APOL1 inhibitors and methods of use
Provided herein are compounds of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, p, R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , R 4 , X 1 , X 2 , X 3 , and X 4 are as defined herein. Also provided are methods of preparing compounds of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided are methods of inhibiting APOL1 and methods of treating an APOL1-mediated disease, disorder, or condition in an individual.
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 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.
2. The compound of claim 1 , 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.
3. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1, or 2.
4. The compound of claim 1 , 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.
5. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 0, 1, or 2.
6. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is halo, —CN, —C 1-3 alkoxy, or —C 1-3 alkyl, wherein
the C 1-3 alkoxy of R 1 is optionally substituted with one or more halo; and
the C 1-3 alkyl of R 1 is optionally substituted with one or more halo.
7. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 0 or 1.
8. The compound of claim 1 , 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.
9. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 3 is absent.
10. The compound of claim 1 , 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.
11. The compound of claim 10 , 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—,
12. The compound of claim 1 , 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 .
13. The compound of claim 12 , 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.
14. The compound of claim 12 , 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.
15. The compound of claim 1 , 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 ).
16. The compound of claim 1 , 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.
17. The compound of claim 1 , 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 ).
18. The compound of claim 1 , 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 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 optionally substituted with one or more of R b .
19. The compound of claim 1 , 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 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 heteroaryl optionally substituted with one or more R c .
20. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, is selected from the group consisting of
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
21. 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, wherein the method 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.
22. 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 x ), 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 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.
23. A pharmaceutical composition, comprising (i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
24. A method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of
a) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or b) a pharmaceutical composition comprising (i) a compound of claim 1 , or a stereoisomer
or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
25. A method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual
a) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or
b) a pharmaceutical composition of comprising (i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients;
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.
26. A kit, comprising:
(i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition-comprising (i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients, and
(ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof;
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.
27. The compound of claim 1 , wherein the compound is a compound of formula (II-A):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R b and the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R c .
28. The compound of claim 1 , wherein the compound is a compound of formula (I-E5):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
a dashed line represents a single or double bond;
r is an integer from 0-1;
Y 3 , Y 4 and Y 5 are each independently C or N, optionally substituted by one or more H or R c ;
R c1 is OH is —OH; and
R c2 is H, C 1-6 alkyl, or C 3-10 cycloalkyl, wherein the C 1-6 alkyl of R c2 is optionally substituted with one or more OH.
29. The compound of claim 1 , wherein the compound is selected from the group consisting of
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
30. The compound of claim 1 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 30 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonyl ethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
32. The compound of claim 31 , wherein the compound is 5-chloro-1′-[2-({2-[(1R)-1-methanesulfonylethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
33. The compound of claim 31 , wherein the compound is 5-chloro-1′-[2-({2-[(1S)-1-methanesulfonylethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
34. The compound of claim 1 , wherein the compound is 5-chloro-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 34 , wherein the compound is 5-chloro-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
36. The compound of claim 1 , wherein the compound is 1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 36 , wherein the compound is 1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
38. The compound of claim 1 , wherein the compound is 5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 38 , wherein the compound is 5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
40. The compound of claim 39 , wherein the compound is chloro-1′-[(2S)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
41. The compound of claim 39 , wherein the compound is chloro-1′-[(2R)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
42. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-(4-{[(trans)-3-hydroxycyclobutyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
43. The compound of claim 42 , wherein the compound is 5-chloro-1′-[2-(4-{[(trans)-3-hydroxycyclobutyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
44. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(trans)-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
45. The compound of claim 44 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(trans)-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
46. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
47. The compound of claim 46 , wherein the compound is 5-chloro-1′-[2-({3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
48. The compound of claim 1 , wherein the compound is 4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide having the structure
or a pharmaceutically acceptable salt thereof.
49. The compound of claim 48 , wherein the compound is 4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide having the structure
50. The compound of claim 1 , wherein the compound is 1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
51. The compound of claim 50 , wherein the compound is 1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
52. The compound of claim 1 , wherein the compound is 2-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-2-methylpropanamide having the structure
or a pharmaceutically acceptable salt thereof.
