APOL1 inhibitors and methods for use

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 151,605 filed on February 19, 2021.BACKGROUND OF THE INVENTION

[0002] 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).

[0003] 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 (N388Δ, Y389Δ), capable of interfering with these resistance mechanisms (Genovese, G. et al. Science. (2010) 329, 841-845). However, individuals with any binary combination of these variants (G1 / G1, G2 / G2, or G1 / G2), have a greater risk of developing a variety of chronic kidney diseases, including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN) (Genovese, G. et al. Science. (2010) 329, 841-845; Tzur, S. et al. Hum. Genet. (2010) 128, 345-350; Kopp, J. B. et al. J. Am. Soc. Nephrol. (2011) 22, 2129-2137), sickle cell nephropathy (Ashley-Koch, A. E. et al. Br. J. Haematol. (2011) 155, 386-394), lupus nephritis (Freedman, B. I. et al. Arthritis Rheumatol. (2014) 66, 390-396), and an increased rate of Glomerular Filtration Rate (GFR) decline in diabetic kidney disease (Parsa, A. et al. N. Engl. J. Med. (2013) 369, 2183-2196). The APOL1 high-risk genotype has also been associated with COVID-19 associated nephropathy and other viral nephropathies (Shetty, A. et al. J. Am. Soc. Nephrol. (2021) 32, 33-40; Chang, J. H. et al. Am. J. Kidney Dis. (2019) 73, 134-139). Moreover, decreased renal allograft survival has been observed after deceased-donor kidney transplantations from APOL1 high-risk genotype donors (Freedman, B. I. et al. Transplantation. (2016) 100, 194-202). In addition, having two APOL1 risk alleles increases risk for preeclampsia (Reidy, K. J. et al. Am. J. Hum. Genet. (2018) 103, 367-376) and sepsis (Chaudhary, N. S. et al. Clin. J. Am. Soc. Nephrol. (2019) 14, 1733-1740). 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.

[0004] Numerous studies have shown that APOL1 risk variants are toxic when overexpressed in human cells (Wan, G. et al. J. Biol. Chem. (2008) 283, 21540-21549; Lan, X. et al. Am. J. Physiol. Renal Physiol. (2014) 307, F326-F336; Olabisi, O. A. et al. Proc. Natl. Acad. Sci. USA. (2016) 113, 830-837; Ma, L. et al. J. Am. Soc. Nephrol. (2017) 28, 1093-1105; Lannon, H. et al. Kidney Int. (2019) 96, 1303-1307). Recent findings suggest that this toxicity is associated with APOL1 pore function (Giovinazzo, J. A. et al. eLife. (2020) 9, e51185). Thus, there is a need to develop compounds suitable for inhibiting APOL1 activity and methods for inhibiting the activity of APOL1 using such compounds. US 2020 / 0377479 describes compounds comprising two cyclic units joined by a linking unit which act as APOL1 inhibitors, and their use in treating focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease. US 2004 / 024024 describes compounds having a similar structure which act as MMP (matric metalloprotease) inhibitors. WO 91 / 13865 describes compounds also having this structure which act as antiarrhythmic agents.BRIEF SUMMARY OF THE INVENTION

[0005] 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 also find use in treating other APOL1-mediated disorders such as preeclampsia and sepsis. Additionally, for individuals with the APOL1 high-risk genotype, the disclosed compounds and compositions could have utility in preventing the onset of non-diabetic renal disease and / or delaying the progression of any form of chronic kidney disease. The disclosed chemical matter could also have utility in preventing and / or delaying progressive renal allograft loss in patients who have received a kidney transplant from a high-risk APOL1 genotype donor. Any references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).

[0006] In one aspect, provided herein is a compound of formula (A'): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; L is selected from the group consisting of: (i) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R x< is H, or R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; R 1< and R 2< are independently H, halo, or -OH, or one of R 1< and R 2< is taken together with R x< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1< and R 2< is H, halo, or - OH; R 3< is H, -OH, halo, or C 1-6 alkoxy; and R 4< and R 5< are independently H, or R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that either: (1) R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more -OH, C 1-6 alkyl, or C 1-6 alkoxy, or (2) R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (ii) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); p is 0 or 1, provided that, when p is 1, then E is O; R 6< is H or -OH; R y< is H, or R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 7< is H, or R 7< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 8< and R 9< are independently H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8< and R 9< is H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8< and R 9< is H or C 1-6 alkyl; and R 10< is H, or R 10< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that: (1) R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R 8< and R 9< is taken together with R 10< and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and (iii) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R z< is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl; R 11< and R 12< are independently H, -OH, halo, or C 1-6 alkyl; and R 13< and R 14< are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X 1< -X 4< ; and X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

[0007] In one aspect, provided herein is a compound of formula (A): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; L is selected from the group consisting of: (i) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R x< is H, or R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; R 1< and R 2< are independently H, halo, or -OH, or one of R 1< and R 2< is taken together with R x< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1< and R 2< is H, halo, or - OH; R 3< is H, -OH, halo, or C 1-6 alkoxy; and R 4< and R 5< are independently H, or R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that either: (1) R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more -OH, C 1-6 alkyl, or C 1-6 alkoxy, or (2) R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (ii) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); p is 0 or 1, provided that, when p is 1, then E is O; R 6< is H or -OH; R y< is H, or R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 7< is H, or R 7< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 8< and R 9< are independently H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8< and R 9< is H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8< and R 9< is H or C 1-6 alkyl; and R 10< is H, or R 10< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that: (1) R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R 8< and R 9< is taken together with R 10< and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and (iii) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R z< is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl; R 11< and R 12< are independently H, -OH, halo, or C 1-6 alkyl; and R 13< and R 14< are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X 1< -X 4< ; and X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

[0008] Any embodiments provided herein of a compound of formula (A), 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 (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0009] In one aspect, 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 X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , A, Q, and Y are as defined for a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In another variation, X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , A, Q, and Y of formula (I) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0010] In one aspect, provided herein is a compound of formula (II):

[0011] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< , X 2< , X 3< , X 4< , R 6< , R 7< , R 8< , R 9< , R 10< , R a< , R b< , R c< , R y< , p, E, Q, and Y are as defined for a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In another variation, X 1< , X 2< , X 3< , X 4< , R 6< , R 7< , R 8< , R 9< , R 10< , R a< , R b< , R c< , R y< , p, E, Q, and Y of formula (II) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.In one aspect, provided herein is a compound of formula (III): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< , X 2< , X 3< , X 4< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R z< , G, Q, and Y are as defined for a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In another variation, X 1< , X 2< , X 3< , X 4< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R z< , G, Q, and Y of formula (III) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0012] In one aspect, provided herein is a compound of formula (B-2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< , X 2< , X 3< , X 4< , and L are as defined for a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In another variation, X 1< , X 2< , X 3< , X 4< , and L of formula (B-2) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0013] In one aspect, provided herein is a compound of formula (B-5): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< , X 2< , X 3< , X 4< , and L are as defined for a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In another variation, X 1< , X 2< , X 3< , X 4< , and L of formula (B-5) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0014] In one aspect, provided herein is a compound of formula (C-1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< , X 2< , X 3< , X 4< , and L are as defined for a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In another variation, X 1< , X 2< , X 3< , X 4< , and L of formula (C-1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0015] In one aspect, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (A), or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5), or (C-1), 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 (A'), or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5), or (C-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

[0016] In one aspect, provided herein is a compound of formula (A') or (A), or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5), or (C-1), 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 (A) or (A') or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5) or (C-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients, for use in treating or delaying the development of a disease, disorder, or condition selected from: a kidney disease; or a disease, disorder, or condition 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.

[0017] In one aspect, provided herein is a kit, comprising (i) a compound of formula (A), or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5), or (C-1), 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 another variation, provided herein is a kit, comprising (i) a compound of formula (A'), or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5), or (C-1), 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.

[0018] Also described herein are methods of preparing a compound of formula (A) or (A'), or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5), or (C-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.DETAILED DESCRIPTION OF THE INVENTION

[0019] Unless clearly indicated otherwise, the terms "a," "an," and the like, refer to one or more.

[0020] 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.

[0021] "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.

[0022] 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).

[0023] "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).

[0024] 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.

[0025] As used herein, the term "therapeutically effective amount" or "effective amount" intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.

[0026] 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.

[0027] 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.

[0028] 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., C 1-20 alkyl), 1-16 carbons (i.e., C 1-16 alkyl), 1-12 carbons (i.e., C 1-12 alkyl), 1-10 carbons (i.e., C 1-10 alkyl), 1-8 carbons (i.e., C 1-8 alkyl), 1-6 carbons (i.e., C 1-6 alkyl), 1-4 carbons (i.e., C 1-4 alkyl), or 1-3 carbons (i.e., C 1-3 alkyl). 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".

[0029] The term "alkoxy", as used herein, refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0030] 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., C 6-20 aryl), 6 to 16 annular carbon atoms (i.e., C 6-16 aryl), 6 to 12 annular carbon atoms (i.e., C 6-12 aryl), or 6 to 10 annular carbon atoms (i.e., C 6-10 aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0031] 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 C 3-20 cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C 3-16 cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C 3-12 cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C 3-10 cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C 3-8 cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C 3-6 cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C 3-5 cycloalkyl). 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.

[0032] The term "halo", as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0033] 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 group 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, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

[0034] 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 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]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.

[0035] 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 - CH 3 , -CH 2 Cl, -CHCl 2 , and -CCl 3 moieties.

[0036] It is understood that aspects and embodiments described herein as "comprising" include "consisting of" and "consisting essentially of " embodiments.

[0037] 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. 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.

[0038] 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 2< H, 3< H, 11< C, 13< C, 14< C, 13< N, 15< N, 15< O, 17< O, 18< O, 31< P, 32< P, 35< S, 18< F, 36< Cl, 123< I, and 125< I, respectively. In some embodiments, a compound of formula (A), or formula (A') is provided wherein one or more hydrogen is replaced by deuterium or tritium.

[0039] 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.

[0040] 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. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255-270 2008.

[0041] 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), and chiral SFC (supercritical fluid chromatography). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

[0042] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0043] Where enantiomeric and / or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,

[0044] Where enantiomeric forms exist of a given structure, flat bonds and the presence of a " * " symbol indicate that the composition is made up of at least 90%, by weight, of a single isomer with unknown stereochemistry, e.g.,

[0045] Where enantiomeric and / or diastereomeric forms exist of a given structure, wedged or hashed bonds indicate the composition is made up of at least 90%, by weight, of a single enantiomer or diastereomer with known stereochemistry, e.g.,

[0046] Where enantiomeric and / or diastereomeric forms exist of a given structure with two stereocenters, flat bonds and the presence of two "&1" symbols indicate the composition is made up of a pair of enantiomers with unknown relative stereochemistry, e.g.,

[0047] Where enantiomeric and / or diastereomeric forms exist of a given structure with two stereocenters, wedged and / or dashed bonds and the presence of two "&1" symbols indicate the composition is made up of a pair of enantiomers with known relative stereochemistry, e.g.,

[0048] Where enantiomeric and / or diastereomeric forms exist of a given structure with two stereocenters, wedged and / or dashed bonds and the presence of two "or1" symbols indicate the composition is made up of at least 90%, by weight, a single stereoisomer with known relative stereochemistry but unknown absolute stereochemistry, e.g.,

[0049] Where enantiomeric and / or diastereomeric forms exist of a given structure with two stereocenters, flat bonds and the presence of two " * " symbols indicate the composition is made up of at least 90%, by weight, of a single enantiomer or diastereomer with unknown stereochemistry, e.g.,

[0050] Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th< Ed. The following examples are intended to be illustrative only and not limiting in any way. °Cdegrees CelsiusLiHMDSlithium bis(trimethylsilyl)amideµLmicrolitermCPBA or m-CPBAmeta-chloroperoxybenzoic acid[M+XX] +< observed massMeOHmethanolAC 50 half-maximal activity concentrationMeCNacetonitrileAcOHacetic acidmmultiplet (NMR)AIBNazobisisobutyronitrilemgmilligramsappapparent (NMR)minminutesbbroad (as in "br s" to indicate a broad singlet)mLmilliliterBH 3 · THFborane-tetrahydrofuran complexmmolmillimoleBBr 3 boron tribromidemMmillimolarCalc'dcalculatedMmolarity or molarCbz-Cl or CbzClbenzyl chloroformateMSmass spectrometryCO 2 carbon dioxideMsClmethanesulfonyl chlorideCs 2 CO 3 cesium carbonateMTBEmethyl tert-butyl etherddeuterated (NMR solvents)n / anot applicableddoublet (NMR)NH 4 ammoniumdddoublet of doublets (NMR)NH 4 OHammonium hydroxideDCE1,2-dichloroethaneNH 4 HCO 3 ammonium bicarbonateDCMdichloromethaneNa 2 SO 4 sodium sulfateDIADdiisopropyl azodicarboxylateNaBH 3 CNsodium cyanoborohydrideDMFN,N-dimethylformamideNMRnuclear magnetic resonanceDMPDess-Martin periodinaneNaOHsodium hydroxideEC 50 half-maximal effective concentrationPd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene ]dichloropalladium(II)EtOAcethyl acetatePd / Cpalladium on carbonEtOHethanolpHpotential of hydrogenggramsPPh 3 triphenyl phosphinehhoursssinglet (NMR)HhydrogenSFCsupercritical fluid chromatographyHClhydrochloric acidttriplet (NMR)HPLChigh-performance liquid chromatographyTBABtetrabutylammonium bromideIn vacuoin a vacuumTEAtriethylamineIUPACInternational Union of Pure and Applied ChemistryTFAtrifluoroacetic acidMHzmegahertzTHFtetrahydrofuranJJ-coupling value (NMR)TMADtetramethylazodicarboxamideK 2 CO 3 potassium carbonateTMSCltrimethylsilyl chloride COMPOUNDS

[0051] Provided herein is a compound of formula (A'): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; L is selected from the group consisting of: (i) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R x< is H, or R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; R 1< and R 2< are independently H, halo, or -OH, or one of R 1< and R 2< is taken together with R x< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1< and R 2< is H, halo, or - OH; R 3< is H, -OH, halo, or C 1-6 alkoxy; and R 4< and R 5< are independently H, or R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that either: (1) R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more -OH, C 1-6 alkyl, or C 1-6 alkoxy, or (2) R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (ii) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); p is 0 or 1, provided that, when p is 1, then E is O; R 6< is H or -OH; R y< is H, or R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 7< is H, or R 7< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 8< and R 9< are independently H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8< and R 9< is H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8< and R 9< is H or C 1-6 alkyl; and R 10< is H, or R 10< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that: (1) R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R 8< and R 9< is taken together with R 10< and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and (iii) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R z< is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl; R 11< and R 12< are independently H, -OH, halo, or C 1-6 alkyl; and R 13< and R 14< are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X 1< -X 4< ; and X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

[0052] Provided herein is a compound of formula (A): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; L is selected from the group consisting of: (i) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R x< is H, or R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; R 1< and R 2< are independently H, halo, or -OH, or one of R 1< and R 2< is taken together with R x< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1< and R 2< is H, halo, or - OH; R 3< is H, -OH, halo, or C 1-6 alkoxy; and R 4< and R 5< are independently H, or R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that either: (1) R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more -OH, C 1-6 alkyl, or C 1-6 alkoxy, or (2) R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (ii) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); p is 0 or 1, provided that, when p is 1, then E is O; R 6< is H or -OH; R y< is H, or R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 7< is H, or R 7< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 8< and R 9< are independently H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8< and R 9< is H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8< and R 9< is H or C 1-6 alkyl; and R 10< is H, or R 10< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that: (1) R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R 8< and R 9< is taken together with R 10< and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and (iii) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R z< is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl; R 11< and R 12< are independently H, -OH, halo, or C 1-6 alkyl; and R 13< and R 14< are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X 1< -X 4< ; and X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

[0053] Any embodiments provided herein of a compound of formula (A), 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 (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0054] In some embodiments, provided is a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is such that the compound of formula (A) is a compound of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , A Q, and Y of formula (I) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0055] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is O, such that the compound is of formula (I-A1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, the X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , Q, and Y of formula (I-A1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0056] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is NH, such that the compound is of formula (I-A2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, A is N(C 1-6 alkyl). In some embodiments, A is N(CH 3 ). In some variations, X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , Q, and Y of formula (I-A2) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0057] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is CH 2 , such that the compound is of formula (I-A3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, A is CH(C 1-6 alkyl). In some embodiments, A is CH(CH 3 ). In some variations, X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , Q, and Y of formula (I-A3) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0058] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), (I-A2), or (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy. In some embodiments, R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy. In some embodiments, R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy. In some embodiments, R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy. R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy. R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy. In some variations, the the embodiments provided herein also apply to a compound of formula (A') or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0059] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-B1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-B1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0060] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-B2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-B2) are as defined of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0061] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-B3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-B3) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0062] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-C1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-C1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0063] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-C2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-C2) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0064] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-C3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-C3) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0065] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-D1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-D1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0066] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-D2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-D2) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0067] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-D3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-D3) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0068] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-E1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-E1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0069] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-E2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-E2) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0070] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-E3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-E3) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0071] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-E1), (I-E2), or (I-E3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

[0072] In some embodiments, provided herein is a compound of formula (A') or formula (I), such as a compound of formula (I-E1), (I-E2), or (I-E3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0073] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-F1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-F1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-F2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-F2) are as defined for compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-F3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-F3) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-G1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-G1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0077] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-G2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-G2) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the compound is of formula (I-G3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R g< , R x< , Q, Y and n of formula (I-G3) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), or (I-G3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is an integer from 0-6. In some embodiments, n is an integer from 0-5. In some embodiments, n is an integer from 0-4. In some embodiments, n is an integer from 0-3. In some embodiments, n is an integer from 0-2. In some embodiments, n is 0 or 1. In some embodiments, n is an integer from 1-6. In some embodiments, n is an integer from 1-5. In some embodiments, n is an integer from 1-4. In some embodiments, n is an integer from 1-3. In some embodiments, n is 1 or 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 a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), or (I-G3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy. In some embodiments, R g< is - OH, C 1-6 alkyl, or C 1-6 alkoxy. In some embodiments, R g< is -OH, halo, C 1-3 alkyl, or C 1-3 alkoxy. In some embodiments, R g< is -OH, methyl, or methoxy. In some embodiments, R g< is -OH. In some embodiments, R g< is C 1-6 alkyl. In some embodiments, R B< is methyl. In some embodiments, R g< is C 1-6 alkoxy. In some embodiments, R g< is methoxy. In some embodiments, R g< is halo. In some embodiments, R g< is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), or (I-G3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1 and R g< is C 1-6 alkyl. In some embodiments, n is 1 and R g< is methyl. In some embodiments, n is 2 and each R g< is C 1-6 alkyl. In some embodiments, n is 2 and each R g< is methyl. In some embodiments, n is 1 and R g< is -OH. In some embodiments, n is 1 and R g< is C 1-6 alkoxy. In some embodiments, n is 1 and R g< is methoxy.

