APOL1 INHIBITORS AND METHODS OF USE

1 . A compound of formula (A′):

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

Q is absent or is —N—(C 1-6 alkyl);

Y is O or —N—(C 1-6 alkyl),

provided that, when Q is —N(C 1-6 alkyl), then Y is O;

R a , R b , and R c are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a , R b , or R c is independently optionally substituted with one or more —OH, C 1-6 alkoxy, or —S(O) 2 -C 1-6 alkyl,

or any two of R a , R b , and R c are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a , R b , and R c is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a , R b , or R c is independently optionally substituted with one or more —OH, C 1-6 alkoxy, or —S(O) 2 -C 1-6 alkyl;

L is selected from the group consisting of:

 wherein

A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl);

R x is H,

or R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

R 1 and R 2 are independently H, halo, or —OH,

or one of R 1 and R 2 is taken together with R x , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1 and R 2 is H, halo, or —OH;

R 3 is H, —OH, halo, or C 1-6 alkoxy; and

R 4 and R 5 are independently H,

or R 4 and R 5 are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl,

provided that either:

(1) R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, or

(2) R 4 and R 5 are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl,

 wherein

E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl);

p is 0 or 1,

provided that, when p is 1, then E is O;

R 6 is H or —OH;

R y is H,

or R y is taken together with R 7 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl,

or R y is taken together with one of R 8 and R 9 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl;

R 7 is H,

or R 7 is taken together with R y , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl;

R 8 and R 9 are independently H or C 1-6 alkyl,

or one of R 8 and R 9 is taken together with R y , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8 and R 9 is H or C 1-6 alkyl,

or one of R 8 and R 9 is taken together with R 10 , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8 and R 9 is H or C 1-6 alkyl; and

R 10 is H,

or R 10 is taken together with one of R 8 and R 9 , and the atoms to which they are attached, to form a C 3-8 cycloalkyl,

provided that:

(1) R y is taken together with R 7 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or

(2) R y is taken together with one of R 8 and R 9 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or

(3) one of R 8 and R 9 is taken together with R 10 and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and

 wherein

G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl);

R z is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl;

R 11 and R 12 are independently H, —OH, halo, or C 1-6 alkyl; and

R 13 and R 14 are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl,

or R 13 and R 14 are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl,

wherein, for each of (i)-(iii), #denotes the point of attachment to the phenyl ring bearing moiety Q, and ##denotes the point of attachment to the phenyl ring bearing moieties X 1 -X 4 ; and

X 1 , X 2 , X 3 , and X 4 are, independently of each other, H, halo, —CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo,

provided that at least one of X 1 , X 2 , X 3 , and X 4 is halo, —CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

2 . The compound of claim 1 , wherein the compound is a compound of formula (A):

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

X 1 , X 2 , X 3 , and X 4 are, independently of each other, H, halo, —CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo,

provided that at least one of X 1 , X 2 , X 3 , and X 4 is halo, —CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.

3 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is,

such that the compound is of formula (I):

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

4 . The compound of claim 3 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is O, such that the compound is of formula (I-A):

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

5 . The compound of claim 4 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy.

6 . The compound of claim 4 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy.

7 . The compound of claim 5 or claim 6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-B1):

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

8 . The compound of claim 7 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

9 . The compound of claim 7 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1 or 2.

10 . The compound of claim 7 or claim 9 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R g is, independently at each occurrence, C 1-6 alkyl.

11 . The compound of any one of claims 7, 9, and 10 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R g is, independently at each occurrence, methyl.

12 . The compound of claim 5 or claim 6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-C1):

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

13 . The compound of claim 5 or claim 6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-D1):

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

14 . The compound of claim 12 or claim 13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

15 . The compound of claim 12 or claim 13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1 or 2.

16 . The compound of any one of claims 12, 13, and 15 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R g is, independently at each occurrence, —OH or C 1-6 alkoxy.

17 . The compound of any one of claims 12, 13, 15, and 16 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R g is, independently at each occurrence, —OH or methoxy.

18 . The compound of claim 5 or claim 6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-E1):

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

19 . The compound of claim 18 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

20 . The compound of claim 5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-F1):

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

21 . The compound of claim 20 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

22 . The compound of claim 5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-G1):

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

23 . The compound of claim 22 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

24 . The compound of 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 and R 5 are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl.

25 . The compound of claim 4 or claim 24 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-H1):

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

26 . The compound of claim 25 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 , R 2 , and R 3 are each H.

27 . The compound of claim 3 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is CH 2 , such that the compound is of formula (I-A3):

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

28 . The compound of claim 27 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1 and R 2 is H, halo, or —OH.

