APOL1 INHIBITORS AND METHODS OF USE

Abstract

As used herein, the formula (A'): JPEG2024509760000436.jpg3993, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , X 3 , X 4 , R a , R b , R c wherein, L, Q, and Y are as defined herein. Also provided are methods of inhibiting APOL1 and methods of preparing compounds of formula (A'). Also provided are methods of inhibiting APOL1 and methods of treating an APOL1-mediated disease, disorder, or condition in an individual.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 151,605, filed February 19, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Apolipoprotein L1 (APOL1) is a pore-forming innate immune factor that protects individuals against trypanosome parasites (Vanhamme, L. et al. Nature (2003) 422, 83-87). Secreted forms of APOL1 circulate in the blood as part of a distinct high-density lipoprotein (HDL) complex known as trypanosome lytic factor (TLF) (Rifkin, MR Proc. Natl. Acad. Sci. USA (1978) 75, 3450-3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910-1916). TLF is internalized by the parasite through endocytosis (Hager, K Met al. J. Cell Biol. (1994) 126, 155-167). In trypanosomes, APOL1 forms a cation pore, causing ion flux, swelling, and eventual lysis (Rifkin, MR Exp. Parasitol. (1984) 58, 81-93; Molina-Portela, MP et al. Mol. Biochem. Parasitol. (2005) 144, 218-226; Perez-Morga, D. et al. Science. (2005) 309, 469-472; Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA. (2015) 112, 2894-2899).

[0003] Some Trypanosoma brucei subspecies (T. brucei and T. gambiense) have developed resistance mechanisms to APOL1-dependent killing (Pays, E. et al. Nat. Rev. Microbiol. (2014) 12, 575-584). Positive selection yielded APOL1 variants G1 (S342G, I384M) and G2 (N388△, Y389△) that can circumvent 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) are at increased risk of focal segmental glomerular sclerosis (FSGS), renal disease caused by hypertension, 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 increased rates of glomerular filtration rate (GFR) decline in diabetic kidney disease (Parsa, A. et al. N. Engl. J. Med. (2013) 369, 2183-2196). APOL1 high-risk genotypes have also been associated with COVID-19-associated nephropathy and other viral nephropathy (Shetty, A. et al. J. Am. Soc. Nephrol. (2021) 32, 33-40; Chang, J. Het al. Am. J. Kidney Dis. (2019) 73, 134-139). Furthermore, reduced renal graft survival has been observed after deceased donor kidney transplantation from APOL1 high-risk genotype donors (Freedman, BI et al. Transplantation. (2016) 100, 194-202).Additionally, having two APOL1 risk alleles increases the risk of preeclampsia (Reidy, KJ et al. Am. J. Hum. Genet. (2018) 103, 367-376) and sepsis (Chaudhary, NS et al. Clin. J. Am. Soc. Nephrol. (2019) 14, 1733-1740). There are no approved treatments 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 APOL1 high-risk genotypes. 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, OA 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 related to APOL1 pore function (Giovinazzo, JA et al. eLife. (2020) 9, e51185). Therefore, there is a need to develop compounds suitable for inhibiting APOL1 activity and methods for using such compounds to inhibit APOL1 activity. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Vanhamme, L. et al. Nature (2003) 422, 83-87 [Non-patent document 2] Rifkin, M.R. Proc. Natl. Acad. Sci. USA. (1978) 75, 3450 - 3454 [Non-Patent Document 3] Raper, J. et al. Infect. Immun. (1999) 67, 1910 - 1916 [Non-Patent Document 4] Hager, K.M. et al. J. Cell Biol. (1994) 126, 155 - 167 [Non-Patent Document 5] Rifkin, M.R. Exp. Parasitol. (1984) 58, 81 - 93 [Non-Patent Document 6] Molina-Portela, M.P. et al. Mol. Biochem. Parasitol. (2005) 144, 218 - 226 [Non-Patent Document 7] Perez-Morga, D. et al. Science. (2005) 309, 469 - 472 [Non-Patent Document 8] Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA. (2015) 112, 2894 - 2899 [Non-Patent Document 9] Pays, E. et al. Nat. Rev. Microbiol. (2014) 12, 575 - 584 [Non-Patent Document 10] Genovese, G. et al. Science. (2010) 329, 841 - 845 [Non-Patent Document 11] Tzur, S. et al. Hum. Genet. (2010) 128, 345 - 350 [Summary of the Invention] [Means for Solving the Problems]

[0005] The present disclosure describes compounds and compositions that may be useful in treating APOL1-mediated diseases, including various chronic kidney diseases such as FSGS, hypertension-related kidney disease, HIV / AIDS, sickle cell nephropathy, lupus nephritis, diabetic kidney disease, viral nephropathy, COVID-19-associated nephropathy, and APOL1-associated nephropathy. The compounds and compositions of the present invention may also be useful in treating other APOL1-mediated disorders, such as preeclampsia and sepsis. Additionally, for individuals with a high-risk APOL1 genotype, the disclosed compounds and compositions may be useful in preventing the onset of non-diabetic kidney disease and / or slowing the progression of any form of chronic kidney disease. The disclosed chemical entities may also be useful in preventing and / or delaying progressive kidney graft loss in patients who have received kidney transplants from donors with a high-risk APOL1 genotype.

[0006] In one aspect, the present invention provides a compound represented by formula (A'): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or -N-(C 1~6 alkyl), Y is O or -N-(C 1~6 alkyl), However, 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; or R a , R b, and R c Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; L, [ka] (In the formula, A is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R x is H or or R x But R 1 and R 2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is an alkoxy, R 1 and R 2 is independently H, halo, or —OH; or R 1 and R 2 One of them is R x and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R gsubstituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is alkoxy, and R 1 and R 2 the other of which is H, halo, or —OH; R 3 is H, -OH, halo, or C 1~6 is an alkoxy, R 4 and R 5 are independently H or or R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl, however, (1)R x But R 1 and R 2 together with the atom to which they are attached to form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from the group consisting of one or more of -OH, halo, C 1~6 Alkyl or C 1~6 optionally substituted with alkoxy, or (2)R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl), [ka] (In the formula, E is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), p is 0 or 1, provided that when p is 1, E is O; R 6 is H or —OH, R y is H or or R y But R 7and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or or R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 7 is H or or R 7 But R y and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 8 and R 9 are independently H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R y and together with the atoms to which they are attached form a 3- to 8-membered heterocyclyl, and R 8 and R 9 The other of these is H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 Forming a cycloalkyl, R 8 and R 9 The other of these is H or C 1~6 is alkyl, R 10 is H or or R 10 But R 8 and R 9 together with the atoms to which they are attached, 3~8 forming a cycloalkyl, however, (1)R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (2)Ry But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (3)R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 forming a cycloalkyl), and [ka] (In the formula, G is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R z But H or C 1~6 alkyl, C 1~6 Alkyl is one or more C 3~8 optionally substituted with cycloalkyl; R 11 and R 12 are independently H, —OH, halo, or C 1~6 is alkyl, R 13 and R 14 However, independently, H, C 1~6 Alkyl or C 3~8 is cycloalkyl, or or R 13 and R 14 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl) and for each of (i) through (iii), # indicates the point of attachment to the phenyl ring-bearing moiety Q and ## indicates the point of attachment to the phenyl ring-bearing moiety X. 1 ~X 4 indicates the point of attachment to X 1 , X 2 , X 3 , and X 4 are, independently of each other, H, halo, -CN, C 1~6 Alkyl, C 1~6Alkoxy or SF5, C 1~6 Alkyl or C 1~6 the alkoxy is optionally substituted with one or more halo; However, X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF5, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo.

[0007] In one aspect, the present invention provides a compound of formula (A): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or -N-(C 1~6 alkyl), Y is O or -N-(C 1~6 alkyl), However, 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; or R a , R b , and R c Any two of these, together with the atoms to which they are attached, form a C 3~6cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; L, [ka] (In the formula, A is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R x is H or or R x But R 1 and R 2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is an alkoxy, R 1 and R 2 is independently H, halo, or —OH; or R 1 and R 2 One of them is R x and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6is alkoxy, and R 1 and R 2 the other of which is H, halo, or —OH; R 3 is H, -OH, halo, or C 1~6 is an alkoxy; R 4 and R 5 are independently H or or R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl, however, (1)R x But R 1 and R 2 together with the atom to which they are attached to form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from the group consisting of one or more of -OH, halo, C 1~6 Alkyl or C 1~6 optionally substituted with alkoxy, or (2)R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl), [ka] (In the formula, E is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), p is 0 or 1, provided that when p is 1, E is O; R 6 is H or —OH, R y is H or or R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or or R y But R 8and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 7 is H or or R 7 But R y and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 8 and R 9 are independently H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R y and together with the atoms to which they are attached form a 3- to 8-membered heterocyclyl, and R 8 and R 9 The other of these is H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 Forming a cycloalkyl, R 8 and R 9 The other of these is H or C 1~6 is alkyl, R 10 is H or or R 10 But R 8 and R 9 together with the atoms to which they are attached, 3~8 forming a cycloalkyl, however, (1)R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (2)R y But R 8 and R 9together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (3)R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 forming a cycloalkyl), and [ka] (In the formula, G is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R z But H or C 1~6 alkyl, C 1~6 Alkyl is one or more C 3~8 optionally substituted with cycloalkyl; R 11 and R 12 are independently H, —OH, halo, or C 1~6 is alkyl, R 13 and R 14 However, independently, H, C 1~6 Alkyl or C 3~8 is cycloalkyl, or or R 13 and R 14 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl) and for each of (i) through (iii), # indicates the point of attachment to the phenyl ring-bearing moiety Q and ## indicates the point of attachment to the phenyl ring-bearing moiety X. 1 ~X 4 indicates the point of attachment to 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, C 1~6 Alkyl or C 1~6the alkoxy is optionally substituted with one or more halo; However, X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl or C 1~6 Alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo.

[0008] Any embodiment 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, is also an embodiment 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] As used herein, in one aspect, there is provided a compound of formula (I): [ka] 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 In another variation, X in formula (I) is a pharmaceutically acceptable salt of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. 1 , X 2 , X 3 , X 4 , R1 , 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.

[0010] In one aspect, the present invention provides a compound of formula (II): [ka] 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 the compounds 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. 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 one aspect, herein, there is provided a compound of formula (III): [ka] 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 In another variation, X of formula (III) is a pharmaceutically acceptable salt of a compound of formula (III), wherein X, Q, and Y are as defined for the 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. 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.

[0011] In one aspect, the present specification provides a compound represented by formula (B-2): [ka] 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 is as defined for the compounds 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. 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.

[0012] In one aspect, the present specification provides a compound represented by formula (B-5): [ka] 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 is as defined for the compounds 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. 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.

[0013] In one aspect, the present specification provides a compound represented by formula (C-1): [ka] 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 is as defined for the compounds 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. 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.

[0014]

[0013] Provided herein, in one aspect, 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.

[0014] Provided herein, in another variation, 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.

[0015] Provided herein, in one aspect, is a method of modulating APOL1 in a cell, the method comprising exposing the cell to a composition comprising an effective amount of a compound of formula (A), or any embodiment or variant 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 to a pharmaceutical composition comprising (i) a compound of formula (A), or any embodiment or variant 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 method of modulating APOL1 in a cell, the method comprising exposing the cell to a composition comprising an effective amount of 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, or to 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] Provided herein, in one aspect, is a method of inhibiting APOL1 in a cell, the method comprising exposing the cell to a composition comprising an effective amount of a compound of formula (A), or any embodiment or variant 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 to a pharmaceutical composition comprising (i) a compound of formula (A), or any embodiment or variant 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. Provided herein, in another variation, is a method of inhibiting APOL1 in a cell, the method comprising exposing the cell to a composition comprising an effective amount of 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, or to 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.

[0017] Provided herein, in one aspect, is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a composition comprising a compound of formula (A), or any embodiment or variant 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 any embodiment or variant 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 method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a composition comprising a compound of formula (A'), or any embodiment or variant 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 any embodiment or variant 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.

[0018]

[0013] Provided herein, in one aspect, 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.

[0014] Provided herein, in another variation, 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.

[0019] Provided herein in some aspects are methods for 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

[0020] Unless expressly indicated otherwise, the terms "a," "an," etc. refer to one or more.

[0021] As used herein, "about" a parameter or value includes and describes the parameter or value itself. For example, "about X" includes and describes X itself.

[0022] "Individual" refers to mammals, including humans and non-human mammals. Examples of individuals include, but are not limited to, some primates and humans. In some embodiments, an individual refers to a human.

[0023] As used herein, an "at risk" individual is an individual who is at risk of developing a disease or condition. An "at risk" individual may or may not have a detectable disease or condition, and may or may not exhibit detectable disease prior to the treatment methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. Individuals who have one or more of these risk factors have a higher likelihood of developing a disease or condition than individuals who do not have these risk factors.

[0024] "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: reducing one or more symptoms resulting from a disease or condition; reducing the severity of a disease or condition; delaying or preventing the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition); and alleviating the disease, such as by causing regression of clinical symptoms (e.g., ameliorating a disease state, enhancing the effect of another drug, slowing the progression of a disease, improving quality of life, and / or prolonging survival).

[0025] As used herein, "delaying the onset of a disease or condition" means to postpone, inhibit, slow, decelerate, stabilize, and / or postpone the onset of the disease or condition. This delay can be of varying lengths of time, depending on the disease being treated and / or the medical history of the individual. As will be apparent to one of skill in the art, a sufficient or significant delay can, in fact, encompass prevention, in that the individual does not develop the disease or condition.

[0026] As used herein, the term "therapeutically effective amount" or "effective amount" refers to a sufficient amount of a compound of the present disclosure or a pharmaceutical salt thereof to provide treatment when administered to an individual. As understood in the art, an effective amount may be one or more doses, e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount may also be considered in the context of administering one or more therapeutic agents; a single agent may be considered to be administered in an effective amount if, in conjunction with one or more other agents, a desired or beneficial result may be obtained or achieved.

[0027] As used herein, "unit dosage form" refers to physically discrete units suitable as unit dosages, each containing a predetermined amount of active ingredient or compound, which may be in a pharmaceutically acceptable carrier.

[0028] As used herein, "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, e.g., the material can be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

[0029] The term "alkyl," as used herein, refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 1 to 20 carbons (i.e., C 1~20 alkyl), 1 to 16 carbons (i.e., C 1~16 alkyl), 1 to 12 carbons (i.e., C 1~12 alkyl), 1 to 10 carbons (i.e., C 1~10 alkyl), 1 to 8 carbons (i.e., C 1~8 alkyl), 1 to 6 carbons (i.e., C 1~6 alkyl), 1 to 4 carbons (i.e., C 1~4 alkyl), or 1 to 3 carbons (i.e., C 1~3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or molecular formula, all positional isomers having that number of carbon atoms are encompassed (e.g., "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-butyl, and "propyl" includes n-propyl and isopropyl). Certain commonly used alternative names may be used and will be understood by those skilled in the art. For example, a divalent group, such as a divalent "alkyl" group, may be referred to as an "alkylene."

[0030] 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, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0031] 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 refers to, for example, a ring having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 16 ring carbon atoms (i.e., C 6~16 aryl), 6 to 12 ring carbon atoms (i.e., C 6~12 aryl), or 6 to 10 ring carbon atoms (i.e., C 6~10 Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0032] 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, which may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, where the ring moiety contains at least one cyclic double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety containing at least one non-aromatic ring, regardless of the point of attachment to the rest of the molecule. As used herein, cycloalkyl refers to, for example, a ring having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 16 ring carbon atoms (i.e., C 3~16 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), 3 to 6 ring carbon atoms (i.e., C 3~6 cycloalkyl), or 3 to 5 ring carbon atoms (i.e., C 3~5 Cycloalkyl includes rings containing cycloalkyl groups. 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, norvomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, cycloalkyl also includes spirocycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0033] The term "halo," as used herein, refers to the atoms occupying Group VIIA of the periodic table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodine).

[0034] The term "heteroaryl," as used herein, refers to an aromatic (fully unsaturated) ring moiety containing one or more ring 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, heteroaryl includes, for example, 5 to 20 ring atoms (i.e., 5-20-membered heteroaryl), 5 to 16 ring atoms (i.e., 5-16-membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12-membered heteroaryl), 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl), 5 to 8 ring atoms (i.e., 5-8-membered heteroaryl), or 5 to 6 ring atoms (i.e., 5-6-membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety containing one or more ring heteroatoms is considered heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety can be attached to the remainder of the molecule through any ring carbon or any ring heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include 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, isopropyl, ... These include, but are not limited to, 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 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, and the heteroaryl may be attached via either ring of the fused system.

