US patent application 18/617,266 — APOL1 inhibitors and methods of use

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patent application Ser. No. 18/098,070, filed Jan. 17, 2023, which claims priority to U.S. Provisional Application Ser. No. 63/300,592, filed Jan. 18, 2022, U.S. Provisional Application Ser. No. 63/311,668, filed Feb. 18, 2022, U.S. Provisional Application Ser. No. 63/332,553, filed Apr. 19, 2022, U.S. Provisional Application Ser. No. 63/400,359, filed Aug. 23, 2022, and U.S. Provisional Application Ser. No. 63/422,341, filed Nov. 3, 2022, each of which is hereby incorporated herein by reference in its entirety.

›BACKGROUND OF THE INVENTION

Apolipoprotein L1 (APOL1) is a pore forming innate immunity factor, protecting individuals from trypanosome parasites (Vanhamme, L. et al. Nature (2003) 422, 83-87). The secreted form of APOL1 circulates in blood as part of distinct high-density lipoprotein (HDL) complexes, known as trypanosome lytic factors (TLFs) (Rifkin, M. R. Proc. Natl. Acad. Sci. USA . (1978) 75, 3450-3454; Raper, J. et al. Infect. Immun . (1999) 67, 1910-1916). TLFs are internalized by the parasites through endocytosis (Hager, K. M. et al. J. Cell Biol . (1994) 126, 155-167). Within trypanosomes, APOL1 forms cation pores, causing ion flux, swelling, and eventual lysis (Rifkin, M. R. Exp. Parasitol . (1984) 58, 81-93; Molina-Portela, M. P. et al. Mol. Biochem. Parasitol . (2005) 144, 218-226; Pérez-Morga, D. et al. Science . (2005) 309, 469-472; Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA . (2015) 112, 2894-2899).

Several Trypanosoma brucei subspecies ( T.b. rhodesiense and T.b. gambiense ) developed resistance mechanisms to APOL1-dependent killing (Pays, E. et al. Nat. Rev. Microbiol . (2014) 12, 575-584). Positive selection resulted in APOL1 variants, G1 (S342G, I384M) and G2 (N388Δ, Y389Δ), capable of interfering with these resistance mechanisms (Genovese, G. et al. Science . (2010) 329, 841-845). However, individuals with any binary combination of these variants (G1/G1, G2/G2, or G1/G2), have a greater risk of developing a variety of chronic kidney diseases, including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN) (Genovese, G. et al. Science . (2010) 329, 841-845; Tzur, S. et al. Hum. Genet . (2010) 128, 345-350; Kopp, J. B. et al. J. Am. Soc. Nephrol . (2011) 22, 2129-2137), sickle cell nephropathy (Ashley-Koch, A. E. et al. Br. J. Haematol . (2011) 155, 386-394), lupus nephritis (Freedman, B. I. et al. Arthritis Rheumatol . (2014) 66, 390-396), and an increased rate of Glomerular Filtration Rate (GFR) decline in diabetic kidney disease (Parsa, A. et al. N. Engl. J. Med . (2013) 369, 2183-2196). The APOL1 high-risk genotype has also been associated with COVID-19 associated nephropathy and other viral nephropathies (Shetty, A. et al. J. Am. Soc. Nephrol . (2021) 32, 33-40; Chang, J. H. et al. Am. J. Kidney Dis . (2019) 73, 134-139). Moreover, decreased renal allograft survival has been observed after deceased-donor kidney transplantations from APOL1 high-risk genotype donors (Freedman, B. I. et al. Transplantation . (2016) 100, 194-202). In addition, having two APOL1 risk alleles increases risk for preeclampsia (Reidy, K. J. et al. Am. J. Hum. Genet . (2018) 103, 367-376) and sepsis (Chaudhary, N. S. et al. Clin. J. Am. Soc. Nephrol . (2019) 14, 1733-1740). There are no approved therapies for APOL1-associated nephropathy, and patients are treated based on the standard of care for their underlying form of chronic kidney disease. This presents a clear unmet need for therapies targeted to people with the APOL1 high-risk genotype.