[0082] In some embodiments, provided herein is a compound of formula (A') or formula (I), such as a compound of formula (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), or (I-G3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1 and R g< is C 1-6 alkyl. In some embodiments, n is 1 and R g< is methyl. In some embodiments, n is 2 and each R g< is C 1-6 alkyl. In some embodiments, n is 2 and each R g< is methyl. In some embodiments, n is 1 and R g< is -OH. In some embodiments, n is 1 and R g< is C 1-6 alkoxy. In some embodiments, n is 1 and R g< is methoxy. In some embodiments, n is 2, one or R g< is methyl, and the other of R g< is -OH.

[0083] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), or (I-G3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4< and R 5< are independently H. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl. In some embodiments, R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl. In some embodiments, R 4< and R 5< are taken, together with the atoms to which they are attached, to form cyclobutyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4< and R 5< are taken, together with the atoms to which they are attached, to form cyclobutyl, wherein the compound is of formula (I-H1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , Q, and Y of formula (I-H1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4< and R 5< are taken, together with the atoms to which they are attached, to form cyclobutyl, wherein the compound is of formula (I-H2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , Q, and Y of formula (I-H2) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4< and R 5< are taken, together with the atoms to which they are attached, to form cyclobutyl, wherein the compound is of formula (I-H3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 3< , R 4< , R 5< , R a< , R b< , R c< , R x< , Q, and Y of formula (I-H3) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-H1), (I-H2), or (I-H3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1< and R 2< are each H. In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-H1), (I-H2), or (I-H3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x< is H. In some embodiments, R 1< , R 2< , and R x< are each H. In some embodiments, the embodiments provided herein also apply to a compound of formula (A') or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0089] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), or (I-H3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3< is H, -OH, halo, or C 1-6 alkoxy. In some embodiments, R 3< is H. In some embodiments, R 3< is -OH, halo, or C 1-6 alkoxy. In some embodiments, R 3< is H or -OH. In some embodiments, R 3< is -OH. In some embodiments, R 3< is halo. In some embodiments, R 3< is C 1-6 alkoxy. In some embodiments, R 3< is methoxy.

[0090] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), or (I-G3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3< , R 4< , and R 5< are each H. In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (I-H1), (I-H2), or (I-H3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1< , R 2< , R 3< , and R x< are each H. In some embodiments, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is In some embodiments, L is and the compound of formula (A) is a compound of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 7< , R 8< , R 9< , R 10< , R a< , R b< , R c< , R y< , p, E, Q, and Y of formula (II) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein E is O, wherein the compound is of formula (II-A1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 7< , R 8< , R 9< , R 10< , R a< , R b< , R c< , R y< , p, Q, and Y of formula (II-A1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein E is NH, wherein the compound is of formula (II-A2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, E is N(C 1-6 alkyl). In some embodiments, E is N(CH 3 ). In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 7< , R 8< , R 9< , R 10< , R a< , R b< , R c< , R y< , p, Q, and Y of formula (II-A2) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0093] In some embodiments, provided herein is a compound of formula (A) or formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein E is CH 2 , wherein the compound is of formula (II-A3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, E is CH(C 1-6 alkyl). In some embodiments, E is CH(CH 3 ). In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 7< , R 8< , R 9< , R 10< , R a< , R b< , R c< , R y< , p, Q, and Y of formula (II-A3) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0094] In some embodiments, provided herein is a compound of formula (A) or formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl. In some embodiments, R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-6 membered heterocyclyl. In some embodiments, R y< is taken together with R 7< , and the atoms to which they are attached, to form a 5-8 membered heterocyclyl. In some embodiments, R y< is taken together with R 7< , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl. In some embodiments, R y< is taken together with R 7< , and the atoms to which they are attached, to form a 5-membered heterocyclyl. In some embodiments, R y< is taken together with R 7< , and the atoms to which they are attached, to form a 6-membered heterocyclyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0095] In some embodiments of the foregoing, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A1), (II-A2), or (II-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 1. In other embodiments, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A1), (II-A2), or (II-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 0. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, and p is 1, wherein the compound is of formula (II-B1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-B1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 5-membered heterocyclyl, and p is 0, wherein the compound is of formula (II-C1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-C1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 5-membered heterocyclyl, and p is 0, wherein the compound is of formula (II-C2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-C2) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 5-membered heterocyclyl, and p is 0, wherein the compound is of formula (II-C3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-C3) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, and p is 0, wherein the compound is of formula (II-D1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-D1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, and p is 0, wherein the compound is of formula (II-D2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-D2) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y< is taken together with R 7< , and the atoms to which they are attached, to form a 6-membered heterocyclyl, and p is 0, wherein the compound is of formula (II-D3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-D3) are as defined for a compound of formula (A'), 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 the foregoing, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), or (II-D3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6< is -OH. In some embodiments, R 6< is -OH, R 8< is C 1-6 alkyl, and R 9< is C 1-6 alkyl. In some embodiments, R 6< is -OH, R 8< is methyl, and R 9< is methyl. In some embodiments, R 6< is -OH, R 8< is H, and R 9< is H. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl. In some embodiments, one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-6 cycloalkyl. In some embodiments, one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-4 cycloalkyl. In some embodiments, one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form cyclobutyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form cyclobutyl, wherein the compound is of formula (II-E1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 6< , R 8< , R 9< , R 10< , R a< , R b< , R c< , Q, and Y of formula (II-E1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (II), such as a compound of formula (II-E1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6< is -OH and R 7< is H. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is In some embodiments, provided herein is a compound of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is wherein the compound is of formula (III): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R z< , G, Q, and Y of formula (III) are as defined for a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G is O, wherein the compound is of formula (III-A1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R z< , Q, and Y of formula (III-A1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G is NH, wherein the compound is of formula (III-A2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, G is N(C 1-6 alkyl). In some embodiments, G is N(CH 3 ). In some variations, X 1< , X 2< , X 3< , X 4< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R z< , Q, and Y of formula (III-A2) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G is CH 2 , wherein the compound is of formula (III-A3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, G is CH(C 1-6 alkyl). In some embodiments, G is CH(CH 3 ). In some variations, X 1< , X 2< , X 3< , X 4< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R z< , Q, and Y of formula (III-A3) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (III), such as a compound of formula (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R z< is H. In some embodiments, R z< is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl. In some embodiments, R z< is unsubstituted C 1-6 alkyl. In some embodiments, R z< is unsubstituted C 1-3 alkyl. In some embodiments, R z< is unsubstituted methyl or unsubstituted ethyl. In some embodiments, R z< is unsubstituted ethyl. In some embodiments, R z< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with one or more C 3-8 cycloalkyl. In some embodiments, R z< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with one or more C 3-6 cycloalkyl. In some embodiments, R z< is methyl, wherein the methyl is substituted with cyclopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (III), such as a compound of formula (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R 11< and R 12< is -OH and the other of R 11< and R 12< is H, halo, or C 1-6 alkyl. In some embodiments, one of R 11< and R 12< is -OH and the other of R 11< and R 12< is H. In some embodiments, one of R 11< and R 12< is -OH and the other of R 11< and R 12< is C 1-6 alkyl. In some embodiments, one of R 11< and R 12< is -OH and the other of R 11< and R 12< is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0113] In some embodiments, provided herein is a compound of formula (A) or formula (III), such as a compound of formula (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 13< and R 14< are both H. In some embodiments, R 13< and R 14< are both C 1-6 alkyl. In some embodiments, R 13< and R 14< are both methyl. In some embodiments, one of R 13< and R 14< is H and the other of R 13< and R 14< is C 1-6 alkyl or C 3-8 cycloalkyl. In some embodiments, one of R 13< and R 14< is H and the other of R 13< and R 14< is C 1-6 alkyl. In some embodiments, one of R 13< and R 14< is H and the other of R 13< and R 14< is methyl. In some embodiments, one of R 13< and R 14< is H and the other of R 13< and R 14< is C 3-8 cycloalkyl. In some embodiments, one of R 13< and R 14< is H and the other of R 13< and R 14< is cyclopropyl. In some embodiments, R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl. In some embodiments, R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-6 membered heterocyclyl. In some embodiments, R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 5-8 membered heterocyclyl. In some embodiments, R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 5-6 membered heterocyclyl. In some embodiments, R 13< and R 14< are taken, together with the atoms to which they are attached, to form tetrahydrofuranyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A), such as a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo. In some embodiments, three of X 1< , X 2< , X 3< , and X 4< are H and one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo. In some embodiments, two of X 1< , X 2< , X 3< , and X 4< are H and two of X 1< , X 2< , X 3< , and X 4< are independently halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

[0115] In some embodiments, provided herein is a compound of formula (A'), such as a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5< , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5< , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo. In some embodiments, three of X 1< , X 2< , X 3< , and X 4< are H and one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5< , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo. In some embodiments, two of X 1< , X 2< , X 3< , and X 4< are H and two of X 1< , X 2< , X 3< , and X 4< are independently halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5< , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

[0116] In some embodiments, provided herein is a compound of formula (A), such as a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1< and X 2< are each H, one of X 3< and X 4< is H, and the other of X 3< and X 4< is halo. In some embodiments, X 1< and X 2< are each H, one of X 3< and X 4< is H, and the other of X 3< and X 4< is chloro. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A), such as a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1< and X 2< is H and the other of X 1< and X 2< is C 1-6 alkyl, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is ethyl, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is C 1-6 alkoxy, wherein the C 1-6 alkoxy is optionally substituted with one or more halo, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is methoxy, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is -O-CHF 2 , and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is halo, and one of X 3< and X 4< is H and the other of X 3< and X 4< is halo. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is chloro, and one of X 3< and X 4< is H and the other of X 3< and X 4< is chloro. In some embodiments, X 1< and X 2< are each H, and X 3< and X 4< are each halo. In some embodiments, X 1< and X 2< are each H, and X 3< and X 4< are each chloro. In some embodiments, X 1< and X 2< are each H, and one of X 3< and X 4< is H and the other of X 3< and X 4< is - CN. In some embodiments, provided herein is a compound of formula (A), such as a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1< and X 2< is H and the other of X 1< and X 2< is C 1-6 alkyl, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is ethyl, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is C 1-6 alkoxy, wherein the C 1-6 alkoxy is optionally substituted with one or more halo, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is methoxy, and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is -O-CHF 2 , and X 3< and X 4< are each H. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is -O-CHF 2 , and one of X 3< and X 4< is H and the other of X 3< and X 4< is chloro. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is halo, and one of X 3< and X 4< is H and the other of X 3< and X 4< is halo. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is C 1-6 alkyl, and one of X 3< and X 4< is H and the other of X 3< and X 4< is halo. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is methyl, and one of X 3< and X 4< is H and the other of X 3< and X 4< is halo. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is C 1-6 alkoxy, one of X 3< and X 4< is H and the other of X 3< and X 4< is halo. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is methoxy, one of X 3< and X 4< is H and the other of X 3< and X 4< is halo. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is chloro, and one of X 3< and X 4< is H and the other of X 3< and X 4< is chloro. In some embodiments, X 1< and X 2< are each H, and X 3< and X 4< are each halo. In some embodiments, X 1< and X 2< are each H, and X 3< and X 4< are each chloro. In some embodiments, X 1< and X 2< are each H, one of X 3< and X 4< is chloro and the other of X 3< and X 4< is fluoro. In some embodiments, X 1< and X 2< are each H, and one of X 3< and X 4< is H and the other of X 3< and X 4< is -CN. In some embodiments, X 1< and X 2< are each H, and one of X 3< and X 4< is H and each of X 3< and X 4< is -CN. In some embodiments, X 1< and X 2< are each H, and one of X 3< and X 4< is C 1-6 alkyl and the other of X 3< and X 4< is -CN. In some embodiments, X 1< and X 2< are each H, and one of X 3< and X 4< is halo and the other of X 3< and X 4< is - CN. In some embodiments, X 1< and X 2< are each H, and one of X 3< and X 4< is -CF 3 and the other of X 3< and X 4< is -CN. In some embodiments, one of X 1< and X 2< is H and the other of X 1< and X 2< is C 1-6 alkyl, one X 3< and X 4< is halo and the other of X 3< and X 4< is -CN. In some embodiments, X 1< and X 2< are each H, one of X 3< and X 4< is H and the other of X 3< and X 4< is -SF 5 .

[0117] In some embodiments, the phenyl ring bearing moieties X 1< , X 2< , X 3< , and X 4< is selected from the group consisting of In some embodiments, the phenyl ring bearing moieties X 1< , X 2< , X 3< , and X 4< is In some embodiments, the phenyl ring bearing moieties X 1< , X 2< , X 3< , and X 4< is selected from the group consisting of In some embodiments, the phenyl ring bearing moieties X 1< , X 2< , X 3< , and X 4< is selected from the group consisting of and In some embodiments, the phenyl ring bearing moieties X 1< , X 2< , X 3< , and X 4< is

[0118] In some embodiments, provided herein is a compound of formula (A), such as a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is absent. In some embodiments, provided herein is a compound of formula (A), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (B): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R a< , R b< , R c< , L and Y of formula (B) are as defined for formula (B) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is O, wherein the compound is of formula (B-1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R a< , R b< , R c< , and L of formula (B1) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A), formula (B), or formula (B-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is ,

[0121] In some embodiments, provided herein is a compound of formula (A'), formula (B), or formula (B-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is

[0122] In some embodiments, provided herein is a compound of formula (A), formula (B), or formula (B-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form oxetanyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A), formula (B), or formula (B-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each H, wherein the compound is of formula (B-2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , and L of formula (B-2) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0124] In some embodiments, provided herein is a compound of formula (A), formula (B), formula (B-1), or formula (B-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1< and X 2< is H and the other of X 1< and X 2< is chloro, X 3< is H, and X 4< is H, wherein the compound is of formula (B-3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, L of formula (B-3) is as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is -N(C 1-6 alkyl). In some embodiments, Y is -N(CH 3 ), wherein the compound is of formula (B-4): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R a< , R b< , R c< , and L of formula (B-4) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A), formula (B), or formula (B-4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is,

[0127] In some embodiments, provided herein is a compound of formula (A'), formula (B), or formula (B-4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is,

[0128] In some embodiments, provided herein is a compound of formula (A), formula (B), or formula (B-4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form oxetanyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl.

[0129] In some embodiments, provided herein is a compound of formula (A'), formula (B), or formula (B-4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form oxetanyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form azetidinyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl.

[0130] In some embodiments, provided herein is a compound of formula (A), formula (B), or formula (B-4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each H, wherein the compound is of formula (B-5): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , and L of formula (B-5) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0131] In some embodiments, provided herein is a compound of formula (A), formula (B), formula (B-4), or formula (B-5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1< and X 2< is H and the other of X 1< and X 2< is chloro, X 3< is H, and X 4< is H, wherein the compound is of formula (B-6): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, L of formula (B-6) is as defined for is a compound of formula (A'), 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, provided herein is a compound of formula (A), such as a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is -N(C 1-6 alkyl). In some embodiments, Q is -N(CH 3 ). In some embodiments, provided herein is a compound of formula (A), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (C): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , R a< , R b< , R c< , and L of formula (C) are as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A) or formula (C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is or

[0134] In some embodiments, provided herein is a compound of formula (A') or formula (C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, two of R a< , R b< , and R c< are independently H, and one of R a< , R b< , and R c< is

[0135] In some embodiments, provided herein is a compound of formula (A) or formula (C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or - S(O) 2 -C 1-6 alkyl. In some embodiments, any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form oxetanyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl. In some variations, the embodiments provided herein also apply to a compound of formula (A') 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, provided herein is a compound of formula (A) or formula (C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a< , R b< , and R c< are each H, wherein the compound is of formula (C-1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X 1< , X 2< , X 3< , X 4< , and L of formula (C-1) are as defined for a compound of formula (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0137] In some embodiments, provided herein is a compound of formula (A), formula (C), or formula (C-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1< and X 2< is H and the other of X 1< and X 2< is chloro, X 3< is H, and X 4< is H, wherein the compound is of formula (C-2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, L of formula (C-2) is as defined for a compound of formula (A'), 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, provided herein is a compound of formula (A), such as a compound of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is or any embodiment or variation thereof, as described elsewhere herein, including, for example, as in a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0139] In some embodiments, provided herein is a compound of formula (A'), such as a compound of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is or any embodiment or variation thereof, as described elsewhere herein, including, for example, as in a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0140] In some embodiments, provided herein is a compound of formula (A), such as a compound of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or a stereoisomer or tatomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is or any embodiment or variation thereof, as described elsewhere herein, including, for example, as in a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0141] In some embodiments, provided herein is a compound of formula (A'), such as a compound of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or a stereoisomer or tatomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is or any embodiment or variation thereof, as described elsewhere herein, including, for example, as in a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0142] In some embodiments, provided herein is a compound of formula (A), such as a compound of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is or any embodiment or variation thereof, as described elsewhere herein, including, for example, as in a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0143] In some embodiments, provided herein is a compound of formula (A'), such as a compound of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is or any embodiment or variation thereof, as described elsewhere herein, including, for example, as in a compound of formula (I), (I-A1), (I-A2), (I-A3), (I-B1), (I-B2), (I-B3), (I-C1), (I-C2), (I-C3), (I-D1), (I-D2), (I-D3), (I-E1), (I-E2), (I-E3), (I-F1), (I-F2), (I-F3), (I-G1), (I-G2), (I-G3), (I-H1), (I-H2), (I-H3), (II), (II-A1), (II-A2), (II-A3), (II-B1), (II-C1), (II-C2), (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0144] In some embodiments, provided herein is a compound of formula (A), or formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein L is selected from the group consisting of, wherein # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X 1< -X 4< .