[0035] The term "heterocyclyl," as used herein, refers to a saturated or partially unsaturated cyclic moiety containing one or more ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes both monocyclic and polycyclic ring moieties, which may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety containing at least one ring heteroatom is considered heterocyclyl, regardless of the point of attachment to the rest of the molecule (i.e., the heterocyclyl moiety can be attached to the rest of the molecule through any ring carbon or any ring heteroatom of the heterocyclyl moiety). Furthermore, the term heterocyclyl is intended to encompass any polycyclic ring moiety containing at least one ring heteroatom, provided that the polycyclic ring moiety contains at least one non-aromatic ring, regardless of the point of attachment to the rest of the molecule. As used herein, heterocyclyl includes, for example, 3 to 20 ring atoms (i.e., 3-20-membered heterocyclyl), 3 to 16 ring atoms (i.e., 3-16-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3-12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3-10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3-8-membered heterocyclyl), 3 to 6 ring atoms (i.e., 3-6-membered heterocyclyl), 3 to 5 ring atoms (i.e., 3-5-membered heterocyclyl), 5 to 8 ring atoms (i.e., 5-8-membered heterocyclyl), or 5 to 6 ring atoms (i.e., 5-6-membered heterocyclyl).Examples of heterocyclyl groups are, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoquinol ... Includes isoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl group, 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 spiroheterocyclyl 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 may be attached via either ring of the fused system.

[0036] 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 occur. Thus, 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 at the specified atom, moiety, or group may or may not be replaced by atoms, moieties, or groups other than hydrogen. By way of example, and not limitation, the phrase "methyl optionally substituted with one or more chloro" encompasses the moieties -CH, -CHCl, -CHCl, and -CCl.

[0037] Aspects and embodiments described herein as "comprising" are to be understood to include "consisting of" and "consisting essentially of" embodiments.

[0038] The term "pharmaceutically acceptable salt" of a given compound, as used herein, refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. See, for example, "Handbook of Pharmaceutical Salts Properties, Selection, and Use," International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), incorporated herein by reference. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, 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-toluenesulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Similarly, 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, 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, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0039] Isotopically labeled forms of the compounds described herein can be prepared. Isotopically labeled compounds have the structures shown 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, phosphorus, fluorine, chlorine, and iodine, for example, 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. In some embodiments, compounds of Formula (A) or Formula (A') are provided in which one or more hydrogens are replaced with deuterium or tritium.

[0040] Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with each other. By way of example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, the compounds of this disclosure will be understood by those skilled in the art to include both the amide and imidic acid tautomers. Thus, for example, an amide-containing compound is understood to include its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to include its amide tautomer.

[0041] Prodrugs of the compounds disclosed herein or pharmaceutically acceptable salts thereof are also provided herein. Prodrugs are compounds that can be administered to an individual and release the compounds disclosed herein as parent drug compounds in vivo. It should be understood that prodrugs can be prepared by modifying functional groups in the parent drug compound so that the modifications are cleaved in vivo to release the parent drug compound. For example, see Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255-270 (2008), which is incorporated herein by reference.

[0042] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- (or, in the case of amino acids, (D)- or (L)-). The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms, and mixtures thereof, in any proportion. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthesizers or chiral reagents or resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) 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 otherwise specified, the present disclosure is intended to include both E and Z geometric isomers. Similarly, cis and trans are used in their conventional sense to describe relative spatial relationships.

[0043] "Stereoisomers" refer to compounds consisting of the same atoms connected by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose structures are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0044] Where enantiomeric and / or diastereomeric forms of a given structure exist, a planar bond indicates that all stereoisomeric forms of the structure shown may be present, for example: [ka]

[0045] If enantiomeric forms of a given structure exist, planar bonds and * The presence of the symbol indicates that the composition consists of at least 90% by weight of a single isomer of unknown stereochemistry, for example: [ka]

[0046] Where enantiomeric and / or diastereomeric forms of a given structure exist, a wedge or hash bond indicates that the composition consists of at least 90% by weight of a single enantiomer or diastereomer of the known stereochemistry, for example, [ka]

[0047] Where enantiomeric and / or diastereomeric forms of a given structure exist having two stereocenters, the presence of a planar bond and two "&1" symbols indicates that the composition consists of a pair of enantiomers with unknown relative stereochemistry, e.g., [ka]

[0048] Where enantiomeric and / or diastereomeric forms of a given structure exist having two stereocenters, the presence of a wedge and / or dashed bond and two "&1" symbols indicates that the composition consists of a pair of enantiomers with known relative stereochemistry, for example: [ka]

[0049] Where enantiomeric and / or diastereomeric forms of a given structure having two stereocenters exist, the presence of a wedge and / or dashed bond and two "or1" symbols indicates that the composition consists of at least 90% by weight of a single stereoisomer of known relative stereochemistry but unknown absolute stereochemistry, e.g., [ka]

[0050] When enantiomeric and / or diastereomeric forms of a given structure exist that have two stereocenters, the planar bonds and two " * The presence of the " symbol indicates that the composition consists of at least 90% by weight of a single enantiomer or diastereomer of unknown stereochemistry, for example: [ka]

[0051] Abbreviations used are conventional in the art and are taken from 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. [Table 1]

[0052] compound As used herein, the formula (A'): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or -N-(C 1~6 alkyl), Y is O or -N-(C 1~6 alkyl), However, 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; or R a , R b , and R c Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C1~6 optionally substituted with alkyl; L, [ka] (In the formula, A is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R x is H or or R x But R 1 and R 2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is an alkoxy; R 1 and R 2 is independently H, halo, or —OH; or R 1 and R 2 One of them is R x and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is alkoxy, and R 1 and R 2 the other of which is H, halo, or —OH; R 3 is H, -OH, halo, or C 1~6 is an alkoxy; R 4 and R 5 are independently H or or R 4 and R 5together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl, however, (1)R x But R 1 and R 2 together with the atom to which they are attached to form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from the group consisting of one or more of -OH, halo, C 1~6 Alkyl or C 1~6 optionally substituted with alkoxy, or (2)R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl), [ka] (In the formula, E is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), p is 0 or 1, provided that when p is 1, E is O; R 6 is H or —OH, R y is H or or R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or or R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 7 is H or or R 7 But R y and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 8 and R 9are independently H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R y and together with the atoms to which they are attached form a 3- to 8-membered heterocyclyl, and R 8 and R 9 The other of these is H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 Forming a cycloalkyl, R 8 and R 9 The other of these is H or C 1~6 is alkyl, R 10 is H or or R 10 But R 8 and R 9 together with the atoms to which they are attached, 3~8 forming a cycloalkyl, however, (1)R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (2)R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (3)R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 forming a cycloalkyl), and [ka] (In the formula, G is O, NH, N(C1~6 alkyl), CH2, or CH(C 1~6 alkyl), R z But H or C 1~6 alkyl, C 1~6 Alkyl is one or more C 3~8 optionally substituted with cycloalkyl; R 11 and R 12 are independently H, —OH, halo, or C 1~6 is alkyl, R 13 and R 14 However, independently, H, C 1~6 Alkyl or C 3~8 is cycloalkyl, or or R 13 and R 14 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl) and for each of (i) through (iii), # indicates the point of attachment to the phenyl ring-bearing moiety Q and ## indicates the point of attachment to the phenyl ring-bearing moiety X. 1 ~X 4 indicates the point of attachment to 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 SF5, C 1~6 Alkyl or C 1~6 the alkoxy is optionally substituted with one or more halo; However, X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF5, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo.

[0053] As used herein, the term "compound of formula (A): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or -N-(C 1~6 alkyl), Y is O or -N-(C 1~6 alkyl), However, 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; or R a , R b , and R c Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; L, [ka] (In the formula, A is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R x is H or or R x But R 1 and R 2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is an alkoxy, R 1 and R 2 is independently H, halo, or —OH; or R 1 and R 2 One of them is R x and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is alkoxy, and R 1 and R 2 the other of which is H, halo, or —OH; R 3 is H, -OH, halo, or C 1~6 is an alkoxy, R 4 and R 5 are independently H or or R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl, however, (1)R x But R 1 and R 2together with the atom to which they are attached to form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from the group consisting of one or more of -OH, halo, C 1~6 Alkyl or C 1~6 optionally substituted with alkoxy, or (2)R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl), [ka] (In the formula, E is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), p is 0 or 1, provided that when p is 1, E is O; R 6 is H or —OH, R y is H or or R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or or R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 7 is H or or R 7 But R y and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 8 and R 9 are independently H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R yand together with the atoms to which they are attached form a 3- to 8-membered heterocyclyl, and R 8 and R 9 The other of these is H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 Forming a cycloalkyl, R 8 and R 9 The other of these is H or C 1~6 is alkyl, R 10 is H or or R 10 But R 8 and R 9 together with the atoms to which they are attached, 3~8 forming a cycloalkyl, however, (1)R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (2)R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (3)R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 forming a cycloalkyl), and [ka] (In the formula, G is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R z But H or C 1~6 alkyl, C1~6 Alkyl is one or more C 3~8 optionally substituted with cycloalkyl; R 11 and R 12 are independently H, —OH, halo, or C 1~6 is alkyl, R 13 and R 14 However, independently, H, C 1~6 Alkyl or C 3~8 is cycloalkyl, or or R 13 and R 14 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl) and for each of (i) through (iii), # indicates the point of attachment to the phenyl ring-bearing moiety Q and ## indicates the point of attachment to the phenyl ring-bearing moiety X. 1 ~X 4 indicates the point of attachment to 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, C 1~6 Alkyl or C 1~6 the alkoxy is optionally substituted with one or more halo; However, X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl or C 1~6 Alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo.

[0054] Any embodiment 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, is also an embodiment 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.

[0055] In some embodiments, compounds of Formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are provided, wherein L is [ka] and therefore the compound of formula (A) is of formula (I): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I) 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.

[0056] Provided herein, in some embodiments, 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 has the formula (I-A1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-A1) 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 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] Provided herein, in some embodiments, 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 has the formula (I-A2): [ka] 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 In some variations, X in formula (I-A2) is N(CH). In some embodiments, A is N(CH). In some variations, X in formula (I-A2) is N(CH). 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 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] Provided herein, in some embodiments, 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, such that the compound has the formula (I-A3): [ka] 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 In some variations, X in formula (I-A3) is CH(CH). In some embodiments, A is CH(CH). In some variations, X in formula (I-A3) is CH(CH). 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 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.

[0059] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), (I-A2), or (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 In some embodiments, R x is R 1 and R 2 together with the atom to which they are attached form a 3- to 6-membered heterocyclyl, wherein the 3- to 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 In some embodiments, R x is R 1 and R 2 together with the atom to which they are attached form a 5- to 8-membered heterocyclyl, wherein the 5- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 In some embodiments, R x is R 1 and R 2 together with the atom to which they are attached form a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 Alkoxy. R x is R 1 and R 2together with the atom to which they are attached form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 Alkoxy. R x is R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 alkoxy, and the compound has the formula (I-B1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-B1) 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 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.

[0061] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-B2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-B2) 1 , X 2 , X 3 , X 4 , R 3 , R 4 , R 5 , R a , R b , R c , Rg , R x , Q, Y, and n are as defined for 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-B3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-B3) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-C1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-C1) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R gsubstituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 alkoxy, and the compound has the formula (I-C2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-C2) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 alkoxy, and the compound has the formula (I-C3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-C3) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-D1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-D1) 1 , X 2 , X 3 , X 4 , R 3 , R 4 , R 5 , R a , R b , R c , Rg , R x , Q, Y, and n 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-D2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-D2) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-D3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-D3) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R gsubstituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-E1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-E1) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-E2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-E2) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-E3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-E3) 1 , X 2 , X 3 , X 4 , R 3 , R 4 , R 5 , R a , R b , R c , Rg , R x , Q, Y, and n 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.

[0072] Provided herein, in some embodiments, is a compound of Formula (A) or Formula (I), e.g., 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.

[0073] Provided herein, in some embodiments, is a compound of Formula (A) or Formula (I), e.g., 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.

[0074] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-F1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-F1) 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 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.

[0075] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 alkoxy, and the compound has the formula (I-F2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-F2) 1 , X 2 , X 3 , X 4 , R 3 , R 4 , R 5 , R a , R b , R c , Rg , R x , Q, Y, and n 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 alkoxy, and the compound has the formula (I-F3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-F3) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 alkoxy, and the compound has the formula (I-G1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-G1) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is selected from n independently selected R gsubstituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 alkoxy, and the compound has the formula (I-G2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-G2) 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 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R x But R 1 and R 2 together with the atom to which they are attached form a 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, wherein n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl, or C 1~6 alkoxy, and the compound has the formula (I-G3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-G3) 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 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.

[0080] Provided herein, in some embodiments, is a compound of Formula (A) or Formula (I), e.g., 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 to 6. In some embodiments, n is an integer from 0 to 5. In some embodiments, n is an integer from 0 to 4. In some embodiments, n is an integer from 0 to 3. In some embodiments, n is an integer from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is an integer from 1 to 6. In some embodiments, n is an integer from 1 to 5. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is an integer from 1 to 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.

[0081] Provided herein, in some embodiments, are compounds of Formula (A) or Formula (I), e.g., compounds 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 -OH, halo, C 1~6Alkyl or C 1~6 In some embodiments, R g -OH, C 1~6 Alkyl or C 1~6 In some embodiments, R g -OH, halo, C 1~3 Alkyl or C 1~3 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 In some embodiments, R g is methyl. In some embodiments, R g is C 1~6 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 compounds 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.

[0082] Provided herein, in some embodiments, is a compound of Formula (A) or Formula (I), e.g., 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 C 1~6 In some embodiments, n is 1 and R gIn some embodiments, n is 2 and each R g is C 1~6 In some embodiments, n is 2 and each R g is methyl. In some embodiments, n is 1 and R g In some embodiments, n is 1 and R g is C 1~6 In some embodiments, n is 1 and R g is methoxy.

[0083] Provided herein, in some embodiments, is a compound of Formula (A') or Formula (I), e.g., 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 C 1~6 In some embodiments, n is 1 and R g In some embodiments, n is 2 and each R g is C 1~6 In some embodiments, n is 2 and each R g is methyl. In some embodiments, n is 1 and R g In some embodiments, n is 1 and R g is C 1~6 In some embodiments, n is 1 and R g In some embodiments, n is 2 and one or more R g is methyl and R g The other is -OH.

[0084] Provided herein, in some embodiments, are compounds of Formula (A) or Formula (I), e.g., compounds 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 is independently H. In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 and R 5 together with the atoms to which they are bonded, C 3~8 In some embodiments, R 4 and R 5 together with the atoms to which they are attached, C 3~6 In some embodiments, R 4 and R 5 together with the atom to which they are attached form a cyclobutyl. In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A1), or a pharmaceutically acceptable salt of any of the foregoing, wherein R4 and R 5 together with the atom to which they are attached to form a cyclobutyl, and the compound has the formula (I-H1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-H1) 1 , X 2 , X 3 , X 4 , R 3 , R 4 , R 5 , R a , R b , R c , R x , 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.

[0087] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A2), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 and R 5 together with the atom to which they are attached to form a cyclobutyl, and the compound has the formula (I-H2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-H2) 1 , X 2 , X 3 , X 4 , R 3 , R 4 , R 5 , R a , R b , R c , R x, 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.

[0088] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds of Formula (I-A3), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 and R 5 together with the atom to which they are attached to form a cyclobutyl, and the compound has the formula (I-H3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (I-H3) 1 , X 2 , X 3 , X 4 , R 3 , R 4 , R 5 , R a , R b , R c , R x , 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.

[0089] Provided herein in some embodiments are compounds of Formula (A) or Formula (I), e.g., compounds 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 2and each is H. Provided herein, in some embodiments, are compounds of Formula (A) or Formula (I), e.g., compounds 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 compounds 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.

[0090] Provided herein, in some embodiments, are compounds of Formula (A) or Formula (I), e.g., compounds 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 In some embodiments, R 3 is H. In some embodiments, R 3 is -OH, halo, or C 1~6 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 In some embodiments, R 3 is methoxy.

[0091] Provided herein, in some embodiments, are compounds of Formula (A) or Formula (I), e.g., compounds 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 and each is H. Provided herein, in some embodiments, are compounds of Formula (A) or Formula (I), e.g., compounds 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 is H. In some embodiments, the embodiments provided herein also apply to compounds 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. Provided herein, in some embodiments, are compounds of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is [ka] In some embodiments, L is [ka] and the compound of formula (A) is of formula (II): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II) 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.

[0092] Provided herein, in some embodiments, 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 and the compound has the formula (II-A1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-A1) 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 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] Provided herein, in some embodiments, 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; and the compound has the formula (II-A2): [ka] 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 In some variations, X in formula (II-A2) is N(CH). In some embodiments, E is N(CH). In some variations, X in formula (II-A2) is N(CH). 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 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] Provided herein, in some embodiments, 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 CH2, and the compound has the formula (II-A3): [ka] 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 In some variations, X in formula (II-A3) is CH(CH). In some embodiments, E is CH(CH). In some variations, X in formula (II-A3) is CH(CH). 1 , X 2 , X3 , X 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R b , R c , R y , p, 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.