53. The compound of claim 52 , wherein the compound is 2-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-2-methylpropanamide having the structure
54. The compound of claim 1 , wherein the compound is 1′-{2-[4-(1,1-dioxo-1λ 6 -thiomorpholine-4-carbonyl)-3-(trifluoromethyl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
55. The compound of claim 54 , wherein the compound is 1′-{2-[4-(1,1-dioxo-1λ 6 -thiomorpholine-4-carbonyl)-3-(trifluoromethyl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
56. The compound of claim 1 , wherein the compound is 1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
57. The compound of claim 56 , wherein the compound is 1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
58. The compound of claim 57 , wherein the compound is (S)-1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile.
59. The compound of claim 57 , wherein the compound is (R)-1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile.
60. The compound of claim 1 , wherein the compound is 5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
61. The compound of claim 60 , wherein the compound is 5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
62. The compound of claim 61 , wherein the compound is 5-chloro-1′-(2-{4-[(trans)-3-hydroxy-1-methanesulfonylcyclobutyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
63. The compound of claim 61 , wherein the compound is 5-chloro-1′-(2-{4-[(cis)-3-hydroxy-1-methanesulfonylcyclobutyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
64. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-(3-fluoro-4-{6-methane sulfonyl-2,6-diazaspiro[3.3]heptane-2-carbonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
65. The compound of claim 64 , wherein the compound is 5-chloro-1′-[2-(3-fluoro-4-{6-methane sulfonyl-2,6-diazaspiro[3.3]heptane-2-carbonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
66. The compound of claim 1 , wherein the compound is 5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
67. The compound of claim 66 , wherein the compound is 5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
68. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
69. The compound of claim 68 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
70. The compound of claim 1 , wherein the compound is 5-chloro-1′-(2-{[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
71. The compound of claim 70 , wherein the compound is 5-chloro-1′-(2-{[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
72. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(trans)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
73. The compound of claim 72 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(trans)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
74. The compound of claim 1 , wherein the compound is 5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
75. The compound of claim 74 , wherein the compound is 5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
76. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
77. The compound of claim 76 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
78. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
79. The compound of claim 78 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
80. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-( 2 H 3 )methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
81. The compound of claim 80 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-( 2 H 3 )methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
82. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
83. The compound of claim 82 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
84. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
85. The compound of claim 84 , wherein the compound is 5-chloro-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
86. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
87. The compound of claim 86 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
88. The compound of claim 1 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
89. The compound of claim 88 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
90. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({2-methyl-1-[(cis)-3-hydroxy-3-methyl cycl ° butyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
91. The compound of claim 90 , wherein the compound is 5-chloro-1′-[2-({2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
92. The compound of claim 1 , wherein the compound is 5-chloro-1′-[2-({7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
93. The compound of claim 92 , wherein the compound is 5-chloro-1′-[2-({7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
94. The method of claim 25 , wherein the disease, disorder, or condition is chronic kidney disease.
95. The method of claim 94 , wherein the compound is selected from the group consisting of
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
96. The method of claim 94 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonyl ethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
97. The method of claim 96 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
98. The method of claim 97 , wherein the compound is 5-chloro-1′-[2-({2-[(1R)-1-methanesulfonylethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
99. The method of claim 97 , wherein the compound is 5-chloro-1′-[2-({2-[(1 s)-1-methane sulfonyl ethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
100. The method of claim 94 , wherein the compound is 5-chloro-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
101. The method of claim 100 , wherein the compound is 5-chloro-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
102. The method of claim 94 , wherein the compound is 1′-{2-[3,5-difluoro-4-(3-methanesulfonyl oxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
103. The method of claim 102 , wherein the compound is 1′-{2-[3,5-difluoro-4-(3-methanesulfonyl oxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
104. The method of claim 94 , wherein the compound is 5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
105. The method of claim 104 , wherein the compound is 5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
106. The method of claim 105 , wherein the compound is chloro-1′-[(2S)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
107. The method of claim 105 , wherein the compound is chloro-1′-[(2R)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
108. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-(4-{[(trans)-3-hydroxycyclobutyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
109. The method of claim 108 , wherein the compound is 5-chloro-1′-[2-(4-{[(trans)-3-hydroxycyclobutyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
110. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(trans)-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
111. The method of claim 110 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(trans)-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
112. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
113. The method of claim 112 , wherein the compound is 5-chloro-1′-[2-({3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
114. The method of claim 94 , wherein the compound is 4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide having the structure
or a pharmaceutically acceptable salt thereof.