[0145] In some embodiments, provided herein is a compound of formula (A), or formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein L and the phenyl ring bearing moieties X 1< -X 4< together form a structure selected from the group consisting of

[0146] In some embodiments, provided herein is a compound of formula (A), or formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein the phenyl ring bearing Q is selected from the group consisting of , and

[0147] In some embodiments, provided herein is a compound of formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein L and the phenyl ring bearing moieties Q together form a structure selected from the group consisting of

[0148] It is to be understood that any variation or embodiment of X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , R 9< , R 10< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R g< , R x< , R y< , R z< , n, p, A, E, G, L, Q, and Y provided herein can be combined with every other variation or embodiment of X 1< , X 2< , X 3< , X 4< , R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , R 9< , R 10< , R 11< , R 12< , R 13< , R 14< , R a< , R b< , R c< , R g< , R x< , R y< , R z< , n, p, A, E, G, L, Q, and Y, the same as if each and every combination had been individually and specifically described.

[0149] In some embodiments, provided herein is a compound of formula (A'), formula (A), or any variation of embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Table 1 Compound No.StructureChemical name1 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane2 (R) or (S)-1-(3-chlorophenethyl)-3 -((4-(methylsulfonyl)phenoxy)methyl)azepane3 (S) or (R)-1-(3-chlorophenethyl)-3 -((4-(methylsulfonyl)phenoxy)methyl)azepane4 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-3-ol5 (R) or (S)-1-(3-chlorophenethyl)-3 -((4-(methylsulfonyl)phenoxy)methyl)piperidin-3-ol6 (S) or (R) -1-(3-chlorophenethyl)-3 -((4-(methylsulfonyl)phenoxy)methyl)piperidin-3-ol7 N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide8 (S) or (R)-N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide9 (R) or (S)-N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide10 N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide11 (R) or (S)-N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide12 (S) or (R)-N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide13 (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine14 (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine15 (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine16 (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine17 1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol18 (R) or (S)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-1-yl)ethan-1-ol19 (S) or (R)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-1-yl)ethan-1-ol20 1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-1-yl)ethanol21 (R) or (S)-1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-1-yl)ethanol22 (S) or (R)-1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-1-yl)ethanol23 (S)-1-((R) or (S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine24 (S)-1-((S) or (R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine25 (R)-1-((R) or (S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine26 (R)-1-((S) or (R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine27 rac-trans or cis-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-4-ol28 rac-cis or trans-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-4-ol29 (3S,4R) or (3R,4R) or (3S,4S) or (3R,4S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-4-ol30 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-4-ol31 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-4-ol32 (3S,4S) or (3R,4S) or (3S,4R) or (3R,4R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidin-4-ol33 rac-trans or cis-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine34 rac-cis or trans-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine35 (3S,4R) or (3R,4R) or (3S,4S) or (3R,4S)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine36 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine37 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine38 (3S,4S) or (3R,4S) or (3S,4R) or (3R,4R)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine39 1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl) piperidine40 (S) or (R)-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl) piperidine41 (R) or (S)-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl) piperidine42 1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine43 (S) or (R)-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine44 (R) or (S)-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine45 rac-trans-N-(4-((1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide46 N-(4-(((3S,4S) or (3R,4R) - 1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide47 N-(4-(((3R,4R) or (3S,4S) - 1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide48 trans-N-(4-(3-((3-chlorophenethyl)amino)cyclobutoxy)phenyl)-N-methylmethanesulfonamide49 (S)-N-(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide50 (R)-N-(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide51 (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine52 rac-trans-1-(3-chlorophenethyl)-3 -methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine53 rac-trans or cis-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine54 rac-cis or trans-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine55 (2R,4S) or (2R,4R) or (2S,4R) or (2S,4S)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine56 (2R,4R) or (2S,4R) or (2S,4S) or (2R,4S)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine57 (2S,4R) or (2S,4S) or (2R,4S) or (2R,4R)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine58 (2S,4S) or (2R,4S) or (2R,4R) or (2S,4R)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidine59 (S)-N-(4-(3-((3-chlorophenethyl)(cycloprop ylmethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide60 (S)-N-(4-(3-((3-chlorophenethyl)(ethyl) amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide61 (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide62 (2S)-1-(2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol63 (S)-1-((S) or (R)-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol64 (S)-1-((R) or (S)-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy) propan-2- ol65 N-(4-((S)-3-((trans-3-(3-chlorophenyl)cyclobutyl)am ino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide66 (S)-1-((trans-3-(3-chlorophenyl)cyclobutyl)am ino)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol67 (R)-1-((trans-3-(3-chlorophenyl)cyclobutyl)am ino)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol68 N-(4-((2S)-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide69 N-(4-((S)-3-((S) or (R)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide70 N-(4-((S)-3-((R) or (S)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide71 N-(4-((2R)-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide72 N-(4-((R)-3-((S) or (R)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide73 N-(4-((R)-3-((R) or (S)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide74 N-(4-((2S)-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide75 N-(4-((S)-3-((S) or (R)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide76 N-(4-((S)-3-((R) or (S)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide77 N-(4-((2R)-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide78 N-(4-((R)-3-((S) or (R)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide79 N-(4-((R)-3-((R) or (S)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide80 N-(4-((2S)-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide81 N-(4-((S)-3-((S) or (R)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide82 N-(4-((S)-3-((R) or (S)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide83 N-(4-((2R)-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide84 N-(4-((R)-3-((R) or (S)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide85 N-(4-((R)-3-((S) or (R)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide86 (S)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide87 (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide88 N-(4-((R)-3-(((S) or (R)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide89 N-(4-((R)-3-(((R) or (S)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide90 (S)-N-(4-(3-((2,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide91 (S)-N-(4-(3-((3,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide92 N-(4-((2R)-3-((3-(3-chlorobenzyl)tetrahydrofura n-3-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide93 (S)-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol94 (R)-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol95 N-(4-((S)-3-(((S) or (R)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide96 N-(4-((S)-3-(((R) or (S)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide97 (R)-1-((1-(3-chlorophenyl)-2-methylpropan-2-yl)amino)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol98 (S)-N-(4-(2-hydroxy-3-((2-methoxyphenethyl)amino) propoxy)phenyl)-N-methylmethanesulfonamide99 (S)-N-(4-(3-((3-cyanophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide100 (S)-N-(4-(3-((2-ethylphenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide101 (S)-N-(4-(3-((2-(difluoromethoxy)phenethyl) amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide102 (2R)-1-((2-(3-chlorophenyl)-1-cyclopropylethyl)amino)-3-(4-(methylsulfonyl)phenoxy) propan-2-ol103 (R) or (S)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide104 (S) or (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide105 N-(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phen yl)-N-methylmethanesulfonamide106 (R) or (S)-N-(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phen yl)-N-methylmethanesulfonamide107 (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methanesulfonylethanesulfo nyl)phenoxy]methyl}-4-methylpyrrolidine108 3-chloro-5-{2-[(3S,4S)-3-{[4-(2-methanesulfonylethanesulfo nyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile109 rac-trans-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phe noxy]methyl}-4-methylpyrrolidine110 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine111 (3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine112 2-(4-{[(3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl) ethan-1-ol113 2-(4-{[(3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl) ethan-1-ol114 3-chloro-5-[(1S or 1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile115 3-chloro-5-[(1R or 1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl] ethyl]benzonitrile116 3-[(1R or 1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile117 3-[(1S or 1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile118 5-[(1R or 1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile119 5-[(1S or 1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile120 3-chloro-5-{1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile121 3-chloro-5-[(1S or 1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile122 3-chloro-5-[(1R or 1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile123 1-(3-chlorophenyl)-2-((3S,4S)-3-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidin-1-yl)ethan-1-ol124 (1R or 1S)-1-(3-chlorophenyl)-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethan-1-ol125 (1S or 1R)-1-(3-chlorophenyl)-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethan-1-ol126 3-[1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile127 3-[(1S or 1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile128 3-[(1R or 1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile129 5-{1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile130 5-[(1R or 1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile131 5-[(1S or 1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile132 5-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile133 (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidine134 (2S,5S)-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy) methyl]-2-methylpiperidine135 rac-cis or trans-3-{2-[4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile136 rac-trans or cis-3-{2-[4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile137 3-{2-[(2S,4R or 2R,4S or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile138 3-{2-[(2R,4S or 2S,4R or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile139 3-{2-[(2S,4S or 2S,4R or 2R,4S or 2R,4R)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile140 3-{2-[(2R,4R or 2S,4S or 2S,4R or 2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile141 5-chloro-3-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile142 3-chloro-5-[(2R or 2S)-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile143 3-chloro-5-[(2S or 2R)-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile144 5-chloro-3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile145 5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile146 3-chloro-5-[1-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile147 3-chloro-5-[(2R or 2S)-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile148 3-chloro-5-[(2S or 2R)-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile149 3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl] ethyl } benzonitrile150 rac-cis-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidine151 (3R,4S or 3S,4R)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidine152 (3S,4R or 3R,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidine153 (2R,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidine154 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidine155 (3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidine156 3-{2-[(2R,4S)-4-{ [4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile157 3-{2-[(2R,4S)-2-methyl-4-({4-[methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) pyrrolidin-1-yl]ethyl}benzonitrile158 3-{2-[(2R,4S)-2-methyl-4-({4-[(R or S)methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)p yrrolidin-1-yl]ethyl}benzonitrile159 3-{2-[(2R,4S)-2-methyl-4-({4-[(S or R)methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) pyrrolidin-1-yl]ethyl}benzonitrile160 (2R,5S)-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy) methyl]-2-methylpiperidine161 3-{2-[(2R,4S)-4-{ [4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile162 3-{2-[(2R,4S)-4-{[4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile163 (3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methyl-1-{2-[3-(pentafluoro-λ 6< -sulfanyl)phenyl]ethyl}pyrro lidine164 3-chloro-5-{2-[(2R,4S)-4-{[4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile165 3-chloro-5-{2-[(2R,4S)-4-{[4-(2-hydroxyethanesulfonyl)phe noxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile166 3-chloro-5-{2-[(3S,4S)-3-{[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile167 3-chloro-5-{2-[(3S,4S)-3-{[4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile168 3-12-[(3S,4S)-3-1[4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile169 3-{2-[(3S,4S)-3-methyl-4-({4-[methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) pyrrolidin-1-yl]ethyl}benzonitrile170 3-{2-[(3S,4S)-3-methyl-4-({4-[(R or S)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) pyrrolidin-1-yl]ethyl}benzonitrile171 3-{2-[(3S,4S)-3-methyl-4-({4-[(S or R)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) pyrrolidin-1-yl]ethyl}benzonitrile172 3-{2-[(3S,4S)-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile173 3-{2-[(3S,4S)-3-{ [4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile174 3-chloro-5-{2-[(3S,4S)-3-{[4-(2-hydroxyethanesulfonyl)phe noxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile175 rac-trans-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}-4-methylpyrrolidine176 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}-4-methylpyrrolidine177 (3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}-4-methylpyrrolidine181 (3S,4S)-1-[2-(3-chloro-5-fluorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidine182 3-chloro-5-{2-[(3S)-3-{ [4-(2-hydroxyethanesulfonyl) phenoxy]methyl}piperazin-1-yl]ethyl}benzonitrile183 3-chloro-5-{2-[(3S)-3-{ [4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl} piperazin-1-yl]ethyl}benzonitrile184 (3S)-1-[2-(3-chlorophenyl)ethyl]-3-{ [4-(3-methanesulfonylpropanesulf onyl)phenoxy]methyl}piper azine185 (3S)-3-{ [4-(azetidine-3-sulfonyl)phenoxy]methyl}-1-[2-(3-chlorophenyl)ethyl]piperazi ne186 3-chloro-5-{2-[(3S)-3-(14-[methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) piperazin-1-yl]ethyl}benzonitrile187 3-chloro-5-{2-[(3S)-3-({4-[(S or R)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) piperazin-1-yl]ethyl}benzonitrile188 3-chloro-5-{2-[(3S)-3-({4-[(R or S)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl) piperazin-1-yl]ethyl}benzonitrile189 3-chloro-5-{2-[(3S)-3-[(4-methanesulfonylphenoxy) methyl]piperazin-1-yl]ethyl}benzonitrile190 (3S)-1-[2-(3,5-dichlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]piperazine191 (3S)-1-[2-(5-chloro-2-methoxyphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)m ethyl]piperazine192 (3S)-1-{2-[5-chloro-2-(difluoromethoxy)phenyl] ethyl}-3-[(4-methanesulfonylphenoxy) methyl]piperazine193 3-{2-[(3S)-3-[(4-methanesulfonylphenoxy) methyl]piperazin-1-yl]ethyl }-5-(trifluoromethyl)benzonitrile194 3-chloro-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile195 3-fluoro-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile196 3-bromo-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile197 (3S)-1-[2-(5-chloro-2-methylphenyl)ethyl]-3-[(4-methanesulfonylphenoxy) methyl]piperazine198 3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy) methyl]-4-methylpyrrolidin-1-yl]ethyl}-5-methylbenzonitrile199 rac-cis or trans-3-chloro-5-{2-[4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile200 3-chloro-5-{2-[(2R,4S or 2S,4R or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile201 3-chloro-5-{2-[(2S,4R or 2R,4S or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile202 rac-trans or cis-3-chloro-5-{2-[4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile203 3-chloro-5-(2-((2R,4S or 2S,4R or 2R,4R or 2S,4S)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidin-1-yl)ethyl)benzonitrile204 3-chloro-5-(2-((2R,4S or 2S,4R or 2S,4S or 2R.4R)-2-methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidin-1-yl)ethyl)benzonitrile205 rac-cis-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy) methyl]-3-methylpyrrolidin-3-ol206 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy) methyl]-3-methylpyrrolidin-3-ol207 (3S,4S or 3R,4R)-1-(3-chlorophenethyl)-3 -methyl-4-((4-(methylsulfonyl)phenoxy) methyl)pyrrolidin-3-ol208 rac-trans-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy) methyl]-3-methylpyrrolidin-3-ol209 (3R,4S or 3S,4R)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol210 (3S,4R or 3R,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy) methyl]-3-methylpyrrolidin-3-ol211 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy) methyl]-2-methylpiperazine212 rac-cis or trans-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy) methyl]-2-methylpiperazine213 rac-trans or cis-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy) methyl]-2-methylpiperazine214 (1R) or (1S)-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethan-1-ol215 (1S) or (1R)-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy) methyl]-2-methylpyrrolidin-1-yl]ethan-1-ol

