Inhibitors of APOL1 and methods of using same

Patent metadata

Field	Value
Publication number	US-12116343-B2
Application number	US-202117161474-A
Country	US
Kind code	B2
Filing date	Jan 28, 2021
Priority date	Jan 29, 2020
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

Abstract

The disclosure provides at least one entity chosen from compounds of Formula (I)

pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, compositions comprising the same, and methods of using the same, including use in treating APOL1 mediated kidney disease.

First claim

The invention claimed is:

1. A compound chosen from compounds of Formula (I):

pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:
(i) Ring A is a 3- to 7-membered ring wherein the ring is a cyclic alkyl or a heterocycle;
(ii) Q is N or CR 5 ;
(iii) each R 1 is independently chosen from
halogen groups,
hydroxy,
thiol,
amino,
cyano,
—OC(O)C 1 -C 6 linear, branched, and cyclic alkyl groups,
—C(O)OC 1 -C 6 linear, branched, and cyclic alkyl groups,
—NHC(O)C 1 -C 6 linear, branched, and cyclic alkyl groups,
—C(O)NHC 1 -C 6 linear, branched, and cyclic alkyl groups,
—NHC(O)aryl groups,
—C(O)NHaryl groups,
—NHC(O)heteroaryl groups,
—C(O)NHheteroaryl groups,
—NHS(O) 2 C 1 -C 6 linear, branched, and cyclic alkyl groups,
—S(O) 2 NHC 1 -C 6 linear, branched, and cyclic alkyl groups,
—NHS(O) 2 aryl groups,
—S(O) 2 NHaryl groups,
—NHS(O) 2 heteroaryl groups,
—S(O) 2 NHheteroaryl groups,
—NHC(O)NHC 1 -C 6 linear, branched, and cyclic alkyl groups,
—NHC(O)NHaryl groups,
—NHC(O)NHheteroaryl groups,
C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 2 -C 6 linear, branched, and cyclic alkenyl groups,
C 1 -C 6 linear, branched, and cyclic hydroxyalkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups,
C 1 -C 6 linear, branched, and cyclic thioalkyl groups,
C 1 -C 6 linear, branched, and cyclic haloalkyl groups,
C 1 -C 6 linear, branched, and cyclic haloaminoalkyl groups,
C 1 -C 6 linear, branched, and cyclic halothioalkyl groups,
C 1 -C 6 linear, branched, and cyclic haloalkoxy groups,
benzyloxy, benzylamino, or benzylthio groups,
3- to 6-membered heterocycloalkenyl groups,
3- to 6-membered heterocycloalkyl groups, and
5- and 6-membered heteroaryl groups; or

two R 1 groups, together with the carbon atoms to which they are attached, form a C 4 -C 8 cycloalkyl group, an aryl group, or a heteroaryl group;
(iv) each R 2 is independently chosen from
halogen groups,
hydroxy,
thiol,
amino,
cyano,
—NHC(O)C 1 -C 6 linear, branched, and cyclic alkyl groups,
—C(O)NHC 1 -C 6 linear, branched, and cyclic alkyl groups,
—NHC(O)aryl groups,
—C(O)NHaryl groups,
—NHC(O)heteroaryl groups,
—C(O)NHheteroaryl groups,
—NHS(O) 2 C 1 -C 6 linear, branched, and cyclic alkyl groups,
—S(O) 2 NHC 1 -C 6 linear, branched, and cyclic alkyl groups,
—NHS(O) 2 aryl groups,
—S(O) 2 NHaryl groups,
—NHS(O) 2 heteroaryl groups,
—S(O) 2 NHheteroaryl groups,
—NHC(O)NHC 1 -C 4 linear, branched, and cyclic alkyl groups,
—NHC(O)NHaryl groups,
—NHC(O)NHheteroaryl groups,
C 1 -C 4 linear, branched, and cyclic alkyl groups,
C 2 -C 4 linear, branched, and cyclic alkenyl 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 thioalkyl groups,
C 1 -C 4 linear, branched, and cyclic haloalkyl groups,
C 1 -C 4 linear, branched, and cyclic haloaminoalkyl groups,
C 1 -C 4 linear, branched, and cyclic halothioalkyl groups, and
C 1 -C 4 linear, branched, and cyclic haloalkoxy groups;

(v) m is chosen from 1, 2, 3, and 4;
(vi) n is chosen from 1, 2, 3, 4, and 5;
(vii) X is chosen from divalent C 1 -C 8 linear, branched, and cyclic alkyl groups and divalent C 1 -C 8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with one to four groups independently chosen from:
C 1 -C 6 alkyl groups,
aryl groups,
heteroaryl groups,
halogen groups,
hydroxy, and
amino;

(viii) Y is chosen from divalent amino, divalent oxygen, divalent C 1 -C 8 linear, branched, and cyclic alkyl groups, divalent C 1 -C 8 linear, branched, and cyclic alkoxy groups, divalent C 1 -C 8 linear, branched, and cyclic aminoalkyl groups, and divalent C 1 -C 8 linear, branched, and cyclic thioalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with one to three groups independently chosen from
C 1 -C 6 alkyl groups optionally substituted with hydroxy,
C 3 -C 6 cyclic alkyl,
aryl groups,
heteroaryl groups,
halogen groups,
hydroxy, and
amino,

or wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally fused to a C 3 -C 6 cyclic alkyl;
(ix) o is chosen from 0, 1, 2, 3, and 4;
(x) p is chosen from 0, 1, 2, 3, and 4;
(xi) R 3 is chosen from:
hydrogen,
C 1 -C 6 linear and branched alkylsulfonyl groups,
C 1 -C 6 linear and branched alkoxy groups optionally substituted with a C 3 -C 6 cyclic alkyl group or a 3- to 6-membered heterocycle,
C 1 -C 6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from:
halogen groups,
hydroxy,
oxo,
C 1 -C 6 linear and branched alkoxy groups,
C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
amido groups,

heterocyclic groups optionally substituted with one to four groups independently chosen from:
halogen groups,
oxo,
hydroxy, and
C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,

aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C 1 -C 6 linear alkyl groups, and
C 1 -C 7 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with one to five groups independently chosen from:
amino groups,
hydroxy,
oxo,
cyano,
carboxylic acid,
halogen groups,
amido groups optionally substituted with one or two groups independently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups and C 1 -C 6 linear, branched, and cyclic hydroxyalkyl groups,
C 3 -C 6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C 1 -C 6 linear and branched alkoxy groups, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy,
C 2 -C 6 linear and branched alkynyl groups,
C 2 -C 6 linear and branched alkoxy groups optionally substituted with at least one hydroxy,
C 1 -C 6 linear and branched alkylsulfonyl groups,
aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
carbonyl-(4-methylpiperazin-1-yl),
carbonyl-(N-morpholino),
4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, oxo, hydroxy, C 1 -C 6 linear and branched alkoxy groups, and C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one to three groups independently chosen from halogen groups, hydroxy,

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 Stephane
• Fader Lee
• Sturino Claudio
• Szychowski Janek

Classifications

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D413/12

  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

• C07D403/14

  containing three or more hetero rings · CPC title