[0095] Provided herein in some embodiments are compounds 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 But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl. y is R 7 and together with the atom to which they are attached form a 3- to 6-membered heterocyclyl. y is R 7 and together with the atom to which they are attached form a 5- to 8-membered heterocyclyl. y is R 7 and together with the atom to which they are attached form a 5- to 6-membered heterocyclyl. y is R 7 and together with the atom to which they are attached form a 5-membered heterocyclyl. y is R 7 and together with the atom to which they are attached form a 6-membered heterocyclyl. In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments of the foregoing are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A1), (II-A2), or (II-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, where p is 1. Provided herein in other embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A1), (II-A2), or (II-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, where p is 0. In some variations, the embodiments provided herein also apply to compounds of Formula (A'), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, or any variations or embodiments thereof.

[0097] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y But R 7 and together with the atom to which they are attached form a 6-membered heterocyclyl, p is 1, and the compound has the formula (II-B1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-B1) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c, 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.

[0098] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y But R 7 and together with the atom to which they are attached form a 5-membered heterocyclyl, p is 0, and the compound has the formula (II-C1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-C1) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c , 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.

[0099] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y But R 7 and together with the atom to which they are attached form a 5-membered heterocyclyl, p is 0, and the compound has the formula (II-C2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-C2) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c , 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.

[0100] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y But R 7 and together with the atom to which they are attached form a 5-membered heterocyclyl, p is 0, and the compound has the formula (II-C3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-C3) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c, 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.

[0101] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y But R 7 and together with the atom to which they are attached form a 6-membered heterocyclyl, p is 0, and the compound has the formula (II-D1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-D1) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c , 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.

[0102] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y But R 7 and together with the atom to which they are attached form a 6-membered heterocyclyl, p is 0, and the compound has formula (II-D2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-D2) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c , 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.

[0103] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds of Formula (II-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y But R 7 and together with the atom to which they are attached form a 6-membered heterocyclyl, p is 0, and the compound has formula (II-D3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-D3) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c, 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.

[0104] Provided herein in some embodiments of the foregoing are compounds of Formula (A) or Formula (II), e.g., compounds 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 and R 8 is C 1~6 alkyl, and R 9 is C alkyl. In some embodiments, R 6 is -OH and R 8 is methyl and R 9 is methyl. In some embodiments, R 6 is -OH and R 8 is H and R 9 is H. In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 8 and R 9 One of them is R 10 , together with the atoms to which they are attached, form C 3~8 In some embodiments, R 8 and R 9 One of them is R 10, together with the atoms to which they are attached, form C 3~6 In some embodiments, R 8 and R 9 One of them is R 10 , together with the atoms to which they are attached, form C 3~4 In some embodiments, R 8 and R 9 One of them is R 10 and together with the atom to which they are attached form cyclobutyl. In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 8 and R 9 One of them is R 10 together with the atom to which they are attached to form a cyclobutyl, and the compound has the formula (II-E1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (II-E1) 1 , X 2 , X 3 , X 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , R c, 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.

[0107] Provided herein in some embodiments are compounds of Formula (A) or Formula (II), e.g., compounds 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 compounds 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] Provided herein in some embodiments are compounds of Formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is [ka] Provided herein in some embodiments are compounds of Formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is [ka] and the compound has the formula (III): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (III) 1 , X 2 , X 3 , X 4 , R 11 , R 12 , R 13 , R14 , 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.

[0109] Provided herein, in some embodiments, 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 and the compound has the formula (III-A1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (III-A1) 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 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] Provided herein, in some embodiments, 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; and the compound has the formula (III-A2): [ka] 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 In some variations, X in formula (III-A2) is N(CH). In some embodiments, G is N(CH). In some variations, X in formula (III-A2) is N(CH). 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 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] Provided herein, in some embodiments, 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 CH2, and the compound has the formula (III-A3): [ka] 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 In some variations, X in formula (III-A3) is methyl. In some embodiments, G is methyl. In some variations, X in formula (III-A3) is methyl. 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 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.

[0112] Provided herein in some embodiments are compounds of Formula (A) or Formula (III), e.g., compounds 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, C 1~6 Alkyl is one or more C 3~8 In some embodiments, R z is the unsubstituted C 1~6 In some embodiments, R z is the unsubstituted C 1~3 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, C 1~6 Alkyl has one or more C 3~8 In some embodiments, R z is C 1~6 alkyl, C 1~6 Alkyl is one or more C 3~6 In some embodiments, R z is methyl, and the methyl is substituted with cyclopropyl. In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (III), e.g., compounds 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 11 and R 12 one of which is -OH and R 11 and R 12 the other of which is H, halo, or C 1~6 In some embodiments, R 11 and R 12 one of which is -OH and R 11 and R 12 The other of R is H. In some embodiments, R 11 and R 12 one of which is -OH and R 11 and R 12 The other one is C 1~6 In some embodiments, R 11 and R 12 one of which is -OH and R 11 and R 12 and the other of is methyl. In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds of Formula (A) or Formula (III), e.g., compounds 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 In some embodiments, R 13 and R 14and are both methyl. In some embodiments, R 13 and R 14 One of the is H and R 13 and R 14 The other one is C 1~6 Alkyl or C 3~8 In some embodiments, R 13 and R 14 One of the is H and R 13 and R 14 The other one is C 1~6 In some embodiments, R 13 and R 14 One of the is H and R 13 and R 14 The other of R is methyl. 13 and R 14 One of the is H and R 13 and R 14 The other one is C 3~8 In some embodiments, R 13 and R 14 One of the is H and R 13 and R 14 Another of R is cyclopropyl. 13 and R 14 are taken together with the atoms to which they are attached to form a 3- to 8-membered heterocyclyl. 13 and R 14 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl. 13 and R 14 are taken together with the atoms to which they are attached to form a 5- to 8-membered heterocyclyl. 13 and R 14 are taken together with the atoms to which they are attached to form a 5- to 6-membered heterocyclyl. 13 and R 14together with the atom to which they are attached form tetrahydrofuranyl. In some variations, the embodiments provided herein also apply to compounds 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.

[0115]

[0023] As used herein, in some embodiments, compounds of Formula (A), e.g., 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), (I-H4), (I-H5), (I-H6), (I-H7), (I-H8), (I-H9), (I-H10), (I-H11), (I-H12), (I-H13), (I-H14), (I-H15), (I-H16), (I-H17), (I-H18), (I-H19), (I-H20), (I-H21), (I-H22), (I-H23), (I-H24), (I-H25), (I-H26), (I-H27), (I-H28), (I-H29), (I-H30), (I-H31), (I-H32), (I-H33), (I-H34), (I-H35), (I-H36), (I-H37), (I-H38), (I-H39), (I-H40), (I-H41), (I-H39), (I-H42), (I-H35), (I-H36), (I-H37), (I-H43), (I-H38), (I-H44), (I-H39), (I-H45), (I-H46), ( and (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, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo, provided that X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl, or C 1~6 Alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo. In some embodiments, X 1 , X 2 , X3 , and X 4 Three of them are H and X 1 , X 2 , X 3 , and X 4 One of the following is a halo, -CN, C 1~6 Alkyl, or C 1~6 Alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo. In some embodiments, X 1 , X 2 , X 3 , and X 4 Two of them are H and X 1 , X 2 , X 3 , and X 4 two of which may be independently selected from halo, -CN, C 1~6 Alkyl, or C 1~6 Alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo.

[0116]

[0023] As used herein, in some embodiments, compounds of Formula (A), e.g., 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), (I-H4), (I-H5), (I-H6), (I-H7), (I-H8), (I-H9), (I-H10), (I-H11), (I-H12), (I-H13), (I-H14), (I-H15), (I-H16), (I-H17), (I-H18), (I-H19), (I-H20), (I-H21), (I-H22), (I-H23), (I-H24), (I-H25), (I-H26), (I-H27), (I-H28), (I-H29), (I-H30), (I-H31), (I-H32), (I-H33), (I-H34), (I-H35), (I-H36), (I-H37), (I-H38), (I-H39), (I-H40), (I-H41), (I-H39), (I-H42), (I-H35), (I-H36), (I-H37), (I-H43), (I-H38), (I-H44), (I-H39), (I-H45), (I-H46), ( and (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 4are, independently of each other, H, halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF 5 and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo, provided that X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF 5 and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo. In some embodiments, X 1 , X 2 , X 3 , and X 4 Three of them are H and X 1 , X 2 , X 3 , and X 4 One of the following is a halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF 5 and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo. In some embodiments, X 1 , X 2 , X 3 , and X 4 Two of them are H and X 1 , X 2 , X 3 , and X 4 two of which may be independently selected from halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF 5 and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more halo.

[0117]

[0023] As used herein, in some embodiments, compounds of Formula (A), e.g., 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), (I-H4), (I-H5), (I-H6), (I-H7), (I-H8), (I-H9), (I-H10), (I-H11), (I-H12), (I-H13), (I-H14), (I-H15), (I-H16), (I-H17), (I-H18), (I-H19), (I-H20), (I-H21), (I-H22), (I-H23), (I-H24), (I-H25), (I-H26), (I-H27), (I-H28), (I-H29), (I-H30), (I-H31), (I-H32), (I-H33), (I-H34), (I-H35), (I-H36), (I-H37), (I-H38), (I-H39), (I-H40), (I-H41), (I-H39), (I-H42), (I-H35), (I-H36), (I-H37), (I-H43), (I-H38), (I-H44), (I-H39), (I-H45), (I-H46), ( and (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 H, and X 3 and X 4 One of the two is H and X 3 and X 4 In some embodiments, the other of X is halo. 1 and X 2 are H and X 3 and X 4 One of them is H and X 3 and X 4and the other 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. As used herein, in some embodiments, a compound of Formula (A), e.g., 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), (I-H4), (I-H5), (I-H6), (I-H7), (I-H8), (I-H9), (I-H10), (I-H11), (I-H12), (I-H13), (I-H14), (I-H15), (I-H16), (I-H17), (I-H18), (I-H19), (I-H20), (I-H21), (I-H22), (I-H23), (I-H24), (I-H25), (I-H26), (I-H27), (I-H28), (I-H29), (I-H30), (I-H31), (I-H32), (I-H33), (I-H34), (I-H35), (I-H36), (I-H37), (I-H38), (I-H39), (I-H49), (I-H41), (I-H32), (I-H33), (I-H34), (I-H3 and (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 One of the two is H and X 1 and X 2 The other one is C 1~6 is alkyl, and X 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is ethyl, 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other one is C 1~6 Alkoxy, C 1~6 The alkoxy is optionally substituted with one or more halo, and X 3 and X 4are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is methoxy. 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is -O-CHF2, 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other one is a halo, and the other one is an X 3 and X 4 One of them is H and X 3 and X 4 Others of X are halo. 1 and X 2 One of them is H and X 1 and X 2 The other is chloro, and X 3 and X 4 One of them is H and X 3 and X 4 Others of X are chloro. 1 and X 2 are H and X 3 and X 4 and each is halo. In some embodiments, X 1 and X 2 are H and X 3 and X 4 and each is chloro. In some embodiments, X 1 and X 2 are H and X 3 and X 4 One of them is H and X 3 and X 4and the other is -CN. As used herein, in some embodiments, compounds of formula (A), such as compounds 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- and (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 One of the two is H and X 1 and X 2 The other one is C 1~6 is alkyl, and X 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is ethyl, 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other one is C 1~6 Alkoxy, C 1~6 The alkoxy is optionally substituted with one or more halo, and X 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is methoxy. 3 and X4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is -O-CHF2, 3 and X 4 are each H. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is -O-CHF2, 3 and X 4 One of them is H and X 3 and X 4 Others of X are chloro. 1 and X 2 One of them is H and X 1 and X 2 The other one is a halo, and the other one is an X 3 and X 4 One of them is H and X 3 and X 4 Others of X are halo. 1 and X 2 One of them is H and X 1 and X 2 The other one is C 1~6 is alkyl, and X 3 and X 4 One of them is H and X 3 and X 4 Others of X are halo. 1 and X 2 One of them is H and X 1 and X 2 The other of X is methyl, 3 and X 4 One of them is H and X 3 and X 4 Others of X are halo. 1 and X 2 One of them is H and X 1 and X2 The other one is C 1~6 is alkoxy, and X 3 and X 4 One of them is H and X 3 and X 4 Others of X are halo. 1 and X 2 One of them is H and X 1 and X 2 The other of X is methoxy. 3 and X 4 One of them is H and X 3 and X 4 Others of X are halo. 1 and X 2 One of them is H and X 1 and X 2 The other is chloro, and X 3 and X 4 One of them is H and X 3 and X 4 Others of X are chloro. 1 and X 2 are H and X 3 and X 4 and each is halo. In some embodiments, X 1 and X 2 are H and X 3 and X 4 and each is chloro. In some embodiments, X 1 and X 2 are H and X 3 and X 4 One of them is chloro, and X 3 and X 4 Others of X are fluoro. 1 and X 2 are H and X 3 and X 4 One of them is H and X 3 and X 4 Another of X is -CN. 1 and X2 are H and X 3 and X 4 One of them is H and X 3 and X 4 and each is -CN. In some embodiments, X 1 and X 2 are H and X 3 and X 4 One of them is C 1~6 is alkyl, and X 3 and X 4 Another of X is -CN. 1 and X 2 are H and X 3 and X 4 One of them is a halo, and X 3 and X 4 Another of X is -CN. 1 and X 2 are H and X 3 and X 4 One of the groups is -CF3, and X 3 and X 4 Another of X is -CN. 1 and X 2 One of them is H and X 1 and X 2 The other one is C 1~6 alkyl, and one X 3 and X 4 is the halo, and X 3 and X 4 Another of X is -CN. 1 and X 2 are H and X 3 and X 4 One of them is H and X 3 and X 4 The other is -SF5.

[0118] In some embodiments, the phenyl ring-bearing moiety X 1 , X 2 , X 3 , and X 4 teeth, [ka] In some embodiments, the phenyl ring-bearing moiety X 1 , X 2 , X 3 , and X 4 teeth, [ka] In some embodiments, the phenyl ring-bearing moiety X 1 , X 2 , X 3 , and X 4 teeth, [ka] In some embodiments, the phenyl ring-bearing moiety X 1 , X 2 , X 3 , and X 4 teeth, [ka] In some embodiments, the phenyl ring-bearing moiety X 1 , X 2 , X 3 , and X 4 teeth, [ka] is.

[0119] As used herein, in some embodiments, compounds of formula (A), e.g., compounds 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. Provided herein, in some embodiments, 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): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (B) 1 , X 2 , X 3 , X 4 , R a , R b , R c , L, and Y are as defined for Formula (B) and 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] Provided herein in some embodiments are compounds 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 and the compound has the formula (B-1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (B1) 1 , X 2 , X 3 , X 4 , R a , R b , R c 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.

[0121] Provided herein in some embodiments are compounds 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is C 1~6 alkyl, and R a , R b , or R c C1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is [ka] is.

[0122] Provided herein in some embodiments are compounds 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and Rc two of which are independently H and R a , R b , and R c One of them is [ka] is.

[0123] Provided herein in some embodiments are compounds 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 Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c any two of these together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a, R b , and R c Any two of these, together with the atoms to which they are attached, form an oxetanyl group, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds 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, and the compound has the formula (B-2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (B-2) 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.

[0125] Provided herein in some embodiments are compounds 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 X 1 and X 2 One of the two is H and X 1 and X 2 The other one is chloro, and X 3 is H and X 4 is H, and the compound has the formula (B-3): [ka] 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.

[0126] Provided herein in some embodiments are compounds 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 In some embodiments, Y is —N(CH 3 ), wherein the compound has the formula (B-4): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (B-4) 1 , X 2 , X 3 , X 4 , R a , R b , R cand 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.

[0127] Provided herein in some embodiments are compounds 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is [ka] is.

[0128] Provided herein in some embodiments are compounds 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is [ka] is.

[0129] Provided herein in some embodiments are compounds 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 cAny two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c any two of these together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c Any two of these, together with the atoms to which they are attached, form an oxetanyl group, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 Optionally substituted with alkyl.

[0130] Provided herein in some embodiments are compounds 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 Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c any two of these together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c Any two of these, together with the atoms to which they are attached, form an oxetanyl group, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , Rb , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c Any two of these, together with the atoms to which they are attached, form an azetidinyl, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 Optionally substituted with alkyl.

[0131] Provided herein in some embodiments are compounds 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, and the compound has the formula (B-5): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (B-5) 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.