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

›BRIEF SUMMARY OF THE INVENTION · 1 of 5

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

In one aspect, provided is a compound of formula (II):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 10;

R 1 , if present is, independently at each occurrence selected from the group consisting of halo, —CN, C 1-6 alkoxy, and C 1-6 alkyl, wherein

the C 1-6 alkoxy of R 1 is optionally substituted with one or more halo, and the C 1-6 alkyl of R 1 is optionally substituted with one or more halo;

R 2 is H, C 1-6 alkyl, C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more deuterium, halo, —OH, —NH 2 , or C 1-6 alkoxy, and

the C 3-10 cycloalkyl of R 2 is optionally substituted with one or more —OH;

R 3 , if present, is C 1-6 alkyl;

L 1 is C 1-6 alkylene, wherein

the C 1-6 alkylene of L 1 is optionally substituted with one or more deuterium or C 1-6 alkyl, and wherein

the C 3-10 cycloalkyl of L 3 is optionally substituted with one or more —OH or C 1-6 alkyl, the C 1-6 alkylene of L 3 is optionally substituted with one or more —OH or C 1-6 alkyl, wherein

the C 1-6 alkyl of R d is optionally substituted with one or more —OH,

(iv) —NS(O)—(C 1-6 alkyl) 2 , wherein the C 1-6 alkyl is optionally substituted with one or more —OH,

(v) —C(O)—N(R e ) 2 wherein R e is independently at each occurrence H, C 1-6 alkyl, or 3-10 membered heterocycle, wherein

the 3-10 membered heterocycle of R e is optionally substituted with one or more oxo, or both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein

the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein

the C 1-6 alkyl is optionally substituted with one or more —OH,

(iii) 3-10 membered heterocyclyl optionally substituted with one or more C 1-6 alkyl, or

(iv) NH(C 1-6 alkyl);

R 5 is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein

the C 1-6 alkyl of R 5 is optionally substituted with one or more halo or —OH, and the C 1-6 alkoxy of R 5 is optionally substituted with one or more halo;

X 3 is N or C(R 6 )

X 4 is N or C(R 7 );

and

R 6 and R 7 are each independently H or halo.

In one aspect, provided is a compound of formula (I′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 10;

R 1 , if present is, independently at each occurrence selected from the group consisting of halo, —CN, C 1-6 alkoxy, or C 1-6 alkyl, wherein

the C 1-6 alkoxy of R 1 is optionally substituted with one or more halo, and the C 1-6 alkyl of R 1 is optionally substituted with one or more halo;

R 2 is H, C 1-6 alkyl, C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein

the C 1-6 alkyl of R 2 is optionally substituted with one or more halo, —OH, —NH 2 , or C 1-6 alkoxy, and the C 3-10 cycloalkyl of R 2 is optionally substituted with one or more —OH;

R 3 , if present, is C 1-6 alkyl;

L 1 is C 1-6 alkylene, wherein the C 1-6 alkylene of L 1 is optionally substituted with one or more C 1-6 alkyl, and wherein the C 1-6 alkyl is further optionally substituted with one or more —OH or C 1-6 alkoxy;

L 2 is O or N(R x ), wherein R x is H or C 1-6 alkyl; and

either

(1) L 3 is absent or is O, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 1-6 alkylene, wherein

the C 3-10 cycloalkyl is optionally substituted with one or more —OH or C 1-6 alkyl, the C 1-6 alkylene of L 3 is optionally substituted with one or more —OH or C 1-6 alkyl, and the 3-10 membered heterocyclyl is optionally substituted with one or more —OH; X 1 and X 2 are each independently N or C(R 5 ); and R 4 is: (i) —S(O) 2 —R a ; (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R 4 is optionally substituted with one or more C 1-6 alkyl; (iii) —N(R d ) 2 , wherein R d is independently at each occurrence H, C 1-6 alkyl, or —S(O) 2 —R a , wherein the C 1-6 alkyl of R d is optionally substituted with one or more —OH, (iv) —NS(O)—(C 1-6 alkyl) 2 , wherein the C 1-6 alkyl is optionally substituted with one or more —OH, (v) —C(O)—N(R e ) 2 wherein R e is independently at each occurrence H, C 1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH 2 , —NH—S(O) 2 —R a , or —S(O) 2 —R a , (vi) 3-10 membered heterocyclyl optionally substituted with one or more C 1-6 alkyl, —OH, oxo, or —S(O) 2 R a , (vii) —S(O)—N(C 1-6 alkyl)-(C 1-6 alkyl), (viii) —CN, (ix) —(CH 2 ) q OH, wherein q is an integer from 0-6, (x) —C(O)—C 1-6 alkyl, or (xi) —P(O)(C 1-6 alkyl) 2 ;

or

(2) L 3 is absent; and

one of X 1 and X 2 is N or C(R 5 ); and the other of X 1 and X 2 is N or C that is taken together with R 4 and the atoms to which they are attached to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein

›BRIEF SUMMARY OF THE INVENTION · 2 of 5

the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is, independently at each occurrence, selected from the group consisting of halo, oxo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —S(O) 2 —R a , C 3-10 cycloalkyl, and 3-10 membered heterocyclyl, wherein

the C 1-6 alkyl of R b is optionally substituted with one or more halo, OH, —S(O) 2 —C 1-6 alkyl, or C 3-10 cycloalkyl, and wherein the C 3-10 cycloalkyl of the C 1-6 alkyl of R b is further optionally substituted with one or more C 1-6 alkyl or —OH and the C 3-10 cycloalkyl of R b is optionally substituted with one or more —OH, C 3-10 cycloalkyl, or C 1-6 alkyl, and wherein the C 1-6 alkyl of the C 3-10 cycloalkyl of R b is further optionally substituted with one or more —OH, and

the 5-20 membered heteroaryl is optionally substituted with one or more R c , wherein R c is, independently at each occurrence, selected from the group consisting of halo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —S(O) 2 —R a , C 3-10 cycloalkyl, and 3-10 membered heterocyclyl, wherein

the C 1-6 alkyl of R c is optionally substituted with one or more —S(O) 2 —C 1-6 alkyl, the C 3-10 cycloalkyl of R c is optionally substituted with one or more —OH or C 1-6 alkyl, and the 3-10 membered heterocyclyl of R c is optionally substituted with one or more —OH or C 1-6 alkyl, and wherein the C 1-6 alkyl of the 3-10 membered heterocyclyl of R c is further optionally substituted with one or more —OH;

R a is, independently at each occurrence:

(i) C 1-6 alkyl optionally substituted with one or more halo, —OH, —S(O) 2 —C 1-6 alkyl, or —N(C 1-6 alkyl)-C(O)—C 1-6 alkyl, (ii) C 3-10 cycloalkyl optionally substituted with one or more —OH, —C(O) 2 —C 1-6 alkyl, —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , or —C(O)—C 3-10 heterocyclyl, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more —OH, or (iii) 3-10 membered heterocyclyl optionally substituted with one or more C 1-6 alkyl;

R 5 is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl of R 5 is optionally substituted with one or more halo, or —OH and wherein the C 1-6 alkoxy of R 5 is optionally substituted with one or more halo; and

R 6 and R 7 are each independently H or halo.

In one aspect, provided is a compound of formula (I):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 10;

R 1 if present is, independently at each occurrence, selected from the group consisting of halo, —CN, C 1-6 alkoxy or —C 1-6 alkyl, wherein

the C 1-6 alkoxy of R 1 is optionally substituted with one or more halo, and the C 1-6 alkyl of R 1 is optionally substituted with one or more halo;

R 2 is H, C 1-6 alkyl, C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein

the C 1-6 alkyl of R 2 is optionally substituted with one or more halo, —OH, —NH 2 , or C 1-6 alkoxy, and the C 3-10 cycloalkyl of R 2 is optionally substituted with one or more —OH;

R 3 , if present, is C 1-6 alkyl;

L 1 is C 1-6 alkylene, wherein the C 1-6 alkylene of L 1 is optionally substituted with one or more C 1-6 alkyl, and wherein the C 1-6 alkyl is further optionally substituted with one or more —OH or C 1-6 alkoxy;

L 2 is O or N(R x ), wherein R x is H or C 1-6 alkyl; and

either

(1) L 3 is absent or is O, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 1-6 alkylene, wherein

the C 1-6 alkylene of L 3 is optionally substituted with one or more C 1-6 alkyl, and the 3-10 membered heterocyclyl is optionally substituted with one or more —OH; X 1 and X 2 are each independently N or C(R 5 ); and R 4 is: (i) —S(O) 2 —R a , (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R 4 is optionally substituted with one or more C 1-6 alkyl, (iii) —N(R d ) 2 , wherein R d is independently at each occurrence H, C 1-6 alkyl, or —S(O) 2 —R a , wherein the C 1-6 alkyl of R d is optionally substituted with one or more —OH, (iv) —NS(O)—(C 1-6 alkyl) 2 , wherein the C 1-6 alkyl of R d is optionally substituted with one or more —OH, (v) —C(O)—N(R e ) 2 wherein R e is independently at each occurrence H, C 1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R e together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH 2 , NH—S(O) 2 —R a , or —S(O) 2 —R a , (vi) 3-10 membered heterocyclyl optionally substituted with one or more C 1-6 alkyl or oxo, (vii) —S(O)—N(C 1-6 alkyl)-(C 1-6 alkyl), or (viii) —CN;