[0150] In some embodiments, a compound of formula (A) or (A') is selected from the group consisting of: 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane; 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-3-ol; N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide; 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine; 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; 1-(3-chlorophenyl)-2-(3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol; 1-(3-chlorophenyl)-2-(3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethanol; 1-(2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol; 1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine; 1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperidine; 1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; N-(4-(1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((3-chlorophenethyl)amino)cyclobutoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; 1-(3-chlorophenethyl)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; 1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; N-(4-(3-((3-chlorophenethyl)(cyclopropylmethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((3-chlorophenethyl)(ethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((3-chlorophenethyl)amino)-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide; 1-(2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; N-(4-(3-(3-(3-chlorophenyl)cyclobutyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; 1-(3-(3-chlorophenyl)cyclobutyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; N-(4-((2)-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((2)-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((2,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((3,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((3-(3-chlorobenzyl)tetrahydrofuran-3-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; 1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; 1-((1-(3-chlorophenyl)-2-methylpropan-2-yl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; N-(4-(2-hydroxy-3-((2-methoxyphenethyl)amino)propoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((3-cyanophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((2-ethylphenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(3-((2-(difluoromethoxy)phenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; 1-((2-(3-chlorophenyl)-1-cyclopropylethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phenyl)-N-methylmethanesulfonamide; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperidine; 1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; 2-[4-({1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl}methoxy)benzenesulfonyl]ethan-1-ol; 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; 2-[4-({1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl}methoxy)benzenesulfonyl]ethan-1-ol; 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperazine; 1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperazine; 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperazine; 1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidine; 1-[2-(3,5-dichlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]piperazine; 1-[2-(5-chloro-2-methylphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]piperazine; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}piperazine; 3-(2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 3-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperidine; 3-chloro-5-(1-hydroxy-2-f3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 1-(3-chlorophenyl)-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethan-1-ol; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 3-chloro-5-(2-{3-[(4-methanesulfonylphenoxy)methyl]piperazin-1-yl}ethyl)benzonitrile; 3-chloro-5-(2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 3-chloro-5-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-chloro-5-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 1-(3-chlorophenyl)-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethan-1-ol; 1-(3-chlorophenyl)-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethan-1-ol; 3-chloro-5-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-chloro-5-(1-hydroxy-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-chloro-5-(1-hydroxy-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-chloro-5-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-1-[2-(3-chlorophenyl)ethyl]piperazine; 3-chloro-5-[2-(4-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-chloro-5-[2-(4-{[4-(2-hydroxyethanesulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-chloro-5-[2-(3-{[4-(2-hydroxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-fluoro-5-(2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-[(4-methanesulfonylphenoxy)methyl]-4-methyl-1-{2-[3-(pentafluoro-lambda6-sulfanyl)phenyl]ethyl } pyrrolidine; 3-chloro-5-[2-(3-{[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-chloro-5-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-chloro-5-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 1-[2-(5-chloro-2-methoxyphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]piperazine; 3-chloro-5-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-chloro-5-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 1-{2-[5-chloro-2-(difluoromethoxy)phenyl]ethyl}-3-[(4-methanesulfonylphenoxy)methyl]piperazine; 1-(3-chlorophenyl)-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethan-1-ol; 1-(3-chlorophenyl)-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethan-1-ol; 3-chloro-5-[2-(3-{[4-(2-methanesulfonylethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl)ethyl]benzonitrile; 1-[2-(3-chloro-5-fluorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 3-[2-(4-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-chloro-5-(1-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}propan-2-yl)benzonitrile; 3-[2-(3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-chloro-5-[2-(3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-chloro-5-(1-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}propan-2-yl)benzonitrile; 3-chloro-5-(1-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}propan-2-yl)benzonitrile; 1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methanesulfonylethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 3-chloro-5-(1-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}propan-2-yl)benzonitrile; 5-chloro-3-(2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)-2-methylbenzonitrile; 5-chloro-3-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)-2-methylbenzonitrile; 3-(1-hydroxy-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-chloro-5-(1-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}propan-2-yl)benzonitrile; 3-chloro-5-[2-(3-{[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}piperazin-1-yl)ethyl]benzonitrile; 3-(2-{3-[(4-methanesulfonylphenoxy)methyl]piperazin-1-yl}ethyl)-5-(trifluoromethyl)benzonitrile; 3-(2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)-5-methylbenzonitrile; 3-[2-(3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-chloro-5-[2-(3-{[4-(2-hydroxyethanesulfonyl)phenoxy]methyl}piperazin-1-yl)ethyl]benzonitrile; 5-(2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzene-1,3-dicarbonitrile; 5-(2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzene-1,3-dicarbonitrile; 3-[2-(4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl)ethyl]-5-chlorobenzonitrile; 3-[2-(3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl)ethyl]-5-chlorobenzonitrile; 3-bromo-5-(2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-[2-(4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl)ethyl]benzonitrile; 3-(1-hydroxy-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-{2-[3-methyl-4-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzonitrile; 3-{2-[3-methyl-4-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[3-methyl-4-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[2-methyl-4-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 5-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzene-1,3-dicarbonitrile; 5-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzene-1,3-dicarbonitrile; 5-(1-hydroxy-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzene-1,3-dicarbonitrile; 5-(1-hydroxy-2-{4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl}ethyl)benzene-1,3-dicarbonitrile; 3-{2-[2-methyl-4-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[2-methyl-4-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 5-(1-hydroxy-2-{3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl}ethyl)benzene-1,3-dicarbonitrile; 3-chloro-5-{2-[3-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[3-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile; and 3-chloro-5-{2-[3-({4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Isotopically labeled forms of any of the foregoing are also embraced, such as deuterated or tritiated forms (wherein at least one hydrogen is replaced by at least one deuterium or tritium) of any of the specific compounds detailed herein. Mixtures of any of the foregoing are also embraced and described. Prodrugs of any of the foregoing are also embraced herein.

[0151] In some embodiments, a compound of formula (A) or (A') is selected from the group consisting of: 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane; (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane; (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane; 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-3-ol; (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-3-ol; (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-3-ol; N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; (R)-N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide; (R)-N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide; (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine; (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine; (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; 1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol; (R)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol; (S)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol; 1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethanol; (R)-1-(3-chlorophenyl)-2-((R)-3-((4-(methylsuifonyl)phenoxy)methyl)piperidin-1-yl)ethanol; (S)-1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethanol; (S)-1-((R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; (S)-1-((S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; (R)-1-((R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; (R)-1-((S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; rac-trans or cis-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol; rac-cis or trans-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol; (3S,4R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol; (3R,4R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol; (3R,4S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol; (3S,4S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol; rac-trans-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine; rac-cis-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine; (3S,4R)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; (3R,4R)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; (3R,4S)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; (3S,4S)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine; 1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperidine; (S)-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperidine; (R)-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperidine; 1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine; (S)-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine; (R)-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; rac-trans-N-(4-((1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(((3S,4S)-1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; N-(4-(((3R,4R)-1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; trans-N-(4-(3-((3-chlorophenethyl)amino)cyclobutoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; (R)-N-(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide; (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; rac-trans-1-(3-chlorophenethyl)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; rac-trans-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; rac-cis-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; (2R,4S)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; (2R,4R)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; (2S,4R)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; (2S,4S)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidine; (S)-N-(4-(3-((3-chlorophenethyl)(cyclopropylmethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((3-chlorophenethyl)(ethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide; (2S)-1-(2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; (S)-1-((S)-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; (S)-1-((R)-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; N-(4-((S)-3-((trans-3-(3-chlorophenyl)cyclobutyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-1-((trans-3-(3-chlorophenyl)cyclobutyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; (R)-1-((trans-3-(3-chlorophenyl)cyclobutyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; N-(4-((2S)-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((S)-3-((S)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((S)-3-((R)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((2R)-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-((S)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-((R)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((2S)-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((S)-3-((S)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((S)-3-((R)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((2R)-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-((S)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-((R)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((2S)-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((S)-3-((S)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((S)-3-((R)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((2R)-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-((R)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-((S)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-(((S)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((R)-3-(((R)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((2,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((3,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((2R)-3-((3-(3-chlorobenzyl)tetrahydrofuran-3-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; (R)-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; N-(4-((S)-3-(((S)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((S)-3-(((R)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (R)-1-((1-(3-chlorophenyl)-2-methylpropan-2-yl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; (S)-N-(4-(2-hydroxy-3-((2-methoxyphenethyl)amino)propoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((3-cyanophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((2-ethylphenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((2-(difluoromethoxy)phenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide; (2R)-1-((2-(3-chlorophenyl)-1-cyclopropylethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol; (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide; (S)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide; N-(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phenyl)-N-methylmethanesulfonamide; (R)-N-(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phenyl)-N-methylmethanesulfonamide; (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methanesulfonylethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 3-chloro-5-{2-[(3S,4S)-3-{[4-(2-methanesulfonylethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; rac-trans-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; (3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; 2-(4-{[(3R,4R)-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl)ethan-1-ol; 2-(4-{[(3S,4S)-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl)ethan-1-ol; 3-chloro-5-[(1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile; 3-chloro-5-[(1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile; 3-[(1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile; 3-[(1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile; 5-[(1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile; 5-[(1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile; 3-chloro-5-{1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-chloro-5-[(1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile; 3-chloro-5-[(1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile; 1-(3-chlorophenyl)-2-((3S,4S)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidin-1-yl)ethan-1-ol; (1R)-1-(3-chlorophenyl)-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethan-1-ol; (1S)-1-(3-chlorophenyl)-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethan-1-ol; 3-[1-hydroxy-2-[(3 S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile; 3-[(1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile; 3-[(1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile; 5-{1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile; 5-[(1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile; 5-[(1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile; 5-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile; (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; (2S,5S)-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperidine; rac-cis-3-{2-[4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; rac-trans-3-{2-[4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(2S,4R)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl }benzonitrile; 3-{2-[(2S,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(2R,4R)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 5-chloro-3-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile; 3-chloro-5-[(2R)-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile; 3-chloro-5-[(2S)-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile; 5-chloro-3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile; 5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile; 3-chloro-5-[1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile; 3-chloro-5-[(2R)-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile; 3-chloro-5-[(2S)-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile; 3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; rac-cis-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; (3R,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; (3S,4R)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; (2R,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidine; (3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 3-{2-[(2R,4S)-4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(2R,4S)-2-methyl-4-({4-[methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(2R,4S)-2-methyl-4-({4-[(R)methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(2R,4S)-2-methyl-4-({4-[(S)methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; (2R,5S)-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperidine; 3-{2-[(2R,4S)-4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile; 3-{2-[(2R,4S)-4-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; (3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methyl-1-{2-[3-(pentafluoro-λ 6< -sulfanyl)phenyl]ethyl}pyrrolidine; 3-chloro-5-{2-[(2R,4S)-4-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[(2R,4S)-4-{[4-(2-hydroxyethanesulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[(3S,4S)-3-{[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[(3S,4S)-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(3S,4S)-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(3S,4S)-3-methyl-4-({4-[methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(3S,4S)-3-methyl-4-({4-[(R)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(3S,4S)-3-methyl-4-({4-[(S)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(3S,4S)-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[(3S,4S)-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile; 3-chloro-5-{2-[(3S,4S)-3-{[4-(2-hydroxyethanesulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; rac-trans-1-[2-(3-chlorophenyl)ethyl]-3-{ [4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; (3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}-4-methylpyrrolidine; (3S,4S)-1-[2-(3-chloro-5-fluorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidine; 3-chloro-5-{2-[(3S)-3-{[4-(2-hydroxyethanesulfonyl)phenoxy]methyl}piperazin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[(3S)-3-{[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}piperazin-1-yl]ethyl}benzonitrile; (3S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl)phenoxy]methyl}piperazine; (3S)-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-1-[2-(3-chlorophenyl)ethyl]piperazine; 3-chloro-5-{2-[(3S)-3-({4-[methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[(3S)-3-({4-[(S)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile ; 3-chloro-5-{2-[(3S)-3-({4-[(R)-methyl(methylimino)oxo-λ 6< -sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile ; 3-chloro-5-{2-[(3S)-3-[(4-methanesulfonylphenoxy)methyl]piperazin-1-yl]ethyl}benzonitrile; (3S)-1-[2-(3,5-dichlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]piperazine; (3S)-1-[2-(5-chloro-2-methoxyphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]piperazine; (3S)-1-{2-[5-chloro-2-(difluoromethoxy)phenyl]ethyl}-3-[(4-methanesulfonylphenoxy)methyl]piperazine; 3-{2-[(3S)-3-[(4-methanesulfonylphenoxy)methyl]piperazin-1-yl]ethyl}-5-(trifluoromethyl)benzonitrile; 3-chloro-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-fluoro-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-bromo-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}benzonitrile; (3S)-1-[2-(5-chloro-2-methylphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl]piperazine; 3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl}-5-methylbenzonitrile; rac-cis-3-chloro-5-{2-[4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[(2S,4R)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; rac-trans-3-chloro-5-{2-[4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl}benzonitrile; 3-chloro-5-(2-((2R,4R)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidin-1-yl)ethyl)benzonitrile; 3-chloro-5-(2-((2S,4S)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidin-1-yl)ethyl)benzonitrile; rac-cis-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; (3R,4R)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; (3S,4S)-1-(3-chlorophenethyl)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl)pyrrolidin-3-ol; rac-trans-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; (3R,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; (3S,4R)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl]-3-methylpyrrolidin-3-ol; 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperazine; rac-cis-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperazine; rac-trans-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl]-2-methylpiperazine; (1R)-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethan-1-ol; and (1S)-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethan-1-ol, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Isotopically labeled forms of any of the foregoing are also embraced, such as deuterated or tritiated forms (wherein at least one hydrogen is replaced by at least one deuterium or tritium) of any of the specific compounds detailed herein. Mixtures of any of the foregoing are also embraced and described. Prodrugs of any of the foregoing are also embraced herein.

[0152] Compound Names included in Table 1 and in the lists in the paragraphs above were generated using ChemDraw ®< software version 18.1.0.458 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update #3.COMPOSITIONS

[0153] Provided herein are pharmaceutical compositions comprising one or more compounds of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a pharmaceutical composition comprising (i) of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

[0154] Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Examples of suitable excipients are well-known to those skilled in the art. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Academic Press, 23rd ed. (2020), which is incorporated herein by reference.

[0155] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, oral, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0156] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0157] The specific dose level of a compound as described herein will depend upon a variety of factors such as the age, body weight and sex of the individual as well as the route of administration and other factors. In some embodiments, a dosage is expressed as a number of milligrams of a compound described herein per kilogram of the individual's body weight (mg / kg). Dosages of between about 0.1 mg / kg and 100-150 mg / kg may be appropriate.

[0158] The compound may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life.METHODS OF TREATMENT

[0159] The compounds provided herein may be used in a method of modulating APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The compounds provided herein may also be used in a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. Isotopically labeled forms of any of the foregoing are also embraced, including, but not limited to, deuterated or tritiated forms (wherein at least one hydrogen is replaced by at least one deuterium or tritium) of any of the specific compounds detailed herein.

[0160] The compounds provided herein may be used in a method of inhibiting APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The compounds provided herein may also be used in a method of inhibiting APOL1 in a cell, comprising exposing the cell to a pharmaceutical composition comprising an effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0161] The compounds provided herein may be used in a method of inhibiting APOL1 in an individual, comprising administering to the individual an effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The compounds provided herein may also be used in a method of inhibiting APOL1 in an individual, comprising administering to the individual a pharmaceutical composition comprising an effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0162] The compounds provided herein may inhibit APOL1 at a concentration of less than 10 µM, less than 1 µM, less than 0.5 µM, or less than 0.1 µM. The compounds provided herein may inhibit APOL1 at a concentration of 1 to 10 µM, 0.01 to 1 µM, or 0.01 to 10 µM.

[0163] The compounds provided herein may reduce cell death caused by overexpression of APOL1. The compounds provided herein may reduce cell death caused by overexpression APOL1 at a concentration of less than 10 µM, less than 1 µM, less than 0.5 µM, or less than 0.1 µM. The compounds provided herein may reduce cell death caused by APOL1 overexpression at a concentration of 1 to 10 µM, 0.01 to 1 µM, or 0.01 to 10 µM.

[0164] The compounds provided herein may have an EC 50 of less than 1 µM, less than 0.5 µM, or less than 0.1 µM. The compounds provided herein may have an EC 50 of 1 to 10 µM, 0.01 to 1 µM, or 0.01 to 10 µM.

[0165] The compounds provided herein may have an AC 50 of less than 1 µM, less than 0.5 µM, or less than 0.1 µM. The compounds provided herein may have an AC 50 of 1 to 10 µM, 0.01 to 1 µM, or 0.01 to 10 µM. The AC 50 value may reflect the compound's ability to prevent calcium influx by inhibiting APOL1.

[0166] The compounds provided herein may inhibit a cation channel. The compounds of the present disclosure may inhibit a calcium channel. The compounds of the present disclosure may reduce calcium transport.

[0167] The compounds provided herein may be used in a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The compounds provided herein may also be used in a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0168] Provided herein is a compound of formula (A) or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing for use in treating or delaying the development of a disease, disorder, or condition in an individual in need thereof selected from a kidney disease; or a disease, disorder, or condition 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. Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients for use in treating or delaying the development of a disease, disorder, or condition in an individual in need thereof selected from a kidney disease; or a disease, disorder, or condition 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.

[0169] In some embodiments, the disease is a chronic kidney disease. In some embodiments, the disease is hypertension-attributed kidney disease. In some embodiments, the kidney disease, disorder, or condition is an APOL1-mediated kidney disease, disorder, or condition. In some embodiments, the kidney disease, disorder, or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, viral nephropathy, COVID-19 associated nephropathy, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, and diabetic kidney disease.

[0170] In some embodiments, the disorder is an APOL1-mediated disorder, such as preeclampsia and sepsis. In some embodiments, the individual is genetically predisposed to developing the APOL1-mediated disorder.

[0171] The compounds provided herein may also be used in a method of delaying development of progressive renal allograft loss in a kidney transplant recipient comprising administering to the kidney transplant recipient a therapeutically effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the kidney transplant recipient receives a kidney from a high-risk APOL1 genotype donor. In some embodiments, the kidney transplant recipient is administered a therapeutically effective amount of the compound for a period of time before receiving the kidney transplant. In some embodiments, the kidney transplant recipient is administered a therapeutically effective amount of the compound subsequent to receiving the kidney transplant.

[0172] The compounds provided herein may also be used in a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the individual has an APOL1 mutation. Also provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, wherein the individual has an APOL1 mutation.

[0173] The compounds provided herein may also be used in a method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition. In some embodiments, the APOL1-mediated disease, disorder, or condition is preeclampsia or sepsis and the individual has two APOL1 risk alleles. In some embodiments, the APOL1-mediated disease, disorder, or condition is a chronic kidney disease and the individual has any binary combination of G1 and G2 APOL1 risk alleles. In some embodiments, the chronic kidney disease is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), hypertension-attributed kidney disease, sickle cell nephropathy, viral nephropathy, COVID-19 associated nephropathy, lupus nephritis, diabetic kidney disease, or APOL1-associated nephropathy. The compounds as provided herein may also be used in a method of delaying the development of progressive renal allograft loss in an individual who has received a kidney transplantation from a high-risk APOL1 genotype donor.

[0174] In some embodiments, the individual has a gain-of-function mutation in APOL1. In some embodiments, the individual has an APOL1 risk allele. In some embodiments, the APOL1 risk allele is a missense variant. In some embodiments, the APOL1 risk allele is a G1 variant. In some embodiments, the G1 variant is G1 G< (p.S342 G) or G1 M< (p.I384 M). In some embodiments, the APOL1 risk allele is the G2 variant. In some embodiments, the G2 variant is NYK388-389K. In some embodiments, the APOL1 risk variant is a mutation in the serum resistance-associated (SRA) binding domain of the APOL1 protein.