[0132] Provided herein in some embodiments are compounds 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 X 1 and X 2 One of the two is H and X 1 and X 2 The other one is chloro, and X 3 is H and X 4 is H, and the compound has the formula (B-6): [ka] 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 and 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.

[0133] As used herein, in some embodiments, compounds of formula (A), e.g., 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 1~6In some embodiments, Q is -N(CH3). Provided herein, in some embodiments, 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): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (C) 1 , X 2 , X 3 , X 4 , R a , R b , R c 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.

[0134] Provided herein in some embodiments are compounds 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is C 1~6 alkyl, and R a , Rb , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is [ka] is.

[0135] Provided herein in some embodiments are compounds 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c two of which are independently H and R a , R b , and R c One of them is C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, R a , Rb , and R c two of which are independently H and R a , R b , and R c One of them is [ka] is.

[0136] Provided herein in some embodiments are compounds 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 Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 In some embodiments, R a , R b , and R c any two of these together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some embodiments, Ra , R b , and R c Any two of these, together with the atoms to which they are attached, form an oxetanyl group, and R a , R b , and R c The others are H or C 1~6 alkyl, and R a , R b , or R c C 1~6 Alkyl independently contains one or more -OH, C 1~6 Alkoxy, or -S(O)2-C 1~6 In some variations, the embodiments provided herein also apply to compounds 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] Provided herein in some embodiments are compounds 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, and the compound has the formula (C-1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations, X of formula (C-1) 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.

[0138] Provided herein in some embodiments are compounds 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 X 1 and X 2 One of the two is H and X 1 and X 2 The other one is chloro, and X 3 is H and X 4 is H and the compound has the formula (C-2): [ka] 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.

[0139] As used herein, in some embodiments, for example, compounds represented by 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), ( Compounds of formula (A), including compounds of formula (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, for example, compounds of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein L is [ka] ), or any embodiment or variation thereof as described elsewhere herein, is provided.

[0140] As used herein, in some embodiments, for example, compounds represented by 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), ( Compounds of formula (A'), including compounds of formula (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, for example, compounds of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein L is [ka] ), or any embodiment or variation thereof as described elsewhere herein, is provided.

[0141] As used herein, in some embodiments, for example, compounds represented by 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), ( Compounds of formula (A), including compounds of formula (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, for example, compounds of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein L is [ka] ), or any embodiment or variation thereof as described elsewhere herein, is provided.

[0142] As used herein, in some embodiments, for example, compounds represented by 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), ( Compounds of formula (A'), including compounds of formula (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, for example, compounds of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein L is [ka] ), or any embodiment or variation thereof as described elsewhere herein, is provided.

[0143] As used herein, in some embodiments, for example, compounds represented by 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), ( Compounds of formula (A), including compounds of formula (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, for example, compounds of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein L is [ka] ), or any embodiment or variation thereof as described elsewhere herein, is provided.

[0144] As used herein, in some embodiments, for example, compounds represented by 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), ( Compounds of formula (A'), including compounds of formula (II-C3), (II-D1), (II-D2), (II-D3), (II-E1), (III), (III-A1), (III-A2), or (III-A3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, for example, compounds of formula (B), (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (C), (C-1), or (C-2), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein L is [ka] ), or any embodiment or variation thereof as described elsewhere herein, is provided.

[0145] Provided herein, in some embodiments, are compounds of Formula (A) or Formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein L is: [ka] [ka] wherein # indicates the point of attachment to the phenyl ring-bearing moiety Q and ## indicates the point of attachment to the phenyl ring-bearing moiety X 1 ~X 4 indicates the attachment point to

[0146] Provided herein in some embodiments are compounds of Formula (A) or Formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein L and a phenyl ring-bearing moiety X 1 ~X 4 Together, [ka] [ka] [ka] [ka] forming a structure selected from the group consisting of:

[0147] Provided herein, in some embodiments, are compounds of Formula (A) or Formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein the phenyl ring-bearing Q is: [ka] is selected from the group consisting of:

[0148] Provided herein, in some embodiments, are compounds of formula (A'), or a pharmaceutically acceptable salt of any of the foregoing, wherein L and the phenyl ring-bearing moiety Q together represent: [ka] [ka] [ka] [ka] [ka] forming a structure selected from the group consisting of:

[0149] X as provided herein 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. Any variation or embodiment of X, n, p, A, E, G, L, Q, and Y may be used in combination with any of the following: 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 can be combined with any other variation or embodiment.

[0150] Provided herein, in some embodiments, is a compound of Formula (A'), a compound of Formula (A), or any variation of its embodiments, 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 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24] [Table 2-25] [Table 2-26]

[0151] In some embodiments, the 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-methoxyphenyl)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-{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-[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-lambda-6-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-lambda 6-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-lambda 6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[3-methyl-4-({4-[methyl(methylimino)oxo-lambda 6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[2-methyl-4-({4-[methyl(methylimino)oxo-lambda 6-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-lambda 6-sulfanyl]phenoxy}methyl)pyrrolidin-1-yl]ethyl}benzonitrile; 3-{2-[2-methyl-4-({4-[methyl(methylimino)oxo-lambda 6-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-lambda 6-sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile; 3-chloro-5-{2-[3-({4-[methyl(methylimino)oxo-lambda 6-sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile; and 3-chloro-5-{2-[3-({4-[methyl(methylimino)oxo-lambda 6-sulfanyl]phenoxy}methyl)piperazin-1-yl]ethyl}benzonitrile, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also encompassed are isotopically labeled forms of any of the foregoing, such as deuterated or tritiated forms (where at least one hydrogen is replaced with at least one deuterium or tritium) of any of the specific compounds detailed herein. Mixtures of any of the foregoing are also encompassed and described. Prodrugs of any of the foregoing are also encompassed herein.

[0152] In some embodiments, the 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-(methylsulfonyl)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-methoxyphenyl)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-[(3S,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. Also encompassed are isotopically labeled forms of any of the foregoing, such as deuterated or tritiated forms (where at least one hydrogen is replaced with at least one deuterium or tritium) of any of the specific compounds detailed herein. Mixtures of any of the foregoing are also encompassed and described. Prodrugs of any of the foregoing are also encompassed herein.

[0153] The compound names contained in Table 1 and the list in the preceding paragraph were generated using ChemDraw® software version 18.1.0.458 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update#3.

[0154] composition 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. Provided herein, in some embodiments, are pharmaceutical compositions comprising (i) 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.

[0155] 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 encompassed by the term excipient, including, but not limited to, binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable tablets, sweeteners or flavoring agents, suspending / gelling agents, or any substance used as a wet granulator. Examples of suitable excipients are well known to those skilled in the art. Such compositions are prepared by methods well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Academic Press, 23, incorporated by reference. rd Please refer to ed.(2020).

[0156] The pharmaceutical composition may be administered in either a single dose or multiple doses. The pharmaceutical composition may be administered by a variety of methods, including, for example, oral, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0157] The compounds described herein can be administered to individuals in the form of commonly accepted oral compositions, such as tablets, coated tablets, gel capsules in hard or soft shells, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or its derivatives, talc, stearates, or salts thereof. Acceptable carriers for soft-shelled gel capsules include vegetable oils, waxes, fats, semi-solids, and liquid polyols. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0158] The specific dose level of a compound as described herein depends on various factors, such as the age, weight, and sex of the individual, as well as the route of administration and other factors. In some embodiments, the dose is expressed as milligrams of a compound as described herein per kilogram of the individual's body weight (mg / kg). Doses of about 0.1 mg / kg to 100-150 mg / kg may be appropriate.

[0159] The compound may be administered to the individual according to an effective dosing regimen for a desired period or duration, for example, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, which in some variations may be the duration of the individual's life.

[0160] Treatment method Provided herein are methods for 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. Also provided herein are methods for 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, and a composition comprising one or more pharmaceutically acceptable excipients. Also encompassed are isotopically labeled forms of any of the foregoing, including, but not limited to, deuterated or tritiated forms (in which at least one hydrogen is replaced by at least one deuterium or tritium) of any of the specific compounds detailed herein.

[0161] Provided herein is a method of inhibiting APOL1 in a cell, the method 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. Also provided herein is a method of inhibiting APOL1 in a cell, the method 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, and one or more pharmaceutically acceptable excipients.

[0162] Provided herein are methods 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. Also provided herein are methods of inhibiting APOL1 in an individual, comprising administering to the individual an effective amount of 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.

[0163] In some embodiments, the compounds provided herein inhibit APOL1 at concentrations of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein inhibit APOL1 at concentrations of 1-10 μM, 0.01-1 μM, or 0.01-10 μM.

[0164] In some embodiments, the compounds provided herein reduce cell death caused by overexpression of APOL1. In some embodiments, the compounds provided herein reduce cell death caused by overexpression of APOL1 at concentrations of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein reduce cell death caused by overexpression of APOL1 at concentrations of 1-10 μM, 0.01-1 μM, or 0.01-10 μM.

[0165] In some embodiments, the compounds provided herein have an EC50 of less than 1 μM, less than 0.5 μM, or less than 0.1 μM. 50 In some embodiments, the compounds provided herein have an EC of 1-10 μM, 0.01-1 μM, or 0.01-10 μM. 50 It has.

[0166] In some embodiments, the compounds provided herein have an AC of less than 1 μM, less than 0.5 μM, or less than 0.1 μM. 50 In some embodiments, the compounds provided herein have an AC of 1-10 μM, 0.01-1 μM, or 0.01-10 μM. 50 In some embodiments, AC 50 The values ​​reflect the ability of the compound to prevent calcium influx by inhibiting APOL1.

[0167] In some embodiments, compounds provided herein inhibit cation channels. In some embodiments, compounds of the present disclosure inhibit calcium channels. In some embodiments, compounds of the present disclosure decrease calcium transport.

[0168] Provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A) or Formula (A'), or any variant or embodiment thereof as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of 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 variant 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.

[0169] Provided herein is a method of treating a renal 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. Also provided herein is a method of treating a renal 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.

[0170] In some embodiments, the individual has chronic kidney disease. In some embodiments, the individual has kidney disease caused by hypertension. In some embodiments, the kidney disease, kidney injury, or condition is an APOL1-mediated kidney disease, kidney injury, or condition. In some embodiments, the kidney disease, kidney injury, or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), kidney disease caused by hypertension, viral nephropathy, COVID-19-associated nephropathy, human immunodeficiency virus-associated nephropathy (HIVAN), sickle cell nephropathy, lupus nephritis, and diabetic kidney disease.

[0171] Also provided herein are methods of treating an APOL1-mediated disorder, such as pre-eclampsia and sepsis, comprising administering to an individual in need thereof 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 individual is genetically predisposed to developing an APOL1-mediated disorder.

[0172] Also provided herein are methods for delaying the onset of progressive renal graft 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 after receiving the kidney transplant.

[0173] Provided herein is a method of treating a renal disease, disorder, or condition in an individual in need thereof, the method 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 renal disease, disorder, or condition in an individual in need thereof, the method 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.

[0174] The compounds provided herein can also be used in a method of delaying the onset 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 at risk of developing an APOL1-mediated disease, disorder, or condition. In some embodiments, the APOL1-mediated disease, disorder, or condition is pre-eclampsia or sepsis, and the individual has two APOL1 risk alleles. In some embodiments, the APOL1-mediated disease, disorder, or condition is chronic kidney disease, and the individual has any binary combination of the G1 and G2 APOL1 risk alleles. In some embodiments, the chronic kidney disease is focal segmental glomerulosclerosis (FSGS), kidney disease due to hypertension, human immunodeficiency virus-associated nephropathy (HIVAN), kidney disease due to hypertension, sickle cell nephropathy, viral nephropathy, COVID-19-associated nephropathy, lupus nephritis, diabetic kidney disease, or APOL1-associated nephropathy. The compounds provided herein may also be used in methods to delay the onset of progressive kidney graft loss in individuals who have received a kidney transplant from a high-risk APOL1 genotype donor.

[0175] 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 a G1 G (p.S342G) or G1 M (p.I384M). 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.

[0176] Also provided herein is 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.

[0177] Also provided herein are methods of preventing renal failure 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. In some embodiments, the compound prevents tissue necrosis. In some embodiments, the compound prevents apoptosis. In some embodiments, the compound reduces inflammation.

[0178] In some embodiments, the compounds provided herein reduce or eliminate one or more symptoms of kidney disease, ie, nausea, vomiting, loss of appetite, fatigue and weakness, sleep disturbances, urinary frequency problems, muscle tingling and cramping, swelling, itching, chest pain, shortness of breath, and / or high blood pressure.

[0179] In some embodiments, the compounds provided herein reduce the rate of kidney damage and / or the 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 by at least 1 month, at least 2 months, at least 3 months, or at least 1 year.

[0180] In some embodiments, the compounds slow 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 by at least 1 month, at least 2 months, at least 3 months, at least 6 months, or at least 1 year. In some embodiments, the compounds provided herein eliminate the need for a kidney transplant.

[0181] In some embodiments, the individual has chronic kidney disease at stage 1, stage 2, stage 3A, stage 3B, stage 4, or stage 5. In some embodiments, renal function is assessed using an estimated glomerular filtration rate (eGFR) renal function test.

[0182] In some embodiments, the administration is oral.

[0183] kit The present disclosure further provides kits for carrying out the methods of the present invention. The kits may include a compound as described herein or a pharmaceutically acceptable salt thereof and suitable packaging. The kits may include one or more containers containing any of the compounds described herein. In one embodiment, the kits include a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a label and / or instructions for using the compound in the treatment of a disease or disorder described herein. The kits may include a unit dosage form of the compound.

[0184] 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 its 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 its use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. Also provided is an article of manufacture 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. Also provided herein is an article 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, bottle, ampoule, pre-filled syringe, or intravenous bag.

[0185] Methods for assaying APOL1 activity Provided herein are methods for assessing APOL1 inhibition in a cell, the methods comprising inducing APOL1 expression in the 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 APOL1G2. In some embodiments, the cell stably expresses a genetically encoded calcium indicator and inducibly expresses 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.

[0186] Provided herein are methods for assessing rescue of HEK cell death caused by APOL1 overexpression, comprising inducing APOL1 expression in cells, contacting the cells with an APOL1 inhibitor, exposing the cells to a luminescent reagent, and measuring luminescence. In some embodiments, inducing APOL1 expression comprises contacting the cells with doxycycline. In some embodiments, the cells overexpress 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.

[0187] Preparation method The present disclosure further provides methods for preparing the compounds of the present invention. Provided herein, in some aspects, are methods for 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.

[0188] In some embodiments, the process 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 reacting a compound of Formula (A-I1): [ka] [In the formula, Q is absent or -N-(C 1~6 alkyl), Y is O or -N-(C 1~6 alkyl), However, 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; or R a , R b , and R c Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; V 1 but, [ka] (In the formula, A is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R x is H or or R x But R 1 and R 2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is an alkoxy; R 1 and R 2 is independently H, halo, or —OH; or R 1 and R 2 One of them is R x and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is alkoxy, and R 1 and R 2 the other of which is H, halo, or —OH; R 4 and R5 are independently H or or R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl, however, (1)R x But R 1 and R 2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is alkoxy, or (2)R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl), [ka] (In the formula, E is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R 6 is H or —OH, R y is H), and [ka] (In the formula, G is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R z But H or C 1~6 alkyl, C 1~6 Alkyl is one or more C 3~8 optionally substituted with cycloalkyl; R 11 and R12 are independently H, —OH, halo, or C 1~6 alkyl) a compound selected from the group consisting of Formula (A-I2): [ka] [In the formula, The dashed lines represent single or double bonds; W 1 is oxo, halo, or sulfonate; V 2 but, [ka] (In the formula, R 3 is H, -OH, halo, or C 1~6 alkoxy) [ka] (In the formula, p is 0 or 1, provided that when p is 1, E is O; R 7 is H, R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 Forming a cycloalkyl, R 8 and R 9 The other of these is H or C 1~6 is alkyl, R 10 But R 8 and R 9 together with the atoms to which they are attached, 3~8 forming a cycloalkyl), and [ka] (In the formula, R 13 and R 14However, independently, H, C 1~6 Alkyl or C 3~8 is cycloalkyl, or or R 13 and R 14 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl) and for each of (i) to (iii), # is selected from the group consisting of W 1 indicates the point of attachment to the phenyl ring-bearing moiety X 1 ~X 4 indicates the point of attachment to 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 SF5, C 1~6 Alkyl or C 1~6 the alkoxy is optionally substituted with one or more halo; However, X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF5, C 1~6 Alkyl or C 1~6 alkoxy optionally substituted with one or more halo to provide a compound of formula (A) or (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0189] In some embodiments, the compound of formula (A) or (A') is a) alkylating an amine of formula (A-I1) with an alkyl halide or a sulfonate 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.

