APOL1 INHIBITORS AND METHODS OF USE

1 . 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 1-6 alkyl is further optionally substituted with one or more —OH or C 1-6 alkoxy;

L 2 is O or N(R′), 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 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 is optionally substituted with one or more —OH, and

the 3-10 membered heterocyclyl of L 3 is optionally substituted with one or more —OH or C 1-6 alkyl;

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 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 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

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 —OH, 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, deuterium, or halo, and

the 5-20 membered heteroaryl is optionally substituted with one or more R e , wherein R e 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 e is optionally substituted with one or more —S(O) 2 —C 1-6 alkyl,

the C 3-10 cycloalkyl of R e is optionally substituted with one or more —OH or C 1-6 alkyl, and

the 3-10 membered heterocyclyl of R e 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 e 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,

(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.

2 . The compound of claim 1 , wherein the compound 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′), 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

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 e , wherein

R e 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 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.

3 . The compound of claim 1, or claim 2 , 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, wherein:

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),

(viii) —CN; or

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

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 , 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 is optionally substituted with one or more halo; and

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

4 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 2 is —O—, such that the compound is a compound of formula (I-A):

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

5 . The compound of any one of claims 1-4 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1, or 2.

6 . The compound of any one of claims 1-5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is H, C 1-3 alkyl, C 3-6 cycloalkyl, or 3-10 membered heterocyclyl, wherein the C 1-3 alkyl of R 2 is optionally substituted with one or more deuterium, halo, —OH, —NH 2 , or C 1-3 alkoxy, and the C 3-6 cycloalkyl of R 2 is optionally substituted with one or more —OH.

7 . The compound of any one of claims 1-6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 0, 1, or 2.

8 . The compound of any one of claims 1-7 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is halo, —CN, or —C 1-3 alkyl, wherein the C 1-3 alkyl of R 1 is optionally substituted with one or more halo.

9 . The compound of any one of claims 1-8 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 0 or 1.

10 . The compound of any one of claims 1-9 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is C 1-6 alkyl.

11 . The compound of any one of claims 1-10 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 1 is C 1-3 alkylene, wherein the C 1-3 alkylene of L 1 is optionally substituted with one or more deuterium or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with —OH or C 1-3 alkoxy.

12 . The compound of any one of claims 1-11 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 1 is selected from the group consisting of

wherein, for each L 1 , * denotes the point of attachment to L 2 and ** denotes the point of attachment to the remainder of the molecule.

13 . The compound of any one of claims 1-12 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 2 is O.

14 . The compound of any one of claims 1-13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 3 is absent.

15 . The compound of any one of claims 1-13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 3 is —O—, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 1-6 alkylene, 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 is optionally substituted with one or more —OH, and

the 3-10 membered heterocyclyl of L 3 is optionally substituted with one or more —OH or C 1-6 alkyl.

16 . The compound of any one of claims 1-13, and 15 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 3 is selected from the group consisting of —O—,

17 . The compound of any one of claims 1-16 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is S(O) 2 −R a , 5-10 membered heteroaryl, —N(R d ) 2 , —NS(O)—(C 1-3 alkyl) 2 , —C(O)—N(R e ) 2 , 3-6 membered heterocyclyl, —S(O)(N—C 1-3 alkyl)-(C 1-3 alkyl), —CN, —OH, —C(O)—C 1-3 alkyl, or —P(O)(C 1-3 alkyl) 2 , wherein

the 5-20 membered heteroaryl of R 4 is optionally substituted with one or more C 1-3 alkyl, and

the 3-6 membered heterocyclyl optionally substituted with one or more —OH, oxo, C 1-3 alkyl, or —S(O) 2 —R a .

18 . The compound of claim 17 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a is C 1-6 alkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, wherein

the C 1-6 alkyl of R a is 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,

the C 3-10 cycloalkyl of R a is 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, and

the 3-10 membered heterocyclyl of R a is optionally substituted with one or more C 1-6 alkyl.

19 . The compound of claim 17 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, 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, and wherein R a is C 1-6 alkyl.

20 . The compound of claim 17 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R e is independently at each occurrence H, C 1-6 alkyl, or 3-10 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo.

21 . The compound of claim 17 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein 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 , wherein R a is C 1-6 alkyl.

22 . The compound of any one of claims 1-21 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each of X 1 and X 2 is C(R 5 ).

23 . The compound of any one of claims 1-21 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each of X 1 and X 2 is N.

24 . The compound of any one of claims 1-21 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1 and X 2 is N and the other is C(R 5 ).

25 . The compound of any one of claims 1-21 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1 and X 2 is N or CR 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 optionally substituted with one or more of R b .

26 . The compound of claim 25 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R b is independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C 1-3 alkyl, —C(O)—C 1-3 alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-3 alkyl), —C(O)—N(C 1-3 alkyl) 2 , —S(O) 2 —R a , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, wherein the C 1-3 alkyl of R b is optionally substituted with one or more halo, OH, —S(O) 2 —C 1-3 alkyl, or C 3-6 cycloalkyl, and wherein the C 3-6 cycloalkyl of the C 1-3 alkyl of R b is further optionally substituted with one or more C 1-3 alkyl or —OH and the C 3-6 cycloalkyl of R b is optionally substituted with one or more —OH, C 3-6 cycloalkyl, or C 1-3 alkyl, and wherein the C 1-3 alkyl of the C 3-6 cycloalkyl of R b is further optionally substituted with one or more —OH, deuterium, or halo.

