Apol1 inhibitors and methods of use thereof

Abstract

Provided herein are compounds of formula (I'): or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein n,p, R1a, R1b, R1c, R1d, R2, R3, R4, L1, L2, L3, X1, X2, X3, X4, and X5 are as defined herein. Also provided are methods of preparing compounds of formula (I'), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing. Also provided are methods of inhibiting APOL1 and methods of treating an APOL1-mediated disease, disorder, or condition, such as kidney disease or diabetic retinopathy, in an individual.

Description

Docket No.: 79275-20028.40 APOL1 INHIBITORS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 526,158 filed on July 11, 2023, which is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION

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

[0003] Apolipoprotein L1 (APOL1) is a pore forming innate immunity factor, protecting individuals from trypanosome parasites (Vanhamme, L. et al. Nature (2003) 422, 83–87). The secreted form of APOL1 circulates in blood as part of distinct high-density lipoprotein (HDL) complexes, known as trypanosome lytic factors (TLFs) (Rifkin, M. R. Proc. Natl. Acad. Sci. USA. (1978) 75, 3450–3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910–1916). TLFs are internalized by the parasites through endocytosis (Hager, K. M. et al. J. Cell Biol. (1994) 126, 155–167). Within trypanosomes, APOL1 forms cation pores, causing ion flux, swelling, and eventual lysis (Rifkin, M. R. Exp. Parasitol. (1984) 58, 81–93; Molina-Portela, M. P. et al. Mol. Biochem. Parasitol. (2005) 144, 218–226; Pérez-Morga, D. et al. Science. (2005) 309, 469–472; Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA. (2015) 112, 2894–2899). APOL1 is secreted from the liver as part of an HDL particle that is taken up by T. brucei where it forms a pore that results in lysis of the parasite (Rifkin, M. R. Proc. Natl. Acad. Sci. USA. (1978) 75, 3450-3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910-1916). APOL1 is also expressed in other cell types throughout the body, including endothelial cells and podocytes, where it can be induced by various inflammatory cytokines (Nystrom et al. JAK inhibitor blocks COVID-19 cytokine-induced JAK / STAT / APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022 Jun 8;7(11): e157432). APOL1 expressed in cell types outside of liver is thought to be largely intracellular (Cheng et al, J Lipid Res. 2015 Aug;56(8):1583-93. Doi: 10.1194 / jlr.M059733; Shukha et al, J Am Soc Nephrol. 2017 Apr; 28(4): 1079–1083).sf-59631891Docket No.: 79275-20028.40

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

[0005] Numerous studies have shown that APOL1 risk variants are toxic when overexpressed in human cells (Wan, G. et al. J. Biol. Chem. (2008) 283, 21540–21549; Lan, X. et al. Am. J. Physiol. Renal Physiol. (2014) 307, F326–F336; Olabisi, O. A. et al. Proc. Natl. Acad. Sci. USA.sf-59631892Docket No.: 79275-20028.40 (2016) 113, 830–837; Ma, L. et al. J. Am. Soc. Nephrol. (2017) 28, 1093–1105; Lannon, H. et al. Kidney Int. (2019) 96, 1303–1307). Recent findings suggest that this toxicity is associated with APOL1 pore function (Giovinazzo, J. A. et al. eLife. (2020) 9, e51185). Thus, there is a need to develop compounds suitable for inhibiting APOL1 activity and methods for inhibiting the activity of APOL1 using such compounds.

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

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

[0008] This disclosure describes compounds and compositions that may be useful for the treatment of APOL1-mediated diseases, including a variety of chronic kidney diseases such as FSGS, hypertension-attributed kidney disease, HIVAN, sickle cell nephropathy, lupus nephritis, diabetic kidney disease, viral nephropathy, COVID-19 associated nephropathy, and APOL1- associated nephropathy. The compounds and compositions may treat other APOL1-mediated disorders such as preeclampsia and sepsis. Additionally, for individuals with the APOL1 high-sf-59631893Docket No.: 79275-20028.40 risk genotype, the disclosed compounds and may prevent the onset of non-diabetic renal disease and / or delaying the progression of any form of chronic kidney disease. The disclosed chemical matter may also prevent and / or delay progressive renal allograft loss in patients who have received a kidney transplant from a high-risk APOL1 genotype donor.

[0009] This disclosure also describes methods for treating diabetic retinopathies including non- proliferative diabetic retinopathy, proliferative diabetic retinopathy, vision threatening diabetic retinopathy, and diabetic macular edema comprising administration of an APOL1 inhibitor or composition comprising an APOL1 inhibitor. Additionally, the disclosed methods may prevent the onset of diabetic retinopathies and / or delay the progression of diabetic retinopathies. The APOL1 inhibitor may be administered as a single agent or in combination with other agents including, e.g., anti-VEGF agents, Angiopoietin 2 blocking agents, dual VEGF-Angiopoietin 2 blocking agents, corticosteroids, and / or laser therapy.

[0010] A genetic link between a missense variant in APOL1 and DME has been established (Stockwell, A.D. et al, Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights APOL1 as a high-risk locus in patients with diabetic macular edema. PLoS Genetics 19(8) (2023): e1010609; herein incorporated by reference in its entirety). This variant contains glutamic acid instead of lysine at position 150 (E150 APOL1). E150 APOL1 has been shown to enhance the cytotoxic effects of APOL1 when overexpressed (Lannon et al, Apolipoprotein L1 (APOL1) risk variant toxicity depends on the haplotype background. Kidney International (2019) 96, 1303–1307; herein incorporated by reference in its entirety) and may explain the association of this APOL1 variant with diseases of the eye. APOL1 has been shown to be expressed in various cell types in the eye including endothelial cells and fibroblasts (Gautam et al. Multi-species single-cell transcriptomic analysis of ocular compartment regulons. Nat Commun. 2021 Sep 28;12(1):5675; herein incorporated by reference in its entirety).

[0011] DME and DR are associated with higher levels of inflammation, and inflammatory cytokines in the eye (Mason, R.H. et al, Changes in aqueous and vitreous inflammatory cytokine levels in proliferative diabetic retinopathy: a systematic review and meta-analysis. Eye 2022 Jun 7, doi: https: / / doi.org / 10.1038 / s41433-022-02127-x; herein incorporated by reference in its entirety). Inflammatory cytokines like interferons, IL-1β and TNF-α are known inducers of APOL1 in endothelial cells (Nichols et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015 Feb;87(2):332-42; Nystrom et al. JAK inhibitor blockssf-59631894Docket No.: 79275-20028.40 COVID-19 cytokine-induced JAK / STAT / APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022 Jun 8;7(11):e157432; each herein incorporated by reference in its entirety). Interferon therapy can lead to retinopathy and macular edema, through mechanisms that remain unclear (Tokai et al. Interferon-associated retinopathy and cystoid macular edema. Arch Ophthalmol. 2001 Jul;119(7):1077-9; Zubir et al. Interferon-α- induced retinopathy in chronic hepatitis C treatment: summary, considerations, and recommendations. Graefes Arch Clin Exp Ophthalmol. 2019 Mar;257(3):447-452; each herein incorporated by reference in its entirety). Since interferon is a potent inducer of APOL1, it is plausible that these ocular effects could be driven through interferon mediated induction of APOL1 in eye tissues. In support of this concept, endothelial specific APOL1 expression has been reported to cause vascular leak in mouse models, consistent with the vascular leak seen in DR and DME (Wu et al, APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis. Immunity. 2021 Nov 9; 54(11): 2632–2649.e6; herein incorporated by reference in its entirety).

[0012] A cytotoxic APOL1 variant (E150 APOL1) is genetically associated with diabetic eye disease, and the overexpression of this variant drives toxicity in cellular models. APOL1 is expressed in the eye in cell types known to be relevant to the pathophysiology of diabetic eye disease including endothelial cells. Therapeutic use of interferon, which induces APOL1 expression in endothelial cells, is also associated with ocular side effects including retinopathy and macular edema. APOL1 induction in mouse models results in vascular leak, consistent with the role of vascular leak in diabetic eye diseases. APOL1 pore blockers have been shown to protect cells from cytotoxicity associated with kidney disease associated variants. Therefore, APOL1 inhibitors as disclosed herein may be therapeutically beneficial in patients with or at risk of developing DME or DR. Moreover, the APOL1 inhibitors as disclosed herein may be administered by a variety of routes including, e.g., oral administration.

[0013] In one aspect, provided provided is a compound of formula (I’):sf-59631895Docket No.: 79275-20028.40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl;sf-59631896Docket No.: 79275-20028.40 either: (1) X5is -C-; L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra;sf-59631897Docket No.: 79275-20028.40 (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH, andsf-59631898Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which ,wherein # represents a point of attachment to the remainder of the structure; (3) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); andsf-59631899Docket No.: 79275-20028.40 the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, or CHF2; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together withR4, and the atoms to which they are attached, to form wherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to formsf-596318910Docket No.: 79275-20028.40L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more - OH or C1-6alkyl, andsf-596318911Docket No.: 79275-20028.40 Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; (5) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; or (6) X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo,sf-596318912Docket No.: 79275-20028.40 the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6 alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or - S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH; Rais, independently at each occurrence: (i) C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or - N(C1-6alkyl)-C(O)-C1-6alkyl; (ii) C3-10cycloalkyl optionally substituted with one or more -OH, -C(O)2-C1-6alkyl, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, or –C(O)-C3-10heterocyclyl, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH; (iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl; or (iv) NH(C1-6alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6);sf-596318913Docket No.: 79275-20028.40 X4is N or C(R7); and R6and R7are each independently H or halo.

[0014] In one aspect, provided provided is a compound of formula (I):, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, whereinsf-596318914Docket No.: 79275-20028.40 the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; either: (1) L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl;(iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether withsf-596318915Docket No.: 79275-20028.40 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3- 10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis optionally substituted with one or more halo, OH, -S(O)2-C1-6alkyl, or C3-10cycloalkyl, and whereinsf-596318916Docket No.: 79275-20028.40 the C3-10cycloalkyl of the C1-6alkyl of Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2 or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which ,wherein # represents a point of attachment to the remainder of the structure; (3) L3is absent; and one of X1and X2is N or C(R5); andsf-596318917Docket No.: 79275-20028.40 the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CH2F; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, tosf-596318918Docket No.: 79275-20028.40wherein # represents a point of attachment to the remainder of the structure; or (4) L3is absent; and one of X1and X2is N or C(R5); andthe other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and whereinsf-596318919Docket No.: 79275-20028.40 each Rfis further optionally substituted with one or more - OH or C1-6alkyl; Rais, independently at each occurrence: (i) C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or -N(C1-6alkyl)-C(O)-C1-6alky; (ii) C3-10cycloalkyl optionally substituted with one or more -OH, -C(O)2-C1-6alkyl, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, or –C(O)-C3-10heterocyclyl, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH; (iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl; or (iv) NH(C1-6alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6); X4is N or C(R7); and R6and R7are each independently H or halo. Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.sf-596318920Docket No.: 79275-20028.40

[0015] In some embodiments of the compound of formula (I), the compound is a compound of ;sf-596318921Docket No.: 79275-20028.40(I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n, p, R1a, R1b, R1c, R1d, R2, R3, R4, R5, R6, R7, L1, L3, X1, X2, X3, X4, and ring A are as defined elsewhere herein. In another variation, n, p, R1a, R1b, R1c, R1d, R2, R3, R4, R5, R6, R7, L1, L3, X1, X2, X3, X4, and ring A are as defined for a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0016] In some embodiments of the compound of formula (I’), the compound is a compound of(I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: p, R1a, R1b, R1c, R1d, R2, R3, R4, L1, X2, X3, X4, and ring E are as defined elsewhere herein.

[0017] In some embodiments the compound of formula (I) is a compound of formula (II): sf-596318922Docket No.: 79275-20028.40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl of R1are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1- 6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; and ring B is selected from the group consisting of:sf-596318923Docket No.: 79275-20028.40, wherein r is an integer from 0 to 2; s is an integer from 0 to 3; t is an integer from 1 to 20; X2cis N or C(R5c); R5a, R5b, and R5care each independently H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3a, X3band X3care each independently N or C(R6), wherein R6is H or halo; X4a, X4band X4care each independently N or C(R7), wherein R7is H or halo; X5aand X6aare each independently NH or -(CH2)x-O- wherein x is 0 or 1; X5b, X6band X7bare each independently N or C, each of which is optionally substituted with one or more H; Rbis, 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-Ra, C3- 10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and sf-596318924Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo; Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; and ring C is a 5-20 membered heteroaryl substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl; wherein, R2is C2-6alkynyl when:sf-596318925Docket No.: 79275-20028.40 a) R1cis Cl or CN; R5ais CF3; and the ring B; b) R1cis Cl or CN; R5bis F, CHF2, -OCHF2 or CN; and the ring B bearing X5b, X6bc) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; R5bis CF3; and the ring B,, wherein # represents a point of attachment to the remainder of the structure.sf-596318926Docket No.: 79275-20028.40

[0018] In some embodiments of the compound of formula (II), the compound is a compound of(II-C); or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n, p, q, r, s, R1a, R1b, R1c, R1d, R2, R3, R4, R5, R6, R7, L1, L3, X2c, X3a, X3b, X3c, X4a, X4b, X4c, X5a, X5b, X6a, X6b, X7b, and ring C are as defined elsewhere herein. In another variation, : n, p, q, r, s, R1a, R1b, R1c, R1d, R2, R3, R4, R5, R6, R7, L1, L3, X2c, X3a, X3b, X3c, X4a, X4b, X4c, X5a, X5b, X6a, X6b, X7b, and ring 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.