[0190] In some embodiments, the compound of Formula (A) or (A') is prepared by a step comprising alkylating an amine of Formula (A-I1) with an alkyl halide or sulfonate 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 diisopropylethylamine.

[0191] In some embodiments, the sulfonate ester compound of Formula (A-I2) is mesylate or tosylate. In some embodiments, the sulfonate ester compound of Formula (A-I2) is mesylate. In some embodiments, the sulfonate ester compound of Formula (A-I2) is tosylate.

[0192] In some embodiments, a 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-I1). 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 cyanoborohydride.

[0193] In some embodiments, the process 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 reacting a compound of Formula (A-I3): [ka] (In the formula, Q is absent or -N-(C 1~6alkyl), Y is O or -N-(C 1~6 alkyl), However, 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, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; or R a , R b , and R c Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; V 2 is halo or OH) The compound Formula (A-I4): [ka] [In the formula, W 2 is H or sulfamate, L, [ka] (In the formula, A is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R x is H or or R x But R 1 and R 2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is an alkoxy, R 1 and R 2 is independently H, halo, or —OH; or R 1 and R 2 One of them is R x and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is alkoxy, and R 1 and R 2 the other of which is H, halo, or —OH; R 3 is H, -OH, halo, or C 1~6 is an alkoxy, R 4 and R 5 are independently H or or R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl, however, (1)R x But R 1 and R2 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is selected from n independently selected R g substituted with a substituent, n is an integer of 0 to 6, and R g -OH, halo, C 1~6 Alkyl or C 1~6 is alkoxy, or (2)R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl), [ka] (In the formula, E is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), p is 0 or 1, provided that when p is 1, E is O; R 6 is H or —OH, R y is H or or R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or or R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 7 is H or or R 7 But R y and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 8 and R 9 are independently H or C 1~6 Is it alkyl? or R 8 and R9 One of them is R y and together with the atoms to which they are attached form a 3- to 8-membered heterocyclyl, and R 8 and R 9 The other of these is H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 Forming a cycloalkyl, R 8 and R 9 The other of these is H or C 1~6 is alkyl, R 10 is H or or R 10 But R 8 and R 9 together with the atoms to which they are attached, 3~8 forming a cycloalkyl, however, (1)R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (2)R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (3)R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 forming a cycloalkyl), and [ka] (In the formula, G is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R zBut H or C 1~6 alkyl, C 1~6 Alkyl is one or more C 3~8 optionally substituted with cycloalkyl; R 11 and R 12 are independently H, —OH, halo, or C 1~6 is alkyl, R 13 and R 14 However, independently, H, C 1~6 Alkyl or C 3~8 is cycloalkyl, or or R 13 and R 14 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl) and for each of (i) through (iii), # indicates the point of attachment to the phenyl ring-bearing moiety Q and ## indicates the point of attachment to the phenyl ring-bearing moiety X. 1 ~X 4 indicates the point of attachment to 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 SF5, C 1~6 Alkyl or C 1~6 the alkoxy is optionally substituted with one or more halo; However, X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl or C 1~6 Alkoxy or SF5, C 1~6 Alkyl or C 1~6 alkoxy optionally substituted with one or more halo to provide a compound of formula (A) or (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0194] In some embodiments, the compound of Formula (A) or (A') is prepared by a step comprising alkylating 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 diisopropylethylamine.

[0195] In some embodiments, the compound of Formula (A) or (A') is prepared by a step comprising alkylating 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 diisopropylethylamine.

[0196] In some embodiments, the process 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 reacting a compound of Formula (A-I5): [ka] [In the formula, Q is absent or -N-(C 1~6 alkyl), Y is O or -N-(C 1~6 alkyl), However, Q is -N(C 1~6 alkyl), then Y is O; R a , R b , and R care each independently H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; or R a , R b , and R c Any two of these, together with the atoms to which they are attached, form a C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, and R a , R b , and R c The other of these is H or C 1~6 alkyl, and R a , R b , or R c C 1~6 The alkyl group may independently be one or more of -OH, C 1~6 Alkoxy or -S(O)2-C 1~6 optionally substituted with alkyl; V 3 but, [ka] (In the formula, A is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R 1 is H, halo, or —OH; R 4 and R 5 together with the atoms to which they are bonded, C 3~8 forming a cycloalkyl), [ka] (In the formula, E is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6alkyl), R 6 is H or —OH), and [ka] (In the formula, G is O, NH, N(C 1~6 alkyl), CH2, or CH(C 1~6 alkyl), R 11 is H, -OH, halo, or C 1~6 alkyl) a compound selected from the group consisting of Formula (A-I6): [ka] [In the formula, V 4 but, [ka] (In the formula, R x is H, R 3 is H, -OH, halo, or C 1~6 alkoxy) [ka] (In the formula, p is 0 or 1, provided that when p is 1, E is O; R y is H or or R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or or R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 7 is H or or R7 But R y and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R 8 and R 9 are independently H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R y and together with the atoms to which they are attached form a 3- to 8-membered heterocyclyl, and R 8 and R 9 The other of these is H or C 1~6 Is it alkyl? or R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8 Forming a cycloalkyl, R 8 and R 9 The other of these is H or C 1~6 is alkyl, R 10 is H or or R 10 But R 8 and R 9 together with the atoms to which they are attached, 3~8 forming a cycloalkyl, however, (1)R y But R 7 and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (2)R y But R 8 and R 9 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (3)R 8 and R 9 One of them is R 10 , and together with the atoms to which they are attached, C 3~8forming a cycloalkyl), and [ka] (In the formula, R 13 and R 14 However, independently, H, C 1~6 Alkyl or C 3~8 is cycloalkyl, or or R 13 and R 14 together with the atom to which they are attached form a 3- to 8-membered heterocyclyl) and X is selected from the group consisting of 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 SF5, C 1~6 Alkyl or C 1~6 the alkoxy is optionally substituted with one or more halo; However, X 1 , X 2 , X 3 , and X 4 At least one of the following is halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy or SF5, C 1~6 Alkyl or C 1~6 alkoxy optionally substituted with one or more halo to provide a compound of formula (A) or (A'), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0197] In some embodiments, the compound of Formula (A) or (A') is prepared by a step comprising alkylating an alcohol 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 diisopropylethylamine. [Example]

[0198] The following synthetic reaction schemes, detailed in the schemes, general procedures, and examples, are intended to illustrate only some of the ways in which the compounds of the present disclosure, or embodiments or aspects thereof, may be synthesized. As will be apparent to those skilled in the art, various modifications to these synthetic reaction schemes can be made.

[0199] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if necessary using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0200] While certain exemplary embodiments are shown 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 generally described herein and / or by methods available to those skilled in the art.

[0201] Synthesis Examples As shown in the following schemes, general procedures, and examples, 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 general procedures. The following general methods, and others known to synthetic chemists of ordinary skill in the art, can be applied to all formulas, variations, embodiments, and species described herein. [ka]

[0202] Compounds of Formulas S7-S9 can be prepared by the general synthetic methodology shown in Scheme 1. Where applicable, the moieties and variables shown in Scheme 1 are understood to be as defined elsewhere herein for 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. Additionally, with respect to Scheme 1, m is an integer from 0 to 5, and q is an integer from 0 to 5, with the proviso that 1≦(m+q)≦6.

[0203] The formation of the C-O bond can be achieved by the Mitsunobu reaction with phenols of formula S2 or by the S- N This can be achieved by either N-tert-butyloxycarbonyl (Boc) or N-tert-butyloxycarbonyl (N-Boc) group deprotection can proceed using a protic acid such as hydrochloric acid to provide a compound of formula S5. A compound of formula S7 can be prepared by reductive amination using an aldehyde of formula S6 and a hydride source such as NaBH3CN. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of formulas S8 and S9. [ka]

[0204] Compounds of formulas S7-S9 may be prepared by an alternative general synthetic method as shown in Scheme 2. Where applicable, the moieties and variables shown in Scheme 2 are understood to be as defined elsewhere herein for 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. Additionally, with respect to Scheme 2, m is an integer from 0 to 5, q is an integer from 0 to 5, with the proviso that 1≦(m+q)≦6, and Z 1 is halo (e.g., chloro or bromo) or a sulfonate ester (e.g., mesylate).

[0205] CO coupling of an aryl halide of formula S10 with an alcohol of formula S1 can be carried out using conditions such as copper(I) iodide, CsCO, and 3,4,7,8-tetramethyl-1,10-phenanthroline in toluene at elevated temperature to give a compound of formula S4. Deprotection of the N-tert-butyloxycarbonyl (Boc) group can proceed using a protic acid such as trifluoroacetic acid to give a compound of formula S5. Compounds of formula S7 can be prepared using a base such as KCO, an alkyl halide or alkyl sulfonate ester such as an alkyl bromide of formula S11, and an organic solvent such as MeCN at elevated temperature. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of formulas S8 and S9. [ka]

[0206] Compounds of formulas S7-S9 may be prepared by an alternative general synthetic method as shown in Scheme 3. Where applicable, the moieties and variables shown in Scheme 3 are understood to be as defined elsewhere herein for 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. Additionally, with respect to Scheme 3, m is an integer from 0 to 5, q is an integer from 0 to 5, with the proviso that 1≦(m+q)≦6, and Z 2 is halo (e.g., chloro or bromo) or a sulfonate ester (e.g., mesylate).

[0207] The formation of the CO bond can be achieved by the reaction of an alkyl halide such as an alkyl bromide of formula S12 or an alkyl sulfonate ester with a phenol of formula S2 in the presence of a base such as K2CO3. N The deprotection of the N-tert-butyloxycarbonyl (Boc) group can proceed using a protic acid such as HCl to give a compound of formula S5. Compounds of formula S7 can be prepared by reductive amination using an aldehyde of formula S6 and a hydride source such as NaBH3CN. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of formulas S8 and S9. [ka]

[0208] Compounds of formula S17 may be prepared by an alternative general synthetic method as shown in Scheme 4. Where applicable, the moieties and variables shown in Scheme 4 are understood to be as defined elsewhere herein for 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.

[0209] Compounds of formula S17 having (S)-stereochemistry can be obtained 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. Alternatively, treatment of phenol S2 with (R)-oxiran-2-ylmethanol S14 and Mitsunobu conditions such as PPh3 and DIAD can also provide (S)-S15. Epoxide ring opening to provide compounds of formula S17 proceeds in the presence of an amine of formula S16 as a solution in hot ethanol, or in the presence of triethylamine if the salt form of amine S16 is used. If the epimeric OH stereochemistry of compounds of formula S17 is desired, the previous synthetic scheme can be modified to utilize (S)-2-(chloromethyl)oxirane or (S)-oxiran-2-ylmethanol. [ka]

[0210] Compounds of formula S24 can be prepared according to Scheme 5. Reductive amination of a monoprotected piperazine such as S18 with an aldehyde such as S6 provides compound S19. Removal of the N-tert-butyloxycarbonyl (Boc) group after treatment with a protic acid such as HCl in a solvent such as MeOH provides compound S20. Treatment with thionyl chloride, triethylamine, and imidazole affords S21. Oxidation to oxathiazolidine-2,2-dioxide occurs after treatment with ruthenium(III) chloride and sodium periodate in a mixed solvent system of acetonitrile and water to provide S22. Heating S22 with a phenol and potassium carbonate such as S23 in DMF, followed by treatment with aqueous HCl, provides compounds of formula S24. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of compounds derived from formula S24. [ka]

[0211] An alternative synthetic approach to compounds of formula S24 is shown in Scheme 6. Reaction of piperazine S18 with benzyl chloroformate in the presence of a base such as sodium bicarbonate produces biscarbamate S25. Mitsunobu coupling of phenol S23 with triphenylphosphine and DIAD in THF produces S26. Selective cleavage of the benzyl carbamate can be achieved by treatment with thionyl chloride, triethylamine, and imidazole in DCM to give S27, which can then undergo reductive amination using sodium triacetoxyborohydride to provide compounds of formula S28. Cleavage of the N-tert-butyloxycarbonyl (Boc) group provides S24. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of compounds derived from formula S24. [ka]

[0212] Scheme 7 outlines an approach to compounds of formula S32. Addition of an alkylzinc reagent, generated in situ from benzyl bromide S29, to the iminium ion formed by reaction of piperazine S27 with aldehyde S30 affords S31. Removal of the N-tert-butyloxycarbonyl (Boc) group using a protic acid such as HCl in a solvent such as MeOH affords S32. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of compounds derived from formula S32. [ka]

[0213] A synthetic approach to compounds of formula S28 is shown 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 manipulations can be carried out by cleaving the boronic acid (X1 Suzuki coupling with B(OH)), Pd(dppf)Cl catalyst, and potassium carbonate can be achieved to give S24. Removal of the N-tert-butyloxycarbonyl (Boc) group after reaction with HCl in EtOAc provides compounds of formula S28. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of compounds derived from formula S28. [ka]

[0214] Scheme 9 shows an alternative 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 can be used to provide two or more single stereoisomers of formula S37. [ka]

[0215] Scheme 10 shows an alternative approach to pyrrolidine analogs of formula S48. NaBH4 reduction of the β-ketoester S40 gives the diol S41, which can be converted to S42 with fluorobenzene S42 after heating in DMF with potassium carbonate as a base. N The resulting product can be subjected to an Ar reaction. Oxidation to the ketone S44 can be achieved with Dess-Martin periodinane. Reaction with an alkylmetal reagent such as methylmagnesium bromide provides the 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, affords pyrrolidine S47. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of formula S48. [ka]

[0216] Scheme 11 shows routes to analogs with a substituted piperazine core. Reductive amination of piperazine S49 and aldehyde S6 with 2-methylpyridine borane complex gives S50. Reduction of carboxylic acid S50 with borane-dimethyl sulfide gives alcohol S51, which can be converted to S52 with fluorobenzene S42. N Ar reaction to afford S52. Removal of the N-tert-butyloxycarbonyl (Boc) group with a protic acid such as HCl in a solvent such as MeOH affords piperazine S53. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of formula S54. [ka]

[0217] Scheme 11 shows an approach to compounds of formula S57. Forming an amide bond between an amine such as pyrrolidine S55 and carboxylic acid S6 using EDC and HOBt with a tertiary amine base such as DIEA provides S56. Amide reduction can be achieved after treatment with lithium aluminum hydride to give compounds of formula S57. Chiral preparative SFC or HPLC separation can be used to provide two or more single stereoisomers of compounds derived from formula S57. [ka] Step 1: N-(4-methoxyphenyl)-N-methylmethanesulfonamide [ka]

[0218] 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 the reaction was cooled 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 × 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, 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 [ka]

[0219] To a −78° C. solution of N-(4-methoxyphenyl)-N-methylmethanesulfonamide (G2, 11.4 g, 53.0 mmol) in DCM (100 mL) was added BBr3 (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. The mixture was then extracted with DCM (100 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated 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) [ka]

[0220] 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). Then, 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 dropwise addition of water (20 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, and concentrated. 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 recrystallization (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] + .

[0221] The following intermediates in Table 2 were prepared following a similar procedure as described for Intermediate A using the appropriate starting materials. [Table 3] [ka] Step 1: (tert-Butyl (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate [ka]

[0222] 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 PPh3 (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 equiv.) 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 + NH4]. + . Step 2: (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine [ka]

[0223] 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 by 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] + .