[0175] The compounds provided herein may also be used in a method of inhibiting APOL1 in an individual comprising administering to the individual a therapeutically effective amount of a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0176] The compounds provided herein may also be used in amethod of preventing kidney failure in an individual comprising administering a therapeutically effective amount of a compound of Formula (A), or formula (A') or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing to the individual. In some embodiments, the compound prevents tissue necrosis. In some embodiments, the compound prevents apoptosis. In some embodiments, the compound reduces inflammation.

[0177] In some embodiments, the compounds provided herein reduce or eliminate one or more symptoms of a kidney disease. In some embodiments, the compounds reduce nausea, vomiting, loss of appetite, fatigue and weakness, sleep problems, urinary frequency issues, muscle twinges and cramps, swelling, itching, chest pain, shortness of breath, and / or high blood pressure.

[0178] In some embodiments, the compounds provided herein reduce the rate of kidney damage and / or progression of kidney damage. In some embodiments, the compounds provided herein reduce the rate of kidney failure. In some embodiments, the compounds provided herein reverse kidney damage. In some embodiments, the compounds reduce the need for dialysis. In some embodiments, the compounds provided herein delay the need for dialysis at least one month, at least two months, at least three months, or at least one year.

[0179] In some embodiments, the compounds reduce the rate of or delay the need for a kidney transplant. For example, in some embodiments, the compounds provided herein delay the need for a kidney transplant at least one month, at least two months, at least three months, at least six months, or at least one year. In some embodiments, the compounds provided herein eliminate the need for a kidney transplant.

[0180] In some embodiments, the individual has stage 1, stage 2, stage 3A, stage 3B, stage 4, or stage 5 chronic kidney disease. In some embodiments, kidney function is evaluated using an estimated glomerular filtration rate (eGFR) kidney function test.

[0181] In some embodiments, the administration is oral administration.KITS

[0182] The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound.

[0183] Provided herein are kits, comprising (i) a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.METHODS OF ASSAYING APOL1 ACTIVITY

[0184] Provided herein is a method of assessing APOL1 inhibition in a cell, comprising inducing APOL1 expression in a cell, contacting the cell with an APOL1 inhibitor, and measuring inhibition of calcium transport. In some embodiments, inducing APOL1 expression comprises contacting the cell with doxycycline. In some embodiments, the cell stably expresses a genetically encoded calcium indicator. In some embodiments, the genetically encoded calcium indicator comprises GCaMP6f. In some embodiments, the cell inducibly expresses APOL1 G2. In some embodiments, the cell stably expresses a genetically encoded calcium indicator and inducibly expresses APOL1 G2. In some embodiments, the APOL1 inhibitor is a compound of formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing

[0185] Provided herein is a method of assessing rescue of HEK cell death caused by overexpression of APOL1, inducing APOL1 expression in a cell, contacting the cell with an APOL1 inhibitor, exposing the cell to a luminescence reagent, and measuring luminescence. In some embodiments, inducing APOL1 expression comprises contacting the cell with doxycycline. In some embodiments, the cell overexpresses APOL1G2. In some embodiments, the APOL1 inhibitor is a compound of formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.METHODS OF PREPARING

[0186] The present disclosure further provides methods for preparing the compounds of present invention. In some aspect, provided herein are methods of preparing a compound of formula (A), or formula (A'), or any embodiment or variation thereof, such as a compound of formula (I), (II), (III), (B-2), (B-5), or (C-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0187] In some embodiments, a method for preparing a compound of formula (A) or (A'), 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 (A-I1): wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; and V 1< is selected from the group consisting of: (i) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R x< is H, or R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; R 1< and R 2< are independently H, halo, or -OH, or one of R 1< and R 2< is taken together with R x< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1< and R 2< is H, halo, or -OH; R 4< and R 5< are independently H, or R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that either: (1) R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, or (2) R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (ii) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R 6< is H or -OH; and R y< is H; and (iii) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R z< is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl; and R 11< and R 12< are independently H, -OH, halo, or C 1-6 alkyl; with: a compound of formula (A-I2): wherein: the dashed line represents a single or double bond; W 1< is oxo, halo, or sulfonate ester; V 2< is selected from the group consisting of: (i) wherein R 3< is H, -OH, halo, or C 1-6 alkoxy; (ii) wherein p is 0 or 1, provided that, when p is 1, then E is O; R 7< is H; one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8< and R 9< is H or C 1-6 alkyl; and R 10< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl; and (iii) wherein R 13< and R 14< are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to W 1< , and ## denotes the point of attachment to the phenyl ring bearing moieties X 1< -X 4< ; and X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo; to give a compound of formula (A) or (A') or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0188] In some embodiments, the compound of formula (A) or (A') is prepared by a step comprising: a) alkylation of an amine of formula (A-I1) with an alkyl halide, or sulfonate ester compound of formula (A-I2) in the presence of an inorganic or organic base; or b) reductive amination of an aldehyde or ketone of formula (A-I2) with an amine of formula (A-I1) in the presence of a reducing agent.

[0189] In some embodiments, the compound of formula (A) or (A') is prepared by a step comprising alkylation of an amine of formula (A-I1) with an alkyl halide, or sulfonate ester compound of formula (A-I2) in the presence of an inorganic or organic base. In some embodiments, the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, and sodium bicarbonate. In some embodiments, the organic base is a tertiary amine. In some embodiments, the organic base is selected from the group consisting of trimethylamine, triethylamine, and diisopropylethyamine.

[0190] In some embodiments, the sulfonate ester compound of formula (A-I2) is a mesylate or a tosylate. In some embodiments, the sulfonate ester compound of formula (A-I2) is a mesylate. In some embodiments, the sulfonate ester compound of formula (A-I2) is a tosylate.

[0191] In some embodiments, the compound of formula (A) or (A') is prepared by a step comprising reductive amination of an aldehyde or ketone of formula (A-I2) with an amine of formula (I-II). In some embodiments, the reductive amination proceeds under the action of a reducing agent. In some embodiments, the reducing agent is sodium triacetoxyborohydride, or sodium cyanoborohidride.

[0192] In some embodiments, a method for preparing a compound of formula (A) or (A'), 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 (A-I3): wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; and V 2< is halo or OH, with: a compound of formula (A-I4): wherein: W 2< is H, or sulfamate; L is selected from the group consisting of: (i) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R x< is H, or R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; R 1< and R 2< are independently H, halo, or -OH, or one of R 1< and R 2< is taken together with R x< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1< and R 2< is H, halo, or -OH; R 3< is H, -OH, halo, or C 1-6 alkoxy; and R 4< and R 5< are independently H, or R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that either: (1) R x< is taken together with one of R 1< and R 2< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g< substituents, wherein n is an integer from 0-6, and R g< is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, or (2) R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (ii) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); p is 0 or 1, provided that, when p is 1, then E is O; R 6< is H or -OH; R y< is H, or R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 7< is H, or R 7< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 8< and R 9< are independently H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8< and R 9< is H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8< and R 9< is H or C 1-6 alkyl; and R 10< is H, or R 10< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that: (1) R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R 8< and R 9< is taken together with R 10< and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and (iii) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R z< is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl; R 11< and R 12< are independently H, -OH, halo, or C 1-6 alkyl; and R 13< and R 14< are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X 1< -X 4< ; and X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo; to give a compound of formula (A) or (A') or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0193] In some embodiments, the compound of formula (A) or (A') is prepared by a step comprising alkylation of an alcohol or amine of formula (A-I4) with an alkyl halide compound of formula (A-I3) in the presence of an inorganic or organic base. In some embodiments, the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, and sodium bicarbonate. In some embodiments, the organic base is a tertiary amine. In some embodiments, the organic base is selected from the group consisting of trimethylamine, triethylamine, and diisopropylethyamine.

[0194] In some embodiments, the compound of formula (A) or (A') is prepared by a step comprising alkylation of an alcohol of formula (A-I3) with a sulfamate compound of formula (A-I4) in the presence of an inorganic or organic base. In some embodiments, the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, and sodium bicarbonate. In some embodiments, the organic base is a tertiary amine. In some embodiments, the organic base is selected from the group consisting of trimethylamine, triethylamine and diisopropylethyamine.

[0195] In some embodiments, a method for preparing a compound of formula (A) or (A'), 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 (A-I5): wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a< , R b< , and R c< are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a< , R b< , and R c< are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a< , R b< , and R c< is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a< , R b< , or R c< is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; and V 3< is selected from the group consisting of: (iv) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R 1< is H, halo, or -OH, R 4< and R 5< are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (v) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R 6< is H or -OH; and (vi) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R 11< is H, -OH, halo, or C 1-6 alkyl; with: a compound of formula (A-I6): wherein: V 4< is selected from the group consisting of: (iv) wherein R x< is H, and R 3< is H, -OH, halo, or C 1-6 alkoxy; (v) wherein p is 0 or 1, provided that, when p is 1, then E is O; R y< is H, or R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 7< is H, or R 7< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 8< and R 9< are independently H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R y< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8< and R 9< is H or C 1-6 alkyl, or one of R 8< and R 9< is taken together with R 10< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8< and R 9< is H or C 1-6 alkyl; and R 10< is H, or R 10< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that: (1) R y< is taken together with R 7< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) R y< is taken together with one of R 8< and R 9< , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R 8< and R 9< is taken together with R 10< and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and (vi) wherein R 13< and R 14< are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13< and R 14< are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl; and X 1< , X 2< , X 3< , and X 4< are, independently of each other, H, halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1< , X 2< , X 3< , and X 4< is halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo; to give a compound of formula (A) or (A') or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0196] In some embodiments, the compound of formula (A) or (A') is prepared by a step comprising alkylation of an epoxide compound of formula (A-I5) with an amine compound of formula (A-I6) in the presence of an organic base. In some embodiments, the organic base is a tertiary amine. In some embodiments, the organic base is selected from the group consisting of trimethylamine, triethylamine and diisopropylethyamine.EXAMPLES

[0197] The following synthetic reaction schemes, which are detailed in the Schemes, General Procedures, and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art.

[0198] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0199] Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and / or by methods available to one of ordinary skill in the art.Synthetic Examples

[0200] As depicted in the Schemes, General Procedures, and Examples below, in certain exemplary embodiments, compounds of formula (A), or formula (A'), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein.

[0201] Compounds of formulae S7-S9 may be prepared by the general synthetic method shown in Scheme 1. It is to be understood that, where applicable, the moieties and variables depicted in Scheme 1 are as defined elsewhere herein for a compound of formula (A), or formula (A'), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In addition, with reference to Scheme 1, m is an integer from 0-5 and q is an integer from 0-5, provided that 1 ≤ (m + q) ≤ 6.

[0202] C-O bond formation may be accomplished through either a Mitsunobu reaction with phenols of formula S2 or an S N Ar with aryl fluorides of formula S3 to provide compounds of formula S4. Deprotection of the N-tert-butyloxycarbonyl (Boc) group may proceed using a protic acid such as hydrochloric acid to give compounds of formula S5. Compounds of formula S7 can be prepared through reductive amination using an aldehyde of formula S6 and a hydride source such as NaBH 3 CN. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of formulas S8 and S9.

[0203] Compounds of formulas S7-S9 may be prepared by the alternative general synthetic method shown in Scheme 2. It is to be understood that, where applicable, the moieties and variables depicted in Scheme 2 are as defined elsewhere herein for a compound of formula (A), or formula (A'), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In addition, with reference to Scheme 2: m is an integer from 0-5 and q is an integer from 0-5, provided that 1 ≤ (m + q) ≤ 6; and Z 1< is halo (for example: chloro or bromo) or a sulfonate ester (for example: mesylate).

[0204] C-O coupling of an aryl halide of formula S10 with an alcohol of formula S1 may be performed using conditions such as copper(I) iodide, Cs 2 CO 3 , and 3,4,7,8-tetramethyl-1,10-phenanthroline in toluene at an elevated temperature to afford compounds of formula S4. Deprotection of the N-tert-butyloxycarbonyl (Boc) group may proceed using a protic acid such as trifluoroacetic acid to give compounds of formula S5. Compounds of formula S7 can be prepared using a base such as K 2 CO 3 , an alkyl halide or alkyl sulfonate ester such as alkyl bromide of formula S11, and an organic solvent such as MeCN at elevated temperature. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of formulas S8 and S9.

[0205] Compounds of formulas S7-S9 may be prepared by the alternative general synthetic method shown in Scheme 3. It is to be understood that, where applicable, the moieties and variables depicted in Scheme 3 are as defined elsewhere herein for a compound of formula (A), or formula (A'), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In addition, with reference to Scheme 3: m is an integer from 0-5 and q is an integer from 0-5, provided that 1 ≤ (m + q) ≤ 6; and Z 2< is halo (for example: chloro or bromo) or a sulfonate ester (for example: mesylate).

[0206] C-O bond formation may be accomplished through an S N 2 reaction with alkyl halide or alkyl sulfonate ester such as alkyl bromide of formula S12 with phenols of formula S2 in the presence of bases such as K 2 CO 3 to give compounds of formula S4. Deprotection of the N-tert-butyloxycarbonyl (Boc) group may proceed using a protic acid such as HCl to give compounds of formula S5. Compounds of formula S7 can be prepared through reductive amination using an aldehyde of formula S6 and a hydride source such as NaBH 3 CN. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of formula S8 and S9.

[0207] Compounds of formula S17 may be prepared by the alternative general synthetic method shown in Scheme 4. It is to be understood that, where applicable, the moieties and variables depicted in Scheme 4 are as defined elsewhere herein for a compound of formula (A), or formula (A'), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0208] Compounds of formula S17 with (S)-stereochemistry may be accessed by treating phenols of formula S2 with (R)-2-(chloromethyl)oxirane (S13) in the presence of a phase transfer catalyst such as TBAB and a base such as NaOH. Alternately, treatment of phenol S2 with (R)-oxiran-2-ylmethanol S14 and Mitsunobu conditions such as PPh 3 and DIAD may also provide (S)-S15. Epoxide opening to provide compounds of formula S17 proceeds in the presence of amines of formula S16, triethylamine in cases where the salt form of amine S16 is used, as a solution in ethanol at elevated temperatures. In cases where epimeric -OH stereochemistry of compounds of formula S17 is desired, the above synthetic scheme may be modified to utilize (S)-2-(chloromethyl)oxirane or (S)-oxiran-2-ylmethanol.

[0209] Compounds of formula S24 may be prepared according to Scheme 5. Reductive amination of a mono-protected piperazine such as S18 with an aldehyde such as S6 gives compound S19. Removal of the the N-tert-butyloxycarbonyl (Boc) group upon treatment with a protic acid such as HCl in a solvent such as MeOH gives S20. Treatment with thionyl chloride, triethylamine, and imidazole gives rise to S21. Oxidation to the oxathiazolidine-2,2-dioxide occurs on treatment with ruthenium (III) chloride and sodium periodate in a mixed solvent system of acetonitrile and water to give S22. Heating S22 with a phenol such as S23 and potassium carbonate in DMF, followed by treatment with aqueous HCl, gives compounds of formula S24. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of compounds derived from formula S24.

[0210] An alternative synthetic approach to compounds of formula S24 is depicted in Scheme 6. Reaction of piperazine S18 with benzyl chloroformate in the presence of a base such as sodium bicarbonate generates the bis-carbamate S25. Mitsunobu coupling of phenol S23 with triphenylphosphine and DIAD in THF generates S26. Selective cleavage of the benzyl carbamate may be achieved by treatment with thionyl chloride, triethylamine, and imidazole in DCM to give S27, which may then undergo reductive amination using sodium triacetoxyborohydride provides compounds of formula S28. Cleavage of the the N-tert-butyloxycarbonyl (Boc) group provides S24. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of compounds derived from formula S24.

[0211] Scheme 7 outlines an approach to compounds of formula S32. Addition of an alkylzinc reagent generated in situ from benzyl bromide S29 to an iminium ion formed by reaction of piperazine S27 and aldehyde S30 gives S31. Removal of the N-tert-butyloxycarbonyl (Boc) group using a protic acid such as HCl in a solvent such as MeOH gives S32. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of compounds derived from formula S32.

[0212] A synthetic approach to compounds of formula S28 is depicted in Scheme 8 . Selective removal of the benzyl carbamate of S26 via hydrogenation gives piperazine S27. Reductive amination under the action of sodium triacetoxyborohydride generates S34. Further manipulation may be accomplished by Suzuki coupling with a boronic acid (X 1< B(OH 2 )), Pd(dppf)Cl 2 catalyst, and potassium carbonate to give S24. Removal of the N-tert-butyloxycarbonyl (Boc) group upon reaction with HCl in EtOAc gives compounds of formula S28. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of compounds derived from formula S28.

[0213] Scheme 9 depicts an alternate application of the three-component coupling described in Scheme 7. Coupling of pyrrolidine S35, benzyl bromide S29, and formaldehyde provides compounds of formula S36. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of formula S37.

[0214] Scheme 10 depicts an alternative approach to pyrrolidine analogs of formula S48. NaBH 4 reduction of β-keto ester S40 gives diol S41, which can undergo S N Ar reaction with fluorobenzene S42 upon heating in DMF with potassium carbonate as base. Oxidation to ketone S44 may be achieved with the Dess-Martin periodinane. Reaction with an alkyl metal reagent such as methylmagnesium bromide gives tertiary alcohol S45, as a mixture of isomers. Removal of the N-tert-butyloxycarbonyl (Boc) group with a protic acid such as TFA, followed by reductive amination with aldehyde S6, gives pyrrolidine S47. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of formula S48.

[0215] Scheme 11 depicts a route to analogs bearing substituted piperazine cores. Reductive amination of piperazine S49 and aldehyde S6 with 2-methyl pyridine borane complex gives S50. Reduction of the carboxylic acid S50 with borane-dimethylsulfide gives alcohol S51, which may undergo S N Ar reaction with fluorobenzene S42 to give S52. Removal of the N-tert-butyloxycarbonyl (Boc) group with a protic acid such as HCl in a solvent such as MeOH gives piperazine S53. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of formula S54.

