azetidine-1-carboxylate (97.0 mg, 209 ⁇ mol) in DCM (2 mL) was added TFA (1.92 mL, 25.1 mmol). The mixture was stirred at room temperature for 1 h.
  • Step 8 3-(5-(2-bromoethoxy)-7-(trifluoromethyl)-1,3-benzodiazol-1-yl)azetidine-1- carboxamide
  • a mixture of 1-(azetidin-3-yl)-5-(2-bromoethoxy)-7-(trifluoromethyl)-1,3-benzodiazole (100 mg, 210 ⁇ mol), O-phenyl carbamate (36.0 mg, 263 ⁇ mol) and diisopropylethylamine (109 mg, 840 ⁇ mol) in i-PrOH (2 mL) was stirred at 80 °C for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure.
  • Step 1 1-bromo-3-hydroxy-3-methylbutan-2-one [0676] To a 0 °C solution of 3-hydroxy-3-methyl-butan-2-one (5.00 g, 49.0 mmol) in MeOH (50 mL) under N2 was added Br2 (2.27 mL, 44.1 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred at for 10 h. The reaction mixture was then concentrated under reduced pressure to give 1-bromo-3-hydroxy-3-methyl-butan-2-onel. 1 H NMR (400 MHz, DMSO- d6): ⁇ 4.70 (s, 2H), 1.24 (s, 6H).
  • Step 2 2-(6-methoxy-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)propan-2-ol
  • 5-methoxy-3-(trifluoromethyl)pyridin-2-amine (3.00 g, 15.6 mmol)
  • 1-bromo-3-hydroxy-3-methylbutan-2-one (4.24 g, 23.4 mmol) in 1,4-dioxane (30 mL)
  • NaHCO3 3.28 g, 39.0 mmol
  • Step 3 2-(2-hydroxypropan-2-yl)-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-ol
  • 2-[6-methoxy-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl]propan-2-ol (2.20 g, 8.02 mmol) in DCM (30 mL) under N 2
  • BBr 3 3.86 mL, 40.1 mmol
  • the reaction mixture was stirred at 0 °C for 5 h.
  • Step 1 5-bromo-2-methyl-1-nitro-3-(trifluoromethyl) benzene
  • 2-methyl-1-nitro-3-(trifluoromethyl) benzene 5.00 g, 24.4 mmol
  • concentrated H 2 SO 4 98%, 50 mL
  • 1,3-dibromo-5,5-dimethyl- imidazolidine-2,4-dione 4.18 g, 14.6 mmol
  • the reaction mixture was poured into ice water (100 mL) and extracted with Petroleum ether (50 mL x 3).
  • Step 2 5-bromo-2-methyl-1-nitro-3- (trifluoromethyl) benzene

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Abstract

Sont proposés des composés de formule (II) ou des stéréoisomères ou tautomères de ceux-ci, ou des sels pharmaceutiquement acceptables de l'un quelconque de ceux-ci, où n, m, p, R1, R2, R3, L1, L3, R4, X1, X2, X5, X6, X7, X8, X9, R6 et R7 sont tels que définis dans la description. Sont également proposés des procédés de préparation de composés de formule (II), ou de stéréoisomères ou de tautomères de ceux-ci, ou de sels pharmaceutiquement acceptables de l'un quelconque de ceux-ci. Sont également proposés des procédés d'inhibition d'APOL1 et des procédés de traitement d'une maladie, d'un trouble ou d'un état médié par APOL1, tel qu'une maladie rénale ou une rétinopathie diabétique, chez un individu.
PCT/US2024/037470 2023-07-11 2024-07-10 Inhibiteurs d'apol1 et procédés d'utilisation Pending WO2025015104A2 (fr)

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US12344610B2 (en) 2022-01-18 2025-07-01 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use

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TWI350168B (en) * 2004-05-07 2011-10-11 Incyte Corp Amido compounds and their use as pharmaceuticals
US20080306102A1 (en) * 2007-05-18 2008-12-11 Kowa Co., Ltd. Novel spirooxyindole compounds and drugs containing same
MX2011009571A (es) * 2009-03-13 2011-10-19 Boehringer Ingelheim Int Inhibidores de beta-secretasa.
JP2025503737A (ja) * 2022-01-18 2025-02-04 メイズ セラピューティクス， インコーポレイテッド Ａｐｏｌ１阻害剤及び使用方法

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