27 . The compound of any one of claims 1-21 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X 1 and X 2 is N or CR 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 heteroaryl optionally substituted with one or more R c .

28 . The compound of claim 27 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, R c is independently at each occurrence, selected from the group consisting of halo, C 1-3 alkyl, —C(O)—C 1-3 alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-3 alkyl), —C(O)—N(C 1-3 alkyl) 2 , —S(O) 2 —R a , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, wherein the C 1-6 alkyl of R c is optionally substituted with one or more —S(O) 2 —C 1-3 alkyl, the C 3-10 cycloalkyl of R c is optionally substituted with one or more —OH, or C 1-3 alkyl, and the 3-6 membered heterocyclyl of R c is optionally substituted with one or more —OH or C 1-3 alkyl, and wherein the C 1-3 alkyl of the 3-6 membered heterocyclyl of R c is further optionally substituted with one or more —OH.

29 . The compound of any one of claims 1-28 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 is independently at each occurrence, H, halo, —CN, 3-6 membered heterocyclyl, C 1-3 alkyl, or C 1-3 alkoxy, wherein the C 1-3 alkyl of R 5 is optionally substituted with one or more halo, or —OH and wherein the C 1-3 alkoxy is optionally substituted with one or more halo.

30 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Compounds 1-472 of Table 1.

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

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;

with:

a compound of formula (II′-B):

wherein:

the dashed line represents a single or double bond;

Y 1 is halo, oxo, or a sulfonate ester

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 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 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 is optionally substituted with one or more —OH, and

the 3-10 membered heterocyclyl of L 3 is optionally substituted with one or more —OH or C 1-6 alkyl;

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 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 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

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 —OH, 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, deuterium, or halo, 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,

(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;

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

32 . The method of claim 31 , wherein the compound of claim 1 is prepared by a step comprising:

a) alkylation of an amine of formula (II′-A) with an alkyl halide, or sulfonate ester compound of formula (II′-B) in the presence of an inorganic base; or

b) reductive amination of a ketone of formula (II′-B) with an amine of formula (II′-A).

33 . The method of claim 32 , wherein the inorganic base is selected from the group consisting of potassium carbonate, and sodium bicarbonate.

34 . The method of claim 32 , wherein the reductive amination proceeds under the action of sodium triacetoxyborohydride, titanium tetraiopropoxide and acetic acid.

35 . A method for preparing a compound of formula (II), as recited in claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising a step of reacting a compound of formula (II′—C):

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 1-6 alkyl is further optionally substituted with one or more —OH or C 1-6 alkoxy; and

Y 2 is halo, —OH or —NH 2 ;

with:

a compound of formula (II′-D):

wherein:

Y 3 is —OH or —NH(R′), wherein each R x is independently 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 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 is optionally substituted with one or more —OH, and

the 3-10 membered heterocyclyl of L 3 is optionally substituted with one or more —OH or C 1-6 alkyl;

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 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 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

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 —OH, 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, deuterium, or halo, and

the 5-20 membered heteroaryl is optionally substituted with one or more R e , wherein R e 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 e 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 e 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,

(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;

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

36 . The method of claim 35 , wherein the compound of claim 1 is prepared by a step comprising:

a) coupling of an alcohol compound of formula (II′—C) with a phenol compound of formula (II′-D), or a heterocyclic variant, under Mitsunobu-type reaction conditions; or

b) reacting an alkyl halide compound of formula (II′—C) with a phenol or amine compound of formula (II′-D), in the presence of a catalyst.

37 . The method of claim 36 , wherein the Mitsunobi-type reaction conditions comprises coupling of an alcohol compound of formula (II′—C) with a phenol compound of formula (II′-D), or a heterocyclic variant, in the presence of triphenylphosphine and diisopropyl azodicarboxylate.

38 . The method of claim 37 , wherein the catalyst is silver oxide or potassium carbonate.

39 . A pharmaceutical composition, comprising (i) a compound of any one of claims 1-30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

40 . 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 1-30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 39 .

41 . 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 1-30 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 39 .

42 . 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 1-30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 39 .

43 . The method of claim 42 , 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.

44 . The method of claim 42 or claim 43 , wherein the disease, disorder, or condition is a kidney disease.

45 . The method of any one of claims 40-44 , wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

46 . A method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a compound of any one of claims 1-30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 39 , to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.

47 . The method of claim 46 , wherein the APOL1-mediated disease, disorder, or condition is a kidney disease.

48 . The method of claim 46 or claim 47 , wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.

49 . The method of claim 46 , 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.

50 . The method of any one of claims 40-49 , wherein the individual has an APOL1 mutation.

51 . The method of claim 50 , wherein the APOL1 mutation is a gain-of-function mutation.

52 . The method of any one of claims 42-51 , wherein a therapeutically effective amount of a compound of any one of claims 1-30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 39 , is administered.

53 . A kit, comprising (i) a compound of any one of claims 1-30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 39 , and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

54 . The kit of claim 53 , wherein the disease, disorder, or condition is a kidney disease.

55 . The kit of claim 53 or claim 54 , wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

56 . The kit of any one of claims 53-55 , 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.

57 . The kit of any one of claims 53-56 , wherein the individual has an APOL1 mutation.

58 . The kit of claim 57 , wherein the APOL1 mutation is a gain-of-function mutation.