[0216] Scheme 11 depicts an approach to compounds of formula S57. Amide bond formation between an amine such as pyrrolidine S55 and carboxylic acid S6 using EDC and HOBt with a tertiary amine base such as DIEA to provide S56. Amide reduction can be achieved upon treatment with lithium aluminum hydride to give compounds of formula S57. Chiral preparative SFC or HPLC separation may be utilized to provide two or more single stereoisomers of compounds derived from formula S57. General Procedure for Intermediate A

[0217] Step 1: N-(4-methoxyphenyl)-N-methylmethanesulfonamide

[0218]

[0219] To a solution of 4-methoxy-N-methyl-aniline (G1 , 7.00 g, 51.0 mmol) in DCM (60 mL) was added TEA (14.2 mL, 102 mmol). After cooling the reaction to 0 °C, MsCl (5.13 mL, 66.3 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and quenched by the addition of water (40 mL). The biphasic mixture was extracted with DCM (60 mL x 2). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give N-(4-methoxyphenyl)-N-methylmethanesulfonamide (G2), which was used in the next step without further purification. MS = 216.1 [M+H] +< .Step 2: N-(4-hydroxyphenyl)-N-methylmethanesulfonamide

[0220]

[0221] To a -78 °C solution of N-(4-methoxyphenyl)-N-methylmethanesulfonamide (G2, 11.4 g, 53.0 mmol) in DCM (100 mL) was added BBr 3 (10.2 mL, 106 mmol) dropwise. The mixture was warmed to 0 °C and stirred for 2 h. The reaction mixture was quenched by the dropwise addition of water (70 mL), and the mixture was stirred at room temperature for 20 min. Then the mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na 2 SO 4 , filtered and concentrated under in vacuo to give N-(4-hydroxyphenyl)-N-methyl-methanesulfonamide (G3). MS = 202.2 [M+H] +< .Step 3: (S)-N-methyl-N-(4-(oxiran-2-ylmethoxy)phenyl)methanesulfonamide (Intermediate A)

[0222]

[0223] To a solution of N-(4-hydroxyphenyl)-N-methyl-methanesulfonamide (G3, 4.00 g, 19.9 mmol) and (R)-2-(chloromethyl)oxirane (G4, 3.12 mL, 39.8 mmol) in water (10 mL) and THF (20 mL) was added TBAB (897 mg, 2.78 mmol). Next, a solution of NaOH (1.19 g, 29.8 mmol) in water (10 mL) was added dropwise. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted by the dropwise addition of water (20 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 40 g cartridge, 0-55% EtOAc in petroleum ether). The resulting residue was further purified by re-crystallization (50 mL of 1:10 EtOAc in petroleum ether) to give (S)-N-methyl-N-(4-(oxiran-2-ylmethoxy)phenyl)methanesulfonamide (Intermediate A). MS = 280.0 [M+Na] +< .

[0224] The following intermediates in Table 2 were prepared according to procedures similar to those described for Intermediate A using the appropriate starting materials. Table 2 IntermediateStructureIUPAC NameExact Mass [M+H] +< B (R)-N-methyl-N-(4-(oxiran-2-ylmethoxy)phenyl)methane sulfonamideCalc'd 280.1Found 280.0 [M+Na] +< C (S)-2-((4-(methylsulfonyl)phenoxy) methyl)oxiraneCalc'd 229.1Found 229.0D (R)-2-((4-(methylsulfonyl)phenoxy) methyl)oxiraneCalc'd 229.1Found 229.2E N-methyl-N-(4-((2-methyloxiran-2-yl)methoxy)phenyl)methan esulfonamideCalc'd 193.1Found 193.1[M-CH 3 O 2 S+H] +< F N-methyl-N-(4-((oxiran-2-ylmethyl)amino)phenyl)me thanesulfonamideCalc'd 279.1 Found 279.0 [M+Na] +< General Procedure for Intermediate G

[0225] Step 1: (tert-butyl (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate

[0226]

[0227] To a solution of tert-butyl (R)-3-(hydroxymethyl)piperidine-1-carboxylate (G6, 1.00 g, 4.64 mmol) and 4-methylsulfonylphenol (G5, 800 mg, 4.64 mmol) in THF (20 mL) was added PPh 3 (2.44 g, 9.29 mmol). The mixture was cooled to 0 °C and DIAD (1.88 g, 9.29 mmol, 1.81 mL, 2.00 eq) was added dropwise. After stirring at room temperature for 12 h, the reaction mixture was concentrated in vacuo. The residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 1-25% EtOAc in petroleum ether) to give (tert-butyl (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (G7). MS = 387.2 [M+NH 4 ] +< .Step 2: (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine

[0228]

[0229] To a solution of (tert-butyl (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (7, 780 mg, 2.11 mmol, 1.00 eq) in EtOAc (5 mL) was added HCl / EtOAc (4 M, 10 mL). The mixture was stirred at room temperature for 2 h. The suspension was triturated with MTBE (100 mL) and the resulting solid was isolated through filtration to give (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Intermediate G ) which was used in the next step without further purification. MS = 270.1 [M+H] +< .

[0230] The following intermediate in Table 3 was prepared according to procedures similar to those described for Intermediate G using the appropriate starting materials. Table 3 IntermediateStructureIUPAC NameExact Mass [M+H] +< H (S)-3-((4-(methylsulfonyl)phenoxy) methyl)piperidineCalc'd 270.1Found 270.1 General Procedure for Intermediate I

[0231] Step 1: 3-bromo-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0232]

[0233] To a solution of 3-bromo-2-methyl-benzonitrile (G8, 5.00 g, 25.5 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32.6 g, 255 mmol) in THF (80 mL) under N 2 was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (685 mg, 2.55 mmol) and [Ir(cod)(OMe)] 2 (845 mg, 1.28 mmol). Then the mixture was stirred at 80 °C for 8 h under N 2 . The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO 80 g cartridge, 0-20% EtOAc:Hexane) to give 3-bromo-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (G9). 1< H NMR (400 MHz, CDCl 3 ): δ 8.15 (s, 1H), 7.98 (s, 1H), 2.65 (s, 3H), 1.35 (s, 12H).Step 2: 3-bromo-5-chloro-2-methylbenzonitrile

[0234]

[0235] To solution of 3-bromo-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (G9, 3.10 g, 9.63 mmol) in MeOH (30 mL) and H 2 O (10 mL) was added CuCl 2 (3.88 g, 28.9 mmol) at room temperature, then the mixture was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-5% EtOAc:Hexane) to give 3-bromo-5-chloro-2-methyl-benzonitrile (G10). 1< H NMR (400 MHz, CDCl 3 ): δ 7.78 (s, 1H), 7.57 (s, 1H), 2.61 (s, 3H).Step 3: (E)-5-chloro-3-(2-ethoxyvinyl)-2-methylbenzonitrile

[0236]

[0237] To a solution of 3-bromo-5-chloro-2-methyl-benzonitrile (G10, 300 mg, 1.30 mmol) and 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (296 mg, 1.50 mmol) in 1,4-dioxane (5 mL) under N 2 were added K 2 CO 3 (360 mg, 2.60 mmol) and Pd(dppf)Cl 2 (95.2 mg, 130 µmol). Then the mixture was stirred at 80 °C for 16 h. The reaction mixture was allowed to cool to room temperature, diluted with H 2 O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 4 g cartridge, 0-5% EtOAc:Hexane) to give 5-chloro-3-[(E)-2-ethoxyvinyl]-2-methyl-benzonitrile (G11). MS = 222.1 [M+H] +< .Step 4: 5-chloro-2-methyl-3-(2-oxoethyl)benzonitrile (Intermediate I)

[0238]

[0239] To a solution of 5-chloro-3-[(E)-2-ethoxyvinyl]-2-methyl-benzonitrile (G11, 1.50 g, 6.77 mmol) in THF (12 mL) was added aqueous HCl (4 M, 12 mL), and then the mixture was stirred at 50 °C for 5 h. The reaction mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 12 g cartridge, 0-50% EtOAc:Hexane) to give 5-chloro-2-methyl-3-(2-oxoethyl)benzonitrile (Intermediate I). MS = 194.0 [M+H] +< .General Procedure for Intermediate J

[0240] Step 1: 4-((2-(methylsulfonyl)ethyl)thio)phenol

[0241]

[0242] To a solution of 4-sulfanylphenol (G12, 4.75 g, 37.7 mmol) and 1-methylsulfonylethylene (4 g, 37.7 mmol) in DMF (40 mL) was added K 2 CO 3 (7.81 g, 56.5 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with H 2 O (100 mL) and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 40 g cartridge, 0-40% EtOAc:Hexane) to give 4-((2-(methylsulfonyl) ethyl) thio) phenol (G13). MS = 231.1 [M-H] -< .Step 2: 4-((2-(methylsulfonyl)ethyl)sulfonyl)phenol (Intermediate J)

[0243]

[0244] To a solution of 4-(2-methylsulfonylethylsulfanyl) phenol (G13, 3.00 g, 12.9 mmol) in THF (40 mL) at room temperature was added a mixture of NaIO 4 (5.50 g, 25.8 mmol) in H 2 O (10 mL). The mixture was then stirred at 40 °C for 16 h. The reaction mixture was diluted with saturated aqueous Na 2 SO 3 (20 mL), extracted with EtOAc (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 40 g cartridge, 0-100% EtOAc:Hexane) to give 4-(2-methylsulfonylethylsulfonyl) phenol (Intermediate J). MS = 263.1 [M-H] -< .General Procedure for Intermediate K

[0245] Step 1: 3-(oxiran-2-yl)benzonitrile (Intermediate K)

[0246]

[0247] To a suspension of NaH (73 mg, 1.83 mmol, 60% by weight in mineral oil) in THF (5 mL) was added a solution of trimethylsulfonium iodide (374 mg, 1.83 mmol) in DMSO (3 mL) under N 2 . After 10 min, a solution of 3-formylbenzonitrile (G14, 200 mg, 1.53 mmol) in THF (2 mL) was slowly added. The reaction mixture was degassed and purged with N 2 for 3 times, and then the mixture was stirred at room temperature for 12 h under N 2 . The reaction mixture was quenched by addition of H 2 O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 4 g cartridge, 0-50% EtOAc:Hexane) to give 3-(oxiran-2-yl)benzonitrile (Intermediate K). MS = 146.1 [M+H] +< .General Procedure for Intermediate M

[0248] Step 1: 4-((2-methoxyethyl)thio)phenol

[0249]

[0250] A mixture of 4-sulfanylphenol (G12, 1 g, 7.93 mmol,), 1-bromo-2-methoxyethane (1.10 g, 7.93 mmol) and Cs 2 CO 3 (2.58 g, 7.93 mmol) in DMF (12 mL) was stirred at 60°C for 3 h. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage 20 g cartridge, 0-20% EtOAc:Hexane) to give 4-(2-methoxyethylsulfanyl)phenol (G18). MS = 183.1 [M-H] -< .Step 2: 4-((2-methoxyethyl)sulfonyl)phenol (Intermediate M)

[0251]

[0252] A mixture of 4-(2-methoxyethylsulfanyl)phenol (G18, 700 mg, 3.80 mmol) and NaIO 4 (2.44 g, 11.4 mmol) in THF (6 mL) and H 2 O (6 mL) was stirred at 70 °C for 16 h. The mixture was filtered, quenched with saturated aqueous Na 2 S 2 O 3 (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage 20 g cartridge, 0-70% EtOAc:Hexane) to give 4-(2-methoxyethylsulfonyl)phenol (Intermediate M). MS = 217.1 [M+H] +< .

[0253] The following intermediate in Table 4 was prepared according to procedures similar to those described for Intermediate M using the appropriate starting materials. Table 4 IntermediateStructureIUPAC NameExact Mass [M-H] -< N 4-(2-hydroxy ethylsulfonyl)phenolCalc'd 201.1Found 201.1 General Procedure for Intermediate O and Intermediate P

[0254] Step 1: tert-butyl 3-((4-hydroxyphenyl)thio)azetidine-1-carboxylate

[0255]

[0256] To a solution of tert-butyl 3-bromoazetidine-1-carboxylate (1.87 g, 7.93 mmol) in DMF (30 mL) at room temperature were added Cs 2 CO 3 (5.16 g, 15.85 mmol) and 4-sulfanylphenol (G12, 1.00 g, 7.93 mmol), and the resulting mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 12 g cartridge, 0-100% EtOAc:hexane) to give tert-butyl 3-(4-hydroxyphenyl)sulfanylazetidine-1-carboxylate (G19). MS = 282.1 [M+H] +< .Step 2: tert-butyl 3-((4-hydroxyphenyl)sulfonyl)azetidine-1-carboxylate (Intermediate O)

[0257]

[0258] To a solution of tert-butyl 3-(4-hydroxyphenyl)sulfanylazetidine-1-carboxylate (G19, 50 mg, 178 µmol) in DCM (2 mL) at 0 °C was added m-CPBA (46 mg, 267 µmol, 77% purity) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by addition saturated aqueous Na 2 SO 3 (5 mL), and then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by by flash silica gel chromatography (Biotage 4 g cartridge, 0-50% EtOAc:Hexane) to give tert-butyl 3-(4-hydroxyphenyl)sulfonylazetidine-1-carboxylate (Intermediate O). MS = 258.0 [M-C 4 H 8 +H] +< .Step 3: 4-(azetidin-3-ylsulfonyl)phenol

[0259]

[0260] To a solution of tert-butyl 3-(4-hydroxyphenyl)sulfonylazetidine-1-carboxylate (Intermediate O , 0.5 g, 1.91 mmol) in MeOH (3 mL) was added HCl / MeOH (4 M, 3 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure to give 4-(azetidin-3-ylsulfonyl)phenol HCl salt (G20), which was taken to the next step without further purification. MS = 214.1 [M+H] +< .Step 4: 4-((1-methylazetidin-3-yl)sulfonyl)phenol (Intermediate P)

[0261]

[0262] To a solution of 4-(186zetidine-3-ylsulfonyl)phenol (G20, 400 mg, 1.60 mmol, HCl salt) in MeOH (5 mL) and AcOH (0.05 mL) were added HCHO (120 mg, 4.00 mmol) and borane-2-methylpyridine complex (205 mg, 1.90 mmol). The mixture was stirred at 40 °C for 16 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO 3 (10 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 12 g cartridge, 0-100% EtOAc:Hexane) to give 4-(1-methylazetidin-3-yl)sulfonylphenol (Intermediate P). MS = 228.0 [M+H] +< .General Procedure for Intermediate Q

[0263] Step 1: methyl 5-chloro-2-methoxybenzoate

[0264]

[0265] To a solution of methyl 5-chloro-2-hydroxy-benzoate (G21, 2.00 g, 10.7 mmol) in DMF (20 mL) were added K 2 CO 3 (2.96 g, 21.4 mmol) and CH 3 I (7.61 g, 53.6 mmol). The mixture was stirred at 40 °C for 16 h. The reaction mixture was then cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-10% EtOAc:Hexane) to give methyl 5-chloro-2-methoxy-benzoate (G22). MS = 201.0 [M+H] +< .Step 2: (5-chloro-2-methoxyphenyl)methanol

[0266]

[0267] To a solution of methyl 5-chloro-2-methoxy-benzoate (G22, 1.50 g, 7.48 mmol) in THF (15 mL) was added LiBH 4 (2 M in THF, 7.5 mL, 15.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 , filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-50% EtOAc:Hexane) to give (5-chloro-2-methoxy-phenyl)methanol (G23). 1< H NMR (400 MHz, CDCl 3 ): δ 7.30 (d, J = 2.8 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.66 (s, 2H), 3.86 (s, 3H).Step 3: 2-(bromomethyl)-4-chloro-1-methoxybenzene (Intermediate Q)

[0268]

[0269] To a solution of (5-chloro-2-methoxy-phenyl)methanol (G23, 1.10 g, 6.37 mmol) in DCM (50 mL) at 0 °C was added PBr 3 (1.73 g, 6.37 mmol). The reaction mixture was then stirred at room temperature for 16 h. The mixture was concentrated, diluted with water (50 mL) and neutralized by addition of saturated aqueous NaHCO 3 to pH=7-8, then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated to give 2-(bromomethyl)-4-chloro-1-methoxy-benzene (Intermediate Q). 1< H NMR (400 MHz, CDCl 3 ): δ 7.27 (d, J = 2.8 Hz, 1H), 7.21 (dd, J= 5.6 Hz, 2.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.45 (s, 2H), 3.85 (s, 3H).General Procedure for Intermediate R

[0270] Step 1: methyl 5-chloro-2-(difluoromethoxy)benzoate

[0271]

[0272] To a mixture of methyl 5-chloro-2-hydroxy-benzoate (G24, 1.50 g, 8.04 mmol,) in MeCN (75 mL) and H 2 O (37.5 mL) were added KOH (2.71 g, 48.2 mmol) and [bromo(difluoro)methyl]-trimethylsilane (3.27 g, 16.1 mmol) at 0 °C. The mixture was then stirred at room temperature for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (25 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced presure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-20% EtOAc:Hexane) to give methyl 5-chloro-2-(difluoromethoxy)benzoate (G25). 1< H NMR (400 MHz, DMSO-d 6 ): δ 7.86 (d, J = 2.8 Hz, 1H), 7.75 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.20 (t, J= 73.6 Hz, 1H), 7.21 - 7.03 (m, 1H), 3.85 (s, 3H).Step 2: (5-chloro-2-(difluoromethoxy)phenyl)methanol

[0273]

[0274] To a mixture of methyl 5-chloro-2-(difluoromethoxy)benzoate (G25, 200 mg, 845 µmol) in THF (5 mL) at 0 °C was added LiBH 4 (4 M in THF, 634 µL, 2.54 mmol) dropwise under N 2 , the mixture was then stirred at room temperature for 16 h under N 2 . The reaction mixture was poured into saturated aqueous NH 4 Cl (5 mL), then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give [5-chloro-2-(difluoromethoxy)phenyl]methanol (G26), which was used without further purification. MS = 190.9 [M-H 2 O+H] +< .Step 3: 2-(bromomethyl)-4-chloro-1-(difluoromethoxy) benzene (Intermediate R)

[0275]

[0276] To a solution of [5-chloro-2-(difluoromethoxy)phenyl]methanol (G26, 170 mg, 815 µmol) in DCM (3 mL) was added PBr 3 (221 mg, 815 µmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was then poured into water (15 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 4g cartridge, 0-10% EtOAc:Hexane) to give 2-(bromomethyl)-4-chloro-1-(difluoromethoxy)benzene (Intermediate R). 1< H NMR (400 MHz, DMSO-d 6 ): δ 7.69 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.0 Hz, 2.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.31 (t, J = 73.2 Hz, 1H), 4.63 (s, 2H).General Procedure for Intermediate S

[0277] Step 1: 2-(3, 5-dichlorophenyl) acetaldehyde (Intermediate S)

[0278]

[0279] To a mixture of 2-(3,5-dichlorophenyl)ethanol (G27, 1.00 g, 5.23 mmol) in DCM (10 mL) was added DMP (2.66 g, 6.28 mmol). The mixture was then stirred at room temperature for 3 h under N 2 . The reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 12 g cartridge, 0-20% EtOAc:Hexane) to give 2-(3, 5-dichlorophenyl) acetaldehyde (Intermediate S). 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.68 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.46 (s, 1H), 3.86 (s, 2H).

