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:

m is 0 or 1;

Y is O or —N(C 1-6 alkyl), wherein the C 1-6 alkyl of the —N(C 1-6 alkyl) is optionally substituted with one or more R g substituents;

Z 1 , Z 2 , Z 3 , and Z 4 are, independently of each other, —N—, —CH— or —C(R f )—;

R a , R b , and R c are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, or 3-8 membered heterocycle wherein,

the C 1-6 alkyl of R a , R b , or R c is optionally substituted with one or more R h substituents, and

the 3-8 membered heterocycle of R a , R b , or R c is optionally substituted with one or more R i substituents,

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 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is optionally substituted with one or more R i substituents, and the other of R a , R b , and R c is H or C 1-6 alkyl, C 3-6 cycloalkyl, or 3-8 membered heterocycle wherein,

the C 1-6 alkyl of R a , R b , or R c is optionally substituted with one or more R h substituents, and

the 3-8 membered heterocycle of R a , R b , or R c is optionally substituted with one or more R 1 substituents;

R d and Rare each independently H or C 1-6 alkyl,

or R d and R e are taken together with the atoms to which they are attached to form a C 3-6 cycloalkyl or a 3-6 membered heterocycle;

R f is, independently at each occurrence, —CN, halo, C 1-6 alkyl, C 1-6 alkoxy, or —N(R j ) 2 , wherein the C 1-6 alkyl of R f is optionally substituted with one or more halo;

R g is, independently at each occurrence, —S(O) 2 C 1-6 alkyl;

R h is, independently at each occurrence, —OH, C 1-6 alkoxy, —N(R j ) 2 , C(O)R k , or —S(O) 2 C 1-6 alkyl;

R i is, independently at each occurrence, oxo, C 1-6 alkyl, or C(O)R k ;

R j is independently at each occurrence H, C 1-6 alkyl or C(O)C 1-6 alkyl;

R k is, independently at each occurrence C 1-6 alkyl or C 1-6 alkoxy;

L is selected from the group consisting of:

wherein

R x and R 1 are taken together with the atoms to which they are attached to form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is substituted with n independently selected R m substituents, wherein n is an integer from 0-6, and R m is C 1-6 alkyl, or C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R n substituents, and R n is, independently at each occurrence, —OH;

R 2 is H, —OH, or C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more OH; and

R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R 3 is optionally substituted with one or more OH;

provided that when L is (i), either:

(1) m is 1,

(2) at least one of Z 1 , Z 2 , Z 3 , and Z 4 is —N— or —C(R f )—,

(3) R 3 is other than H,

(4) at least one of R a , R b , and R c is heterocycle, or

(5) at least one of R g , R i , R j , R k , and R n is present;

wherein

R y , R 4 , and R 5 are taken together with the atoms to which they are attached to form a 8-20 membered bicyclic heterocycle, wherein the 8-20 membered bicyclic heterocycle is substituted with n independently selected R m substituents, wherein n is an integer from 0-6, and R m is C 1-6 alkyl, or C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R n substituents, and R n is, independently at each occurrence, —OH; and

wherein

R z and R 6 are taken together with the atoms to which they are attached to form a 3-8 membered heterocycleheterocycle substituted with n independently selected R m substituents, wherein n is an integer from 0-6, and R m is C 1-6 alkyl or C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R n substituents, and R n is, independently at each occurrence, —OH; and

R 7 is taken, together with one of X 1 and X 2 and the atoms to which they are attached, to form a C 4-8 cycloalkyl;

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

X 1 , and X 2 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,

or one of X 1 and X 2 is taken together with R 7 and the atoms to which it is attached to form a C 4-8 cycloalkyl, and the other of X 1 or X 2 is 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; and

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.

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

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

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

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

p is 0, 1, or 2; and

V 1 and V 2 are each independently —CH 2 —, —NH—, or —O—.

4 . The compound of any one of claims 1 to 3 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A1):

or a stereoisomer or a 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 n is 0.

6 . The compound of claim 4 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1.

7 . The compound of claim 6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R m is, independently at each occurrence, C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more —OH.

8 . The compound of claim 6 or claim 7 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R m is, independently at each occurrence, CH 3 , or CH 2 OH.

9 . The compound of any one of claims 1 to 3 , wherein the compound is a compound of formula (I-A2):

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

10 . The compound of claim 9 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

11 . The compound of claim 1 , wherein the compound is a compound of formula (II):

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

12 . The compound of claim 1 or claim 11 , wherein the compound is a compound of formula (II-A):

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

q is 1, or 2 and

r is 0 or 1.

13 . The compound of claim 12 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each of q and r is 1.

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 1 , wherein the compound is a compound of formula (III):

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

16 . The compound of claim 1 or claim 15 , or a stereoisomer or tautomer thereof, wherein the compound is a compound of formula (III-A):

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

s is 0, 1, or 2 and

t is 0 or 1.

17 . The compound of any one of claims 1, 15, or 16 , wherein the compound is a compound of formula (III-A2):

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

18 . The compound of claim 17 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1.

19 . The compound of claim 17 or claim 18 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R m is, independently at each occurrence, C 1-6 alkyl.

20 . The compound of any one of claims 17 to 19 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R m is, independently at each occurrence, —CH 3 .

