US 11,866,446 B2
Inhibitors of APOL1 and methods of using same
Jun Myun Ahn, Waltham, MA (US); Samantha Angle, Cambridge, MA (US); Michael Aaron Brodney, Newton, MA (US); Jingrong Cao, Newton, MA (US); John E. Cochran, Marshfield, MA (US); Jon H. Come, Cambridge, MA (US); Leslie A. Dakin, Framingham, MA (US); Elena Dolgikh, Boston, MA (US); Brad D. Maxwell, Holliston, MA (US); Suganthini S. Nanthakumar, Newton, MA (US); Hardwin O'Dowd, Cambridge, MA (US); Jessica Howard Olsen, Jamaica Plain, MA (US); Timothy J. Senter, Arlington, MA (US); Akira Joseph Shimizu, Framingham, MA (US); Steven David Stone, Quincy, MA (US); and Haoxuan Wang, Somerville, MA (US)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Aug. 26, 2021, as Appl. No. 17/446,135.
Claims priority of provisional application 63/070,705, filed on Aug. 26, 2020.
Prior Publication US 2022/0106327 A1, Apr. 7, 2022
Int. Cl. C07D 495/20 (2006.01); C07D 519/00 (2006.01)
CPC C07D 495/20 (2013.01) [C07D 519/00 (2013.01)] 55 Claims
 
1. A compound represented by the following structural formula:

OG Complex Work Unit Chemistry
a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
X1 is selected from S and —CR2a and X2 is selected from S and —CR2b, wherein:
one of X1 and X2 is S;
when X1 is S, then X2 is —CR2b; and
when X2 is S, then X1 is —CR2a;
R1 is selected from hydrogen, halogen, cyano, —OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and phenyl, wherein:
the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and C1-C4 alkoxy;
the C1-C6 alkoxy of R1 is optionally substituted with 1 to 3 groups independently selected from halogen;
the C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)NH2, —C(═O)NH(C1-C4 alkyl), and —C(═O)N(C1-C4 alkyl)2; and
the phenyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)NH2, —C(═O)NH(C1-C4 alkyl), and —C(═O)N(C1-C4 alkyl)2;
R2a is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl, wherein:
the C1-C6 alkyl of R2a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy;
R2b is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl;
R3a is selected from halogen, cyano, —OH, C1-C6 alkyl, and ═O; wherein:
the C1-C6 alkyl of R3a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
R3b is selected from C1-C2 alkyl and ═O; wherein:
the C1-C2 alkyl of R3b is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
custom character, for each occurrence, is a single bond when R3a is selected from halogen, cyano, —OH, C1-C6 alkyl or when R3b is selected from C1-C2 alkyl; or alternatively custom character, for each occurrence, is a double bond when R3a is ═O or when R3b is ═O;
R4 is selected from C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C2-C6 alkynyl, and

OG Complex Work Unit Chemistry
wherein:
the C1-C6 alkyl of R4 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkoxy, —C(═O)NH2, —C(═O)NH(C1-C4 alkyl), —C(═O)N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5 to 10-membered heterocyclyl, phenyl, and 5 to 10-membered heteroaryl;
Ring A is selected from C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, C6 and C10 aryl, and 5 to 10-membered heteroaryl, wherein Ring A is optionally substituted with 1, 2, 3, 4, or 5 Ra groups; wherein:
Ra, for each occurrence, is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl,
C1-C6 haloalkoxy, —C(═O)NRhRi, —NRhRi, —NRhC(═O)Rk, —NRhC(═O)ORk, —NRhC(═O)NRiRj, —NRhS(═O)pRk, —ORk, —OC(═O)Rk, —OC(═O)ORk, —OC(═O)NRhRi, —[O(CH2)q]rO(C1-C6 alkyl), —S(═O)pRk, —S(═O)pNRhRi, —C(═O)ORk, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl; wherein:
the C1-C6 alkyl, C1-C6 alkoxy, and the C2-C6 alkenyl of Ra are each optionally substituted with 1 to 3 groups independently selected from C6 to C10 aryl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rm groups), cyano, —C(═O)Rk, —C(═O)ORk, —C(═O)NRhRi, —NRhRi,
—NRhC(═O)Rk, —NRhC(═O)ORk, —NRhC(═O)NRiRj, —NRhS(═O)pRk, —ORk, —OC(═O)Rk, —OC(═O)ORk, —OC(═O)NRhRi, —S(═O)pRk, —S(═O)pNRhRi, and C3-C6 carbocyclyl (optionally substituted with 1 to 3 Rm groups);
the C3-C12 carbocyclyl, the 3 to 12-membered heterocyclyl, the C6 and C10 aryl, and the 5 to 10-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C1-C4 alkyl, —NRhRi, and —ORk; wherein:
Rh, Ri, and Rj, for each occurrence, are each independently selected from hydrogen, C1-C4 alkyl, C6-C10 aryl, and C3-C6 cycloalkyl; wherein:
the C1-C4 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
Rk, for each occurrence, are each independently selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; wherein:
the C1-C4 alkyl of any one of Rk is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
Rm, for each occurrence, is independently selected from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, —S(═O)pRk, and —ORk; wherein:
the C1-C6 alkyl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
R5 is selected from C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl; wherein:
the C1-C6 alkyl of R5 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C4 alkoxy,
—C(═O)NH2, —C(═O)NH(C1-C4 alkyl), and —C(═O)N(C1-C4 alkyl)2;
the C3-C12 carbocyclyl, the 3 to 12-membered heterocyclyl, the C6 and C10 aryl, and the 5 to 10-membered heteroaryl of R5 are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl) (optionally substituted with —OH), —N(C1-C4 alkyl)2, C1-C5 alkyl (optionally substituted with —OH), C1-C4 alkoxy, —C(═O)NH2, —C(═O)NH(C1-C4 alkyl), —NHC(═O)(C1-C4 alkyl),
—C(═O)(C1-C4 alkoxy), and —C(═O)N(C1-C4 alkyl)2;
k is an integer selected from 0, 1, and 2, wherein:
when R3a is selected from halogen, cyano, —OH, and C1-C6 alkyl, k is 1 or 2; and
when R3a is ═O, k is 1;
m is an integer selected from 0, 1, and 2, wherein:
when R3b is selected from C1-C2 alkyl, m is 1 or 2; and
when R3b is ═O, m is 1;
p is an integer selected from 1 and 2; and
q and r are each an integer selected from 1, 2, 3, and 4.