[0280] The following intermediate in Table 5 was prepared according to procedures similar to those described for Intermediate S using the appropriate starting materials. Table 5 IntermediateStructureIUPAC Name 1< H NMR (400 MHz, DMSO-d 6 ):T 2-(2-bromo-5-chlorophenyl)acetaldehydeδ 9.70 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2.4 Hz, 1H), 3.98 (s, 2H).U 3-(2-oxoethyl)benzonitrileδ 9.80 (t, J = 2.0 Hz, 1H), 7.63 - 7.52 (m, 4H), 3.92 - 3.88 (m, 2H). General Procedure for Intermediate V

[0281] Step 1: (E)-3-chloro-5-(2-ethoxyvinyl) benzonitrile

[0282]

[0283] To a solution of 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (503 mg, 2.54 mmol) and 3-bromo-5-chloro-benzonitrile (G28, 500 mg, 2.31 mmol) in dioxane (10 mL) were added K 2 CO 3 (958 mg, 6.93 mmol) and Pd(dppf)Cl 2 (169 mg, 231 µmol) under N 2 . The reaction mixture was then stirred at 100 °C for 16 h under N 2 . The reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (E)-3-chloro-5-(2-ethoxyvinyl)benzonitrile (G29), which was taken to the next step without further purification. 1< H NMR (400 MHz, CDCl 3 ): δ 7.40 (s, 1H), 7.36 (s, 1H), 7.35 (s, 1H), 7.05 (d, J = 13.2 Hz, 1H), 5.73 (d, J = 12.8 Hz, 1H), 3.94 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).Step 2: 3-chloro-5-(2-oxoethyl) benzonitrile (Intermediate V)

[0284]

[0285] To a solution of (E)-3-chloro-5-(2-ethoxyvinyl)benzonitrile (G29, 750 mg, 3.61 mmol) in THF (4 mL) was added HCl (3 M in H 2 O, 4 mL). The reaction mixture was then stirred at 50 °C for 16 h. The reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 4 g cartridge, 0-30% EtOAc:Hexane) to give 3-chloro-5-(2-oxoethyl)benzonitrile (Intermediate V). 1< H NMR (400 MHz, CDCl 3 ): δ 9.81 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 3.80 (s, 2H).

[0286] The following intermediate in Table 6 was prepared according to procedures similar to those described for Intermediate V using the appropriate starting materials. Table 6 IntermediateStructureIUPAC Name 1< H NMR (400 MHz, CDCl 3 )W 5-(2-oxoethyl) isophthalonitrileδ 9.86 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 3.49 (s, 2H). General Procedure for Intermediate X

[0287] Step 1: 3-chloro-5-vinylbenzonitrile

[0288]

[0289] To a solution of 3-bromo-5-chloro-benzonitrile (G28, 2.50 g, 11.5 mmol), potassium vinyltrifluoroborate (3.09 g, 23.1 mmol) in dioxane (25 mL) and H 2 O (2.5 mL) were added K 2 CO 3 (3.19 g, 23.1 mmol) and Pd(dppf)Cl 2 (845 mg, 1.15 mmol). The mixture was purged with N 2 three times and then stirred at 80 °C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (BIOTAGE 20 g cartridge, 0-10% EtOAc:Hexane) to give 3-chloro-5-vinyl-benzonitrile (G30). 1< H NMR (400 MHz, CDCl 3 ): δ 7.60 (s, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 6.69 - 6.62 (m, 1H), 5.85 (d, J = 17.6 Hz, 1H), 5.47 (d, J = 10.8 Hz, 1H).Step 2: 3-chloro-5-(oxiran-2-yl) benzonitrile (Intermediate X)

[0290]

[0291] To a solution of 3-chloro-5-vinyl-benzonitrile (G30, 500 mg, 3.06 mmol) in DCM (5 mL) was added mCPBA (931 mg, 4.58 mmol, 85% purity) at 0 °C, the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured into saturated aqueous Na 2 SO 3 (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (120 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 12 g cartridge, 0-100% EtOAc:Hexane) to give 3-chloro-5-(oxiran-2-yl)benzonitrile (Intermediate X ).The following intermediate in Table 7 was prepared according to procedures similar to those described for Intermediate X using the appropriate starting materials. Table 7 IntermediateStructureIUPAC Name 1< H NMR (400 MHz, CDCl 3 ):Y 5-(oxiran-2-yl) benzene-1, 3-dicarbonitrileδ 7.69 (s, 1H), 7.62 - 7.61 (m, 2H), 3.77 - 3.75 (m, 1H), 3.07 - 3.05 (m, 1H), 2.58 - 2.56 (m, 1H). General Procedure for Intermediate Z

[0292] Step 1: 3-(bromomethyl)-5-(trifluoromethyl) benzonitrile (Intermediate Z)

[0293]

[0294] A mixture of 3-methyl-5-(trifluoromethyl) benzonitrile (G31, 750 mg, 4.05 mmol), NBS (865 mg, 4.86 mmol) and AIBN (67 mg, 405 µmol) in DCE (7.5 mL) was stirred at 90 °C for 6 h. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The organic layer was concentrated under reduced presure. The residue was purified twice by flash silica gel chromatography (Biotage 12 g cartridge, 0-1% EtOAc:Hexane) to give 3-(bromomethyl)-5-(trifluoro methyl)benzonitrile (Intermediate Z). MS = 264.0 / 266.1 [M+H] +< .General Procedure for Intermediate AA

[0295] Step 1: methyl 2-((4-hydroxyphenyl)thio)-2-methylpropanoate

[0296]

[0297] To a mixture of 4-sulfanylphenol (G12, 2.00 g, 15.8 mmol) and methyl 2-bromo-2-methyl-propanoate (2.40 g, 13.3 mmol) in DMF (30 mL) was added Cs 2 CO 3 (7.20 g, 22.1 mmol). The mixture was then stirred at 80 °C for 16 h. The reaction mixture was diluted with saturated aqueous NH 4 Cl (30 mL), extracted with EtOAc (30 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 12 g cartridge, 0-100% EtOAc:Hexane) to give methyl 2-(4-hydroxyphenyl) sulfanyl-2-methyl-propanoate (G32). MS = 225.2 [M-H] -< .Step 2: methyl 2-((4-hydroxyphenyl) sulfonyl)-2-methylpropanoate

[0298]

[0299] To a solution of methyl 2-(4-hydroxyphenyl) sulfanyl-2-methyl-propanoate (G32, 2.30 g, 10.2 mmol) in THF (30 mL) was added a solution of NaIO 4 (6.52 g, 30.5 mmol) in H 2 O (6 mL). The mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with saturated aqueous Na 2 SO 3 (15 mL), extracted with EtOAc (10 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-30% EtOAc:Hexane) to give methyl 2-(4-hydroxyphenyl) sulfonyl-2-methyl-propanoate (G33). MS = 257.1 [M-H] -< .Step 3: 4-((1-hydroxy-2-methylpropan-2-yl) sulfonyl)phenol

[0300]

[0301] To a solution of methyl 2-(4-hydroxyphenyl) sulfonyl-2-methyl-propanoate (G33, 2.30 g, 8.90 mmol) in THF (30 mL) at 0 °C was added LiAlH 4 (507 mg, 13.4 mmol). The mixture was stirred at room temperature for 2 h. The residue was diluted with aqueous NaOH (5 M, 2 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 4 g cartridge, 0-100% EtOAc:Hexane to give 4-(2-hydroxy-1, 1-dimethyl-ethyl) sulfonylphenol (Intermediate AA). MS = 229.0 [M-H] -< .General Procedure for Intermediate AB

[0302] Step 1: tert-butyl 3-((4-hydroxyphenyl) thio) azetidine-1-carboxylate

[0303]

[0304] To a solution of 4-sulfanylphenol (G12, 10.0 g, 79.2 mmol) in DMF (100 mL) were added K 2 CO 3 (10.9 g, 79.2 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (22.4 g, 79.2 mmol). The mixture was then stirred at 40 °C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with H 2 O (80 mL) and brine (80 mL), dried over (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (100 mL) at room temperature for 5 h and filtered to give tert-butyl 3-(4-hydroxyphenyl)sulfanylazetidine-1-carboxylate (G19). MS = 226.1 [M-C 4 H 8 +H] +< .Step 2: tert-butyl 3-((4-hydroxyphenyl) sulfonyl) azetidine-1-carboxylate

[0305]

[0306] To a solution of tert-butyl 3-(4-hydroxyphenyl) sulfanylazetidine-1-carboxylate (G19, 6.50 g, 13.9 mmol) in THF (60 mL) and H 2 O (20 mL) was added NaIO 4 (8.80 g, 41.6 mmol, ). The mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous Na 2 SO 3 (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-100% EtOAc:Hexane ) to give tert-butyl 3- (4- hydroxyphenyl) sulfonylazetidine-1-carboxylate (Intermediate O). MS = 312.2 [M-H] -< .Step 3: 4-(azetidin-3-ylsulfonyl) phenol

[0307]

[0308] To a solution of tert-butyl 3-(4-hydroxyphenyl) sulfonylazetidine-1-carboxylate (Intermediate O, 1.5 g, 4.79 mmol) in MeOH (4 mL) was added HCl / MeOH (4 M, 12 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-(azetidin-3-ylsulfonyl) phenol HCl salt (G20), which was used without further purification. MS = 214.1 [M+H] +< .Step 4: allyl 3-((4-hydroxyphenyl) sulfonyl) azetidine-1-carboxylate (Intermediate AB)

[0309]

[0310] To a solution of 4-(azetidin-3-ylsulfonyl)phenol (G20, 1.1 g, 4.41 mmol, HCl salt) in DCM (10 mL) were added TEA (1.11 g, 11.0 mmol, 1.53 mL) and allyl chloroformate (584 mg, 4.85 mmol) at 0 °C. The mixture was then stirred at room temperature for 3 h. The reaction mixture was diluted with H 2 O (30 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 12 g cartridge, 0-100% EtOAc:Hexane) to give allyl 3-(4-hydroxyphenyl)sulfonylazetidine-1-carboxylate (Intermediate AB). MS = 298.1 [M+H] +< .General Procedure for Intermediate AC

[0311] Step 1: 3-(bromomethyl)-5-chlorobenzonitrile (Intermediate AC)

[0312]

[0313] To a solution of 3-chloro-5-(hydroxymethyl)benzonitrile (G34, 500 mg, 2.98 mmol) in DCM (10 mL) was added PBr 3 (807 mg, 2.98 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 10 h, then the reaction mixture was concentrated. The residue was diluted with water (10 mL) and neutralized by addition of saturated aqueous NaHCO 3 to pH = 7, then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give 3-(bromomethyl)-5-chloro-benzonitrile (Intermediate AC), which was taken to the next step without further purification. 1< H NMR (400 MHz, CDCl 3 ): δ 7.63 (s, 1H), 7.58 (s, 2H), 4.43 (s, 2H).General Procedure for Intermediate AD

[0314] Step 1: 3-(methylsulfonyl)propyl methanesulfonate

[0315]

[0316] To a solution of 3-methylsulfonylpropan-1-ol (G35, 500 mg, 3.62 mmol) in DCM (5 mL) at 0 °C were added Et 3 N (732 mg, 7.24 mmol) and methylsulfonyl methanesulfonate (945 mg, 5.43 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude 3-(methylsulfonyl)propyl methanesulfonate (G36), which was taken to the next step without further purification. 1< H NMR (400 MHz, DMSO-d 6 ): δ 4.30 (t, J = 6.4 Hz, 2H), 3.23 - 3.01 (m, 5H), 3.01 (s, 3H), 2.13 - 2.08 (m, 2H).Step 2: 4-((3-(methylsulfonyl)propyl)thio)phenol

[0317]

[0318] To a mixture of 3-(methylsulfonyl)propyl methanesulfonate (G36, 390 mg, 1.80 mmol) and 4-sulfanylphenol (G12, 318 mg, 2.52 mmol) in CH 3 CN (5 mL) was added Cs 2 CO 3 (705 mg, 2.16 mmol). The mixture was then stirred at room temperature for 2 h. The reaction mixture was then diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 12 g cartridge, 0-50% EtOAc:Hexane) to give 4-(3-methylsulfonylpropylsulfanyl)phenol (G37). MS = 245.1 [M-H] -< .Step 3: 4-((3-(methylsulfonyl)propyl)sulfonyl)phenol (Intermediate AD)

[0319]

[0320] To a solution of 4-(3-methylsulfonylpropylsulfanyl)phenol (G37, 370 mg, 1.50 mmol) in THF (2 mL) and H 2 O (2 mL) was added NaIO 4 (964 mg, 4.51 mmol) at 0 °C. The mixture was then stirred at 70 °C for 12 h. The reaction mixture was quenched by addition of saturated aqueous Na 2 SO 3 (10 mL), and then diluted with H 2 O (5 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 12 g cartridge, 0-50% EtOAc:Hexane) to give 4-(3-methylsulfonylpropylsulfonyl)phenol (Intermediate AD). MS = 277.1 [M-H] -< .General Procedure for Intermediate AE

[0321] Step 1: tert-butyl (3S,4S)-3-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate

[0322]

[0323] To a solution of (3S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidine-3-carboxylic acid (G38, 5.00 g, 21.8 mmol) in THF (50 mL) was added BH 3 (10 M in Me 2 S, 10.9 mL, 109 mmol) at 0 °C. Then the reaction was stirred at room temperature for 16 h. The reaction mixture was quenched by addition of MeOH (40 mL) and stirred 0.5 h. The mixture was then diluted with water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and the filtrate was concentrated to give tert-butyl (3S,4S)-3-(hydroxymethyl)-4-methyl-pyrrolidine-1-carboxylate (G39). MS = 160.2 [M-C 4 H 8 +H] +<...

Claims

1. A compound of formula (A'): or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or is -N-(C1-6alkyl); Y is O or -N-(C1-6alkyl), provided that, when Q is -N(C1-6alkyl), then Y is O; Ra, Rb, and Rc are each independently H or C1-6alkyl, wherein the C1-6alkyl of Ra, Rb, or Rc is independently optionally substituted with one or more -OH, C1-6alkoxy, or -S(O)2-C1-6alkyl, or any two of Ra, Rb, and Rc are taken, together with the atoms to which they are attached, to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, and the other of Ra, Rb, and Rc is H or C1-6alkyl, wherein the C1-6alkyl of Ra, Rb, or Rc is independently optionally substituted with one or more -OH, C1-6alkoxy, or -S(O)2-C1-6alkyl; L is selected from the group consisting of: (i) wherein A is O, NH, N(C1-6alkyl), CH2, or CH(C1-6alkyl); Rx is H, or Rx is taken together with one of R1 and R2, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected Rg substituents, wherein n is an integer from 0-6, and Rg is -OH, halo, C1-6alkyl, or C1-6alkoxy; R1 and R2 are independently H, halo, or -OH, or one of R1 and R2 is taken together with Rx, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected Rg substituents, wherein n is an integer from 0-6, and Rg is -OH, halo, C1-6alkyl, or C1-6alkoxy, and the other of R1 and R2 is H, halo, or -OH; R3 is H, -OH, halo, or C1-6alkoxy; and R4 and R5 are independently H, or R4 and R5 are taken, together with the atoms to which they are attached, to form a C3-8cycloalkyl, provided that either: (1) Rx is taken together with one of R1 and R2, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected Rg substituents, wherein n is an integer from 0-6, and Rg is -OH, halo, C1-6alkyl, or C1-6alkoxy, or (2) R4 and R5 are taken, together with the atoms to which they are attached, to form a C3-8cycloalkyl, (ii) wherein E is O, NH, N(C1-6alkyl), CH2, or CH(C1-6alkyl); p is 0 or 1, provided that, when p is 1, then E is O; R6 is H or -OH; Ry is H, or Ry is taken together with R7, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or Ry is taken together with one of R8 and R9, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R7 is H, or R7 is taken together with Ry, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R8 and R9 are independently H or C1-6alkyl, or one of R8 and R9 is taken together with Ry, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R8 and R9 is H or C1-6alkyl, or one of R8 and R9 is taken together with R10, and the atoms to which they are attached, to form a C3-8cycloalkyl, and the other of R8 and R9 is H or C1-6alkyl; and R10 is H, or R10 is taken together with one of R8 and R9, and the atoms to which they are attached, to form a C3-8cycloalkyl, provided that: (1) Ry is taken together with R7, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) Ry is taken together with one of R8 and R9, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R8 and R9 is taken together with R10 and the atoms to which they are attached, to form a C3-8cycloalkyl, and (iii) wherein G is O, NH, N(C1-6alkyl), CH2, or CH(C1-6alkyl); Rz is H or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more C3-8cycloalkyl; R11 and R12 are independently H, -OH, halo, or C1-6alkyl; and R13 and R14 are independently H, C1-6alkyl, or C3-8cycloalkyl, or R13 and R14 are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X1-X4; and X1, X2, X3, and X4 are, independently of each other, H, halo, -CN, C1-6alkyl, C1-6alkoxy, or SF5, wherein the C1-6alkyl or C1-6alkoxy is optionally substituted with one or more halo, provided that at least one of X1, X2, X3, and X4 is halo, -CN, C1-6alkyl, C1-6alkoxy, or SF5, wherein the C1-6alkyl or C1-6alkoxy is optionally substituted with one or more halo.