[0019] Any embodiments provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. Thus, it is understood and described that each embodiment provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a sf-596318927Docket No.: 79275-20028.40 pharmaceutically acceptable salt of any of the foregoing, such as embodiments related n, p, R1a, R1b, R1c, R1d, R2, R3, R4, L1, L2, L3, X1, X2, X3, X4, and X5apply formula (I-A) (I-B), (I-C), (I- D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the same as if each and every embodiment were specifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein.

[0020] In one aspect, provided herein is 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), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A,) (I-B), (I-C), (I-D), (I- E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0021] In one aspect, provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (II), (II-A), (II-B), or (II-C), 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), (II), (II-A), (II-B), or (II-C), 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 (I’), (I), (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G),sf-596318928Docket No.: 79275-20028.40 (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0022] In one aspect, provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

[0023] In one aspect, provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (II), (II-A), (II-B), or (II-C), 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), (II), (II-A), (II-B), or (II-C), 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 (I’), (I), (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0024] In one aspect, provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II- B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.sf-596318929Docket No.: 79275-20028.40

[0025] In one aspect, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (II), (II-A), (II-B), or (II- C), 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), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of treating an APOL1- mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I), (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0026] In one aspect, provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (II), (II-A), (II-B), or (II-C), 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), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-596318930Docket No.: 79275-20028.40

[0027] In one aspect, provided herein is a method of treating diabetic retinopathy in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation or embodiment thereof, such as a compound of formula (I-A) (I-B), (I-C), (I- D), (I-E), (I-F), (I-G), (II), (II-A), (II-B), or (II-C), 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), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A,) (I-B), (I-C), (I- D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0028] In one aspect, provided herein is 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), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In one aspect, provided herein is 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), (II), (II-A), (II-B), or (II-C), 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 (I’), (I), (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0029] In one aspect, provided herein is a kit, 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), (II), (II-A), (II-B), or (II-C), 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. In anothersf-596318931Docket No.: 79275-20028.40 variation, provided herein is a kit, comprising (i) a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I- E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. This aspect in some embodiments may employ a compound of any of formulas (I’), (I), (I-A,) (I-B), (I-C), (I- D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of the kits disclosed herein, the individual is a human.

[0030] In some aspect, provided herein are methods of preparing a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A) (I-B), (I-C), (I-D), (I- E), (I-F), (I-G), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In another variation, provided herein are methods of preparing a compound of formula (I’), or any embodiment or variation thereof, such as a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0031] All pharmaceutical compositions, methods, kits, uses, or other aspects described herein with reference to formula (I) or (I’), or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein such as formula (I-A,) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), the same as if each and every embodiment were specifically and individually listed. BRIEF DESCRIPTION OF THE FIGURES

[0032] 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.

[0033] FIG. 2 shows the results of an APOL1 E150 G2 mouse transgenic model to validate chronic effects of interferon on APOL1 expression in eye tissue. DETAILED DESCRIPTION OF THE INVENTIONsf-596318932Docket No.: 79275-20028.40

[0034] Unless clearly indicated otherwise, the terms “a,” “an,” and the like, refer to one or more.

[0035] As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

[0036] “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.

[0037] As used herein, an “at risk” individual is an individual who is at risk of developing a disease or condition. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).

[0038] “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).

[0039] As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and / or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

[0040] As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context ofsf-596318933Docket No.: 79275-20028.40 administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.

[0041] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.

[0042] As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

[0043] The term “alkyl”, as used herein, refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C1-20alkyl), 1-16 carbons (i.e., C1-16alkyl), 1-12 carbons (i.e., C1-12alkyl), 1-10 carbons (i.e., C1-10alkyl), 1-8 carbons (i.e., C1-8alkyl), 1-6 carbons (i.e., C1-6alkyl), 1-4 carbons (i.e., C1-4alkyl), or 1-3 carbons (i.e., C1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n- butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3- hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso-propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”.

[0044] The term “alkynyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, alkynyl has 2-20 carbons (i.e., C2-20alkynyl), 2-16 carbons (i.e., C2-16alkynyl), 2-12 carbons (i.e., C2-12alkynyl), 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). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. When an 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 skillsf-596318934Docket No.: 79275-20028.40 in the art. For instance, a divalent group, such as a divalent “alkynyl” group, may be referred to as an “alkynylene”.

[0045] The term “alkoxy”, as used herein, refers to an -O-alkyl moiety. As used herein, alkoxy has, for example, 1-6 carbons (i.e., C1-6alkoxy), or 1-3 carbons (i.e., C1-3alkoxy). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0046] The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C6-20aryl), 6 to 16 annular carbon atoms (i.e., C6-16aryl), 6 to 12 annular carbon atoms (i.e., C6-12aryl), or 6 to 10 annular carbon atoms (i.e., C6-10aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0047] The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C3-8cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C3-6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7-dimethyl -bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.

[0048] The term “halo”, as used herein, refers to atoms occupying group VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0049] The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the groupsf-596318935Docket No.: 79275-20028.40 consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, 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). Examples of 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, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, triazolyl, tetrazolyl, and triazinyl. Examples of the 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.

[0050] The term “heterocyclyl”, as used herein, 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. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety 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). Further, the term 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. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 memberedsf-596318936Docket No.: 79275-20028.40 heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][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, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1- oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of 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. Examples of 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.

[0051] The term “oxo”, as used herein, refers to a =O moiety.

[0052] The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses -CH3, -CH2Cl, - CHCl2, and -CCl3moieties.

[0053] It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.sf-596318937Docket No.: 79275-20028.40

[0054] The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Such compositions are well known in the pharmaceutical art. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl), amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0055] Isotopically labeled forms of the compounds depicted herein may be prepared. 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. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H,3H,11C,13C,14C,13N,sf-596318938Docket No.: 79275-20028.4015N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. In some embodiments, a compound of formula (I), or formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

[0056] Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.

[0057] 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.

[0058] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds orsf-596318939Docket No.: 79275-20028.40 other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

[0059] 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.

[0060] Where enantiomeric and / or diastereomeric forms exist of a given structure, the composition is made up of at least 90%, by weight, dashes or wedges indicate a single enantiomer or diastereomer with known relative or absolute stereochemistry, e.g.,.

[0061] 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.,.

[0062] Where a given structure has potential for cis and trans configuration, and the composition is made up of at least 90%, by weight, astrisks (*) indicate single unknown cis or trans configuration, e.g.,sf-596318940Docket No.: 79275-20028.40

[0063] Where a given structure has potential for enantiomeric and / or diastereomeric forms, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,

[0064] Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd, hereby incorporated herein by reference in its entirety. The following examples are intended to be illustrative only and not limiting in any way. degrees Celsius CH3C(OMe)3 1,1,1-trimethoxyethane μL microliter CO2 carbon dioxide [M+XX]+observed mass Cs2CO3 cesium carbonate AC50half-maximal activity CuCN copper cyanide concentration CuI copper iodide AcOH acetic acid d deuterated (NMR AgNO3silver nitrate solvents) AIBN azobisisobutyronitrile d doublet (NMR) BBr3boron tribromide dd doublet of doublets (BPin)2 Bis(pinacolato)diboron (NMR) br broad (NMR) DCM dichloromethane Br2bromine DIAD diisopropyl Calc’d calculated azodicarboxylate CDI 1,1’-carbonyldiimidazole DIEA N,N- CHCl3 chloroform diisopropylethylaminesf-596318941Docket No.: 79275-20028.40 DMA N,N-dimethylactamide 2-MeTHF 2-methyl tetrahydrofuran DMF N,N-dimethylformamide MHz megahertz DMP Dess–Martin periodinane m multiplet (NMR) DMSO dimethylsulfoxide mg milligrams Fe iron min minutes HATU 1- mL milliliter [Bis(dimethylamino)meth mmol millimole ylene]-1H-1,2,3- mM millimolar triazolo[4,5-b]pyridinium M molarity or molar 3-oxid MeCN acetonitrile hexafluorophosphate MS mass spectrometry HC(OMe)3 trimethoxymethane MTBE methyl tert-butyl ether HNO3 nitric acid N2 nitrogen gas HOAc acetic acid n / a not applicable IC50half-maximal effective NaBH4sodium boronhydride concentration NaBH(OAc)3 Sodium Et3SiH triethylsilane triacetoxyboronhydride EtOAc ethyl acetate NaBO3 Sodium perborate EtOH Ethanol NaH sodium hydride Fe iron NaOH sodium hydroxide g grams NaNO2 sodium nitrite h hours NaSMe sodium thiomethoxide H hydrogen Na2SO3 sodium sulfite H2hydrogen gas Na2SO4sodium sulfate H2O water Na2S2O4sodium dithionite H2SO4 sulfuric acid NBS N-bromosuccinimide HCl hydrochloric acid NCS N-chlorosuccinimide HPLC high-performance liquid NH4Cl ammonium chloride chromatography NH4OH ammonium hydroxide KHMDS potassium NH4HCO3ammonium bicarbonate bis(trimethylsilyl)amide NMR nuclear magnetic I2iodine resonance In vacuo in a vacuum NMP N-methyl-2-pyrrolidone i-PrOH isopropanol Pd / C palladium on carbon IUPAC International Union of Pd(dppf)Cl2[1,1′- Pure and Applied bis(diphenylphosphino)fer Chemistry rocene]dichloropalladium( J J-coupling value (NMR) II) K2CO3 potassium carbonate Pd(PPh3)4palladium KOAc potassium acetate tetra(triphenylphosphine) LiAlH4lithium aluminum hydride pH potential of hydrogen LiOH lithium hydroxide PhI (OAc)2 (Diacetoxyiodo)benzene m-CPBA 3-chloroperbenzoic acid PMB-NH24-methoxybenzylamine MeI methyl iodide PPh3triphenylphosphine MeMgBr methyl magnesium PyAOP (7-Azabenzotriazol-1- bromide yloxy)tripyrrolidinophosp MeCN acetonitrile honium MeOH Methanol hexafluorophosphatesf-596318942Docket No.: 79275-20028.40 rt room temperature tBuOK potassium tert-butoxide s singlet (NMR) t-BuONO tert-butyl nitrite SEMCl (2- TEA Triethylamine (chloromethoxy)ethyl)trim TFA trifluoroacetic acid ethylsilane THF tetrahydrofuran SFC super fluid TMPhen 3,4,7,8-tetramethyl-1,10- chromatography phenanthroline t triplet (NMR) TsOH•H2O p-toluenesulfonic acid T4P 2,4,6-tributyl-1,3,5,2,4,6- monohydrate trioxatriphosphorinane, Zn zinc 2,4,6-trioxide ZnBr2zinc bromide TBSCl tert-butyldimethylsilyl chloride COMPOUNDS

[0065] Provided herein is a compound of formula (I’):, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo;sf-596318943Docket No.: 79275-20028.40 R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; either: (1) X5is -C-; L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6alkyl, or -S(O)2-Ra, whereinsf-596318944Docket No.: 79275-20028.40 the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2 wherein Reis independently at each occurrence H, C1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, whereinsf-596318945Docket No.: 79275-20028.40 the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH, and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to whichsf-596318946Docket No.: 79275-20028.40 they are attached, to,, wherein # represents a point of attachment to the remainder of the structure; (3) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when:sf-596318947Docket No.: 79275-20028.40 a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, or CHF2; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together withR4, and the atoms to which they are attached, towherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2; (4) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, whereinsf-596318948Docket No.: 79275-20028.40 the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1- 6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more - OH or C1-6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; (5) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; or (6) X5is -N-; L3is absent; and one of X1and X2is N or C(R5); andsf-596318949Docket No.: 79275-20028.40 the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or - S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH; Rais, independently at each occurrence: (i) C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or - N(C1-6alkyl)-C(O)-C1-6alkyl;sf-596318950Docket No.: 79275-20028.40 (ii) C3-10cycloalkyl optionally substituted with one or more -OH, -C(O)2-C1-6alkyl, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, or –C(O)-C3-10heterocyclyl, or C1- 6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH; (iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl; or (iv) NH(C1-6alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6); X4is N or C(R7); and R6and R7are each independently H or halo.

[0066] 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, either: (1) X5is -C-; L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra;sf-596318951Docket No.: 79275-20028.40 (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2 wherein Reis independently at each occurrence H, C1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) X5is -C-; L3is absent; andsf-596318952Docket No.: 79275-20028.40 one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH, and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to whichsf-596318953Docket No.: 79275-20028.40 they are attached, to,, wherein # represents a point of attachment to the remainder of the structure; (3) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when:sf-596318954Docket No.: 79275-20028.40 a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, or CHF2; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together withR4, and the atoms to which they are attached, towherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2; (4) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, whereinsf-596318955Docket No.: 79275-20028.40 the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1- 6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more - OH or C1-6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; (5) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; or (6) X5is -N-; L3is absent; and one of X1and X2is N or C(R5); andsf-596318956Docket No.: 79275-20028.40 the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or - S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH. In some embodiments, (1) applies. In some embodiments, (2) applies. In some embodiments, (3) applies. In some embodiments, (4) applies. In some embodiments, (5) applies. In some embodiments, (6) applies.

[0067] Provided herein is a compound of formula (I):sf-596318957Docket No.: 79275-20028.40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl;sf-596318958Docket No.: 79275-20028.40 either: (1) L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2 wherein Reis independently at each occurrence H, C1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra;sf-596318959Docket No.: 79275-20028.40 (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and whereinsf-596318960Docket No.: 79275-20028.40 the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which ,wherein # represents a point of attachment to the remainder of the structure; (3) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, whereinsf-596318961Docket No.: 79275-20028.40 Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CH2F; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, tosf-596318962Docket No.: 79275-20028.40wherein # represents a point of attachment to the remainder of the structure; or (4) L3is absent; and one of X1and X2is N or C(R5); andthe other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and whereinsf-596318963Docket No.: 79275-20028.40 each Rfis further optionally substituted with one or more - OH or C1-6alkyl; Rais, independently at each occurrence: (i) C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or -N(C1-6alkyl)-C(O)-C1-6alky; (ii) C3-10cycloalkyl optionally substituted with one or more -OH, -C(O)2-C1-6alkyl, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, or –C(O)-C3-10heterocyclyl, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH; (iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl; or (iv) NH(C1-6alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6); X4is N or C(R7); and R6and R7are each independently H or halo.

