US 12,116,343 B2
Inhibitors of APOL1 and methods of using same
Leslie A. Dakin, Framingham, MA (US); Timothy J. Senter, Arlington, MA (US); Jingrong Cao, Newton, MA (US); Jon H. Come, Cambridge, MA (US); Francois Denis, St-Lazare (CA); Warren A. Dorsch, Waltham, MA (US); Anne Fortier, Jamaica Plain, MA (US); Martine Hamel, Laval (CA); Elaine B. Krueger, Milton, MA (US); Brian Ledford, Norton, MA (US); Francois Maltais, Stoneham, MA (US); Suganthini S. Nanthakumar, Newton, MA (US); Olivier Nicolas, Montreal (CA); Camil E. Sayegh, Belmont, MA (US); Tiansheng Wang, Concord, MA (US); Stephane Dorich, Ponte-Claire (CA); Lee Fader, Hawkesbury (CA); Claudio Sturino, Ile Bizard (CA); and Janek Szychowski, Montreal (CA)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Jan. 28, 2021, as Appl. No. 17/161,474.
Claims priority of provisional application 63/040,166, filed on Jun. 17, 2020.
Claims priority of provisional application 63/038,278, filed on Jun. 12, 2020.
Claims priority of provisional application 62/967,276, filed on Jan. 29, 2020.
Prior Publication US 2022/0340523 A1, Oct. 27, 2022
Int. Cl. C07D 209/18 (2006.01); C07D 401/12 (2006.01); C07D 403/04 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 405/12 (2006.01); C07D 413/12 (2006.01); C07D 451/02 (2006.01); C07D 491/107 (2006.01)
CPC C07D 209/18 (2013.01) [C07D 401/12 (2013.01); C07D 403/04 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 405/12 (2013.01); C07D 413/12 (2013.01); C07D 451/02 (2013.01); C07D 491/107 (2013.01)] 33 Claims
 
1. A compound chosen from compounds of Formula (I):

OG Complex Work Unit Chemistry
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 CR5;
(iii) each R1 is independently chosen from
halogen groups,
hydroxy,
thiol,
amino,
cyano,
—OC(O)C1-C6 linear, branched, and cyclic alkyl groups,
—C(O)OC1-C6 linear, branched, and cyclic alkyl groups,
—NHC(O)C1-C6 linear, branched, and cyclic alkyl groups,
—C(O)NHC1-C6 linear, branched, and cyclic alkyl groups,
—NHC(O)aryl groups,
—C(O)NHaryl groups,
—NHC(O)heteroaryl groups,
—C(O)NHheteroaryl groups,
—NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups,
—S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups,
—NHS(O)2aryl groups,
—S(O)2NHaryl groups,
—NHS(O)2heteroaryl groups,
—S(O)2NHheteroaryl groups,
—NHC(O)NHC1-C6 linear, branched, and cyclic alkyl groups,
—NHC(O)NHaryl groups,
—NHC(O)NHheteroaryl groups,
C1-C6 linear, branched, and cyclic alkyl groups,
C2-C6 linear, branched, and cyclic alkenyl groups,
C1-C6 linear, branched, and cyclic hydroxyalkyl groups,
C1-C6 linear, branched, and cyclic alkoxy groups,
C1-C6 linear, branched, and cyclic thioalkyl groups,
C1-C6 linear, branched, and cyclic haloalkyl groups,
C1-C6 linear, branched, and cyclic haloaminoalkyl groups,
C1-C6 linear, branched, and cyclic halothioalkyl groups,
C1-C6 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 R1 groups, together with the carbon atoms to which they are attached, form a C4-C8 cycloalkyl group, an aryl group, or a heteroaryl group;
(iv) each R2 is independently chosen from
halogen groups,
hydroxy,
thiol,
amino,
cyano,
—NHC(O)C1-C6 linear, branched, and cyclic alkyl groups,
—C(O)NHC1-C6 linear, branched, and cyclic alkyl groups,
—NHC(O)aryl groups,
—C(O)NHaryl groups,
—NHC(O)heteroaryl groups,
—C(O)NHheteroaryl groups,
—NHS(O)2C1-C6 linear, branched, and cyclic alkyl groups,
—S(O)2NHC1-C6 linear, branched, and cyclic alkyl groups,
—NHS(O)2aryl groups,
—S(O)2NHaryl groups,
—NHS(O)2heteroaryl groups,
—S(O)2NHheteroaryl groups,
—NHC(O)NHC1-C4 linear, branched, and cyclic alkyl groups,
—NHC(O)NHaryl groups,
—NHC(O)NHheteroaryl groups,
C1-C4 linear, branched, and cyclic alkyl groups,
C2-C4 linear, branched, and cyclic alkenyl groups,
C1-C4 linear, branched, and cyclic hydroxyalkyl groups,
C1-C4 linear, branched, and cyclic alkoxy groups,
C1-C4 linear, branched, and cyclic thioalkyl groups,
C1-C4 linear, branched, and cyclic haloalkyl groups,
C1-C4 linear, branched, and cyclic haloaminoalkyl groups,
C1-C4 linear, branched, and cyclic halothioalkyl groups, and
C1-C4 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 C1-C8 linear, branched, and cyclic alkyl groups and divalent C1-C8 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:
C1-C6 alkyl groups,
aryl groups,
heteroaryl groups,
halogen groups,
hydroxy, and
amino;
(viii) Y is chosen from divalent amino, divalent oxygen, divalent C1-C8 linear, branched, and cyclic alkyl groups, divalent C1-C8 linear, branched, and cyclic alkoxy groups, divalent C1-C8 linear, branched, and cyclic aminoalkyl groups, and divalent C1-C8 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
C1-C6 alkyl groups optionally substituted with hydroxy,