115. The method of claim 114 , wherein the compound is 4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide having the structure
116. The method of claim 94 , wherein the compound is 1′-{2-[4-(3-methanesulfonyl oxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
117. The method of claim 116 , wherein the compound is 1′-{2-[4-(3-methanesulfonyl oxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
118. The method of claim 94 , wherein the compound is 2-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-2-methylpropanamide having the structure
or a pharmaceutically acceptable salt thereof.
119. The method of claim 118 , wherein the compound is 2-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-2-methylpropanamide having the structure
120. The method of claim 94 , wherein the compound is 1′-{2-[4-(1,1-dioxo-1λ 6 -thiomorpholine-4-carbonyl)-3-(trifluoromethyl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
121. The method of claim 120 , wherein the compound is 1′-{2-[4-(1,1-dioxo-1λ 6 -thiomorpholine-4-carbonyl)-3-(trifluoromethyl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
122. The method of claim 94 , wherein the compound is 1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
or a pharmaceutically acceptable salt thereof.
123. The method of claim 122 , wherein the compound is 1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile having the structure
124. The method of claim 123 , wherein the compound is (S)-1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile.
125. The method of claim 123 , wherein the compound is (R)-1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile.
126. The method of claim 94 , wherein the compound is 5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
127. The method of claim 126 , wherein the compound is 5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
128. The method of claim 127 , wherein the compound is 5-chloro-1′-(2-{4-[(trans)-3-hydroxy-1-methanesulfonylcyclobutyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
129. The method of claim 127 , wherein the compound is 5-chloro-1′-(2-{4-[(cis)-3-hydroxy-1-methanesulfonylcyclobutyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one.
130. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-(3-fluoro-4-{6-methane sulfonyl-2,6-di azaspiro[3.3]heptane-2-carbonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
131. The method of claim 130 , wherein the compound is 5-chloro-1′-[2-(3-fluoro-4-{6-methane sulfonyl-2,6-di azaspiro[3.3]heptane-2-carbonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
132. The method of claim 94 , wherein the compound is 5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
133. The method of claim 132 , wherein the compound is 5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
134. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
135. The method of claim 134 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
136. The method of claim 94 , wherein the compound is 5-chloro-1′-(2-{[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
137. The method of claim 136 , wherein the compound is 5-chloro-1′-(2-{[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
138. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(trans)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
139. The method of claim 138 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(trans)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
140. The method of claim 94 , wherein the compound is 5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
141. The method of claim 140 , wherein the compound is 5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
142. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
143. The method of claim 142 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
144. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
145. The method of claim 144 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
146. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-( 2 H 3 )methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
147. The method of claim 146 , wherein the compound is 5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-( 2 H 3 )methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
148. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
149. The method of claim 148 , wherein the compound is 5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-m ethylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
150. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
151. The method of claim 150 , wherein the compound is 5-chloro-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
152. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
153. The method of claim 152 , wherein the compound is 5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
154. The method of claim 94 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
155. The method of claim 154 , wherein the compound is 5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
156. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
157. The method of claim 156 , wherein the compound is 5-chloro-1′-[2-({2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
158. The method of claim 94 , wherein the compound is 5-chloro-1′-[2-({7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure
or a pharmaceutically acceptable salt thereof.
159. The method of claim 158 , wherein the compound is 5-chloro-1′-[2-({7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one having the structure