[0068] 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, either: (1) L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is optionally substituted with one or more –OH or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH, andsf-596318964Docket No.: 79275-20028.40 the 3-10 membered heterocyclyl of L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H;sf-596318965Docket No.: 79275-20028.40 b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2or -OCHF2;sf-596318966Docket No.: 79275-20028.40 b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they arec) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which ,wherein # represents a point of attachment to the remainder of the structure; (3) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, andsf-596318967Docket No.: 79275-20028.40 the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CH2F; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, towherein # represents a point of attachment to the remainder of the structure; or (4) L3is absent; and one of X1and X2is N or C(R5); andsf-596318968Docket No.: 79275-20028.40 the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1- 6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more - OH or C1-6alkyl. In some embodiments, (1) applies. In some embodiments, (2) applies. In some embodiments, (3) applies. In some embodiments, (4) applies.

[0069] Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. Any embodiments provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II- C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.sf-596318969Docket No.: 79275-20028.40

[0070] Any embodiments provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. Thus, it is understood and described that each embodiment provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to m, n, R2, R3, R5, R6, R7, R8, R9, R10, R11a, R11b, and X apply to formula (II’) or (II), the same as if each and every embodiment were specifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein. And, each embodiment provided herein of a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to n, p, R1a, R1b, R1c, R1d, R2, R3, R4, L1, L2, L3, X1, X2, X3, X4, and X5also apply to formula (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II’), (II), (II-A), (II-B), or (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0071] 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, 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 (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0072] 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, 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 (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0073] 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, R1a, R1b, R1cand R1dare each independently selected from H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1- 6alkoxy or C1-6alkyl are optionally substituted with one or more halo. In some embodiments, R1a,sf-596318970Docket No.: 79275-20028.40 R1b, R1cand R1dare each independently selected from H, halo, -CN, C1-3alkoxy, and C1-3alkyl, wherein the C1-3alkoxy or C1-3alkyl are optionally substituted with one or more halo. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0074] 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, R1a, R1b, R1cand R1dare each H. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0075] 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, three of R1a, R1b, R1cand R1dare H, and one of R1a, R1b, R1cand R1dis selected from halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl of are optionally substituted with one or more halo. In some embodiments, two of R1a, R1b, R1cand R1dare H, and two of R1a, R1b, R1cand R1dare each independently selected from halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0076] In some embodiments, one of R1a, R1b, R1cand R1dis halo. In some embodiments, one of R1a, R1b, R1cand R1dis Cl. In some embodiments, one of R1a, R1b, R1cand R1dis Br. In some embodiments, one of R1a, R1b, R1cand R1dis F.

[0077] 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, one of R1a, R1b, R1cand R1dis C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more halo. In some embodiments, one of R1a, R1b, R1cand R1dis C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more halo. In some embodiments, one of R1a, R1b, R1cand R1dis C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more F. In some embodiments, one of R1a, R1b, R1cand R1dis methyl, wherein the methyl is optionally substituted with one or more F. In some variations, the embodiments provided herein also apply to any other applicablesf-596318971Docket No.: 79275-20028.40 formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0078] 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, one of R1a, R1b, R1cand R1dis -CN. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0079] 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, one of R1a, R1b, R1cand R1dis C1-6alkoxy, wherein the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments, one of R1a, R1b, R1cand R1dis C1-3alkoxy, wherein the C1-3alkoxy is optionally substituted with one or more halo. In some embodiments, one of R1a, R1b, R1cand R1dis C1-3alkoxy, wherein the C1-3alkoxy is optionally substituted with one or more F. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0080] 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, R2is H. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0081] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is C1-6alkyl. In some embodiments, R2is C1-3alkyl. In some embodients R2is methyl or ethyl. In some embodiments, R2is methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0082] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is C1-6alkyl optionallysf-596318972Docket No.: 79275-20028.40 substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy. In some embodiments, R2is C1-3alkyl optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1- 3alkoxy. In some embodiments, R2is methyl. In some embodiments, R2is ethyl optionally substituted with one or more halo, -OH, -NH2, or C1-6alkoxy. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0083] 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, R2is C2-6alkynyl. In some In some embodiments, R2is selected from the group consistingsome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0084] 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, R2is C3-10cycloalkyl, wherein the C3-10cycloalkyl of R2is optionally substituted with one or more -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0085] 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, R2is 3-15 membered heterocyclyl. In some embodiments, R2is 3-6 membered heterocyclyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0086] 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, R3is C1-6alkyl. In some embodiments, R3is C1-3alkyl. In some embodiments, R3is methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as sf-596318973Docket No.: 79275-20028.40 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.

[0087] 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, the ring bearing R1a, R1b, R1cand R1dand R2is a 2-indolinone optionally substituted at one or more of positions 1, 5, and 7. In some embodiments, the 2-indolinone ring is unsubstituted. In some embodiments, the 2- indolinone ring is substituted at position 1. In some embodiments, the 2-indolinone ring is substituted at position 5. In some embodiments, the 2-indolinone ring is substituted at position 7. In some embodiments, the 2-indolinone ring is substituted at positions 1, and 5. In some embodiments, the 2-indolinone ring is substituted at positions 5 and 7. In some embodiments, the 2-indolinone ring is substituted at positions 1, 5, and 7. In some embodiments positions 1, 5 and 7 are defined as indicated in the structure,, wherein position 1 is a N atom, each of positions 5 and 7 is a C atom, and ## represent the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0088] 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, the ring bearing (R1)m and ,represents the point of attachment to the remainder of the molecule.

[0089] 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, the ring bearing (R3)p is sf-596318974Docket No.: 79275-20028.40, wherein ## represents the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0090] 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, the ring bearing R1a, R1b, R1cand R1d, R2, and (R3)pis selected from the group,some embodiments, the ring bearing R1a, R1b, R1cand R1d, R2, and (R3)p is selected from the groupsome embodiments, the ringsf-596318975Docket No.: 79275-20028.40 embodiments, the ringsome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0091] 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, L1is C1-6alkylene optionally substituted with one or more deuterieum, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with -OH or C1-6alkoxy. In some embodiments, L1is C1-3alkylene optionally substituted with one or more deuterium, or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with -OH or C1-3alkoxy. In some embodiments, L1is methylene. In some embodiments, L1is ethylene. In some embodiments, L1is ethylene optionally substituted with one or more deuterium, or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more -OH or C1-3alkoxy. In some embodiments, L1is selected from the group consisting of , wherein, for each L1, # denotes2the point of attachment to L and ## denotes the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0092] 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, L2is O or N(Rx), wherein Rxis H or C1-6alkyl. In some embodiments, L2is O or N(Rx), wherein Rxis H or C1-3alkyl.

[0093] 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, L2is O. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. sf-596318976Docket No.: 79275-20028.40

[0094] 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, X5is -C-; L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more – OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more – OH, (v) -C(O)-N(Re)2 wherein Reis independently at each occurrence H, C1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2;sf-596318977Docket No.: 79275-20028.40 wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3.

[0095] 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, L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1- 6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more – OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more – OH; (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl);sf-596318978Docket No.: 79275-20028.40 (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0096] 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, L3is absent. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0097] 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, L3is O. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0098] 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, L3is C1-6alkylene, wherein the C1-6alkylene of L3is optionally substituted with one or more -OH, or C1-6alkyl wherein the C1-6alkyl is optionally substituted with one or more -OH. In some embodiments, L3is C1-3alkylene, wherein the C1-6alkylene of L3is optionally substituted with one or more -OH, or C1-6alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0099] 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, L3is C3-10cycloalkyl,sf-596318979Docket No.: 79275-20028.40 wherein the C3-10cycloalkyl of L3is optionally substituted with one or more -OH. In some embodiments, L3is C3-8cycloalkyl, wherein the C3-8cycloalkyl of L3is optionally substituted with one or more -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0100] 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, L3 is 3-10 membered heterocyclyl. In some embodiments, L3is 3-6 membered heterocyclyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0101] 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, R4is -S(O)2-Ra, wherein Rais C1-6alkyl. In some embodiments, R4is -S(O)2-Ra, wherein Rais C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or -N(C1-6alkyl)-C(O)-C1-6alkyl. In some embodiments, R4is -S(O)2-Ra, wherein Rais C1-3alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-3alkyl, or -N(C1-3alkyl)-C(O)-C1-3alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0102] 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, R4is -S(O)2-Ra, wherein Rais C3-10cycloalkyl. In some embodiments, R4is -S(O)2-Ra, wherein Rais C3-10cycloalkyl 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 C1-6alkyl is optionally substituted with one or more -OH. In some embodiments, R4is -S(O)2-Ra, wherein Rais C3-6cycloalkyl 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 C1-6alkyl is optionally substituted with one or more -OH. In some embodiments, R4is -S(O)2-Ra, wherein Rais 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 orsf-596318980Docket No.: 79275-20028.40 more -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0103] 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, R4is -S(O)2-Ra, wherein Rais 3-10 membered heterocyclyl. In some embodiments R4is -S(O)2-Ra, wherein Rais 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl. In some embodiments, R4is -S(O)2-Ra, wherein Rais 3-6 membered heterocyclyl optionally substituted with one or more C1-6alkyl. In some embodiments, wherein R4is -S(O)2-Ra, wherein Rais 3-6 membered heterocyclyl optionally substituted with one or more C1-3alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0104] 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, R4is 5-20 membered heteroaryl. In some embodiments, R4is 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl. In some embodiments, R4is 5-6 membered heteroaryl optionally substituted with one or more C1-6alkyl. In some embodiments, R4is 5-6 membered heteroaryl optionally substituted with one or more C1-3alkyl. In some embodiments, R4is 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 (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0105] 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, R4is -N(Rd)2, wherein each of Rdis independently H, C1-6alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH, and wherein Rais C1-6alkyl. In some embodiments, R4is - N(Rd)2, wherein each of Rdis independently H, C1-3alkyl, or -S(O)2-Ra, wherein the C1-3alkyl of Rdis optionally substituted with one or more -OH, and wherein Rais C1-3alkyl. In some embodiments, R4is -N(Rd)2, wherein each of Rdis independently H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-3alkyl of Rdis optionally substituted with one or more -OH, and wherein Raissf-596318981Docket No.: 79275-20028.40 methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0106] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R4is -C(O)-N(Re)2, wherein each of Reis independently H or C1-6alkyl. In some embodiments, R4is -C(O)-N(Re)2, wherein each of Reis independently H or C1-3 alkyl. In some embodiments, R4is -C(O)-N(Re)2, wherein each of Reis independently H or methyl. In some embodiments, R4is -C(O)-NH2. In some embodiments, R4is -C(O)-NH(CH3). In some embodiments, R4is -C(O)-N(CH3)2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0107] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R4is -C(O)-N(Re)2, wherein each of Reis independently H or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo. In some embodiments, R4is -C(O)-N(Re)2, wherein each of Reis independently H or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0108] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R4is -C(O)-N(Re)2, wherein both Retogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl. In some embodiments R4is -C(O)-N(Re)2, wherein both Retogether 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-Ra, or -S(O)2-Ra, wherein Rais C1-6alkyl. In some embodiments R4is - C(O)-N(Re)2, wherein both Retogether 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-Ra, or -S(O)2-Ra, wherein Rais C1-sf-596318982Docket No.: 79275-20028.403alkyl. In some embodiments R4is -C(O)-N(Re)2, wherein both Retogether 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-Ra, or -S(O)2-Ra, wherein Rais methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0109] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R4is 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH, oxo or -S(O)2Ra. In some embodiments, R4is 3-7 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH, oxo or -S(O)2Ra. In some embodiments, R4is 3-7 membered heterocyclyl optionally substituted with one or more C1-3alkyl, -OH, oxo or -S(O)2Ra. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0110] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R4is -S(O)(N-C1-6alkyl)- (C1-6alkyl). In some embodiments, R4is -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 (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0111] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R4is -CN. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0112] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R4is -(CH2)qOH, wherein q is an integer from 0-6. R4is -(CH2)qOH, wherein q is an integer from 0-2. In some embodiments, R4is -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer orsf-596318983Docket No.: 79275-20028.40 tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0113] 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, R4is -C(O)-C1-6alkyl. In some embodiments, R4is -C(O)-C1-3alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0114] 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, R4is -P(O)(C1-6alkyl)2. In some embodiments, R4is -P(O)(C1-3alkyl)2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0115] 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, each of X1and X2is independently N or C(R5). In some embodiments, each of X1and X2is N. In some embodiments, each of X1and X2is C(R5). In some embodiments, one of X1and X2is CR5, and the other of X1and X2is N. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[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, one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl optionally substituted with one or more of Rb. In some embodiments, one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-8 membered heterocyclyl optionally substituted with one or more of Rb. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.sf-596318984Docket No.: 79275-20028.40

[0117] 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, X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH, and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form ,sf-596318985Docket No.: 79275-20028.40 c) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein # represents a point of attachment to the remainder of the structure.