21 . The compound of any one of claims 1, 15 or 16 , wherein the compound is a compound of formula (III-A3):

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

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

23 . The compound of any one of claims 1 to 22 , or a stereoisomer or tautomer thereof, wherein the compound is a compound of formula (B):

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

24 . The compound of any one of claims 1 to 23 , wherein the compound is a compound of formula (B-2):

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

25 . The compound of any one of claims 1 to 23 , wherein the compound is a compound of formula (B4):

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

26 . The compound of any one of claims 1 to 22 , wherein the compound is a compound of formula (C):

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

27 . The compound of any one of claims 1 to 26 , wherein the ring bearing Z 1 , Z 2 , Z 3 , and Z 4 is selected from the group consisting of

28 . The compound of any one of claims 1 to 26 , wherein the compound is selected from the group consisting of co compound of claim 1 , wherein the compound is a compound of formula (E-Ia), (E-IIa), (E-IIIa), (E-IVa), (E-Va), (E-VIa), or (E-VIIa):

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

29 . The compound of any one of claims 1 to 28 , wherein the compound is selected from the group consisting of compounds 1-12, 14-90, and 93-142 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

30 . A method for preparing a compound of formula (A) as recited in claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises a step of reacting a compound of formula (A-I1):

wherein, R a , R b , R c , R d , R e , Z 1 , Z 2 , Z 3 , Z 4 , Y, and m, are as defined for a compound of formula (A); and

V 1 is selected from the group consisting of:

wherein

R x and R 1 are taken together with the atoms to which they are attached to form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is substituted with n independently selected R m substituents, wherein n is an integer from 0-6, and R m is C 1-6 alkyl, or C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R n substituents, and R n is, independently at each occurrence, —OH; and

wherein

R z and R 6 are taken together with the atoms to which they are attached to form a 3-8 membered heterocycleheterocycle substituted with n independently selected R m substituents, wherein n is an integer from 0-6, and R m is C 1-6 alkyl or C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R n substituents, and R n is, independently at each occurrence, —OH;

with:

a compound of formula (A-I2):

wherein X 1 , X 2 , X 3 , and X 4 are as defined for a compound of formula (A);

the dashed line represents a single or double bond;

W 1 is oxo, halo or sulfonate ester; and

V 2 is selected from the group consisting of:

wherein

R 2 is H, —OH, or C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more OH; and

R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R 3 is optionally substituted with one or more OH;

provided that when V 2 is (i), either:

(1) m is 1,

(2) at least one of Z 1 , Z 2 , Z 3 , and Z 4 is —N— or —C(R f )—,

(3) R 3 is other than H,

(4) at least one of R a , R b , and R c is heterocycle, or

(5) at least one of R g , R i , R j , R k , and R n is present; and

wherein

R 7 is taken, together with one of X 1 and X 2 and the atoms to which they are attached, to form a C 4-8 cycloalkyl;

wherein # denotes the point of attachment to W 1 and ## denotes the point of attachment to the remainder of the molecule.

31 . A method for preparing a compound of formula (A) as recited in claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises a step of reacting a compound of formula (A-I3):

wherein, R a , R b , R c , R d , R e , Z 1 , Z 2 , Z 3 , Z 4 , Y, and m, are as defined for a compound of formula (A); and

V 2 is halo or OH,

with:

a compound of formula (A-I4):

wherein, X 1 , X 2 , X 3 , X 4 , and L are as defined for a compound of formula (A); and

W 2 is H, or sulfamate;

to give a compound of formula (A) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

32 . A method for preparing a compound of formula (A) as recited in claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises a step of reacting a compound of formula (A-I5):

wherein, R a , R b , R c , R d , R e , Z 1 , Z 2 , Z 3 , Z 4 , Y, and m, are as defined for a compound of formula (A); and

V 3 is

 wherein

R x and R 1 are taken together with the atoms to which they are attached to form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is substituted with n independently selected R m substituents, wherein n is an integer from 0-6, and R m is C 1-6 alkyl, or C(O)C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R n substituents, and R n is, independently at each occurrence, —OH;

with:

a compound of formula (A-I6):

wherein X 1 , X 2 , X 3 , and X 4 are as defined for a compound of formula (A); and

V 4 is

provided that when L is (i), either:

(1) m is 1,

(2) at least one of Z 1 , Z 2 , Z 3 , and Z 4 is —N— or —C(R f )—,

(3) R 3 is other than H,

(4) at least one of R a , R b , and R c is heterocycle, or

(5) at least one of R g , R i , R j , R k , and R n is present;

to give a compound of formula (A) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

33 . A pharmaceutical composition, comprising (i) a compound of any one of claims 1 to 29 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

34 . 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 29 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 33 .

35 . 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 29 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 33 .

36 . A method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of any one of claims 1 to 29 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 33 .

37 . The method of claim 36 , wherein a therapeutically effective amount of the compound or the pharmaceutical composition is administered.

38 . The method of claim 36, or claim 37 , wherein the disease, disorder, or condition is a kidney disease.

39 . The method of any one of claims 36 to 38 , wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

40 . The method of claim 36 or claim 37 , 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.

41 . A method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a compound of any one of claims 1 to 29 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 33 , to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.

42 . The method of claim 41 , wherein a therapeutically effective amount of the compound or the pharmaceutical composition is administered.

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

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

45 . The method of claim 41, or claim 42 , wherein the APOL1-mediated disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

46 . The method of any one of claims 36 to 45 , wherein the individual has an APOL1 mutation.

47 . The method of claim 46 , wherein the APOL1 mutation comprises a gain-of-function mutation.

48 . A kit, comprising (i) a compound of any one of claims 1 to 29 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 33 , and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

49 . The kit of claim 48 , wherein the disease, disorder, or condition is a kidney disease.

50 . The kit of claim 48 or claim 49 , wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

51 . The kit of any one of claims 48 to 50 , 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.

52 . The kit of any one of claims 48 to 51 , wherein the individual has an APOL1 mutation.

53 . The kit of claim 52 , wherein the APOL1 mutation comprises a gain-of-function mutation.