[0224] The following intermediates in Table 3 were prepared following a similar procedure as described for Intermediate G using the appropriate starting materials. [Table 4] [ka] Step 1: 3-Bromo-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ka]

[0225] 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 was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (685 mg, 2.55 mmol) and [Ir(cod)(OMe)] (845 mg, 1.28 mmol). The mixture was then stirred at 80 °C under N for 8 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO 80 g cartridge, 0-20% EtOAc:hexanes) 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, CDCl3): 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 [ka]

[0226] To a 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 HO (10 mL) was added CuCl (3.88 g, 28.9 mmol) at room temperature, and the mixture was then stirred at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, 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:hexanes) to give 3-bromo-5-chloro-2-methyl-benzonitrile (G10). 1 H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.57 (s, 1H), 2.61 (s, 3H). Step 3: (E)-5-chloro-3-(2-ethoxyvinyl)-2-methylbenzonitrile [ka]

[0227] 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 was added KCO (360 mg, 2.60 mmol) and Pd(dppf)Cl (95.2 mg, 130 μmol). The mixture was then stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with HO (10 mL), and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, 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:hexanes) 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) [ka]

[0228] 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 the mixture was then stirred at 50 °C for 5 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, 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:hexanes) to give 5-chloro-2-methyl-3-(2-oxoethyl)benzonitrile (Intermediate I). MS = 194.0 [M+H] + . [ka] Step 1: 4-((2-(methylsulfonyl)ethyl)thio)phenol [ka]

[0229] 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 K2CO3 (7.81 g, 56.5 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with HO (100 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, 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:hexanes) to give 4-((2-(methylsulfonyl)ethyl)thio)phenol (G13). MS = 231.1 [MH] - . Step 2: 4-((2-(methylsulfonyl)ethyl)sulfonyl)phenol (Intermediate J) [ka]

[0230] To a solution of 4-(2-methylsulfonylethylsulfanyl)phenol (G13, 3.00 g, 12.9 mmol) in THF (40 mL) was added a mixture of NaIO (5.50 g, 25.8 mmol) in HO (10 mL). The mixture was then stirred at 40 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaSO (20 mL), extracted with EtOAc (20 mL × 3), dried over NaSO, 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:hexanes) to give 4-(2-methylsulfonylethylsulfonyl)phenol (Intermediate J). MS = 263.1 [MH] - . [ka] Step 1: 3-(oxiran-2-yl)benzonitrile (Intermediate K) [ka]

[0231] To a suspension of NaH (73 mg, 1.83 mmol, 60 wt% 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. After 10 min, a solution of 3-formylbenzonitrile (G14, 200 mg, 1.53 mmol) in THF (2 mL) was added slowly. The reaction mixture was degassed and purged with N three times, then the mixture was stirred at room temperature under N for 12 h. The reaction mixture was quenched by the addition of HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over NaSO, 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:hexanes) to give 3-(oxiran-2-yl)benzonitrile (Intermediate K). MS=146.1 [M+H] + . [ka] Step 1: 4-((2-methoxyethyl)thio)phenol [ka]

[0232] A mixture of 4-sulfanylphenol (G12, 1 g, 7.93 mmol), 1-bromo-2-methoxyethane (1.10 g, 7.93 mmol), and CsCO (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 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, 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 [MH]. - . Step 2: 4-((2-Methoxyethyl)sulfonyl)phenol (Intermediate M) [ka]

[0233] A mixture of 4-(2-methoxyethylsulfanyl)phenol (G18, 700 mg, 3.80 mmol) and NaIO (2.44 g, 11.4 mmol) in THF (6 mL) and HO (6 mL) was stirred at 70 °C for 16 h. The mixture was filtered, quenched with saturated aqueous NaSO (15 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over NaSO, 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:hexanes) to give 4-(2-methoxyethylsulfonyl)phenol (Intermediate M). MS = 217.1 [M+H] + .

[0234] The following intermediates in Table 4 were prepared following a similar procedure as described for Intermediate M using the appropriate starting materials. [Table 5] [ka] Step 1: tert-Butyl 3-((4-hydroxyphenyl)thio)azetidine-1-carboxylate [ka]

[0235] To a solution of tert-butyl 3-bromoazetidine-1-carboxylate (1.87 g, 7.93 mmol) in DMF (30 mL) at room temperature, CsCO (5.16 g, 15.85 mmol) and 4-sulfanylphenol (G12, 1.00 g, 7.93 mmol) were added, 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 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, 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) [ka]

[0236] 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 with saturated aqueous NaSO (5 mL) and then extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over NaSO, 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 tert-butyl 3-(4-hydroxyphenyl)sulfonylazetidine-1-carboxylate (Intermediate O). MS=258.0 [M-C4H8+H] + . Step 3: 4-(Azetidin-3-ylsulfonyl)phenol [ka]

[0237] 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 hours. The reaction mixture was then concentrated under reduced pressure to give 4-(azetidin-3-ylsulfonyl)phenol HCl salt (G20), which was carried on to the next step without further purification. MS=214.1 [M+H] + . Step 4: 4-((1-methylazetidin-3-yl)sulfonyl)phenol (Intermediate P) [ka]

[0238] To a solution of 4-(1-azetidin-3-ylsulfonyl)phenol (G20, 400 mg, 1.60 mmol, HCl salt) in MeOH (5 mL) and AcOH (0.05 mL) was 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 the addition of saturated aqueous NaHCO (10 mL) and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, 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:hexanes) to give 4-(1-methylazetidin-3-yl)sulfonylphenol (Intermediate P). MS=228.0[M+H] + . [ka] Step 1: Methyl 5-chloro-2-methoxybenzoate [ka]

[0239] To a solution of methyl 5-chloro-2-hydroxybenzoate (G21, 2.00 g, 10.7 mmol) in DMF (20 mL) was added KCO (2.96 g, 21.4 mmol) and CHCl (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 × 3). The combined organic layers were washed with brine (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-10% EtOAc:hexanes) to give methyl 5-chloro-2-methoxybenzoate (G22). MS = 201.0 [M+H] + . Step 2: (5-chloro-2-methoxyphenyl)methanol [ka]

[0240] To a solution of methyl 5-chloro-2-methoxy-benzoate (G22, 1.50 g, 7.48 mmol) in THF (15 mL) at 0 °C was added LiBH (2 M in THF, 7.5 mL, 15.0 mmol). 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 × 3). The combined organic layers were washed with brine (60 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0-50% EtOAc:hexanes) to give (5-chloro-2-methoxy-phenyl)methanol (G23). 1H NMR (400 MHz, CDCl3): 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) [ka]

[0241] 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 (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), neutralized to pH = 7-8 by addition of saturated aqueous NaHCO, and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated to give 2-(bromomethyl)-4-chloro-1-methoxy-benzene (Intermediate Q). 1 H NMR (400 MHz, CDCl3): 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). [ka] Step 1: Methyl 5-chloro-2-(difluoromethoxy)benzoate [ka]

[0242] To a mixture of methyl 5-chloro-2-hydroxybenzoate (G24, 1.50 g, 8.04 mmol) in MeCN (75 mL) and HO (37.5 mL) at 0 °C, KOH (2.71 g, 48.2 mmol) and [bromo(difluoro)methyl]trimethylsilane (3.27 g, 16.1 mmol) were added. 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 × 3). The combined organic layers were washed with brine (25 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 20 g cartridge, 0–20% EtOAc:hexanes) to give methyl 5-chloro-2-(difluoromethoxy)benzoate (G25). 1 H NMR(400 MHz,DMSO-d6):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 [ka]

[0243] To a mixture of methyl 5-chloro-2-(difluoromethoxy)benzoate (G25, 200 mg, 845 μmol) in THF (5 mL) at 0 °C, LiBH (4 M in THF, 634 μL, 2.54 mmol) was added dropwise under N, and the mixture was then stirred at room temperature under N for 16 h. The reaction mixture was poured into saturated aqueous NH Cl (5 mL) and then extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na SO , 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 O + H] + . Step 3: 2-(bromomethyl)-4-chloro-1-(difluoromethoxy)benzene (intermediate R) [ka]

[0244] To a solution of [5-chloro-2-(difluoromethoxy)phenyl]methanol (G26, 170 mg, 815 μmol) in DCM (3 mL) at 0 °C was added PBr (221 mg, 815 μmol). 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 × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO 4 g cartridge, 0–10% EtOAc:hexanes) to give 2-(bromomethyl)-4-chloro-1-(difluoromethoxy)benzene (Intermediate R). 1 H NMR (400 MHz, DMSO-d6): 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). [ka] Step 1: 2-(3,5-dichlorophenyl)acetaldehyde (Intermediate S) [ka]

[0245] 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 under N for 3 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (8 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, 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:hexanes) to give 2-(3,5-dichlorophenyl)acetaldehyde (Intermediate S). 1 H NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.46 (s, 1H), 3.86 (s, 2H).

[0246] The following intermediates in Table 5 were prepared following a similar procedure as described for Intermediate S using the appropriate starting materials. [Table 6] [ka] Step 1: (E)-3-chloro-5-(2-ethoxyvinyl)benzonitrile [ka]

[0247] 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) was added KCO (958 mg, 6.93 mmol) and Pd(dppf)Cl (169 mg, 231 μmol) under N. The reaction mixture was then stirred at 100 °C under N for 16 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (E)-3-chloro-5-(2-ethoxyvinyl)benzonitrile (G29), which was carried on to the next step without further purification. 1 H NMR (400 MHz, CDCl3): 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) [ka]

[0248] To a solution of (£)-3-chloro-5-(2-ethoxyvinyl)benzonitrile (G29, 750 mg, 3.61 mmol) in THF (4 mL) was added HCl (3 M in HO, 4 mL). The reaction mixture was then stirred at 50 °C for 16 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 4g cartridge, 0-30% EtOAc:hexanes) to give 3-chloro-5-(2-oxoethyl)benzonitrile (Intermediate V). 1H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 3.80 (s, 2H).

[0249] The following intermediates in Table 6 were prepared following a procedure similar to that described for Intermediate V using the appropriate starting materials. [Table 7] [ka] Step 1: 3-Chloro-5-vinylbenzonitrile [ka]

[0250] 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 HO solution (2.5 mL) was added KCO (3.19 g, 23.1 mmol) and Pd(dppf)Cl (845 mg, 1.15 mmol). The mixture was purged with N 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 × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, 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:hexanes) to give 3-chloro-5-vinyl-benzonitrile (G30). 1 H NMR (400 MHz, CDCl3): 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) [ka]

[0251] To a solution of 3-chloro-5-vinyl-benzonitrile (G30, 500 mg, 3.06 mmol) in DCM (5 mL) at 0 °C was added mCPBA (931 mg, 4.58 mmol, 85% purity), and the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured into saturated aqueous NaSO (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (120 mL), dried over NaSO, 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:hexanes) to give 3-chloro-5-(oxiran-2-yl)benzonitrile (Intermediate X). The following intermediates in Table 7 were prepared following a procedure similar to that described for Intermediate X using the appropriate starting materials. [Table 8] [ka] Step 1: 3-(Bromomethyl)-5-(trifluoromethyl)benzonitrile (Intermediate Z) [ka]

[0252] 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 pressure. The residue was purified twice by flash silica gel chromatography (Biotage 12 g cartridge, 0-1% EtOAc:hexanes) to give 3-(bromomethyl)-5-(trifluoromethyl)benzonitrile (Intermediate Z). MS = 264.0 / 266.1 [M+H] + . [ka] Step 1: Methyl 2-((4-hydroxyphenyl)thio)-2-methylpropanoate [ka]

[0253] 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 CsCO (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 NHCl (30 mL), extracted with EtOAc (30 mL × 3), dried over NaSO, 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:hexanes) to give methyl 2-(4-hydroxyphenyl)sulfanyl-2-methyl-propanoate (G32). MS = 225.2 [MH] - . Step 2: Methyl 2-((4-hydroxyphenyl)sulfonyl)-2-methylpropanoate [ka]

[0254] 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 (6.52 g, 30.5 mmol) in HO (6 mL). The mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with saturated aqueous NaSO (15 mL), extracted with EtOAc (10 mL × 3), dried over NaSO, 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:hexanes) to give methyl 2-(4-hydroxyphenyl)sulfonyl-2-methyl-propanoate (G33). MS = 257.1 [MH] - . Step 3: 4-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)phenol [ka]

[0255] 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 (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 NaSO, 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:hexanes) to give 4-(2-hydroxy-1,1-dimethyl-ethyl)sulfonylphenol (Intermediate AA). MS = 229.0 [MH] - . [ka] Step 1: tert-Butyl 3-((4-hydroxyphenyl)thio)azetidine-1-carboxylate [ka]

[0256] To a solution of 4-sulfanylphenol (G12, 10.0 g, 79.2 mmol) in DMF (100 mL) was added KCO (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 × 3). The combined organic layers were washed with HO (80 mL) and brine (80 mL), dried (NaSO), 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-C4H8+H] + . Step 2: tert-Butyl 3-((4-hydroxyphenyl)sulfonyl)azetidine-1-carboxylate [ka]

[0257] To a solution of tert-butyl 3-(4-hydroxyphenyl)sulfanylazetidine-1-carboxylate (G19, 6.50 g, 13.9 mmol) in THF (60 mL) and HO (20 mL) was added NaIO (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 NaSO (60 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, 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:hexanes) to give tert-butyl 3-(4-hydroxyphenyl)sulfonylazetidine-1-carboxylate (Intermediate O). MS = 312.2 [MH] - . Step 3: 4-(Azetidin-3-ylsulfonyl)phenol [ka]

[0258] 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 hours. 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: 3-((4-hydroxyphenyl)sulfonyl)azetidine-1-carboxylate allyl (Intermediate AB) [ka]

[0259] To a solution of 4-(azetidin-3-ylsulfonyl)phenol (G20, 1.1 g, 4.41 mmol, HCl salt) in DCM (10 mL) at 0 °C, TEA (1.11 g, 11.0 mmol, 1.53 mL) and allyl chloroformate (584 mg, 4.85 mmol) were added. The mixture was then stirred at room temperature for 3 h. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, 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:hexanes) to give allyl 3-(4-hydroxyphenyl)sulfonylazetidine-1-carboxylate (Intermediate AB). MS = 298.1 [M+H] + . [ka] Step 1: 3-(Bromomethyl)-5-chlorobenzonitrile (Intermediate AC) [ka]

[0260] To a solution of 3-chloro-5-(hydroxymethyl)benzonitrile (G34, 500 mg, 2.98 mmol) in DCM (10 mL) at 0 °C was added PBr (807 mg, 2.98 mmol). The reaction mixture was then stirred at room temperature for 10 h, and then the reaction mixture was concentrated. The residue was diluted with water (10 mL) and neutralized to pH = 7 by the addition of saturated aqueous NaHCO, then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give 3-(bromomethyl)-5-chloro-benzonitrile (Intermediate AC), which was carried on to the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.58 (s, 2H), 4.43 (s, 2H). [ka] Step 1: 3-(methylsulfonyl)propyl methanesulfonate [ka]

[0261] To a solution of 3-methylsulfonylpropan-1-ol (G35, 500 mg, 3.62 mmol) in DCM (5 mL) at 0 °C, EtN (732 mg, 7.24 mmol) and methylsulfonylmethanesulfonate (945 mg, 5.43 mmol) were added. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude 3-(methylsulfonyl)propyl methanesulfonate (G36), which was carried on to the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): 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 [ka]

[0262] To a mixture of 3-(methylsulfonyl)propyl methanesulfonate (G36, 390 mg, 1.80 mmol) and 4-sulfanylphenol (G12, 318 mg, 2.52 mmol) in CHCN (5 mL) was added CsCO (705 mg, 2.16 mmol). The mixture was then stirred at room temperature for 2 h. The reaction mixture was then diluted with HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over NaSO, 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:hexanes) to give 4-(3-methylsulfonylpropylsulfanyl)phenol (G37). MS = 245.1 [MH] - . Step 3: 4-((3-(methylsulfonyl)propyl)sulfonyl)phenol (Intermediate AD) [ka]

[0263] To a solution of 4-(3-methylsulfonylpropylsulfanyl)phenol (G37, 370 mg, 1.50 mmol) in THF (2 mL) and HO (2 mL) at 0 °C was added NaIO (964 mg, 4.51 mmol). The mixture was then stirred at 70 °C for 12 h. The reaction mixture was quenched by the addition of saturated aqueous NaSO (10 mL), then diluted with HO (5 mL), and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, 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:hexanes) to give 4-(3-methylsulfonylpropylsulfonyl)phenol (Intermediate AD). MS = 277.1 [MH] - . [ka] Step 1: tert-Butyl (3S,4S)-3-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate [ka]

[0264] 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) at 0 °C was added BH (10 M in MeS, 10.9 mL, 109 mmol). The reaction was then stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of MeOH (40 mL) and stirred for 0.5 h. The mixture was then diluted with water (100 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and the filtrate was concentrated to give tert-butyl (3S,4S)-3-(hydroxymethyl)-4-methyl-pyrrolidine-1-carboxylate (G39). MS = 160.2 [M-C4H8+H] + . Step 2: tert-Butyl (3S,4S)-3-methyl-4-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (Intermediate AE) [ka]

[0265] To a solution of tert-butyl (3S,4S)-3-(hydroxymethyl)-4-methyl-pyrrolidine-1-carboxylate (G39, 200 mg, 929 μmol) in DCM (3 mL) at 0° C., EtN (188 mg, 1.86 mmol) and methylsulfonylmethanesulfonate (161 mg, 929 μmol) were added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (5 mL × 3), and washed with Na2 SDrying over O4, filtering and concentrating under reduced pressure gave tert-butyl (3S,4S)-3-methyl-4-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (Intermediate AE). 1 H NMR (400 MHz, CDCl3):δ 4.32-4.28(m,1H),4.16-4.14(m,1H),3.65-3.61(m,3H),3.20-3.18(m ,1H),3.03(s,3H),2.97-2.95(m,1H),2.33-2.20(m,4H),1.46(s,9H).