[0118] 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, L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2or -OCHF2;sf-596318986Docket No.: 79275-20028.40 b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form ,c) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein # represents a point of attachment to the remainder of the structure. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0119] 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, Rbis, 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-Ra, C3-10cycloalkyl, and 3- 10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH, and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, wherein the C1- 6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo. In some embodiments, Rbis, independently at each occurrence, selected from the group consisting of -OH, halo, oxo, C1-3alkyl, -C(O)-C1-3alkyl, -C(O)-NH2, -C(O)-NH(C1- 3alkyl), -C(O)-N(C1-3alkyl)2, -S(O)2-Ra, C3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-3alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-3alkyl or -OH, and the C3-6cycloalkyl of Rbis optionally substituted with one or more -OH, C3-6cycloalkyl, or C1-3alkyl, wherein the C1-3alkyl of the C3-6cycloalkyl of Rbsf-596318987Docket No.: 79275-20028.40 is further optionally substituted with one or more -OH, deuterium or halo. In some embodiments, Rbis selected from the group consisisting of oxo. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0120] 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, Rbis oxo. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0121] 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, Rbis C1-6alkyl. In some embodiments, the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH. In some embodiments, Rbis C1-3alkyl 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 Rbis further optionally substituted with one or more C1-3alkyl or - OH.

[0122] 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, Rbis -C(O)-NH(C1-6alkyl). In some embodiments, Rbis -C(O)-NH(C1-3alkyl). In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0123] 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, Rbis -C(O)-C1-6alkyl.

[0124] 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 Rbis -S(O)2-Ra, wherein Rais C1-6alkyl. In some embodiments, Rbis -S(O)2-Ra, wherein Rais C1-3alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein,sf-596318988Docket No.: 79275-20028.40 such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0125] 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, Rbis C3-10cycloalkyl optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH, deuterium, or halo. In some embodiments, Rbis 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, deuterium, or halo. In some embodiments, Rb. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0126] 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, Rbis 3-10 membered heterocyclyl. In some embodiments, Rbis 3-6 membered heterocyclyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0127] 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, one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heteroaryl. In some embodiments, one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-6 membered heteroaryl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0128] 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, one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heteroaryl optionally substituted with one or more Rc. Insf-596318989Docket No.: 79275-20028.40 some embodiments one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-6 membered heteroaryl optionally substituted with one or more Rc. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0129] In some emobodiments of a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, or CHF2; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to whichsf-596318990Docket No.: 79275-20028.40they are attached, towherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form,wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2.

[0130] 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, L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH;sf-596318991Docket No.: 79275-20028.40 wherein, R2is C2-6alkynyl when: one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CH2F; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to,wherein # represents a point of attachment to the remainder of the structure.

[0131] 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, Rcis 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more –OH, or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH, or C1- 6alkyl,wherein the C1-6alkyl is further optionally substituted with one or more -OH. In some embodiments, Rcis 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-Ra, C3- 6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-3alkyl of Rcis optionally substituted with one or more -S(O)2-C1-3alkyl, the C3-6cycloalkyl of Rcis optionally substituted with one orsf-596318992Docket No.: 79275-20028.40 more -OH, or C1-3alkyl, and the 3-6 membered heterocyclyl of Rcis optionally substituted with one or more -OH, or C1-3alkyl,wherein the C1-3alkyl is further optionally substituted with one or more -OH. In some embodiments, Rcis selected from the group consisting of,. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0132] 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, Rcis C1-6alkyl, -S(O)2-Ra. In some embodiments, Rcis C1-3alkyl. In some embodiments, Rcis methyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0133] 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, Rcis C1-6alkyl optionally substituted with one or more -S(O)2-Ra, wherein Rais C1-6alkyl. In some embodiments, Rcis C1-3alkyl optionally substituted with one or more -S(O)2-Ra, wherein Rais C1-3alkyl. In somesome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0134] 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, Rcis C3-10cycloalkyl optionally substituted with one or more -OH, or C1-6alkyl. In some embodiments, Rcis C3- 6cycloalkyl optionally substituted with one or more -OH, or C1-3alkyl. In some embodiments, Rcsf-596318993Docket No.: 79275-20028.40. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0135] 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, Rcis 3-10 membered heterocyclyl optionally substituted with one or more -OH, or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH. In some embodiments, Rcis 3-6 membered heterocyclyl optionally substituted with one or more -OH, or C1-3alkyl, wherein the C1-3alkyl is further optionally substituted with one or more -OH. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0136] 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, X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of - CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, andsf-596318994Docket No.: 79275-20028.40 the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1- 6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1- 6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl.

[0137] 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, one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heteroaryl substituted with one or more Rf. In some embodiments one of X1and X2is CR5, and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-6 membered heteroaryl substituted with one or more Rf. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0138] 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, L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1- 6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and whereinsf-596318995Docket No.: 79275-20028.40 the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1- 6alkyl.

[0139] 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, Rfis independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl. In some embodiments, Rfis independently at each occurrence, selected from the group consisting of C1-3alkyl, C3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-3alkyl of Rfis substituted with one or more -OH, the C3-6cycloalkyl of Rfis substituted with one or more C1-3alkoxy, and wherein the C1-3alkoxy of the C3-6cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-6 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-3alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-3alkyl. In some embodiments, Rfis selected from the group consisting of. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0140] 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, Rfis independently at each occurrence, C1-6alkyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH; andsf-596318996Docket No.: 79275-20028.40 wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl. In some embodiments, Rfis independently at each occurrence, C1-3alkyl, wherein the C1-3alkyl of Rfis substituted with one or more -OH; and wherein each Rfis further optionally substituted with one or more -OH or C1-3alkyl. In some embodiments, Rfis selected from the group consisting of methyl,. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0141] 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, Rfis independently at each occurrence, C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl. In some embodiments, Rfis independently at each occurrence, C3-6cycloalkyl, wherein the C3-6cycloalkyl of Rfis substituted with one or more C1-3alkoxy, and wherein the C1-3alkoxy of the C3-6cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-3alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0142] 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, Rfis independently at each occurrence, 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl. In some embodiments, Rfis independently at each occurrence, 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-3alkyl; and wherein eachsf-596318997Docket No.: 79275-20028.40 Rfis further optionally substituted with one or more -OH or C1-3alkyl. In some embodiments, Rfis selected from the groupsome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0143] 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, Rfis CN.

[0144] 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, Rfis independently at each occurrence, C1-6alkoxy. In some embodiments, Rfis independently at each occurrence C1-3alkoxy. In some embodiments, Rfis methoxy.

[0145] 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, one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg. In some embodiments, the 5-20 membered heteroaryl is substituted with one or more Rfand further substituted with one or more Rg.

[0146] 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, Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl. In some embodiments, Rgis, independently at each occurrence, selected from the group consisting of C1-3alkyl or C3-6cycloalkyl, wherein the C3-6cycloalkyl of Rgis optionally substituted with one or more -OH or C1-3alkyl.

[0147] 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, X5is -C-; L3is absent; and one of X1and X2is N or C(R5); andsf-596318998Docket No.: 79275-20028.40 the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl.

[0148] 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, Rhis, independently at each occurrence, selected from the group consisting of 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl. In some embodiments, Rhis, independently at each occurrence, selected from the group consisting of 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of Rhis substituted with one or more oxo or C1-3alkyl.

[0149] 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, X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and whereinsf-596318999Docket No.: 79275-20028.40 the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6 alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or -S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH.

[0150] 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, R5is H. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0151] 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, R5is halo. In some embodiments, R5is Cl, or F. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0152] 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, R5is -CN. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0153] 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, R5is C1-6alkyl. In some embodiments, R5is C1-3alkyl. In some embodiments, R5is methyl. In some embodiments, R5is C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo, or -OH. In some embodiments, R5is C1-3alkyl, wherein the C1-3alkyl of R5is optionally substituted with one or more halo, or -OH. In some embodiments, R5is C1-3alkyl, wherein the C1-3alkyl of R5is optionally substituted with one or more fluoro, or -OH. In some embodiments, R5is independently selected from the group consisting of. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such assf-5963189100Docket No.: 79275-20028.40 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.

[0154] 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, R5is halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0155] 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, R5is 3-10 membered heterocyclyl. In some embodiments, R5is 3-6 membered heterocyclyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0156] 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, R5is C1-6alkoxy optionally substituted with one or more halo. In some embodiments, R5is C1-3alkoxy optionally substituted with one or more halo. In some embodiments, R5is C1-3alkoxy optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0157] 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, R6and R7are each independently H or halo. In some embodiments, R6and R7are each independently H or fluoro. In some embodiments, each of R6and R7is H. In some embodiments, each of R6and R7is fluoro. In some embodiments, one of R6and R7is H and the other of R6and R7is fluoro. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0158] 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, L1, L2, and the ring bearingsf-5963189101Docket No.: 79275-20028.40 L3, R4, R6, and R7together form a bi-substituted phenyl with one group bound at the para position relative to the phenyl’s attachment to L2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0159] 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, L1, L2, and the ring bearing L3, R4, R6, and R7together form a tri-substituted phenyl with two groups bound at a meta, and the para positions relative to the phenyl’s attachment to L2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0160] 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, L1, L2, and the ring bearing L3, R4, R6, and R7together form a tetra-substituted phenyl with three groups bound at the meta, and para positions relative to the phenyl’s attachment to L2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0161] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L1, L2, and the ring bearing L3, R4, R6, and R7together form a bi-substituted pyridine with one group bound at the para position relative to the pyridine’s attachment to L2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0162] 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, L1, L2, and the ring bearing L3, R4, R6, and R7together form a tri-substituted pyridine with two groups bound at the meta, and para positions relative to the pyridine’s attachment to L2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compoundsf-5963189102Docket No.: 79275-20028.40 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.

[0163] 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, L1, L2, and the ring bearing L3, R4, R6, and R7together form a bi-substituted pyrimidine with two groups bound at the para position relative to the pyrimidine’s attachment to L2. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0164] 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, L1, L2, and the ring bearing L3, R4, X3, and X4together form a heterocycle selected from the group consisting of ,bearing L3, R4, X3, and X4together form a heterocycle selected from the group consisting of ,bearing L3, R4, X3, and X4together form a heterocycle selected from the group consisting of, sf-5963189103Docket No.: 79275-20028.40some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.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, L1, L2, and the ring bearing L3, R4, X3, and X4together form a heteroaryl selected ,sf-5963189104Docket No.: 79275-20028.40 ,embodiments, L1, L2, and the ring bearing L3, R4, X3, and X4together form a heterocycle selected from the group, , ,and. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0165] 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, L1, L2, and the ring bearing L3, R4, X3, and X4together form a heteroaryl selected from the group consisting of sf-5963189105Docket No.: 79275-20028.40 ,

[0166] 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, L1, L2, and the ring bearing L3, R4, X3, and X4together form a heteroaryl selected from the group consisting of.

[0167] 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, L1, L2, and the ring bearing L3, R4, X3, and X4together form a heterocycle selected from the group consisting of.

[0168] 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, L1, L2, and the ring bearing L3, R4, X3, and X4together. In some embodiments, L1, L2, and the ring bearing L3, R4, X3, and X4togethersf-5963189106Docket No.: 79275-20028.40 embodiments, L1, L2, and the ring bearing L3, R4, X3, and X4together form.