C3-C6 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 C3-C6 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) R3 is chosen from:
hydrogen,
C1-C6 linear and branched alkylsulfonyl groups,
C1-C6 linear and branched alkoxy groups optionally substituted with a C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle,
C1-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from:
halogen groups,
hydroxy,
oxo,
C1-C6 linear and branched alkoxy groups,
C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 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
C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups,
aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups,
heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and
C1-C7 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 C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups,
C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and branched alkoxy groups, C1-C6 linear and branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy,
C2-C6 linear and branched alkynyl groups,
C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy,
C1-C6 linear and branched alkylsulfonyl groups,
aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 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, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 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, and C1-C6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and branched alkoxy groups,
(xii) R4 is chosen from:
hydrogen,
C1-C6 linear and branched alkylsulfonyl groups,
C1-C6 linear and branched alkoxy groups optionally substituted with a C3-C6 cyclic alkyl group or a 3- to 6-membered heterocycle,
C1-C6 cyclic alkyl groups optionally substituted with one to four groups independently chosen from:
halogen groups,
hydroxy,
oxo,
C1-C6 linear and branched alkoxy groups,
C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 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
C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups,
aryl groups optionally substituted with one to four groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups,
heteroaryl groups optionally substituted with one to four groups independently chosen from hydroxy and C1-C6 linear alkyl groups, and
C1-C7 linear and branched alkyl groups, wherein the alkyl groups are 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 C1-C6 linear, branched, and cyclic alkyl groups and C1-C6 linear, branched, and cyclic hydroxyalkyl groups,
C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from halogen groups, C1-C6 linear and branched alkoxy groups, C1-C6 linear and branched alkyl groups optionally substituted with one or two hydroxy groups, and hydroxy,
C2-C6 linear and branched alkynyl groups,
C2-C6 linear and branched alkoxy groups optionally substituted with at least one hydroxy,
C1-C6 linear and branched alkylsulfonyl groups,
aryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 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, C1-C6 linear and branched alkoxy groups, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 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, and C1-C6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C1-C6 linear and branched alkoxy groups,
or R3 and R4, together with the nitrogen atom to which they are attached, form a 4- to 10-membered heterocyclyl group optionally substituted with one to four groups independently chosen from
hydroxy,
oxo,
C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkyl groups,
amide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups,
C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups,
4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and
or R3 and R4, together with the nitrogen atom to which they are attached, form a 4- to 10-membered heterocyclyl group optionally substituted with one to four groups independently chosen from
hydroxy,
oxo,
C1-C6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C1-C6 linear, branched, and cyclic alkoxy groups, oxo, and C3-C6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkyl groups,
amide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with one to four groups independently chosen from C1-C6 linear, branched, and cyclic alkyl groups,
C1-C6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C1-C6 linear, branched, and cyclic alkyl groups, and heterocyclic groups,
4- to 10-membered heterocyclyl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups independently chosen from halogen groups, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C1-C6 linear and branched alkoxy groups; and
(xiii) R5 is absent or is chosen from:
hydrogen,
halogen groups,
hydroxy,
thiol,
amino, and
C1-C6 linear and branched alkyl groups,
wherein when R5 is absent, Q is a bridgehead atom.