[0266] The following intermediates in Table 8 were prepared following a similar procedure as described for Intermediate AE using the appropriate starting materials. [Table 9]

[0267] In the following examples, the numbers in the column headed "Number" in each of Tables 9-25 refer to the corresponding compound number in Table 1. Example 1 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (Compound 1) (R) or (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (Compound 2) (S) or (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (Compound 3) [ka] Step 1: tert-Butyl 3-((4-(methylsulfonyl)phenoxy)methyl)azepane-1-carboxylate [ka]

[0268] To a mixture of tert-butyl-3-(hydroxymethyl)azepane-1-carboxylate (200 mg, 0.872 mmol), 4-(methylsulfonyl)phenol (195 mg, 1.13 mmol), and PPh3 (297 mg, 1.13 mmol) in THF (5 mL) at 0 °C, DIAD (509 μL, 2.62 mmol) was added dropwise. The mixture was stirred at room temperature for 12 h. The reaction mixture was cooled to 0 °C and quenched by the addition of water (20 mL), then extracted with EtOAc (25 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 10 g cartridge, 0-85% EtOAc in petroleum ether) to give tert-butyl 3-((4-(methylsulfonyl)phenoxy)methyl)azepane-1-carboxylate. MS=384.2 [M+H] + . Step 2: 3-((4-(methylsulfonyl)phenoxy)methyl)azepane [ka]

[0269] To a solution of tert-butyl 3-((4-(methylsulfonyl)phenoxy)methyl)azepane-1-carboxylate (260 mg, 0.678 mmol) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 2 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give 3-((4-(methylsulfonyl)phenoxy)methyl)azepane (HCl salt), which was used in the next step without further purification. MS=284.2 [M+H] + . Step 3: 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (Compound 1) [ka]

[0270] A mixture of 3-((4-(methylsulfonyl)phenoxy)methyl)azepane (200 mg, 0.625 mmol, HCl salt), 2-(3-chlorophenyl)acetaldehyde (142 mg, 0.918 mmol) in MeOH (4 mL) was stirred at room temperature for 1 h, and then NaBHCN (66.5 mg, 1.06 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of water (1 mL) and concentrated in vacuo. The crude residue was purified by reverse-phase preparative HPLC (Waters Xbridge BEH C18 column, 10 mM NH4HCO3 in 45-80% MeCN / water) to give 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (compound 1). 1 H NMR(400 MHz,DMSO-d6):δ 7.82(d,J=8.8 Hz,2H),7.28-7.22(m,3H),7.14-7.11(m,3H),3.89-3.82(m,2H),3.14(s,3H),2.77-2. 70(m,1H),2.70-2.60(m,7H),2.06-2.05(m,1H),1.72-1.51(m,5H),1.35-1.33(m,1H). MS=422.3[M+H] + . Step 4: (R) or (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (Compound 2); (S) or (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (Compound 3) [ka]

[0271] 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)azepane (compound 1, 200 mg, 0.475 mmol) was separated by preparative chiral SFC (Phenomenex-cellulose-2, 55% (1:1 MeOH:MeCN) with 0.1% NHOH in CO). The first eluting enantiomer of the title compound, compound 2:1 H NMR(400 MHz,DMSO-d6):δ 7.82(d,J=8.8 Hz,2H),7.29-7.23(m,3H),7.14-7.11(m,3H),3.90-3.83(m,2H),3.15(s,3H),2.78-2. 71(m,1H),2.68-2.57(m,7H),2.01-2.10(m,1H),1.75-1.50(m,5H),1.35-1.32(m,1H). MS=422.3[M+H] + The second eluting enantiomer of the title compound, compound 3): 1 H NMR(400 MHz,DMSO-d6):δ 7.82(d,J=8.8 Hz,2H),7.28-7.23(m,3H),7.15-7.11(m,3H),3.90-3.83(m,2H),3.15(s,3H),2.79-2. 75(m,1H),2.69-2.53(m,7H),2.01-2.10(m,1H),1.75-1.50(m,5H),1.35-1.32(m,1H). MS=422.3[M+H] + .

[0272] The following compounds in Table 9 were prepared following procedures similar to those described for Example 1 using the appropriate starting materials. [Table 10-1] [Table 10-2] Example 2 N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide (Compound 7) (S) or (R)—N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide (Compound 8) (R) or (S)—N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide (Compound 9) [ka] Step 1: 3-((4-(N-methylmethylsulfonamido)phenoxy)methyl)piperidine-1-carboxylate [ka]

[0273] To a mixture of tert-butyl 3-(bromomethyl)piperidine-1-carboxylate (300 mg, 1.08 mmol) and N-(4-hydroxyphenyl)-N-methylmethanesulfonamide (260 mg, 1.29 mmol) in DMF (3 mL) was added KCO (447 mg, 3.24 mmol). The mixture was stirred at 60 °C for 12 h. The reaction mixture was cooled to 0 °C and quenched by the addition of water (15 mL), then extracted with EtOAc (25 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by normal-phase silica gel chromatography (Biotage 10 g cartridge, 0–25% EtOAc in petroleum ether) to give tert-butyl 3-((4-(N-methylmethylsulfonamido)phenoxy)methyl)piperidine-1-carboxylate. MS=343.2[M-C4H7+H] + . Step 2: N-methyl-N-(4-(piperidin-3-ylmethoxy)phenyl)methanesulfonamide [ka]

[0274] To a solution of tert-butyl 3-((4-(N-methylmethylsulfonamido)phenoxy)methyl)piperidine-1-carboxylate (336 mg, 843.1 mmol) in EtOAc (3 mL) was added HCl / EtOAc (4 M, 3 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo to give N-methyl-N-(4-(piperidin-3-ylmethoxy)phenyl)methanesulfonamide (HCl salt), which was used in the next step without further purification. MS=299.3 [M+H] + . Step 3: N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide [ka]

[0275] A mixture of N-methyl-N-(4-(piperidin-3-ylmethoxy)phenyl)methanesulfonamide (181 mg, 0.543 mmol, HCl salt) and 2-(3-chlorophenyl)acetaldehyde (109 mg, 0.706 mmol) in MeOH (2 mL) was stirred at room temperature for 30 minutes, and then NaBHCN (51.2 mg, 0.814 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by the addition of water (0.5 mL) and purified by reverse-phase preparative HPLC (Waters Xbridge BEH C18 column, 10 mM NH4HCO3 in 40-70% MeCN / water) to give N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide (compound 7). 1H NMR(400 MHz,DMSO-d6):δ 7.32-7.19(m,6H),6.94(d,J=8.8 Hz,2H),4.12-4.09(m,1H),3.86-3.81(m,2H),3.18(m,3H),3.17-3.16(m,1H),2.89(s,3H),2 .75-2.72(m,4H),2.06-1.95(m,3H),1.76-1.62(m,2H),1.48-1.47(m,1H),1.23-1.10(m,1H). MS=437.2[M+H] + . Step 4: (S) or (R)—N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide (Compound 8); (R) or (S)—N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide (Compound 9) [ka]

[0276] N-(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)-N-methylmethanesulfonamide (compound 7, 96 mg, 0.220 mmol) was separated by preparative chiral SFC (Chiralcel OD-3 column, 35% ethanol with 0.1% NHOH in CO). The first eluting enantiomer of the title compound, compound 8: 1 H NMR(400 MHz,DMSO-d6):δ 7.33-7.19(m,6H),6.94(d,J=9.2 Hz,2H),3.86-3.81(m,2H),3.18(s,3H),2.90(s,4H),2.77-2.67(m,4H),2 .09-1.92(m,4H),1.75-1.61(m,2H),1.52-1.42(m,1H),1.12-1.09(m,1H). MS=437.2[M+H] + The second eluting enantiomer of the title compound, Compound 9: 1H NMR(400 MHz,DMSO-d6):δ 7.33-7.17(m,6H),6.95(d,J=9.2 Hz,2H),3.89-3.84(m,2H),3.18(s,3H),2.90(s,4H),2.78-2.72(m,4H),2 .08-1.96(m,4H),1.74-1.65(m,2H),1.50-1.49(m,1H),1.14-1.04(m,1H). MS=437.2[M+H] + .

[0277] The following compounds in Table 10 were prepared following procedures similar to those described for compounds 7-9 using the appropriate starting materials. [Table 11] Example 3 (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine (Compound 13) [ka] Step 1: (S)-1-Benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate [ka]

[0278] To a mixture of (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.00 g, 4.62 mmol) and NaHCO (1.17 g, 13.9 mmol) in THF (5 mL) and water (5 mL) at 0 °C, benzyl chloroformate (986 μL, 6.94 mmol) was added. The mixture was stirred at room temperature for 4 h, then quenched by the addition of water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase silica gel chromatography (Biotage 20 g cartridge, 7–50% EtOAc in petroleum ether) to give (S)-1-benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate. MS = 373.2 [M+Na] + . Step 2: (S)-1-Benzyl 4-tert-butyl 2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1,4-dicarboxylate [ka]

[0279] To a mixture of (S)-1-benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (200 mg, 0.571 mmol), 4-methylsulfonylphenol (98.0 mg, 0.571 mmol), and PPh3 (225 mg, 0.856 mmol) in THF (4 mL) at 0 °C, DIAD (222 μL, 1.14 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h and then quenched by the addition of water (20 mL). The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-40% EtOAc in petroleum ether) to give (S)-1-benzyl 4-tert-butyl 2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1,4-dicarboxylate. MS=527.3 [M+Na] + . Step 3: (S)-Benzyl 2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1-carboxylate [ka]

[0280] To a solution of (S)-1-benzyl 4-tert-butyl 2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1,4-dicarboxylate (600 mg, 1.12 mmol) in EtOAc (5 mL) was added HCl / EtOAc (4 M, 12 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was diluted with water (20 mL) and washed with EtOAc (20 mL). The aqueous layer pH was adjusted to pH = 8-9 by the addition of saturated aqueous NaHCO3 and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give (S)-benzyl 2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1-carboxylate, which was used in the next step without further purification. MS = 405.2 [M+H] + . Step 4: (S)-Benzyl 4-(3-chlorophenethyl)-2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1-carboxylate [ka]

[0281] To a solution of (S)-benzyl 2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1-carboxylate (200 mg, 0.494 mmol) and 2-(3-chlorophenyl)acetaldehyde (76.0 mg, 0.494 mmol) in MeOH (2 mL) at 0 °C was slowly added NaBHCN (47.0 mg, 0.742 mmol). The mixture was stirred at room temperature for 1 h, then quenched with water (0.05 mL) and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 10-50% EtOAc in petroleum ether) to give (S)-benzyl 4-(3-chlorophenethyl)-2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1-carboxylate. MS = 543.2 [M+H] + . Step 5: (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine [ka]

[0282] To a solution of (S)-benzyl 4-(3-chlorophenethyl)-2-((4-(methylsulfonyl)phenoxy)methyl)piperazine-1-carboxylate (120 mg, 0.221 mmol) and NaI (331 mg, 2.21 mmol) in MeCN (3 mL) at 0° C. was added TMSCl (280 μL, 2.21 mmol) dropwise. The mixture was stirred at room temperature for 16 h, then quenched with water (0.2 mL) and purified by preparative HPLC (Waters Xbridge BEH C18 column, 10 mM NH4HCO3 in 30-55% MeCN / water) to give (S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperazine (compound 13). 1 H NMR(400 MHz,DMSO-d6,24 / 25 H):δ 7.83(d,J=8.8 Hz,2H),7.32-7.15(m,6H),4.01-3.94(m,2H),3.32(s,3H),3.15-3.14(s,1H),2.8 8-2.85(m,2H),2.76-2.66(m,4H),2.47-2.44(m,2H),2.07-2.00(m,1H),1.89(app t,J=10.0Hz,1H). MS=409.3[M+H] + .

[0283] The following compounds in Table 11 were prepared following a procedure similar to that described for compound 13 using the appropriate starting materials. [Table 12] Example 4 (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Compound 15) [ka]

[0284] To a solution of (R)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Intermediate G, 56.9 mg, 0.186 mmol, HCl salt) in DCM (5 mL) was added TEA (155 μL, 1.11 mmol) and 2-(3-chlorophenyl)acetaldehyde (28.70 mg, 0.186 mmol). The mixture was stirred at room temperature for 30 minutes, and then NaBH(OAc) (157 mg, 0.743 mmol) was added. After stirring for 12 hours, the reaction mixture was quenched with water (5 mL) and then extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase preparative HPLC (Waters Xbridge BEH C18, 10 mM NH4HCO3 in 50-80% MeCN / water) to give (R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (compound 15). 1 H NMR(400 MHz,DMSO-d6):δ 7.82(d,J=6.8 Hz,2H),7.30-7.13(m,6H),4.00-3.93(m,2H),3.15(s,3H),2.90(d,J=7.6 Hz,1H),2.77-2.71(m,3H),2.53-2.52(m,2H),2.05-1.97(m,3H),1.66 -1.64(m,1H),1.64-1.63(m,1H),1.49-1.41(m,1H),1.17-1.12(m,1H). MS=408.2[M+H] + .

[0285] The following compounds in Table 12 were prepared following a procedure similar to that described for compound 15 using the appropriate starting materials. [Table 13] Example 5 1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol (Compound 17) (R) or (S)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol (Compound 18) (S) or (R)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol (Compound 19) [ka] Step 1: 1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethanol [ka]

[0286] To a solution of (S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Intermediate H, 500 mg, 1.63 mmol, HCl salt) and 2-(3-chlorophenyl)oxirane (379 mg, 2.45 mmol) in EtOH (10 mL) was added TEA (455 μL, 3.27 mmol). The mixture was stirred at 80 °C for 8 h, then cooled to room temperature, quenched by the addition of water (1 mL), filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase preparative HPLC (Phenomenex Gemini-NX, 10 mM NH4HCO3 in 25-55% MeCN / water) to give 1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethanol (Compound 17). 1H NMR(400 MHz,DMSO-d6):δ 7.82(d,J=8.8 Hz,2H),7.38(s,1H),7.30-7.27(m,3H),7.16-7.13(m,2H),5.14(s,1H),4.70-4.69(m,1H),3.99-3.92(m,2H),3.15(s,3H),2.95-2.85(m, 1H),2.75-2.74(m,1H),2.46-2.45(m,1H),2.41-2.35(m,1H),2.17-1 .98(m,3H),1.72-1.60(m,2H),1.50-1.45(m,1H),1.15-1.12(m,1H). MS=424.1[M+H] + . Step 2: (R) or (S)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol (Compound 18); (S) or (R)-1-(3-chlorophenyl)-2-((S)-3-(((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol (Compound 19) [ka]

[0287] 1-(3-chlorophenyl)-2-[(3S)-3-[(4-methylsulfonylphenoxy)methyl]-1-piperidyl]ethanol (compound 17, 400 mg, 0.944 mmol) was separated by preparative chiral SFC (DAICEL CHIRALPAK AD-3, 55% ethanol with 0.1% NHOH in CO). The first eluting enantiomer of the title compound, compound 18: 1H NMR(400 MHz,DMSO-d6):δ 7.83(d,J=8.8 Hz,2H),7.38(s,1H),7.30-7.25(m,3H),7.16-7.13(m,2H),5.14(d,J=3.6 Hz,1H),4.71-4.70(m,1H),3.95-3.94(m,2H),3.15(s,3H),2.87-2.74(m,2H),2.46-2.41(m,1H) ,2.40-2.38(m,1H),2.15-1.98(m,3H),1.69-1.60(m,2H),1.50-1.49(m,1H),1.17-1.12(m,1H). MS=424.1[M+H] + The second eluting enantiomer of the title compound, Compound 19: 1 H NMR(400 MHz,DMSO-d6):δ 7.83(d,J=8.8 Hz,2H),7.39-7.13(m,6H),5.15(s,1H),4.71(s,1H),3.99-3.90(m,2H),3.15(s,3H),2.96-2.94(m,1H),2.77-2.75(m, 1H),2.46-2.41(m,1H),2.40-2.38(m,1H),2.14-2.04(m,3H),1.73-1.61(m,2H),1.49-1.46(m,1H),1.14-1.12(m,1H). MS=424.1[M+H] + .

[0288] The following compounds in Table 13 were prepared following a procedure similar to that described for compound 17 using the appropriate starting materials. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] Example 6 (S)-1-((R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine or (S)-1-((S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Compound 23) [ka]

[0289] To a solution of (R) or (S)-1-(3-chlorophenyl)-2-((S)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-ol (Compound 18, 50.0 mg, 0.118 mmol) in THF (2 mL) at 0° C. was added NaH (5.66 mg, 0.142 mmol, 60% dispersion in mineral oil). After stirring at 0° C. for 1 h, MeI (8.08 μL, 0.130 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for 1 h, the reaction mixture was cooled to 0° C., quenched by the addition of water (5 mL), and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase preparative HPLC (Waters Xbridge BEH C18 column, 10 mM NH4HCO3 in 35-70% MeCN / water) to give (S)-1-((R)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine or (S)-1-(((S)-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (compound 23). 1H NMR(400 MHz,DMSO-d6):δ 7.83(d,J=8.8 Hz,2H),7.37-7.34(m,3H),7.27-7.25(m,1H),7.15-7.13(m,2H),4.38(t,J=6.0 Hz,1H),3.93-3.89(m,2H),3.15(s,3H),3.13(s,3H),2.80-2.77(m,2H),2.43-2.40(m,2H),2 .15-2.08(m,2H),1.96-1.95(m,1H),1.70-1.59(m,2H),1.45-1.43(m,1H),1.14-1.11(m,1H). MS=438.1[M+H] + .

