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 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 (I-E):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
ring A is a 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 ;
m is an integer from 0 to 4;
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;
X 2 is N or C (R 5 );
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;
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; and
R 6 and R 7 are each independently H or halo.
2. 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 a compound of formula (I-E4):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
r is an integer from 0-1; and
Y 3 , Y 4 , and Y 5 are each independently C or N, optionally substituted by one or more H or R c , and wherein the dashed line represents a single or double bond.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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 —O— and ** denotes the point of attachment to the remainder of the molecule.
8. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is C(R 5 ).
9. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is N.
10. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is a 5-10 membered heterocyclyl optionally substituted with one or more R b .
11. The compound of claim 10 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is selected from the group consisting of
wherein ## represents a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.
12. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is a 5-10 membered heteroaryl optionally substituted with one or more R c .
13. The compound of claim 12 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is selected from the group consisting of
wherein ## represents a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.
14. 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
or a pharmaceutically acceptable salt of any of the foregoing.
15. 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.
16. A method of inhibiting APOL1 in a cell, comprising exposing the cell to
a) an effective amount of 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) an effective amount of 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.
17. 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 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 (CKD), 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.
18. The method of claim 17 , wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease (CKD), 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, and COVID-19 associated nephropathy.
19. The method of claim 17 , wherein the disease, disorder, or condition is chronic kidney disease (CKD).
20. 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 a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and 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 (CKD), 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.