[0169] 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, n is 1 or 2, and L2is -O-. In some embodiments, n is 2, and L2is -O-. In some embodiments, n is 1, and L2is O. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0170] 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, n is 1, p is 0, L2is O, one of X1and X2is C(R5), wherein R5is H, the other of X1and X2is C that is taken together with R4, 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 Rb, (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more Rc, or (iii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more Rf, and each of R6and R7is H. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0171] 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, n is 1, L2is O, one of X1and X2is C(R5), wherein R5is H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo, or -OH, and wherein the C1-6alkoxy of R5is optionally substituted with one or more halo, the other of X1and X2is C that is taken together with R4, 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 Rb, (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with on or more Rc, or (iii) a 5-10 membered heteroaryl, wherein the 5- 10 membered heteroaryl is optionally substituted with one or more Rf, and each of R6and R7is H. In some embodiments, n is 1, L2is O, one of X1and X2is C(R5), wherein R5is halo, or C1- sf-5963189107Docket No.: 79275-20028.406alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo, the other of X1and X2is C that is taken together with R4, 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 Rb, (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more Rc, or (iii) a 5-10 membered heteroaryl, wherein the 5- 10 membered heteroaryl is optionally substituted with one or more Rf, and each of R6and R7is H. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0172] 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, n is an integer from 1 to 2; p is an integer from 0 to 1; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-3alkoxy, and C1-3alkyl, wherein the C1-3alkoxy or C1-3alkyl are optionally substituted with one or more halo; R2is H, C1-3alkyl, C2-4alkynyl, C3-6cycloalkyl, or 3-10 membered heterocyclyl, wherein the C1-3alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-3alkoxy, and the C3-6cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-3alkyl; L1is C1-3alkylene, wherein the C1-3alkylene of L1is optionally substituted with one or more deuterium or C1- 3alkyl, wherein the C1-3alkyl is further optionally substituted with one or more -OH or C1-3alkoxy; L2is O or N(Rx), wherein Rxis H or C1-3alkyl; and either:sf-5963189108Docket No.: 79275-20028.40 (1) X5is -C-; L3is absent or is O, C3-6cycloalkyl, 3-6 membered heterocyclyl, or C1-3alkylene, wherein the C3-6cycloalkyl of L3is optionally substituted with one or more –OH or C1-3alkyl, the C1-3alkylene of L3is optionally substituted with one or more –OH or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more -OH, and the 3-6 membered heterocyclyl of L3is optionally substituted with one or more –OH or C1-3alkyl; X1and X2are each independently N or C(R5); R4is: (i) -S(O)2-Ra; (ii) 5-10 membered heteroaryl optionally substituted with one or more C1-3alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-3alkyl, or -S(O)2-Ra, wherein the C1-3alkyl of Rdis optionally substituted with one or more -OH, (iv) -NS(O)-(C1-3alkyl)2, wherein the C1-3alkyl is optionally substituted with one or more –OH, (v) -C(O)-N(Re)2 wherein Reis independently at each occurrence H, C1-3 alkyl, or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether with the N to which they are attached are taken together to form a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, NH2, - NH-S(O)2-Ra, or -S(O)2-Ra, (vi) 3-6 membered heterocyclyl optionally substituted with one or more C1-3alkyl, -OH , oxo or -S(O)2Ra,sf-5963189109Docket No.: 79275-20028.40 (vii) -S(O)-N(C1-3alkyl)-(C1-3alkyl), (viii) -CN, (ix) -(CH2)qOH, wherein q is an integer from 0-4, (x) -C(O)-C1-3alkyl, or (xi) -P(O)(C1-3alkyl)2; wherein, R2is C2-4alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, independently at each occurrence, selected from the group consisting of -OH, halo, oxo, C1-3alkyl, -C(O)-C1-3alkyl, -C(O)- NH2, -C(O)-NH(C1-3alkyl), -C(O)-N(C1-3alkyl)2, -S(O)2-Ra, C3- 6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-6alkyl of Rbis optionally substituted with one or more halo, OH, -S(O)2-C1-3alkyl, or C3-6cycloalkyl, and wherein the C3-6cycloalkyl of the C1-3alkyl of Rbis further optionally substituted with one or more C1-3alkyl or -OH and the C3-6cycloalkyl of Rbis optionally substituted with one or more -OH, C3-6cycloalkyl, or C1-3alkyl, and wherein the C1-3alkyl of the C3-6cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo,sf-5963189110Docket No.: 79275-20028.40 wherein, R2is C2-4alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which ,wherein # represents a point of attachment to the remainder of the structure; (3) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, independently at each occurrence, selected from the group consisting of halo, C1-3alkyl, -C(O)-C1-3alkyl, -C(O)-NH2, -C(O)-sf-5963189111Docket No.: 79275-20028.40 NH(C1-3alkyl), -C(O)-N(C1-3alkyl)2, -S(O)2-Ra, C3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-3alkyl of Rcis optionally substituted with one or more -S(O)2-C1-3alkyl, the C3-6cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-6 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-3alkyl, and wherein the C1-3alkyl of the 3-6 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-4alkynyl or C1-6alkyl-OH when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CH2F; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together withR4, and the atoms to which they are attached, towherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to formsf-5963189112Docket No.: 79275-20028.40wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2; or (4) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of -CN, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-6cycloalkyl of Rfis substituted with one or more C1- 6alkoxy, and wherein the C1-3alkoxy of the C3-6cycloalkyl of Rfis optionally substituted with one or more 3-6 membered heterocycle, and wherein the 3-6 membered heterocycle is optionally substituted with one or more C1-3alkyl or C2- 4alkynyl, and the 3-6 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-3alkyl; and wherein each Rfis further optionally substituted with one or more - OH or C1-3alkyl, and; Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, whereinsf-5963189113Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; (5) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; or (6) X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and whereinsf-5963189114Docket No.: 79275-20028.40 the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2- 6 alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or - S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH; Rais, independently at each occurrence: (i) C1-3alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-3alkyl, or - N(C1-3alkyl)-C(O)-C1-3alkyl; (ii) 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, or –C(O)-C3-6heterocyclyl, or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more -OH; (iii) 3-6 membered heterocyclyl optionally substituted with one or more C1-3alkyl; or (iv) NH(C1-3alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-6 membered heterocyclyl, C1-3alkyl, or C1-3alkoxy, wherein the C1-3alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-3alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6); X4is N or C(R7); and R6and R7are each independently H or halo.sf-5963189115Docket No.: 79275-20028.40

[0173] 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, n is an integer from 1 to 2; p is an integer from 0 to 1; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-3alkoxy, and C1-3alkyl, wherein the C1-3alkoxy or C1-3alkyl are optionally substituted with one or more halo; R2is H, C1-3alkyl, C2-4alkynyl, C3-6cycloalkyl, or 3-10 membered heterocyclyl, wherein the C1-3alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-3alkoxy, and the C3-6cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-3alkyl; L1is C1-3alkylene, wherein the C1-3alkylene of L1is optionally substituted with one or more deuterium or C1-3alkyl, wherein the C1-3alkyl is further optionally substituted with one or more -OH or C1-3alkoxy; L2is O or N(Rx), wherein Rxis H or C1-3alkyl; either: (1) L3is absent or is O, C3-6cycloalkyl, 3-6 membered heterocyclyl, or C1-3alkylene, wherein the C3-6cycloalkyl of L3is optionally substituted with one or more –OH or C1-3alkyl, the C1-3alkylene of L3is optionally substituted with one or more –OH or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more -OH, and the 3-6 membered heterocyclyl of L3is optionally substituted with one or more –OH or C1-3alkyl;sf-5963189116Docket No.: 79275-20028.40 X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-10 membered heteroaryl optionally substituted with one or more C1-3alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-3 alkyl, or -S(O)2-Ra, wherein the C1-3alkyl of Rdis optionally substituted with one or more -OH, (iv) -NS(O)-(C1-3alkyl)2, wherein the C1-3alkyl is optionally substituted with one or more –OH, (v) -C(O)-N(Re)2 wherein Reis independently at each occurrence H, C1-3alkyl, or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether with the N to which they are attached are taken together to form a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with one or more halo, oxo, -OH, NH2, - NH-S(O)2-Ra, or -S(O)2-Ra, (vi) 3-6 membered heterocyclyl optionally substituted with one or more C1-3alkyl, -OH , oxo or -S(O)2Ra, (vii) -S(O)-N(C1-3alkyl)-(C1-3alkyl), (viii) -CN, (ix) -(CH2)qOH, wherein q is an integer from 0-4, (x) -C(O)-C1-3alkyl, or (xi) -P(O)(C1-3alkyl)2; wherein, R2is C2-4alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3;sf-5963189117Docket No.: 79275-20028.40 (2) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, independently at each occurrence, selected from the group consisting of -OH, halo, oxo, C1-3alkyl, -C(O)-C1-3alkyl, -C(O)- NH2, -C(O)-NH(C1-3alkyl), -C(O)-N(C1-3alkyl)2, -S(O)2-Ra, C3- 6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-3alkyl of Rbis optionally substituted with one or more halo, OH, -S(O)2-C1-3alkyl, or C3-6cycloalkyl, and wherein the C3-6cycloalkyl of the C1-3alkyl of Rbis further optionally substituted with one or more C1-3alkyl or -OH and the C3-6cycloalkyl of Rbis optionally substituted with one or more -OH, C3-6cycloalkyl, or C1-3alkyl, and wherein the C1-3alkyl of the C3-6cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-4alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2 or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to whichsf-5963189118Docket No.: 79275-20028.40 they are attached, to,, wherein # represents a point of attachment to the remainder of the structure; (3) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, 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-Ra, C3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C1-3alkyl of Rcis optionally substituted with one or more -S(O)2-C1-3alkyl, the C3-6cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-6 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-3alkyl, and wherein the C1-3alkyl of the 3-6 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-4alkynyl when: a) one of X1and X2is N or C(H) and either:sf-5963189119Docket No.: 79275-20028.40 each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CH2F; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to formwherein # represents a point of attachment to the remainder of the structure; or (4) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-3alkyl, C3-6cycloalkyl, and 3-6 membered heterocyclyl, whereinsf-5963189120Docket No.: 79275-20028.40 the C1-6alkyl of Rfis substituted with one or more - OH, the C3-6cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-3alkoxy of the C3-6cycloalkyl of Rfis optionally substituted with one or more 3-6 membered heterocycle, and wherein the 3-6 membered heterocycle is optionally substituted with one or more C1-3alkyl or C2-4alkynyl, and the 3-6 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-3alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-3alkyl; Rais, independently at each occurrence: (i) C1-3alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-3alkyl, or -N(C1-3alkyl)-C(O)-C1-3alkyl, (ii) 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, or –C(O)-C3-6heterocyclyl, or C1-3alkyl, wherein the C1-3alkyl is optionally substituted with one or more -OH, (iii) 3-6 membered heterocyclyl optionally substituted with one or more C1-3alkyl, or (iv) NH(C1-3alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-6 membered heterocyclyl, C1-3alkyl, or C1-3alkoxy, wherein the C1-3alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-3alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6);sf-5963189121Docket No.: 79275-20028.40 X4is N or C(R7); and R6and R7are each independently H or halo.

[0174] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H, C1-6alkyl, or C2-6alkynyl, wherein the C1-6alkyl of R2is optionally substituted with one or more -OH; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; and either: (1) X is -C-; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis oxo or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, or C1-6alkyl, wherein, R2is C2-6alkynyl when:sf-5963189122Docket No.: 79275-20028.40 a) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, tob) R1cis Cl; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached,, wherein # represents a point of attachment to the remainder of the structure; (2) X5is -C-; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, 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 Rc, wherein Rcis, independently at each occurrence, selected from the group consisting of halo, C1-6alkyl, and C3-10cycloalkyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, and the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) R1cis Cl; one of X1and X2is C(F) or C(CHF2); and the other of X1and X2is C that is taken together with R4, and the atoms to whichsf-5963189123Docket No.: 79275-20028.40they are attached, towherein # represents a point of attachment to the remainder of the structure; or b) R1cis Cl; L1is -CH2CH2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to,wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2; or (3) X5is -C-; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of -CN, C1-6alkyl, C1-6alkoxy, C3- 10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more - OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and whereinsf-5963189124Docket No.: 79275-20028.40 the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl; and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; (4) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; or (5) X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, whereinsf-5963189125Docket No.: 79275-20028.40 the 5-20 membered heteroaryl is optionally substituted with one or more Ri, wherein Riis, independently at each occurrence, selected from the group consisting of C3-10cycloalkyl, wherein the C3-10cycloalkyl of Riis optionally substituted with one or more -OH, or C1-6alkyl; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0175] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H, or C2-6alkynyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; either: (1) L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, whereinsf-5963189126Docket No.: 79275-20028.40 the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis oxo or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, or C1-6alkyl, wherein, R2is C2-6alkynyl when: a) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, tob) R1cis Cl; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached,, wherein # represents a point of attachment to the remainder of the structure; (2) L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, 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 Rc, wherein Rcis, independently at each occurrence, selected from the group consisting of C1-6alkyl, and C3-10cycloalkyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more - S(O)2-C1-6alkyl, and the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl,sf-5963189127Docket No.: 79275-20028.40 wherein, R2is C2-6alkynyl when: a) R1cis Cl; one of X1and X2is C(F) or C(CHF2); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, tob) R1cis Cl; L1is -CH2CH2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to ,wherein # represents a point of attachment to the remainder of the structure; or (3) L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and whereinsf-5963189128Docket No.: 79275-20028.40 the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2- 6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0176] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H, C1-6alkyl, or C2-6alkynyl, wherein the C1-6alkyl of R2is optionally substituted with one or more -OH; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; X is -C-;sf-5963189129Docket No.: 79275-20028.40 L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis oxo or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, or C1-6alkyl, wherein, R2is C2-6alkynyl when: a) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form ,b) R1cis Cl; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein # represents a point of attachment to the remainder of the structure; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0177] 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,sf-5963189130Docket No.: 79275-20028.40 n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H; L1is C1-6alkylene; L2is O; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis oxo or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, or C1-6alkyl, provided that neither: a) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to,b) R1cis Cl; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein # represents a point of attachment to the remainder of the structure;sf-5963189131Docket No.: 79275-20028.40 R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0178] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H, C1-6alkyl, or C2-6alkynyl, wherein the C1-6alkyl of R2is optionally substituted with one or more -OH; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; X5is -C-; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, 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 Rc, wherein Rcis, independently at each occurrence, selected from the group consisting of halo, C1-6alkyl, and C3-10cycloalkyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, andsf-5963189132Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) R1cis Cl; one of X1and X2is C(F) or C(CHF2); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to formwherein # represents a point of attachment to the remainder of the structure; or b) R1cis Cl; L1is -CH2CH2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached,wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0179] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H;sf-5963189133Docket No.: 79275-20028.40 L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, 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 Rc, wherein Rcis, independently at each occurrence, selected from the group consisting of C1- 6alkyl, and C3-10cycloalkyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, and the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, provided that neither: a) R1cis Cl; one of X1and X2is C(F) or C(CHF2); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form; nor b) R1cis Cl; L1is -CH2CH2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached,; wherein # represents a point of attachment to the remainder of the structure; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo;sf-5963189134Docket No.: 79275-20028.40 X3is C(R6); X4is C(R7); and R6and R7are each H.