[0290] The following compounds in Table 14 were prepared following a procedure similar to that described for compound 23 using the appropriate starting materials. [Table 15] Example 7 rac-trans or cis-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (Compound 27) rac-cis or trans-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (Compound 28) [ka] Step 1: tert-Butyl 4-hydroxy-3-(hydroxymethyl)piperidine-1-carboxylate [ka]

[0291] To a solution of 1-tert-butyl 3-ethyl 4-oxopiperidine-1,3-dicarboxylate (5.00 g, 18.4 mmol) in EtOH (55 mL) at 0 °C was slowly added NaBH (6.97 g, 184 mmol). The mixture was stirred at 0 °C for 5 h and then quenched with ice-water (40 mL). After stirring for 30 min, the solution was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated in vacuo to give tert-butyl 4-hydroxy-3-(hydroxymethyl)piperidine-1-carboxylate, which was used in the next step without further purification. MS = 176.0 [M-C H + H] + . Step 2: tert-Butyl 4-hydroxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate [ka]

[0292] To a solution of tert-butyl 4-hydroxy-3-(hydroxymethyl)piperidine-1-carboxylate (2.80 g, 12.1 mmol) and 1-fluoro-4-methylsulfonyl-benzene (2.11 g, 12.1 mmol) in DMF (28 mL) was added KCO (4.18 g, 30.3 mmol). The mixture was stirred at 100 °C for 15 h. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase silica gel chromatography (Biotage 20 g cartridge, 0–65% EtOAc in petroleum ether) to give tert-butyl 4-hydroxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate. MS=408.1 [M+Na] + . Step 3: 3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol [ka]

[0293] A solution of tert-butyl 4-hydroxy-3-[(4-methylsulfonylphenoxy)methyl]piperidine-1-carboxylate (1.20 g, 3.11 mmol) in HCl / EtOAc (4 M, 15 mL) was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (HCl salt), which was used in the next step without further purification. MS=286.0 [M+H] + . Step 4: rac-trans or cis-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (Compound 27); rac-cis or trans-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (Compound 28) [ka]

[0294] To a solution of 3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (970 mg, 3.01 mmol, HCl salt) and 2-(3-chlorophenyl)acetaldehyde (559 mg, 3.62 mmol) in MeOH (10 mL) was added TEA (0.839 mL, 6.03 mmol) and AcOH (34.48 μL, 0.603 mmol). After stirring for 30 min, NaBHCN (568 mg, 9.04 mmol) was added. The mixture was stirred at room temperature for 10 h and then quenched with ice-water (10 mL). The mixture was concentrated to remove the solvent and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase preparative HPLC (Waters Xbridge BEH C18 column, 10 mM NH4HCO3 in 30-50% MeCN / water). The first eluting enantiomeric mixture of the title compound, compound 27: 1 H NMR(400 MHz,DMSO-d6):δ 7.86-7.81(m,2H),7.33-7.14(m,6H),4.81-4.78(m,1H),4.26(app dd,J=10.0 Hz,3.2 Hz,1H),4.01(app dd,J=9.6 Hz,8.0 Hz,1H),3.48-3.36(m,1H),3.15(s,3H),3.02(d,J=10.0 Hz,1H),2.88-2.86(m,1H),2.7-2.71(m,2H),2.62-2.58(m,1H),2.31-2.22(m,1H),2.05-1.95(m,2H),1.88-1.82(m,2H),1.50-1.41(m,1H). MS=424.3[M+H] + The second eluting enantiomeric mixture of the title compound, Compound 28: 1H NMR(400 MHz,DMSO-d6):δ 7.82(d,J=8.8 Hz,2H),7.28-7.13(m,6H),4.69(s,1H),4.16-4.12(m,1H),4.04-3.99(m,1H),3.85(s,1H),3.15(s, 3H), 2.76-2.68 (m, 2H), 2.61-2.55 (m, 2H), 2.49-2.33 (m, 4H), 2.10-2.09 (m, 1H), 1.66-1.52 (m, 2H). MS=424.2[M+H] + . Example 8 (3S,4R) or (3R,4R) or (3S,4S) or (3R,4S)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (Compound 29) (3R,4R) or (3S,4S) or (3R,4S) or (3S,4R)-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (Compound 30) [ka]

[0295] A solution of rac-trans- or rac-cis-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl)piperidin-4-ol (compound 27, 0.035 g, 0.083 mmol) in MeOH (1 mL) was separated by preparative chiral SFC (DAICEL CHIRALPAK IG-3, 60% MeOH with 0.1% NHOH in CO). The first eluting enantiomer of the title compound, compound 29: 1H NMR(400 MHz,DMSO-d6):δ 7.84-7.80(m,2H),7.32-7.14(m,6H),4.79(d,J=5.2 Hz,1H),4.25(app dd,J=10.0 Hz,2.8 Hz,1H),4.01(app t,J=8.4 Hz,1H),3.46-3.38(m,1H),3.15(s,3H),3.06-2.97(m,1H),2.92-2.82(m,1H),2.77-2. 68(m,2H),2.64-2.56(m,2H),2.07-1.95(m,2H),1.89-1.77(m,2H),1.51-1.40(m,1H). MS=424.2[M+H] + The second eluting enantiomer of the title compound, Compound 30: 1 H NMR(400 MHz,DMSO-d6):δ 7.84-7.82(m,2H),7.30-7.14(m,6H),4.79(d,J=5.2 Hz,1H),4.25(app dd,J=9.6 Hz,2.8 Hz,1H),4.03-3.98(m,1H),3.29(s,1H),3.15(s,3H),3.02(d,J=10.4 Hz,1H),2.86(d,J=10.4 Hz,1H),2.77-2.64(m,2H),2.62-2.54(m,2H),2.06-1.95(m,2H),1.87-1.76(m,2H),1.50-1.40(m,1H). MS=424.3[M+H] + .

[0296] The following compounds in Table 15 were prepared following a procedure similar to that described for compound 29 using the appropriate starting materials. [Table 16] Example 9 rac-trans or cis-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Compound 33) rac-cis or trans-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Compound 34) [ka] Step 1: tert-Butyl 3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate [ka]

[0297] To a 0°C solution of 1-(tert-butoxycarbonyl)-4-methoxypiperidine-3-carboxylic acid (900 mg, 3.47 mmol) in THF (10 mL) was added BH3·THF (1.0 M, 6.94 mL) dropwise. The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 0°C, quenched with MeOH (20 mL), and then adjusted to pH = 7 by dropwise addition of aqueous NaHCO3. The mixture was extracted with EtOAc (50 mL × 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate, which was used in the next step without further purification. MS = 190.2 [M-C4H7+H] + . Step 2: tert-butyl 4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate [ka]

[0298] To a mixture of 1-fluoro-4-methylsulfonyl-benzene (508 mg, 2.91 mmol) and tert-butyl 3-(hydroxymethyl)-4-methoxy-piperidine-1-carboxylate (715 mg, 2.91 mmol) in DMF (10 mL) was added CsCO (2.85 g, 8.74 mmol). The mixture was stirred at 100 °C for 15 h and then cooled to room temperature. The reaction mixture was diluted with water (30 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase silica gel chromatography (Biotage 20 g cartridge, 0–50% EtOAc in petroleum ether) to give tert-butyl 4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate. MS=344.2[M-C4H7+H] + . Step 3: 4-Methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine [ka]

[0299] To a 0° C. solution of tert-butyl 4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (790 mg, 1.98 mmol) in EtOAc was added HCl / EtOAc (4 M, 10 mL). The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was filtered, and the filter cake was then washed with petroleum ether (10 mL×3) and concentrated under reduced pressure to give 4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (HCl salt), which was used in the next step without further purification. MS=300.1 [M+H] + . Step 4: rac-trans or cis-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Compound 33); rac-cis or trans-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (Compound 34) [ka]

[0300] To a mixture of 4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl)piperidine (527 mg, 1.57 mmol, HCl salt) and 2-(3-ch...

Claims

1. Formula (A'): 【Chemical 319】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, Q is absent or -N-(C １～６ alkyl), Y is O or N-(C １～６ alkyl), However, Q is -N(C １～６ alkyl), Y is O; R ａ , R ｂ , and R ｃ are each independently H or C １～６ alkyl, R ａ , R ｂ , or R ｃ The above C １～６ Alkyl is independently one or more of -OH, C １～６ Alkoxy or -S(O) ２ -C １～６ optionally substituted with alkyl; Or R ａ , R ｂ , and R ｃ Any two of these, together with the atoms to which they are attached, are C ３～６ cycloalkyl or 3- to 6-membered heterocyclyl, R ａ , R ｂ , and R ｃ The other of these is H or C. １～６ alkyl, R ａ , R ｂ , or R ｃ The above C １～６ Alkyl is independently one or more of -OH, C １～６ Alkoxy or -S(O) ２ -C １～６ is optionally substituted with alkyl; L, 【Chemistry 320】 (In the formula, A is O, NH, N(C １～６ Alkyl), CH ２ , or CH(C １～６ alkyl), R ｘ is H or Or R ｘ But, R １ and R ２ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, said 3- to 8-membered heterocyclyl being selected from n independently selected R ｇ is substituted with a substituent, n is an integer from 0 to 6, R ｇ But -OH, halo, C １～６ Alkyl or C １～６ is an alkoxy; R １ and R ２ is independently H, halo, or -OH; Or R １ and R ２ One of the ｘ and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, said 3- to 8-membered heterocyclyl being selected from n independently selected R ｇ is substituted with a substituent, n is an integer from 0 to 6, R ｇ But -OH, halo, C １～６ Alkyl or C １～６ Alkoxy, R １ and R ２ the other of is H, halo, or —OH; R ３ is H, —OH, halo, or C １～６ is an alkoxy; R ４ and R ５ is independently H or Or R ４ and R ５ together with the atoms to which they are attached, C ３～８ It forms a cycloalkyl, however, (1) R ｘ But, R １ and R ２ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, said 3- to 8-membered heterocyclyl being selected from n independently selected R ｇ is substituted with a substituent, n is an integer from 0 to 6, R ｇ But -OH, halo, C １～６ Alkyl or C １～６ is an alkoxy; or (2) R ４ and R ５ together with the atoms to which they are attached, C ３～８ forming a cycloalkyl), 【Chemistry 321】 (In the formula, E is O, NH, N(C １～６ Alkyl), CH ２ , or CH(C １～６ alkyl), p is 0 or 1; With the proviso that when p is 1, E is O; R ６ is H or —OH, R ｙ is H or Or R ｙ But, R ７ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; Or R ｙ But, R ８ and R ９ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R ７ is H or Or R ７ But, R ｙ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl; R ８ and R ９ is independently H or C １～６ Is it an alkyl group? Or R ８ and R ９ One of the ｙ together with the atoms to which they are attached form a 3- to 8-membered heterocyclyl; R ８ and R ９ The other of these is H or C. １～６ Is it an alkyl group? Or R ８ and R ９ One of the １０ , together with the atoms to which they are attached, ３～８ Forming a cycloalkyl, R ８ and R ９ The other of these is H or C. １～６ is alkyl, R １０ is H or Or R １０ But, R ８ and R ９ and together with the atoms to which they are attached, ３～８ It forms a cycloalkyl, however, (1) R ｙ But, R ７ and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (2) R ｙ But, R ８ and R ９ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or (3) R ８ and R ９ One of the １０ , together with the atoms to which they are attached, ３～８ forming a cycloalkyl), and 【Chemistry 322】 (In the formula, 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, １～６ The alkyl group is one or more C ３～８ Optionally substituted with cycloalkyl; R １１ and R １２ is independently H, —OH, halo, or C １～６ is alkyl, R １３ and R １４ independently, H, C １～６ Alkyl or C ３～８ cycloalkyl, or Or R １３ and R １４ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl. and for each of (i) to (iii), # indicates a point of attachment to the phenyl ring-bearing moiety Q and ## indicates a point of attachment to the phenyl ring-bearing moiety X １ ~X ４ indicates the point of attachment to X １ , X ２ , X ３ , and X ４ are each independently H, halo, -CN, C １～６ Alkyl, C １～６ Alkoxy or SF ５ and said C １～６ Alkyl or C １～６ the alkoxy is optionally substituted with one or more halo; However, X １ , X ２ , X ３ , and X ４ At least one of the following is selected from the group consisting of halo, -CN, C １～６ Alkyl, C １～６ Alkoxy or SF ５ and said C １～６ Alkyl or C １～６ The alkoxy is optionally substituted with one or more halo.

2. L 【Chemical 324】 and therefore the compound has the formula (I): 【Chemistry 325】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

3. A is O, such that the compound has the formula (I-A1): 【Chemical 326】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

4. R ｘ But, R １ and R ２ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, said 3- to 8-membered heterocyclyl being selected from n independently selected R ｇ is substituted with a substituent, n is an integer from 0 to 6, R ｇ But -OH, halo, C １～６ Alkyl, or C １～６ 4. The compound of claim 3, wherein R is 1 or 2; or a stereoisomer or tautomer thereof; or a pharma- ceutically acceptable salt of any of the foregoing.

5. R ４ and R ５ together with the atoms to which they are attached, C ３～８ 4. The compound of claim 3, wherein the compound is a cycloalkyl group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

6. A is CH ２ and therefore the compound has the formula (I-A3): 【Chemical 334】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

7. R ｘ But, R １ and R ２ together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, said 3- to 8-membered heterocyclyl being selected from n independently selected R ｇ is substituted with a substituent, n is an integer from 0 to 6, R ｇ But -OH, halo, C １～６ Alkyl, or C １～６ Alkoxy, R １ and R ２ and the other of is H, halo, or -OH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

8. L 【Chemical 336】 and therefore the compound has the formula (II): 【Chemical 337】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

9. E is O, such that the compound has the formula (II-A1): 【Chemical 338】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

10. R ｙ But, R ７ and together with the atom to which they are attached form a 3- to 8-membered heterocyclyl, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

11. R ６ is —OH, and R ８ C １～６ alkyl, R ９ C １～６ 10. The compound of claim 9, wherein R is an alkyl group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

12. R ６ is —OH, and R ８ is H, and R ９ is H, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

13. R ８ and R ９ One of the １０ , together with the atoms to which they are attached, ３～８ 10. The compound of claim 9, wherein the compound is a cycloalkyl group, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

14. R ６ is —OH, and R ７ is H, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

15. L 【Chemical 343】 and therefore the compound has the formula (III): 【Chemical 344】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

16. 2. The compound of claim 1, wherein Q is absent, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

17. 2. The compound of claim 1, wherein Y is O, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

18. Y is N-(C １～６ 2. The compound of claim 1, wherein R is 0, 1 or 2; or R is 1 or 2; or R is 2 or 3; or R is 3 or 4; or R is 4 or 5;

19. Q is -N-(C １～６ 2. The compound of claim 1, wherein R is 0, 1 or 2; or R is 1 or 2; or R is 2 or 3; or R is 3 or 4; or R is 4 or 5;

20. R ａ , R ｂ , and R ｃ is independently at each occurrence H, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

21. X １ is H, and X ２ is H, and X ３ and X ４ One of the groups is a halo, and X ３ and X ４ is H, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

22. Q is absent, Y is O, and R ａ , R ｂ , and R ｃ are each independently H, such that the compound has the formula (B-2): 【Chemical 345】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

23. Q is absent and Y is N(CH ３ ) and R ａ , R ｂ , and R ｃ are each independently H, such that the compound has the formula (B-5): 【Chemical 346】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

24. Q is -N(CH ３ ), Y is O, and R ａ , R ｂ , and R ｃ are each independently H, such that the compound has the formula (C-1): 【Chemical 347】 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

25. 2. The compound of claim 1, wherein the compound is a compound of Table 1, or a pharma- ceutically acceptable salt of any of the foregoing, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

26. 13. A pharmaceutical composition comprising: (i) a compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (ii) one or more pharma- ceutically acceptable excipients.

27. 27. A composition for use in a method of inhibiting APOL1 in a cell, comprising a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 26, wherein the method comprises exposing the cell to the composition.

28. A composition for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need of such treatment, comprising a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 26.

29. 29. The composition of claim 28, wherein the disease, disorder, or condition is chronic kidney disease (CKD).

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