Inhibitors of APOL1 and methods of using same

Patent metadata

Field	Value
Publication number	US-12281102-B2
Application number	US-202117345268-A
Country	US
Kind code	B2
Filing date	Jun 11, 2021
Priority date	Jun 12, 2020
Publication date	Apr 22, 2025
Grant date	Apr 22, 2025

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.

First claim

What is claimed is:

1. A compound, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I:

deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, wherein
(i) R is selected from —NR 3 R 4 , —C(O)R 3 , —OR 3 , —NRSC(O)R 3 , —NRSC(O)OR 3 , —NR 5 SO 2 R 3 , and —NR 5 SO 2 NR 3 R 4 , wherein, when R is —C(O)R 3 , X is N or R 3 is not bonded to the rest of the molecule through a nitrogen atom;
(ii) X is selected from N and CR X ;
(iii) R X is absent or is selected from hydrogen, hydroxy, halogen, and C 1 -C 3 linear and branched alkyl groups, wherein, when R X is absent, X is a bridgehead atom;
(iv) Ring A is a 4- to 7-membered cyclic alkyl or heterocycle, wherein the 4- to 7-membered heterocycle has one heteroatom and wherein the heteroatom is a nitrogen atom;
(v) each n is independently selected from 1, 2, and 3;
(vi) each R 1 is independently selected from:
halogen,
amino, and
C 1 -C 6 linear and branched haloalkyl groups;

(vii) each R 2 is independently selected from:
halogen,
hydroxy,
amino,
cyano,
C 1 -C 4 linear, branched, and cyclic alkyl groups,
C 1 -C 4 linear, branched, and cyclic hydroxyalkyl groups,
C 1 -C 4 linear, branched, and cyclic alkoxy groups,
C 1 -C 4 linear, branched, and cyclic haloalkyl groups, and
C 1 -C 4 linear, branched, and cyclic haloalkoxy groups;

(viii) R 3 and R 4 are independently selected from:
hydrogen,
C 1 -C 6 linear and branched alkylsulfonyl groups optionally substituted with amino,
C 1 -C 6 linear and branched alkoxy optionally substituted with 1-4 groups independently selected from hydroxy, amino, halogen, and oxo,
C 1 -C 3 linear and branched aminoalkyl groups optionally substituted with 1-2 groups independently selected from amido,
C 3 -C 6 cycloalkyl optionally substituted with 1-2 groups independently selected from:
halogen,
hydroxy,
oxo,
amido,
amino substituted with 1-2 groups independently selected from C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups,
aryl optionally substituted with 1-2 groups independently selected from halogen,
C 1 -C 6 linear and branched alkoxy groups,
carbamate optionally substituted with C 1 -C 6 linear or branched alkyl,
C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups optionally substituted with 1-3 groups independently selected from hydroxy, oxo, halogen, C 1 -C 6 linear and branched alkoxy groups, and carbamate optionally substituted with 1-3 groups independently selected from C 1 -C 6 linear and branched alkyl groups, and
C 1 -C 3 hydroxyalkyl,

3- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
halogen,
oxo,
hydroxy,
C 1 -C 6 linear and branched alkoxy groups optionally substituted with oxo,
C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy, oxo, and C 1 -C 6 linear and branched alkoxy groups,
C 1 -C 3 hydroxyalkyl and C 1 -C 3 haloalkyl groups, and
carbamate optionally substituted with 1-2 groups independently selected from C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups,

aryl optionally substituted with 1-4 groups independently selected from halogen, hydroxy, and C 1 -C 6 linear and branched alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
3- to 10-membered heteroaryl optionally substituted with 1-2 groups independently selected from amino, hydroxy, oxo, and C 1 -C 6 linear alkyl optionally substituted with 1-3 groups independently selected from halogen and amino,
C 1 -C 6 linear and branched alkyl groups optionally substituted with 1-4 groups independently selected from:
C 1 -C 4 alkyl groups,
amino optionally substituted with 1-2 groups independently selected from C 1 -C 6 linear and branched alkylsulfonyl groups and C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups (optionally substituted with 1-2 groups independently selected from oxo, hydroxy, amido, and C 1 -C 6 linear and branched alkylsulfonyl groups),
hydroxy,
oxo,
cyano,
carboxylic acid,
carbamate optionally substituted with 1-2 groups independently selected from C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups,
halogen,
amido optionally substituted with 1-2 groups independently selected from C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups and C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic hydroxyalkyl groups,
C 3 -C 6 cyclic alkyl optionally substituted with 1-2 groups independently selected from amino, halogen, hydroxy, oxo, C 1 -C 3 alkyl, C 1 -C 6 linear and branched alkoxy groups, and carbamate (which may be further substituted with C 1 -C 4 linear or branched alkyl),
C 1 -C 6 linear and branched alkoxy groups optionally substituted with hydroxy,
C 1 -C 6 linear and branched alkylsulfonyl groups,
aryl optionally substituted with 1-2 groups independently selected from halogen, hydroxy, and C 1 -C 6 linear and branched alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
4- to 10-membered heterocyclyl optionally substituted with 1-2 groups independently selected from halogen groups, oxo, hydroxy, amido optionally substituted with C 1 -C 3 alkyl, and C 1 -C 6 linear and branched alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from halogen groups, oxo, hydroxy, C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl optionally substituted with 1-3 groups independently selected from halogen, hydroxy, and C 1 -C 6 linear and branched alkoxy groups, and amido groups optionally substituted with 1-2 groups independently selected from C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl,
or R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclyl or heteroaryl optionally substituted with 1-3 groups independently selected from:
amino optionally substituted with 1-2 groups independently selected from C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups, which are optionally substituted with oxo,
halogen,
hydroxy,
oxo,
C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy, amino, and C 1 -C 6 linear and branched alkoxy groups,
C 1 -C 3 linear or branched hydroxyalkyl, and
amide optionally substituted with 1-2 groups independently selected from C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups; and

(ix) R 5 is selected from hydrogen, hydroxy, halogen, and C 1 -C 3 linear and branched alkyl groups.

2. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3 and R 4 are independently selected from:
hydrogen,
C 1 -C 6 linear and branched alkylsulfonyl groups optionally substituted with amino,
C 1 -C 6 linear and branched alkoxy groups optionally substituted with 1-4 groups independently selected from hydroxy, amino, halogen, and oxo,
C 1 -C 3 linear and C 3 branched aminoalkyl groups optionally substituted with 1-2 amido groups,
C 3 -C 6 cyclic alkyl optionally substituted with 1-2 groups independently selected from:
halogen,
hyd

Assignees

• Vertex Pharma

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

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title