[0180] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H, C1-6alkyl, or C2-6alkynyl, wherein the C1-6alkyl of R2is optionally substituted with one or more -OH; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; X5is -C-; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of - CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and whereinsf-5963189135Docket No.: 79275-20028.40 the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl; and Rgis, independently at each occurrence, selected from the group consisting of C1- 6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0181] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H, or C2-6alkynyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O;sf-5963189136Docket No.: 79275-20028.40 L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1- 6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0182] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo;sf-5963189137Docket No.: 79275-20028.40 R2is H, C1-6alkyl, or C2-6alkynyl, wherein the C1-6alkyl of R2is optionally substituted with one or more -OH; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0183] 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, n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo;sf-5963189138Docket No.: 79275-20028.40 R2is H, C1-6alkyl, or C2-6alkynyl, wherein the C1-6alkyl of R2is optionally substituted with one or more -OH; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, independently at each occurrence, selected from the group consisting of C3-10cycloalkyl, wherein the C3-10cycloalkyl of Riis optionally substituted with one or more -OH, or C1-6alkyl; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

[0184] 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, the compound is asf-5963189139Docket No.: 79275-20028.40 ;tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n, p, R1a, R1b, R1c, R1d, R2, R3, R4, R5, R6, R7, L1, L3, X1, X2, X3, and X4are as defined for a compound of formula (I). In some embodiments, the compound of formula (I) is a compound of formula (I- A) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-B) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-C) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-D) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. sf-5963189140Docket No.: 79275-20028.40

[0185] 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, the compound is a compound of(I-E); or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n, p, R1a, R1b, R1c, R1d, R2, R3, R5, R6, R7, L1, L3, X2, X3, and X4are as defined for a compound of formula (I) and ring A is either: (1) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, orsf-5963189141Docket No.: 79275-20028.40 R1cis Cl, CN, CHF2or -OCHF2; ,wherein # represents a point of attachment to the remainder of the structure; (2) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CHF2;sf-5963189142Docket No.: 79275-20028.40 b) R1cis Cl or CN; X2is C(F), C(CHF2), C(OCHF2) or C(CN); and ring A isc) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; X2is C(CF3); and ring A is; wherein # represents a point of attachment to the remainder of the structure; or (3) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1- 6alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0186] In some embodiments, ring A is either:sf-5963189143Docket No.: 79275-20028.40 (1) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; ,wherein # represents a point of attachment to the remainder of the structure;sf-5963189144Docket No.: 79275-20028.40 (2) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CHF2; b) R1cis Cl or CN; X2is C(F), C(CHF2), C(OCHF2) or C(CN); and ring A iswherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; X2is C(CF3); and ring A isrepresents the point of attachment to X5, and && represents the point of attachment to X1or X2; (3) a 5-20 membered heteroaryl, whereinsf-5963189145Docket No.: 79275-20028.40 the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of - CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1- 6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; or (4) a 5-10 membered heterocyclyl substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl.

[0187] 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, the compound is asf-5963189146Docket No.: 79275-20028.40 compound ofa stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n, p, R1a, R1b, R1c, R1d, R2, R3, R5, R6, R7, L1, L3, X3, and X4are as defined for a compound of formula (I) and ring A is either: (1) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) R5is H and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2 or -OCHF2;sf-5963189147Docket No.: 79275-20028.40 b) R1cis Cl; R5is F; andc) R1cis Cl or CN; R5is CF3; and,, wherein # represents a point of attachment to the remainder of the structure; (2) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl when: a) R5is H and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CHF2;sf-5963189148Docket No.: 79275-20028.40 b) R1cis Cl or CN; R5is F, CHF2, OCHF2or CN; andc) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; R5is CF3; and ring A is; wherein # represents a point of attachment to the remainder of the structure; or (3) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1- 6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0188] In some embodiments, ring A is either: (1) a 5-10 membered heterocyclyl, whereinsf-5963189149Docket No.: 79275-20028.40 the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; ,wherein # represents a point of attachment to the remainder of the structure;sf-5963189150Docket No.: 79275-20028.40 (2) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CHF2; b) R1cis Cl or CN; X2is C(F), C(CHF2), C(OCHF2) or C(CN); and ring A iswherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; X2is C(CF3); and ring A isrepresents the point of attachment to X5, and && represents the point of attachment to X1or X2; (3) a 5-20 membered heteroaryl, whereinsf-5963189151Docket No.: 79275-20028.40 the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of - CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1- 6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; or (4) a 5-10 membered heterocyclyl substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl.

[0189] 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, the compound is asf-5963189152Docket No.: 79275-20028.40 compound of(I-G); or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n, p, R1a, R1b, R1c, R1d, R2, R3, R5, R6, R7, L1, L3, X3, and X4are as defined for a compound of formula (I) and ring A is either: (1) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2or -OCHF2; (2) a 5-20 membered heteroaryl, whereinsf-5963189153Docket No.: 79275-20028.40 the 5-20 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl when either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, or CHF2; or (3) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1- 6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl. In some variations, the embodiments provided herein also apply tosf-5963189154Docket No.: 79275-20028.40 any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0190] In some embodiments, ring A is either: (1) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; X2is C(F); andsf-5963189155Docket No.: 79275-20028.40 c) R1cis Cl or CN; X2is C(CF3); and,, wherein # represents a point of attachment to the remainder of the structure; (2) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is optionally substituted with one or more Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CHF2;sf-5963189156Docket No.: 79275-20028.40 b) R1cis Cl or CN; X2is C(F), C(CHF2), C(OCHF2) or C(CN); and ring A iswherein # represents a point of attachment to the remainder of the structure; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; X2is C(CF3); and ring A isrepresents the point of attachment to X5, and && represents the point of attachment to X1or X2; (3) a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of - CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1- 6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, whereinsf-5963189157Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; or (4) a 5-10 membered heterocyclyl substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl.

[0191] 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, the compound is a ;sf-5963189158Docket No.: 79275-20028.40(I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0192] 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, the compound is a compound of(I-H); or a stereoisomer or tautomer thereof, sf-5963189159Docket No.: 79275-20028.40 or a pharmaceutically acceptable salt of any of the foregoing, wherein: p, R1a, R1b, R1c, R1d, R2, R3, R4, L1, X2, X3, and X4are as defined for a compound of formula (I’) and ring E is a 5-20 membered heteroaryl optionally substituted with one or more Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6 alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or -S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH.

[0193] 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, the compound is a compound of formula (II’):,sf-5963189160Docket No.: 79275-20028.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl of R1are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; and ring B is selected from the group consisting of:wherein r is an integer from 0 to 2; sf-5963189161Docket No.: 79275-20028.40 s is an integer from 0 to 3; t is an integer from 1 to 20; u is an integer from 0 to 20; v is an integer from 1 to 20; X2cis N or C(R5c); X2dis N or C(R5d); R5a, R5b, R5c, and R5dare each independently H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3a, X3b, X3c, and X3dare each independently N or C(R6), wherein R6is H or halo; X4a, X4b, X4c, X4dare each independently N or C(R7), wherein R7is H or halo; X5aand X6aare each independently NH or -(CH2)x-O- wherein x is 0 or 1; X5b, X6band X7bare each independently N or C, each of which is optionally substituted with one or more H; Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and whereinsf-5963189162Docket No.: 79275-20028.40 the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo; Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; and ring C is a 5-20 membered heteroaryl substituted with one or more Rf, and further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; ring D is a 5-10 membered heterocyclyl substituted with one or more Rhand further optionally substituted with one or more oxo, whereinsf-5963189163Docket No.: 79275-20028.40 Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; wherein, a) R2is C2-6alkynyl when R1cis Cl or CN; R5ais CF3; and the ring B bearing X5aand X5biswherein # represents a point of attachment to the remainder of the structure; b) R2is C2-6alkynyl or C1-6alkyl-OH when R1cis Cl or CN; R5bis F, CHF2, -OCHF2or CN; and the ring Bwherein # represents a point of attachment to the remainder of the structure; or c) R2is C2-6alkynyl when R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; R5bis CF3;,wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2

[0194] 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, the compound is a compound of formula (II): sf-5963189164Docket No.: 79275-20028.40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl of R1are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; and ring B is selected from the group consisting of:sf-5963189165Docket No.: 79275-20028.40, wherein r is an integer from 0 to 2; s is an integer from 0 to 3; t is an integer from 1 to 20; X2cis N or C(R5c); R5a, R5b, and R5care each independently H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3a, X3band X3care each independently N or C(R6), wherein R6is H or halo; X4a, X4band X4care each independently N or C(R7), wherein R7is H or halo; X5aand X6aare each independently NH or -(CH2)x-O- wherein x is 0 or 1; X5b, X6band X7bare each independently N or C, each of which is optionally substituted with one or more H; Rbis, 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-Ra, C3- 10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and sf-5963189166Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo; Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; and ring C is a 5-20 membered heteroaryl substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl; wherein, R2is C2-6alkynyl when:sf-5963189167Docket No.: 79275-20028.40 a) R1cis Cl or CN; R5ais CF3; and the ring B. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (I’) or (II’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0195] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B issome variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II’) or a stereoisomer sf-5963189168Docket No.: 79275-20028.40 or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0196] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, q is an integer from 0 to 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q 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.

[0197] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R5ais H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH, and the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments, R5ais halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH, and the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments, R5ais halo, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more halo. 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.

[0198] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X3ais N or C(R6), wherein R6is H or halo. In some embodiments, X3ais C(R6), wherein R6is H or halo. In some embodiments, X3ais C(R6), wherein R6is H. 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.

[0199] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X4ais N or C(R7), wherein R7is H or halo. In some embodiments, X4ais C(R7), wherein R7is H or halo. In some embodiments, X4ais C(R7), wherein R7is H. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formulasf-5963189169Docket No.: 79275-20028.40 (II’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0200] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X5aand X6aare each independently NH or -(CH2)x-O- wherein x is 0 or 1. In some embodiments, X5aand X6aare each NH. In some embodiments, one of X5aand X6ais NH and the other of X5aand X6ais -(CH2)x-O- wherein x is 0 or 1. In some embodiments, x is 0. In some embodiments, x 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.

[0201] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B is selected from the ,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.

[0202] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B issome 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. sf-5963189170Docket No.: 79275-20028.40

[0203] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, r is an integer from 0 to 3. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. 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.

[0204] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R5bis H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH, and the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments, R5bis halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH, and the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments, R5bis halo, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more halo. 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.

[0205] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X3bis N or C(R6), wherein R6is H or halo. In some embodiments, X3bis C(R6), wherein R6is H or halo. In some embodiments, X3bis C(R6), wherein R6is H. 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.

[0206] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X4bis N or C(R7), wherein R7is H or halo. In some embodiments, X4bis C(R7), wherein R7is H or halo. In some embodiments, X4bis C(R7), wherein R7is H. 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.sf-5963189171Docket No.: 79275-20028.40

[0207] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X5b, X6band X7bare each independently N or C, each of which is optionally substituted with one or more H. 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.

[0208] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B is selected from the ,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.

[0209] In some embodiments of a compound of formula (II’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B is. sf-5963189172Docket No.: 79275-20028.40

[0210] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B is. 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.

[0211] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, s is an integer from 1 to 20. In some embodiments, s is an integer from 1 to 10. In some embodiments, s is an integer from 1 to 5. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3.

[0212] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X2cis N or C(R5c). In some embodiments, X2cis C(R5c). 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.

[0213] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R5cis H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH, and the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments, R5cis halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH, and the C1-6alkoxy is optionally substituted with one or more halo. In some embodiments, R5cis halo, or C1- 6alkyl, wherein the C1-6alkyl is optionally substituted with one or more halo. 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. sf-5963189173Docket No.: 79275-20028.40

[0214] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X3cis N or C(R6), wherein R6is H or halo. In some embodiments, X3cis C(R6), wherein R6is H or halo. In some embodiments, X3cis C(R6), wherein R6is H. 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.

[0215] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X4cis N or C(R7), wherein R7is H or halo. In some embodiments, X4cis C(R7), wherein R7is H or halo. In some embodiments, X4cis C(R7), wherein R7is H. 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.

[0216] In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B is selected from thethe 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. sf-5963189174Docket No.: 79275-20028.40

[0217] In some embodiments of the compound of formula (II), the compound is a compound of ;pharmaceutically acceptable salt of any of the foregoing, wherein: n, p, r, s, t, R1a, R1b, R1c, R1d, R2, R3, L1, L2, L3, X2c, X3a, X3b, X3c, X4a, X4b, X4c, X5a, X5b, X6a, X6b, X7b, and ring C are as defined for a compound of formula (II). In some embodiments, the compound of formula (II) is a compound of formula (II-A) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II) is a compound of formula (II-B) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II) is a compound of formula (II-C) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein sf-5963189175Docket No.: 79275-20028.40 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.

[0218] In some embodiments, the compound of formula (II-A), is a compound of formulaa stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-A) is a compound of formula (II-A1) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-A) is a compound of formula (II-A2) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-A) is a compound of formula (II-A3) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-A) is a compound of formula (II-A4) or a sf-5963189176Docket No.: 79275-20028.40 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula detailed herein, such as a compound of formula (II’) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0219] In some embodiments, the compound of formula (II-B), is a compound of formulaor tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-B) is a compound of formula (II-B1) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-B) is a compound of formula (II-B2) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-B) is a compound of formula (II-B3) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-B) is a compound of formula (II-B4) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the embodiments provided herein also apply to any other applicable formula sf-5963189177Docket No.: 79275-20028.40 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.

[0220] In some embodiments, the compound of formula (II’-C), is a compound of formula.

[0221] In some embodiments, the compound of formula (II-C), is a compound of formulasome embodiments, the compound of formula (II-C) is a compound of formula (II-C1) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-C) is a compound of formula (II-C2) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (II-C), is a compound of formulaa stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X5c, X6cand X7care each independently N or C, each of which is optionally substituted sf-5963189178Docket No.: 79275-20028.40 with one or more H. 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.

[0222] It is to be understood that any variation or embodiment of n, p, q, r, s, t, R1a, R1b, R1c, R1d, R2, R3, L1, L2L3, X1, X2, X3, X4, R4, R5, R5a, R5b, R5c, R5d, R6, R7, Ra, Rb, Rc, Y1, Y2, Y3, ring A and ring B, provided herein can be combined with every other variation or embodiment of n, p, q, r, s, t, R1a, R1b, R1c, R1d, R2, R3, L1, L2L3, X1, X2, X3, X4, R4, R5, R5a, R5b, R5c, R5d, R6, R7, Ra, Rb, Rc, Y1, Y2, Y3, ring A and ring B, the same as if each and every combination had been individually and specifically described. For example, embodiments where n is 1, p is 0, R1ais H, R1bis H, R1cis Cl, R1dis H, R2is H, L1is ethylene, L2is O, L3is absent, X1is C that is taken together with R4and the atoms to which it is attached to form a 5-membered heteroaryl substituted with Rb, X2is CR5, R5is methyl; X3is CR6, R6is H, X4is CR7and R7is H, can be combined to.