2. The compound of claim 1, wherein the compound is a compound of formula (A): or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X1, X2, X3, and X4 are, independently of each other, H, halo, -CN, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl or C1-6alkoxy is optionally substituted with one or more halo, provided that at least one of X1, X2, X3, and X4 is halo, -CN, C1-6alkyl, or C1-6alkoxy, wherein the C1-6alkyl or C1-6alkoxy is optionally substituted with one or more halo.

3. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is such that the compound is of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; optionally wherein one of (a) or (b) applies: (a) A is O, such that the compound is of formula (I-A): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; (b) A is CH2, such that the compound is of formula (I-A3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

4. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A1) and either: Rx is taken together with one of R1 and R2, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected Rg substituents, wherein n is an integer from 0-6, and Rg is -OH, halo, C1-6alkyl, or C1-6alkoxy; or Rx is taken together with one of R1 and R2, and the atoms to which they are attached, to form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is substituted with n independently selected Rg substituents, wherein n is an integer from 0-6, and Rg is -OH, halo, C1-6alkyl, or C1-6alkoxy.

5. The compound of claim 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-B 1), (I-C1), (I-D1), (I-E1), (I-F1) or (I-G1): wherein in formula (I-B1), n is optionally 0, or n is optionally 1 or 2; wherein in formula (I-C1) n is optionally 0, or n is optionally 1 or 2; wherein in formula (I-D1) n is optionally 0, or n is optionally 1 or 2; wherein in formula (I-E1) n is optionally 0; wherein in formula (I-F1) n is optionally 0; wherein in formula (I-G1) n is optionally 0; or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

6. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is of formula (I-A) and wherein R4 and R5 are taken, together with the atoms to which they are attached, to form a C3-8cycloalkyl; optionally wherein the compound is of formula (I-H1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; wherein R1, R2, and R3 are optionally each H.

7. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A1) and either: (a) Rx is taken together with one of R1 and R2, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected Rg substituents, wherein n is an integer from 0-6, and Rg is -OH, halo, C1-6alkyl, or C1-6alkoxy, and the other of R1 and R2 is H, halo, or -OH; or (b) Rx is taken together with one of R1 and R2, and the atoms to which they are attached, to form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is substituted with n independently selected Rg substituents, wherein n is an integer from 0-6, and Rg is -OH, halo, C1-6alkyl, or C1-6alkoxy, and the other of R1 and R2 is H, halo, or -OH; optionally wherein the compound is of formula (I-C3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

8. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is such that the compound is of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; optionally wherein E is O, such that the compound is of formula (II-A1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; optionally wherein either: (a) Ry in formula (II-A1) is taken together with R7, and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; or (b) Ry is taken together with R7, and the atoms to which they are attached, to form a 5-6 membered heterocyclyl; further optionally wherein one of R8 and R9 is taken together with R10, and the atoms to which they are attached, to form a C3-8cycloalkyl.

9. The compound of claim 8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (II-B1), (II-C1), (II-D1) or (II-E1): wherein in formula (II-C1) optionally R6 is -OH, R8 is C1-6alkyl, and R9 is C1-6alkyl; wherein in formula (II-D1) optionally R6 is -OH, R8 is H, and R9 is H; wherein in formula (II-E1) optionally R6 is -OH and R7 is H; or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is such that the compound is of formula (III): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

11. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein either: (a) Q is absent, Y is O, and Ra, Rb, and Rc are each independently H, such that the compound is of formula (B-2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (b) Q is absent, Y is -N(CH3), and Ra, Rb, and Rc are each independently H, such that the compound is of formula (B-5): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (c) Q is -N(CH3), Y is O, and Ra, Rb, and Rc are each independently H, such that the compound is of formula (C-1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

12. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the following: Compound No.StructureChemical name1 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) azepane2 (R) or (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) azepane3 (S) or (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) azepane4 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-3-ol5 (R) or (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-3-ol6 (S) or (R) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-3-ol7 N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide8 (S) or (R)-N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide9 (R) or (S)-N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide10 N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide11 (R) or (S)-N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide12 (S) or (R)-N-(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-N-methylmethanesulfonamide13 (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperazine14 (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperazine15 (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine16 (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine17 1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethan-1-ol18 (R) or (S)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethan-1-ol19 (S) or (R)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethan-1-ol20 1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethanol21 (R) or (S)-1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethanol22 (S) or (R)-1-(3-chlorophenyl)-2-((R)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethanol23 (S)-1-((R) or (S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine24 (S)-1-((S) or (R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine25 (R)-1-((R) or (S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine26 (R)-1-((S) or (R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine27 rac-trans or cis-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol28 rac-cis or trans-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol29 (3S,4R) or (3R,4R) or (3S,4S) or (3R,4S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol30 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol31 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol32 (3S,4S) or (3R,4S) or (3S,4R) or (3R,4R) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol33 rac-trans or cis-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine34 rac-cis or trans-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine35 (3S,4R) or (3R,4R) or (3S,4S) or (3R,4S)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine36 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R)-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine37 (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R) -1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine38 (3S,4S) or (3R,4S) or (3S,4R) or (3R,4R) -1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine39 1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperi dine40 (S) or (R)-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperi dine41 (R) or (S)-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperi dine42 1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine43 (S) or (R)-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine44 (R) or (S)-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine45 rac-trans-N-(4-((1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide46 N-(4-(((3S,4S) or (3R,4R)-1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide47 N-(4-(((3R,4R) or (3S,4S) -1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide48 trans-N-(4-(3-((3-chlorophenethyl)amino)cyclobuto xy)phenyl)-N-methylmethanesulfonamide49 (S)-N-(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide50 (R)-N-(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide51 (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine52 rac-trans-1-(3-chlorophenethyl)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine53 rac-trans or cis-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine54 rac-cis or trans-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine55 (2R,4S) or (2R,4R) or (2S,4R) or (2S,4S)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine56 (2R,4R) or (2S,4R) or (2S,4S) or (2R,4S)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine57 (2S,4R) or (2S,4S) or (2R,4S) or (2R,4R)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine58 (2S,4S) or (2R,4S) or (2R,4R) or (2S,4R)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine59 (S)-N-(4-(3-((3-chlorophenethyl)(cyclopropylmet hyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide60 (S)-N-(4-(3-((3-chlorophenethyl)(ethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide61 (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide62 (2S)-1-(2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol63 (S)-1-((S) or (R)-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol64 (S)-1-((R) or (S)-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol65 N-(4-((S)-3-((trans-3-(3-chlorophenyl)cyclobutyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide66 (S)-1-((trans-3-(3-chlorophenyl)cyclobutyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol67 (R)-1-((trans-3-(3-chlorophenyl)cyclobutyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol68 N-(4-((2S)-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide69 N-(4-((S)-3-((S) or (R)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide70 N-(4-((S)-3-((R) or (S)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide71 N-(4-((2R)-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide72 N-(4-((R)-3-((S) or (R)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide73 N-(4-((R)-3-((R) or (S)-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide74 N-(4-((2S)-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide75 N-(4-((S)-3-((S) or (R)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide76 N-(4-((S)-3-((R) or (S)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide77 N-(4-((2R)-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide78 N-(4-((R)-3-((S) or (R)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide79 N-(4-((R)-3-((R) or (S)-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide80 N-(4-((2S)-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide81 N-(4-((S)-3-((S) or (R)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide82 N-(4-((S)-3-((R) or (S)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide83 N-(4-((2R)-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide84 N-(4-((R)-3-((R) or (S)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide85 N-(4-((R)-3-((S) or (R)-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide86 (S)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide87 (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide88 N-(4-((R)-3-(((S) or (R)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide89 N-(4-((R)-3-(((R) or (S)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide90 (S)-N-(4-(3-((2,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide91 (S)-N-(4-(3-((3,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide92 N-(4-((2R)-3-((3-(3-chlorobenzyl)tetrahydrofuran-3-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide93 (S)-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol94 (R)-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol95 N-(4-((S)-3-(((S) or (R)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide96 N-(4-((S)-3-(((R) or (S)-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide97 (R)-1-((1-(3-chlorophenyl)-2-methylpropan-2-yl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol98 (S)-N-(4-(2-hydroxy-3-((2-methoxyphenethyl)amino)propox y)phenyl)-N-methylmethanesulfonamide99 (S)-N-(4-(3-((3-cyanophenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide100 (S)-N-(4-(3-((2-ethylphenethyl)amino)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide101 (S)-N-(4-(3-((2-(difluoromethoxy)phenethyl)amin o)-2-hydroxypropoxy)phenyl)-N-methylmethanesulfonamide102 (2R)-1-((2-(3-chlorophenyl)-1-cyclopropylethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol103 (R) or (S)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide104 (S) or (R)-N-(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)-N-methylmethanesulfonamide105 N-(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phenyl)-N-methylmethanesulfonamide106 (R) or (S)-N-(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phenyl)-N-methylmethanesulfonamide107 (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methanesulfonylethanesulfonyl)p henoxy]methyl}-4-methylpyrrolidine108 3-chloro-5-{2-[(3S,4S)-3-{[4-(2-methanesulfonylethanesulfonyl)p henoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile109 rac-trans-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy] methyl}-4-methylpyrrolidine110 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy] methyl}-4-methylpyrrolidine111 (3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy] methyl}-4-methylpyrrolidine112 2-(4-{[(3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl)etha n-1-ol113 2-(4-{[(3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl)etha n-1-ol114 3-chloro-5-[(1S or 1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzonitrile115 3-chloro-5-[(1R or 1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile116 3-[(1R or 1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzonitrile117 3-[(1S or 1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzonitrile118 5-[(1R or 1S)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile119 5-[(1S or 1R)-1-hydroxy-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile120 3-chloro-5-{1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile121 3-chloro-5-[(1S or 1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile122 3-chloro-5-[(1R or 1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile123 1-(3-chlorophenyl)-2-((3S,4S)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-1-yl)ethan-1-ol124 (1R or 1S)-1-(3-chlorophenl)-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethan-1-ol125 (1S or 1R)-1-(3-chlorophenyl)-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethan-1-ol126 3-[1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile127 3-[(1S or 1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile128 3-[(1R or 1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile129 5-{1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile130 5-[(1R or 1S)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile131 5-[(1S or 1R)-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile132 5-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile133 (3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine134 (2S,5S)-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperidine135 rac-cis or trans-3-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile136 rac-trans or cis-3-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile137 3-{2-[(2S,4R or 2R,4S or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile138 3-{2-[(2R,4S or 2S,4R or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile139 3-{2-[(2S,4S or 2S,4R or 2R,4S or 2R,4R)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile140 3-{2-[(2R,4R or 2S,4S or 2S,4R or 2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile141 5-chloro-3-{2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile142 3-chloro-5-[(2R or 2S)-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile143 3-chloro-5-[(2S or 2R)-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile144 5-chloro-3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile145 5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile146 3-chloro-5-[1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile147 3-chloro-5-[(2R or 2S)-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile148 3-chloro-5-[(2S or 2R)-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile149 3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile150 rac-cis-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine151 (3R,4S or 3S,4R)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine152 (3S,4R or 3R,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine153 (2R,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidine154 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine155 (3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine156 3-{2-[(2R,4S)-4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile157 3-{2-[(2R,4S)-2-methyl-4-({4-[methyl(methylimino)oxo-λ6-sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl}benzonitrile158 3-{2-[(2R,4S)-2-methyl-4-({4-[(R or S)methyl(methylimino)oxo-λ6-sulfanyl]phenoxy}methyl)pyrroli din-1-yl]ethyl}benzonitrile159 3-{2-[(2R,4S)-2-methyl-4-({4-[(S or R)methyl(methylimino)oxo-λ6-sulfanyl]phenoxy}methyl)pyrroli din-1-yl]ethyl}benzonitrile160 (2R,5S)-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperidine161 3-{2-[(2R,4S)-4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile162 3-{2-[(2R,4S)-4-{ [4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile163 (3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methyl-1-{2-[3-(pentafluoro-λ6-sulfanyl)phenyl]ethyl}pyrrolidine164 3-chloro-5-{2-[(2R,4S)-4-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile165 3-chloro-5-{2-[(2R,4S)-4-{[4-(2-hydroxyethanesulfonyl)phenoxy] methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile166 3-chloro-5-{2-[(3S,4S)-3-{[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile167 3-chloro-5-{2-[(3S,4S)-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile168 3-{ 2-[(3S,4S)-3-{ [4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile169 3-{2-[(3S,4S)-3-methyl-4-({4-[methyl(methylimino)oxo-λ6-sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl }benzonitrile170 3-{2-[(3S,4S)-3-methyl-4-({4-[(R or S)-methyl(methylimino)oxo-λ6-sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl }benzonitrile171 3-{2-[(3S,4S)-3-methyl-4-({4-[(S or R)-methyl(methylimino)oxo-λ6-sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl}benzonitrile172 3-{2-[(3S,4S)-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile173 3-{2-[(3S,4S)-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile174 3-chloro-5-{2-[(3S,4S)-3-{[4-(2-hydroxyethanesulfonyl)phenoxyl methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile175 rac-trans-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine176 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine177 (3S,4S or 3R,4R)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine181 (3S,4S)-1-[2-(3-chloro-5-fluorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine182 3-chloro-5-{2-[(3S)-3-{[4-(2-hydroxyethanesulfonyl)phenoxy] methyl}piperazin-1-yl]ethyl}benzonitrile183 3-chloro-5-{2-[(3S)-3-1[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}piperaz in-1-yl]ethyl}benzonitrile184 (3S)-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}piperazine185 (3S)-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-1-[2-(3-chlorophenyl)ethyl]piperazine186 3-chloro-5-{2-[(3S)-3-({4-[methyl(methylimino)oxo-λ6-sulfanyl]phenoxy}methyl)piperaz in-1-yl]ethyl}benzonitrile187 3-chloro-5-{2-[(3S)-3-({4-[(S or R)-methyl(methylimino)oxo-λ6-sulfanyl]phenoxy }methyl)piperaz in-1-yl]ethyl }benzonitrile188 3-chloro-5-{2-[(3S)-3-({4-[(R or S)-methyl(methylimino)oxo-λ6-sulfanyl]phenoxy }methyl)piperaz in-1-yl]ethyl}benzonitrile189 3-chloro-5-{2-[(3S)-3-[(4-methanesulfonylphenoxy)methyl] piperazin-1-yl]ethyl}benzonitrile190 (3S)-1-[2-(3,5-dichlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] piperazine191 (3S)-1-[2-(5-chloro-2-methoxyphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] piperazine192 (3S)-1-{2-[5-chloro-2-(difluoromethoxy)phenyl]ethyl}-3-[(4-methanesulfonylphenoxy)methyl] piperazine193 3-{2-[(3S)-3-[(4-methanesulfonylphenoxy)methyl] piperazin-1-yl]ethyl}-5-(trifluoromethyl)benzonitrile194 3-chloro-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile195 3-fluoro-5-{2-[(3S,4S)-3 -[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile196 3-bromo-5-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile197 (3S)-1-[2-(5-chloro-2-methylphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] piperazine198 3-{2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}-5-methylbenzonitrile199 rac-cis or trans-3-chloro-5-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile200 3-chloro-5-12-[(2R,4S or 2S,4R or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile201 3-chloro-5-{2-[(2S,4R or 2R,4S or 2R,4R or 2S,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile202 rac-trans or cis-3-chloro-5-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile203 3-chloro-5-(2-((2R,4S or 2S,4R or 2R,4R or 2S,4S)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-1-yl)ethyl)benzonitrile204 3-chloro-5-(2-((2R,4S or 2S,4R or 2S,4S or 2R.4R)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-1-yl)ethyl)benzonitrile205 rac-cis-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol206 (3R,4R or 3S,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol207 (3S,4S or 3R,4R)-1-(3-chlorophenethyl)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-3-ol208 rac-trans-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol209 (3R,4S or 3S,4R)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol210 (3S,4R or 3R,4S)-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol211 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperazine212 rac-cis or trans-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperazine213 rac-trans or cis-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperazine214 (1R) or (1S)-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethan-1-ol215 (1S) or (1R)-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethan-1-ol or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

13. A pharmaceutical composition, comprising (i) a compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

14. The compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition according to claim 13, for use in treating or delaying the development of a disease, disorder, or condition selected from: a kidney disease; a disease, disorder, or condition 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.

15. A kit, comprising (i) a compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 13, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof; wherein the disease, disorder, or condition is optionally: a kidney disease; or a disease, disorder, or condition 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; optionally wherein the individual has an APOL1 mutation, such as a gain-of-function mutation.