29 . The compound of claim 27 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1 and R 2 is H, halo, or —OH.

30 . The compound of claim 28 or claim 29 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-C3):

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

31 . The compound of claim 30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

32 . The compound of any one of claims 1-24 and 27-31 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 , R 4 , and R 5 are each H.

33 . The compound of any one of claims 1-24 and 27-31 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is —OH, halo, or C 1-6 alkoxy, R 4 is H, and R 5 is H.

34 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is

such that the compound is of formula (II):

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

35 . The compound of claim 34 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein E is O, such that the compound is of formula (II-A1):

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

36 . The compound of claim 35 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y is taken together with R 7 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl.

37 . The compound of claim 35 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R y is taken together with R 7 , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl.

38 . The compound of any one of claims 35 to 37 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 1.

39 . The compound of any one of claims 35 to 38 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (II-B1):

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

40 . The compound of any one of claims 35 to 37 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 0.

41 . The compound of any one of claims 35 to 37 and 40 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (II-C1):

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

42 . The compound of any one of claims 35 to 37, 40, and 41 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6 is —OH, R 8 is C 1-6 alkyl, and R 9 is C 1-6 alkyl.

43 . The compound of any one of claims 35 to 37 and 40 to 42 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6 is —OH, R 8 is methyl, and R 9 is methyl.

44 . The compound of any one of claims 35 to 37 and 40 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (II-D1):

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

45 . The compound of any one of claims 35 to 41 and 44 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6 is —OH, R 8 is H, and R 9 is H.

46 . The compound of claim 35 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R 8 and R 9 is taken together with R 10 , and the atoms to which they are attached, to form a C 3-8 cycloalkyl.

47 . The compound of claim 35 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R 8 and R 9 is taken together with R 10 , and the atoms to which they are attached, to form a C 3-6 cycloalkyl.

48 . The compound of any one of claims 35, 38, 46, and 47 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (II-E1):

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

49 . The compound of any one of claims 35, 38, 46, and 48 , 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.

50 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is,

such that the compound is of formula (III):

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

51 . The compound of any one of claims 1 to 50 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is absent.

52 . The compound of any one of claims 1 to 51 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is O.

53 . The compound of any one of claims 1 to 51 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is —N—(C 1-6 alkyl).

54 . The compound of any one of claims 1 to 51 and 53 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is —N—CH 3 .

55 . The compound of any one of claims 1 to 50 and 52 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is —N—(C 1-6 alkyl).

56 . The compound of any one of claims 1 to 50, 52, and 55 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is —N—CH 3 .

57 . The compound of any one of claims 1 to 56 , 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.

58 . The compound of any one of claims 1 to 57 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is H, X 2 is H, one of X 3 and X 4 is halo, and the other of X 3 and X 4 is H.

59 . The compound of any one of claims 1 to 58 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is H, X 2 is H, one of X 3 and X 4 is chloro, and the other of X 3 and X 4 is H.

60 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is absent, Y is O, and R a , R b , and R c are each independently H, such that the compound is of formula (B-2):

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

61 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is absent, Y is —N(CH 3 ), and R a , R b , and R c are each independently H, such that the compound is of formula (B-5):

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

62 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q is —N(CH 3 ), Y is O, and R a , R b , and R c are each independently H, such that the compound is of formula (C-1):

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

63 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

64 . A pharmaceutical composition, comprising (i) a compound of any one of claims 1 to 63 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

65 . A method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1 to 63 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 64 .

66 . A method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1 to 63 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 64 .

67 . 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 any one of claims 1 to 63 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 64 .

68 . The method of claim 67 , wherein the disease, disorder, or condition is a kidney disease.

69 . The method of claim 67 or claim 68 , wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

70 . The method of claim 67 , wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

71 . A method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 63 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 64 , to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.

72 . The method of claim 71 , wherein the APOL1-mediated disease, disorder, or condition is a kidney disease.

73 . The method of claim 71 or claim 72 , wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.

74 . The method of claim 71 , wherein the APOL1-mediated disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

75 . The method of any one of claims 67 to 74 , wherein the individual has an APOL1 mutation.

76 . The method of claim 75 , wherein the APOL1 mutation is a gain-of-function mutation.

77 . A kit, comprising (i) a compound of any one of claims 1 to 63 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 64 , and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

78 . The kit of claim 77 , wherein the disease, disorder, or condition is a kidney disease.

79 . The kit of claim 77 or claim 78 , wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

80 . The kit of any one of claims 77 to 79 , wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

81 . The kit of any one of claims 77 to 80 , wherein the individual has an APOL1 mutation.

82 . The kit of claim 81 , wherein the APOL1 mutation is a gain-of-function mutation.