or

(2) L 3 is absent; and

one of X 1 and X 2 is N or C(R 5 ); and the other of X 1 and X 2 is N or C that is taken together with R 4 , and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein

the 5-10 membered heterocyclyl is optionally substituted with one or more R b , wherein R b is, independently at each occurrence, selected from the group consisting of halo, oxo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —S(O) 2 —R a , C 3-10 cycloalkyl, and 3-10 membered heterocyclyl, wherein

the C 1-6 alkyl of R b is optionally substituted with one or more halo, OH, or —S(O) 2 —C 1-6 alkyl, and the C 3-10 cycloalkyl of R b is optionally substituted with one or more —OH, and

the 5-20 membered heteroaryl is optionally substituted with one or more R c , wherein R c is, independently at each occurrence, selected from the group consisting of halo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —S(O) 2 —R a , C 3-10 cycloalkyl, and 3-10 membered heterocyclyl, wherein

›BRIEF SUMMARY OF THE INVENTION · 3 of 5

the C 1-6 alkyl of R c is optionally substituted with one or more —S(O) 2 —C 1-6 alkyl, and the C 3-10 cycloalkyl of R c is optionally substituted with one or more —OH;

R a is, independently at each occurrence:

(i) C 1-6 alkyl optionally substituted with one or more halo, —OH, —S(O) 2 —C 1-6 alkyl, or —N(C 1-6 alkyl)-C(O)—C 1-6 alkyl, or (ii) C 3-10 cycloalkyl optionally substituted with one or more —OH, —C(O) 2 —C 1-6 alkyl, —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —C(O)—C 3-10 heterocyclyl, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more —OH, or (iii) 3-10 membered heterocyclyl optionally substituted with one or more C 1-6 alkyl;

R 5 is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl of R 5 is optionally substituted with one or more halo or —OH, and wherein the C 1-6 alkoxy is optionally substituted with one or more halo; and

R 6 and R 7 are each independently H or halo.

Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

Any embodiments provided herein of a compound of formula (I) or (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is 1 or 2; and wherein m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 1 , X 2 , R 6 , and R 7 are as defined elsewhere herein. In another variation, m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , X 1 , X 2 , R 6 , and R 7 of formula (I-A) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-B):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , R 5 , R 6 , and R 7 are as defined elsewhere herein. In another variation, m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , R 5 , R 6 , and R 7 of formula (I-B) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-C):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , and R 5 are as defined elsewhere herein. In another variation, m, p, R 1 , R 2 , R 3 , L 1 , L 3 , R 4 , and R 5 of formula (I-C) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-D):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , L 3 , and R 4 are as defined elsewhere herein. In another variation, m, p, R 1 , R 2 , R 3 , L 1 , L 3 , and R 4 of formula (I-D) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-E):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , X 2 , R 6 , R 7 , and ring A are as defined elsewhere herein. In another variation, m, p, R 1 , R 2 , R 3 , L 1 , X 2 , R 6 , R 7 , and ring A of formula (I-E) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-F):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , R 5 , and ring A are as defined elsewhere herein. In another variation, m, p, R 1 , R 2 , R 3 , L 1 , R 5 , and ring A of formula (I-F) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-G):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , and ring A are as defined elsewhere herein. In another variation, m, p, R 1 , R 2 , R 3 , L 1 , and ring A of formula (I-G) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (II-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R 1 , R 2 , R 3 , L 1 , X 2 , X 3 , X 4 , and ring A are as defined elsewhere herein.

In one aspect, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

›BRIEF SUMMARY OF THE INVENTION · 4 of 5

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

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

In one aspect, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), 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 (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

›BRIEF SUMMARY OF THE INVENTION · 5 of 5

In one aspect, provided herein is a kit, comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. In another variation, provided herein is a kit, comprising (i) a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. In another variation, provided herein is a kit, comprising (i) a compound of formula (II), or any embodiment or variation thereof, such as a compound of (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

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

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 57

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

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

“Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, some primates and humans. In some embodiments, individual refers to a human.

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

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

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

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

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

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

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

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

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

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

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 57

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

The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzindolyl, benzofuranyl, benzonaphthofuranyl, benzoxazolyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, furanyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

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

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

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

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 57

Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively. In some embodiments, a compound of formula (I), or formula (I′) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

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

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

The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

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

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

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

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

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

Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed, hereby incorporated herein by reference in its entirety. The following examples are intended to be illustrative only and not limiting in any way.

