Inhibitors of APOL1 and methods of using same
Inventors
DAKIN, Leslie A. • Senter, Timothy J. • Cao, Jingrong • Come, Jon H. • DENIS, FRANCOIS • DORSCH, Warren A. • FORTIER, Anne • Hamel, Martine • Krueger, Elaine B. • Ledford, Brian • Maltais, Francois • Nanthakumar, Suganthini S. • Nicolas, Olivier • SAYEGH, Camil E. • Wang, Tiansheng • Dorich, Stephanie • FADER, LEE • Sturino, Claudio • Szychowski, Janek
Assignees
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Publication Number
US-12281102-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The disclosure provides at least one compound, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of formula (I), deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, compositions comprising the same, and methods of making and using the same, including use in treating APOL1 mediated kidney disease.
Core Innovation
The invention relates to compounds, deuterated derivatives, and pharmaceutically acceptable salts selected from compounds of Formula I. The compounds are defined by interrelated structural constraints on R, X, RX, Ring A, n, R1, R2, R3, R4, and R5, including explicit connection rules for R and X and a bridgehead condition when RX is absent. Ring A is limited to a 4- to 7-membered cyclic alkyl or heterocycle having one heteroatom that is a nitrogen atom.
R is selected from —NR3R4, —C(O)R3, —OR3, —NRSC(O)R3, —NRSC(O)OR3, —NR5SO2R3, and —NR5SO2NR3R4, with an additional condition when R is —C(O)R3 that X is N or R3 is not bonded to the rest of the molecule through a nitrogen atom. X is selected from N and CRX, and RX is absent or is selected from hydrogen, hydroxy, halogen, and C1-C3 linear and branched alkyl groups. Each n is independently selected from 1, 2, and 3.
R1 is independently selected from halogen, amino, and C1-C6 linear and branched haloalkyl groups, and R2 is independently selected from halogen, hydroxy, amino, cyano, and C1-C4 linear, branched, and cyclic alkyl, hydroxyalkyl, alkoxy, haloalkyl, and haloalkoxy groups. R3 and R4 are independently selected from hydrogen and extensive alkylsulfonyl, alkoxy, aminoalkyl, cycloalkyl, aryl, carbamate, heterocyclyl, and heteroaryl options, with the further option that R3 and R4 together with the nitrogen atom form a 3- to 10-membered heterocyclyl or heteroaryl. R5 is selected from hydrogen, hydroxy, halogen, and C1-C3 linear and branched alkyl groups.
Claims Coverage
The independent claim coverage centers on one Formula I scaffold for compounds, deuterated derivatives, and pharmaceutically acceptable salts. It includes 7 inventive features: the Formula I scaffold definition, R and X connectivity rules, RX absence/bridgehead rule, Ring A size and nitrogen heterocycle limitation, substituent selections for n/R1/R2, substituent selections for R3/R4 including ring formation, and R5 selection.
Formula I scaffold with deuterated derivatives and pharmaceutically acceptable salts
A compound, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, defined by the stated selection constraints.
R and X connectivity rules
R is selected from —NR3R4, —C(O)R3, —OR3, —NRSC(O)R3, —NRSC(O)OR3, —NR5SO2R3, and —NR5SO2NR3R4, and X is selected from N and CRX, with the additional condition that when R is —C(O)R3, X is N or R3 is not bonded to the rest of the molecule through a nitrogen atom.
RX absence and bridgehead rule
RX is absent or is selected from hydrogen, hydroxy, halogen, and C1-C3 linear and branched alkyl groups, and when RX is absent, X is a bridgehead atom.
Ring A size and nitrogen heterocycle limitation
Ring A is a 4- to 7-membered cyclic alkyl or heterocycle, wherein the heterocycle has one heteroatom and the heteroatom is a nitrogen atom.
n, R1, and R2 substituent selections
Each n is independently selected from 1, 2, and 3; each R1 is independently selected from halogen, amino, and C1-C6 linear and branched haloalkyl groups; and each R2 is independently selected from halogen, hydroxy, amino, cyano, and C1-C4 linear, branched, and cyclic alkyl, hydroxyalkyl, alkoxy, haloalkyl, and haloalkoxy groups.
R3 and R4 selection with heterocyclyl and heteroaryl formation
R3 and R4 are independently selected from hydrogen and extensive alkylsulfonyl, alkoxy, aminoalkyl, cycloalkyl, aryl, carbamate, heterocyclyl, and heteroaryl options, including the option that R3 and R4 together with the nitrogen atom form a 3- to 10-membered heterocyclyl or heteroaryl.
R5 selection
R5 is selected from hydrogen, hydroxy, halogen, and C1-C3 linear and branched alkyl groups.
Overall, the claims define a tightly constrained Formula I scaffold covering compounds, deuterated derivatives, and pharmaceutically acceptable salts, with explicit structural limitations on connectivity, ring composition, and substituent classes for R, X, RX, Ring A, n, R1, R2, R3, R4, and R5.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of APOL1-mediated kidney disease, including ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease, with disease association tied to APOL1 genetic alleles (G1 and G2) and inhibition of APOL1 activity.
Treatment of APOL1-mediated kidney disease, including FSGS and non-diabetic kidney disease (NDKD).
Association with APOL1 genetic risk variants G1 (S342G:I384M) and G2 (N388del:Y389del).
Pharmaceutical compositions and methods of use for treating APOL1-mediated kidney disease.
Inhibition of APOL1 activity in a patient context described in the provided summary.
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