[0223] In some embodiments of 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 the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of 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 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.sf-5963189179Docket No.: 79275-20028.40sf-5963189180Docket No.: 79275-20028.40sf-5963189181Docket No.: 79275-20028.40sf-5963189182Docket No.: 79275-20028.40sf-5963189183Docket No.: 79275-20028.40sf-5963189184Docket No.: 79275-20028.40sf-5963189185Docket No.: 79275-20028.40sf-5963189186Docket No.: 79275-20028.40sf-5963189187Docket No.: 79275-20028.40sf-5963189188Docket No.: 79275-20028.40sf-5963189189Docket No.: 79275-20028.40sf-5963189190Docket No.: 79275-20028.40sf-5963189191Docket No.: 79275-20028.40

[0224] In some embodiments, a compound of formula (I’) is selected from the group consisting of: sf-5963189192Docket No.: 79275-20028.40 5-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-methyl-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[7-chloro-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[7-chloro-1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-fluoro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 7-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[7-fluoro-1-(3-hydroxy-3-methylcyclobutyl)-1H-indazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-fluoro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 6-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(2-hydroxy-1,1-dimethylethyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 3-(5-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl)-1λ⁶-1,1-thietanedione; 5-fluoro-1'-{2-[7-fluoro-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 4-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-7-fluoro-1-(3-hydroxy-3- methylcyclobutyl)-1,3-dihydro-1,3-benzimidazol-2-one; 7-chloro-5-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-(3-hydroxy-3- methylcyclobutyl)-1,3-dihydro-1,3-benzimidazol-2-one; 7-fluoro-5-{2-(5-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-(3-hydroxy-3- methylcyclobutyl)-1,3-dihydro-1,3-benzimidazol-2-one; 5-{2-(5-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-(3-hydroxy-3- methylcyclobutyl)-7-(trifluoromethyl)-1,3-dihydro-1,3-benzimidazol-2-one;sf-5963189193Docket No.: 79275-20028.40 5-chloro-1'-{2-[7-fluoro-2-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]-1-methylethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]propyl}spiro[indoline-3,4'-piperidin]-2-one; 6-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-(3-hydroxy-3- methylcyclobutyl)-8-(trifluoromethyl)-1,4-dihydro-3,1-benzoxazin-2-one; 5-fluoro-1'-{2-[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-indazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 1'-{2-[7-chloro-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzimidazol-5-yloxy]ethyl}-5- fluorospiro[indoline-3,4'-piperidin]-2-one; 6-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-8-fluoro-1-(3-hydroxy-3- methylcyclobutyl)-1,4-dihydro-3,1-benzoxazin-2-one; 6-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-3-(3-hydroxy-3- methylcyclobutyl)-4-(trifluoromethyl)-2,3-dihydro-1,3-benzoxazolidin-2-one; 5-fluoro-1'-{2-[7-fluoro-1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(1-mesyl-3-azetidinyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(2-mesyl-1,1-dimethylethyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(1-imino-1-oxo-1λ⁶-3-thietanyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(1-imino-1-oxo-1λ⁶-3-thietanyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-fluoro-1'-{2-[1-(1-mesyl-3-azetidinyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 7-chloro-5-{2-(5-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-(3-hydroxy-3- methylcyclobutyl)-1,3-dihydro-1,3-benzimidazol-2-one; 1'-{2-[7-chloro-1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-1H-1,3-benzimidazol-5- yloxy]ethyl}-5-fluorospiro[indoline-3,4'-piperidin]-2-one;sf-5963189194Docket No.: 79275-20028.40 5-fluoro-1'-{2-[2-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 3-(5-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-7-(trifluoromethyl)-1H-1,3- benzimidazol-2-yl)-1λ⁶-1,1-thietanedione; 5-chloro-1'-{2-[1-(1-mesyl-3-azetidinyl)-2-methyl-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-fluoro-1'-{2-[1-(1-mesyl-3-azetidinyl)-2-methyl-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; and 5-chloro-1'-{2-[2-(1-mesyl-3-azetidinyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one.

[0225] In some embodiments, a compound of formula (I) is selected from the group consisting of: 5-chloro-1'-(2-{7-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-(2-{7-chloro-1-(cis-3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-(2-{7-chloro-2-methyl-1-(cis-3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzimidazol- 5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-fluoro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 7-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-(2-{7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-indazol-5- yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-fluoro-1'-(2-{2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 6-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(2-hydroxy-1,1-dimethylethyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 3-(5-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-7-(trifluoromethyl)-1H-1,3- benzimidazol-1-yl)-1λ⁶-1,1-thietanedione;sf-5963189195Docket No.: 79275-20028.40 5-fluoro-1'-(2-{7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 4-chloro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-7-fluoro-1-[(cis)-3-hydroxy-3- methylcyclobutyl]-1,3-dihydro-1,3-benzimidazol-2-one; 7-chloro-5-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-(cis-3-hydroxy-3- methylcyclobutyl)-1,3-dihydro-1,3-benzimidazol-2-one; 7-fluoro-5-{2-(5-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-[(cis)-3-hydroxy-3- methylcyclobutyl]-1,3-dihydro-1,3-benzimidazol-2-one; 5-{2-(5-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-[(cis)-3-hydroxy-3- methylcyclobutyl]-7-(trifluoromethyl)-1,3-dihydro-1,3-benzimidazol-2-one; 5-chloro-1'-(2-{7-fluoro-2-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzimidazol-5- yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 1'-[(S)-1-methyl-2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl]-5-chlorospiro[indoline-3,4'-piperidin]-2-one; 1'-[(S)-2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy}propyl]-5-chlorospiro[indoline-3,4'-piperidin]-2-one; 6-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-1-[(cis)-3-hydroxy-3- methylcyclobutyl]-8-(trifluoromethyl)-1,4-dihydro-3,1-benzoxazin-2-one; 5-fluoro-1'-(2-{1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5- yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 1'-(2-{7-chloro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzimidazol-5-yloxy}ethyl)-5- fluorospiro[indoline-3,4'-piperidin]-2-one; 6-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-8-fluoro-1-[(cis)-3-hydroxy-3- methylcyclobutyl]-1,4-dihydro-3,1-benzoxazin-2-one; 6-{2-(5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)ethoxy}-3-[(cis)-3-hydroxy-3- methylcyclobutyl]-4-(trifluoromethyl)-2,3-dihydro-1,3-benzoxazolidin-2-one; 5-fluoro-1'-(2-{7-fluoro-2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzimidazol- 5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-{2-[1-(1-mesyl-3-azetidinyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one;sf-5963189196Docket No.: 79275-20028.40 5-chloro-1'-{2-[1-(2-mesyl-1,1-dimethylethyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-(2-{1-[(cis) or (trans)-1-imino-1-oxo-1λ⁶-3-thietanyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-chloro-1'-(2-{1-[(trans) or (cis)-1-imino-1-oxo-1λ⁶-3-thietanyl]-7-(trifluoromethyl)-1H-1,3- benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one; 5-fluoro-1'-{2-[1-(1-mesyl-3-azetidinyl)-7-(trifluoromethyl)-1H-1,3-benzimidazol-5- yloxy]ethyl}spiro[indoline-3...

Claims

Docket No.: 79275-20028.40 CLAIMS WHAT IS CLAIMED IS:

1. A compound of formula (I’):, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo;R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, whereinsf-5963189440Docket No.: 79275-20028.40 the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; either: (1) X5is -C-; L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether withsf-5963189441Docket No.: 79275-20028.40 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis optionally substituted with one or more halo, OH, -S(O)2-C1-6alkyl, or C3-10cycloalkyl, and whereinsf-5963189442Docket No.: 79275-20028.40 the C3-10cycloalkyl of the C1-6alkyl of Rbis further optionally substituted with one or more C1-6alkyl or -OH, and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which ,wherein # represents a point of attachment to the remainder of the structure; (3) X5is -C-;sf-5963189443Docket No.: 79275-20028.40 L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, or CHF2; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together withR4, and the atoms to which they are attached, to form wherein # represents a point of attachment to the remainder of the structure; orsf-5963189444Docket No.: 79275-20028.40 c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2; (4) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and whereinsf-5963189445Docket No.: 79275-20028.40 each Rfis further optionally substituted with one or more - OH or C1-6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; (5) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; or (6) X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis optionally substituted with one or more -OH, -S(O)2-C1-6alkyl, or C1-6alkoxy, and whereinsf-5963189446Docket No.: 79275-20028.40 the C1-6alkoxy of the C1-6alkyl of Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or - S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH; Rais, independently at each occurrence: (i) C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or - N(C1-6alkyl)-C(O)-C1-6alkyl; (ii) C3-10cycloalkyl optionally substituted with one or more -OH, -C(O)2-C1-6alkyl, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, or –C(O)-C3-10heterocyclyl, or C1- 6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH; (iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl; or (iv) NH(C1-6alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo;sf-5963189447Docket No.: 79275-20028.40 X3is N or C(R6); X4is N or C(R7); and R6and R7are each independently H or halo.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I):, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl;sf-5963189448Docket No.: 79275-20028.40 L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; either: (1) L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1-6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more –OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH; (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more –OH; (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether withsf-5963189449Docket No.: 79275-20028.40 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-Ra, or -S(O)2-Ra; (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra; (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl); (viii) -CN; (ix) -(CH2)qOH, wherein q is an integer from 0-6; (x) -C(O)-C1-6alkyl; or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3- 10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis optionally substituted with one or more halo, OH, -S(O)2-C1-6alkyl, or C3-10cycloalkyl, and whereinsf-5963189450Docket No.: 79275-20028.40 the C3-10cycloalkyl of the C1-6alkyl of Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2 or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which ,wherein # represents a point of attachment to the remainder of the structure; (3) L3is absent; and one of X1and X2is N or C(R5); andsf-5963189451Docket No.: 79275-20028.40 the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CH2F; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to; or c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, tosf-5963189452Docket No.: 79275-20028.40wherein # represents a point of attachment to the remainder of the structure; or (4) L3is absent; and one of X1and X2is N or C(R5); andthe other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rf, wherein Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and whereinsf-5963189453Docket No.: 79275-20028.40 each Rfis further optionally substituted with one or more - OH or C1-6alkyl; Rais, independently at each occurrence: (i) C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or -N(C1-6alkyl)-C(O)-C1-6alky; (ii) C3-10cycloalkyl optionally substituted with one or more -OH, -C(O)2-C1-6alkyl, - C(O)-NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, or –C(O)-C3-10heterocyclyl, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH; (iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl; or (iv) NH(C1-6alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6); X4is N or C(R7); and R6and R7are each independently H or halo.

3. The compound of claim 1 or 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein three of R1a, R1b, R1cand R1dare H, and one of R1a, R1b, R1cand R1dis halo.

4. The compound of any of claims 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is H.

5. The compound of any of claims 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is C2-6alkynyl.sf-5963189454Docket No.: 79275-20028.40 6. The compound of any of claims 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is C1-6alkyl optionally substituted with one or more -OH.

7. The compound of any of claims 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L1is selected from the group.

8. The compound of any of claims 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L2is O.

9. The compound of any of claims 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X5is -C-; L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1- 6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more – OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH, (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more – OH,sf-5963189455Docket No.: 79275-20028.40 (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra, (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra, (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl), (viii) -CN, (ix) -(CH2)qOH, wherein q is an integer from 0-6, (x) -C(O)-C1-6alkyl, or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when: a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3.

10. The compound of any of claims 1 and 3-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, whereinsf-5963189456Docket No.: 79275-20028.40 the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F, or -OCHF2; b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form ,c) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein # represents a point of attachment to the remainder of the structure.

11. The compound of any of claims 1 and 3-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X5is -C-; L3is absent; andsf-5963189457Docket No.: 79275-20028.40 one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CHF2; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, toc) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to,sf-5963189458Docket No.: 79275-20028.40wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2.

12. The compound of any of claims 1 or 3-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of - CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl Rgis, independently at each occurrence, selected from the group consisting of C1- 6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl.sf-5963189459Docket No.: 79275-20028.40 13. The compound of any of claims 1 or 3-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl.

14. The compound of any of claims 1 or 3-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Ri, wherein Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and whereinsf-5963189460Docket No.: 79275-20028.40 the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6 alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or -S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH.

15. The compound of any of claims 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5is halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo.

16. The compound of any of claims 1-15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each of R6and R7is H.

17. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo; R2is H; L1is C1-6alkylene; L2is O; X5is -C-; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, whereinsf-5963189461Docket No.: 79275-20028.40 Rbis oxo or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, or C1-6alkyl, provided that neither: a) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to,b) R1cis Cl; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein # represents a point of attachment to the remainder of the structure; R5is, independently at each occurrence, halo, or C1-6alkyl, wherein the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and R6and R7are each H.

18. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1; p is 0; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, and halo;sf-5963189462Docket No.: 79275-20028.40 R2is H; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more C1-6alkyl; L2is O; L3is absent; and one of X1and X2is C(R5); and the other of X1and X2is C that is taken together with R4, 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 Rc, wherein Rcis, independently at each occurrence, selected from the group consisting of C1-6alkyl, and C3-10cycloalkyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1- 6alkyl, and the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, provided that neither: a) R1cis Cl; one of X1and X2is C(F) or C(CHF2); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to formb) R1cis Cl; L1is -CH2CH2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached,; wherein # represents a point of attachment to the remainder of the structure; R5is, independently at each occurrence, halo, or C1-6alkyl, whereinsf-5963189463Docket No.: 79275-20028.40 the C1-6alkyl of R5is optionally substituted with one or more halo; X3is C(R6); X4is C(R7); and 19. R6and R7are each H. The compound of claim 1, 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’):, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl of R1are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl;sf-5963189464Docket No.: 79275-20028.40 L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1- 6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; and ring B is selected from the group consisting of:wherein r is an integer from 0 to 2; s is an integer from 0 to 3; t is an integer from 1 to 20; u is an integer from 0 to 20; v is an integer from 1 to 20; X2cis N or C(R5c); X2dis N or C(R5d); R5a, R5b, R5c, and R5dare each independently H, halo, -CN, 3-10 membered heterocyclyl, C1- 6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3a, X3b, X3c, and X3dare each independently N or C(R6), wherein R6is H or halo; sf-5963189465Docket No.: 79275-20028.40 X4a, X4b, X4c, X4dare each independently N or C(R7), wherein R7is H or halo; X5aand X6aare each independently NH or -(CH2)x-O- wherein x is 0 or 1; X5b, X6band X7bare each independently N or C, each of which is optionally substituted with one or more H; Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo; Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; and ring C is a 5-20 membered heteroaryl substituted with one or more Rf, and further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH,sf-5963189466Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; ring D is a 5-10 membered heterocyclyl substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; wherein, a) R2is C2-6alkynyl when R1cis Cl or CN; R5ais CF3; and the ring B bearing X5aand X5biswherein # represents a point of attachment to the remainder of the structure;sf-5963189467Docket No.: 79275-20028.40 b) R2is C2-6alkynyl or C1-6alkyl-OH when R1cis Cl or CN; R5bis F, CHF2, -OCHF2or CN; and the ring Bwherein # represents a point of attachment to the remainder of the structure; or c) R2is C2-6alkynyl when R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; R5bis CF3;, wherein & represents the point of atta5chment to X , and && represents the point of attachment to X1or X2.

20. The compound of claim 1, 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):, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is an integer from 0 to 2; p is an integer from 0 to 10; sf-5963189468Docket No.: 79275-20028.40 R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl of R1are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; and ring B is selected from the group consisting of:, wherein r is an integer from 0 to 2; s is an integer from 0 to 3; t is an integer from 1 to 20; X2cis N or C(R5c); R5a, R5b, and R5care each independently H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein sf-5963189469Docket No.: 79275-20028.40 the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3a, X3band X3care each independently N or C(R6), wherein R6is H or halo; X4a, X4band X4care each independently N or C(R7), wherein R7is H or halo; X5aand X6aare each independently NH or -(CH2)x-O- wherein x is 0 or 1; X5b, X6band X7bare each independently N or C, each of which is optionally substituted with one or more H; Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo; Rcis, 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-Ra, C3- 10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; and ring C is a 5-20 membered heteroaryl substituted with one or more Rf, whereinsf-5963189470Docket No.: 79275-20028.40 Rfis, independently at each occurrence, selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH, the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1-6alkyl; wherein, R2is C2-6alkynyl when: a) R1cis Cl or CN; R5ais CF3; and the ring BR5bis F, CHF2, -OCHF2or CN; and the ring B bearing X5b, X6band X7bsf-5963189471Docket No.: 79275-20028.40 c) R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; R5bis CF3; and the ring B bearing.

21. The compound of claim 19 or 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula.

22. The compound of claim 21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula sf-5963189472Docket No.: 79275-20028.40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X5c, X6cand X7care each independently N or C, each of which is optionally substituted with one or more H.

23. The compound of claim 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 1-37 of Table 1.

24. A method for preparing a compound of formula (I’), as recited in claim 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: n is an integer from 0 to 2; p is an integer from 0 to 10;sf-5963189473Docket No.: 79275-20028.40 R1a, R1b, R1cand R1dare each independently selected from the group consisting of H, halo, -CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy or C1-6alkyl are optionally substituted with one or more halo; R2is H, C1-6alkyl, C2-6alkynyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2is optionally substituted with one or more deuterium, halo, -OH, -NH2, or C1-6alkoxy, and the C3-10cycloalkyl of R2is optionally substituted with one or more -OH; R3, if present, is C1-6alkyl; with: a compound of formula (I’-B’):, wherein: the dashed line represents a single or double bond; Y1is halo, oxo, or a sulfonate ester L1is C1-6alkylene, wherein the C1-6alkylene of L1is optionally substituted with one or more deuterium or C1- 6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more -OH or C1-6alkoxy; L2is O or N(Rx), wherein Rxis H or C1-6alkyl; and either: (1) X5is -C-;sf-5963189474Docket No.: 79275-20028.40 L3is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein the C3-10cycloalkyl of L3is optionally substituted with one or more –OH or C1- 6alkyl, the C1-6alkylene of L3is 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 L3is optionally substituted with one or more – OH or C1-6alkyl; X1and X2are each independently N or C(R5); and R4is: (i) -S(O)2-Ra; (ii) 5-20 membered heteroaryl optionally substituted with one or more C1-6alkyl; (iii) -N(Rd)2, wherein Rdis independently at each occurrence H, C1-6 alkyl, or -S(O)2-Ra, wherein the C1-6alkyl of Rdis optionally substituted with one or more -OH, (iv) -NS(O)-(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more – OH, (v) -C(O)-N(Re)2wherein Reis independently at each occurrence H, C1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle of Reis optionally substituted with one or more oxo, or both Retogether 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-Ra, or -S(O)2-Ra, (vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, -OH , oxo or -S(O)2Ra, (vii) -S(O)-N(C1-6alkyl)-(C1-6alkyl), (viii) -CN, (ix) -(CH2)qOH, wherein q is an integer from 0-6, (x) -C(O)-C1-6alkyl, or (xi) -P(O)(C1-6alkyl)2; wherein, R2is C2-6alkynyl when:sf-5963189475Docket No.: 79275-20028.40 a) each of R1a, R1b, R1cand R1dis H; b) R1cis Cl, CN or CHF2; or c) R4is -SO2CH3; (2) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein Rbis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rbis 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 Rbis further optionally substituted with one or more C1-6alkyl or -OH and the C3-10cycloalkyl of Rbis optionally substituted with one or more -OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rbis further optionally substituted with one or more -OH, deuterium, or halo, wherein, R2is C2-6alkynyl when: a) one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN, CHF2, CH2F or -OCHF2;sf-5963189476Docket No.: 79275-20028.40 b) R1cis Cl; one of X1and X2is C(F); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form ,c) R1cis Cl or CN; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to form, wherein # represents a point of attachment to the remainder of the structure; (3) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Rc, wherein Rcis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rcis optionally substituted with one or more -S(O)2-C1-6alkyl, the C3-10cycloalkyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and the 3-10 membered heterocyclyl of Rcis optionally substituted with one or more -OH or C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Rcis further optionally substituted with one or more -OH; wherein, R2is C2-6alkynyl or C1-6alkyl-OH when:sf-5963189477Docket No.: 79275-20028.40 one of X1and X2is N or C(H) and either: each of R1a, R1b, R1cand R1dis H, or R1cis Cl, CN or CHF2; b) R1cis Cl or CN; one of X1and X2is C(F), C(CHF2), C(OCHF2) or C(CN); and the other of X1and X2is C that is taken together with R4, and the atoms to whichthey are attached, to form wherein # represents a point of attachment to the remainder of the structure;; or R1cis Cl, CN or CHF2; L1is -CH2CH2- or -CD2CD2-; one of X1and X2is C(CF3); and the other of X1and X2is C that is taken together with R4, and the atoms to which they are attached, to,wherein & represents the point of attachment to X5, and && represents the point of attachment to X1or X2; or (4) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is substituted with one or more Rfand further optionally substituted with one or more Rg, wherein Rfis, independently at each occurrence, selected from the group consisting of - CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Rfis substituted with one or more -OH,sf-5963189478Docket No.: 79275-20028.40 the C3-10cycloalkyl of Rfis substituted with one or more C1-6alkoxy, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Rfis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6alkynyl, and the 3-10 membered heterocyclyl of Rfis substituted with one or more oxo, =NH or -SO2-C1-6alkyl; and wherein each Rfis further optionally substituted with one or more -OH or C1- 6alkyl, and Rgis, independently at each occurrence, selected from the group consisting of C1-6alkyl or C3-10cycloalkyl, wherein the C3-10cycloalkyl of Rgis optionally substituted with one or more -OH or C1-6alkyl; (5) X5is -C-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is substituted with one or more Rhand further optionally substituted with one or more oxo, wherein Rhis, independently at each occurrence, selected from the group consisting of 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Rhis substituted with one or more oxo or C1-6alkyl; or (6) X5is -N-; L3is absent; and one of X1and X2is N or C(R5); and the other of X1and X2is N or C that is taken together with R4, 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 Ri, whereinsf-5963189479Docket No.: 79275-20028.40 Riis, 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-Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C1-6alkyl of Riis 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 Riis optionally substituted with one or more halo, the C3-10cycloalkyl of Riis optionally substituted with one or more halo, -OH, -C(O)NH2, C1-6alkoxy, or C1-6alkyl, and wherein the C1-6alkoxy of the C3-10cycloalkyl of Riis optionally substituted with one or more 3-5 membered heterocycle, and wherein the 3-5 membered heterocycle is optionally substituted with one or more C1-6alkyl or C2-6 alkynyl, the 3-10 membered heterocyclyl of Riis optionally substituted with one or more -OH, oxo, =NH, C1-6alkyl, or -S(O2)-C1-6alkyl, and wherein the C1-6alkyl of the 3-10 membered heterocyclyl of Riis further optionally substituted with one or more -OH; Rais, independently at each occurrence: (i) C1-6alkyl optionally substituted with one or more halo, -OH, -S(O)2-C1-6alkyl, or -N(C1- 6alkyl)-C(O)-C1-6alkyl, (ii) C3-10cycloalkyl optionally substituted with one or more -OH, -C(O)2-C1-6alkyl, -C(O)- NH(C1-6alkyl), -C(O)-N(C1-6alkyl)2, or –C(O)-C3-10heterocyclyl, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH, (iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, or (iv) NH(C1-6alkyl); R5is, independently at each occurrence, H, halo, -CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl of R5is optionally substituted with one or more halo or -OH, and the C1-6alkoxy of R5is optionally substituted with one or more halo; X3is N or C(R6); X4is N or C(R7); andsf-5963189480Docket No.: 79275-20028.40 R6and R7are each independently H or halo; to give a compound of formula (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

25. The method of claim 24, further 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.

26. The method of claim 25, wherein the inorganic base is selected from the group consisting of potassium carbonate and sodium bicarbonate.

27. A pharmaceutical composition, comprising (i) a compound of any of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

28. 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 claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27.

29. A method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any of claims 1-23 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27.

30. A method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of any of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27.

31. The method of claim 30, wherein the disease, disorder, or condition is a kidney disease orsf-5963189481Docket No.: 79275-20028.40 diabetic retinopathy.

32. The method of claim 31, 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.

33. The method of any of claims 30-32, wherein the disease, disorder, or condition is a kidney disease.

34. The method of any of claims 30-33, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

35. The method of claim 30, wherein the disease, disorder, or condition is diabetic retinopathy.

36. The method of claim 35, 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.

37. The method of claim 35 or 36, wherein the administration comprises oral administration or intravitreal injection.

38. The method of claim 37, wherein the administration comprises oral administration.

39. The method of claim 37, wherein the administration comprises intravitrael injection.

40. The method of any of claims 35-39, 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.

41. A method of delaying the development of an APOL1-mediated disease, disorder, orsf-5963189482Docket No.: 79275-20028.40 condition, comprising administering a compound of any of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.

42. The method of claim 41, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease or diabetic retinopathy.

43. The method of claim 41 or 42, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease.

44. The method of any of claims 41-43, wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.

45. The method of claim 41, 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.

46. The method of claim 41 or 42, wherein the APOL-1 mediated disease, disorder, or condition is diabetic retinopathy.

47. The method of claim 46, 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.

48. The method of claim 46 or 47, wherein the administration comprises oral administrationsf-5963189483Docket No.: 79275-20028.40 or intravitreal injection.

49. The method of claim 48, wherein the administration comprises oral administration.

50. The method of claim 48, wherein the administration comprises intravitreal injection.

51. The method of any of claims 45-50, 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.

52. The method of any of claims 28-51, wherein the individual has an APOL1 mutation.

53. The method of claim 52, wherein the APOL1 mutation is a gain-of-function mutation.

54. The method of any of claims 28-53, wherein a therapeutically effective amount of a compound of any of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, is administered.

55. The method of any of claim 30-54, wherein the individual is a human.

56. A kit, comprising (i) a compound of any of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

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

58. The kit of claim 56 or 57, wherein the disease, disorder, or condition is a kidney disease.

59. The kit of any of claims 56-58, wherein the disease, disorder, or condition is a chronicsf-5963189484Docket No.: 79275-20028.40 kidney disease (CKD).

60. The kit of any of claims 56-59, 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.

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

62. The kit of claim 61, 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.

63. The kit of claim 61 or 62, wherein the administration comprises oral administration or intravitreal injection.

64. The kit of claim 63, wherein the administration comprises oral administration.

65. The kit of claim 63, wherein the administration comprises intravitreal injection.

66. The kit of any of claims 61-65, 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.

67. The kit of any of claims 56-66, wherein the individual has an APOL1 mutation.

68. The kit of claim 67, wherein the APOL1 mutation is a gain-of-function mutation.

69. The kit of any of claim 56-68, wherein the individual is a human.

70. A compound of any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition ofsf-5963189485Docket No.: 79275-20028.40 claim 27, for use in modulating APOL1 in a cell.

71. A compound of any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

72. A compound of any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, for use in delaying the development of an APOL1-mediated disease, disorder, or condition.

73. Use of a compound of any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, in the manufacture of a medicament for use in modulating APOL1 in a cell.

74. Use of a compound of any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, in the manufacture of a medicament for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

75. Use of a compound of any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 27, in the manufacture of a medicament for use in delaying the development of an APOL1- mediated disease, disorder, or condition.sf-5963189486

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