° C. degrees Celsius μL microliter μW microwave [M + XX] + observed mass AC 50 half-maximal activity concentration Ac 2 O acetic anhydride AIBN azobisisobutyronitrile app apparent (NMR) br broad (NMR) BH 3 •THF borane-tetrahydrofuran complex BBr 3 boron tribromide BnCl benzyl chloride B(Pin) 2 bis(pinacolato)diboron Calc’d calculated Cbz-Cl benzyl chloroformate CCl 4 carbontetrachloride CDI carbonyldiimidazole CHCl 3 chloroform CO 2 carbon dioxide CS 2 CO 3 cesium carbonate CuI copper iodide d deuterated (NMR solvents) d doublet (NMR) dd doublet of doublets (NMR) DAST diethylaminosulfur trifluoride DMA N,N-dimethylacetamide DCE 1,2-dichloroethane DCM dichloromethane DIAD diisopropyl azodicarboxylate DIEA N,N-diisopropylethylamine DME dimethoxyethane DMEDA N,N-dimethylethylenediamine DMA dimethylacetamide DMF N,N-dimethylformamide DPPF 1,1′- bis(diphenylphosphino)ferrocene EC 50 half-maximal effective concentration EDCI 1-ethyl-3-(3-dimethylamino- propyl)carbodiimide Et 3 N triethyl amine EtOAc ethyl acetate EtOH ethanol g grams h hours H hydrogen H 2 hydrogen gas H 2 O water H 2 O 2 hydrogen peroxide HATU N-[(Dimethylamino)-1H-1,2,3- triazolo-[4,5-b]pyridin-1- ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide HCl hydrochloric acid HOBt hydroxybenzotriazole HPLC high-performance liquid chromatography In vacuo in a vacuum (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 [4,4′-Bis(1,1-dimethylethyl)- 2,2′-bipyridine-N1,N1′]bis[3,5- difluoro-2-[5-(trifluoromethyl)- 2-pyridinyl-N]phenyl-C] Iridium(III) hexafluorophosphate IUPAC International Union of Pure and Applied Chemistry J J-coupling value (NMR) K 2 CO 3 potassium carbonate KI potassium iodide KOAc potassium acetate KOH potassium hydroxide LiAlH 4 lithium aluminum hydride LiHMDS lithium bis(trimethylsilyl)amide LiOH lithium hydroxide MeOH methanol MeCN acetonitrile MHz megahertz m multiplet (NMR) mg milligrams min minutes mL milliliter mmol millimole mM millimolar M molarity or molar m-CPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeSO 2 Na sodium methanesulfinate MS mass spectrometry MsCl methanesulfonyl chloride Ms 2 O methanesulfonic anhydride MTBE methyl tert-butyl ether n/a not applicable NaBH(OAc) 3 sodium triacetoxyborohydride NaH sodium hydride NBS N-bromosuccinimide NH 4 ammonium NH 4 OH ammonium hydroxide NH 4 HCO 3 ammonium bicarbonate Na 2 SO 4 sodium sulfate NaBH 3 CN sodium cyanoborohydride NMP 1-methyl-2-pyrrolidinone NMR nuclear magnetic resonance NaIO 4 sodium periodate NaOH sodium hydroxide OsO 4 osmium tetraoxide Pd/C palladium on carbon PCy 3 tricyclohexylphosphine Pd 2 (dba) 3 tris(dibenzylideneacetone) dipalladium(0) Pd(PPh 3 ) 2 bis(triphenylphosphine) palladium(II) chloride Pd(dba)3 tris(dibenzylideneacetone) dipalladium(0) pH potential of hydrogen PPh 3 triphenyl phosphine PSI pounds per square inch s singlet (NMR) SEMCl (2-chloromethoxyethyl) trimethylsilane SFC super fluid chromatography SOCl 2 thionyl chloride t triplet (NMR) T3P propanephosphonic acid anhydride TBAB tetrabutylammonium bromide TBAI tetrabutylammonium iodide TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMSCl trimethylsilyl chloride Xantphos 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene Zn(CN) 2 zinc cyanide

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 57

Compounds

Provided herein is a compound of formula (II):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 10;

R 1 , if present is, independently at each occurrence selected from the group consisting of halo, —CN, C 1-6 alkoxy, and C 1-6 alkyl, wherein

the C 1-6 alkoxy of R 1 is optionally substituted with one or more halo, and the C 1-6 alkyl of R 1 is optionally substituted with one or more halo;

R 2 is H, C 1-6 alkyl, C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein

the C 1-6 alkyl of R 2 is optionally substituted with one or more deuterium, halo, —OH, —NH 2 , or C 1-6 alkoxy, and the C 3-10 cycloalkyl of R 2 is optionally substituted with one or more —OH;