Inhibitors of APOL1 and methods of using same
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.
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, and C 1 -C 6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C 1 -C 6 linear and branched alkoxy groups,
(xii) R 4 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 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, and C 1 -C 6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C 1 -C 6 linear and branched alkoxy groups,
or R 3 and R 4 , 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,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups, oxo, and C 3 -C 6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkyl groups,
amide groups optionally substituted with one to four groups independently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with one to four groups independently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C 1 -C 6 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 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 or two 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; and
or R 3 and R 4 , 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,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups, oxo, and C 3 -C 6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkyl groups,
amide groups optionally substituted with one to four groups independently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with one to four groups independently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C 1 -C 6 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 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 or two 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; and
(xiii) R 5 is absent or is chosen from:
hydrogen,
halogen groups,
hydroxy,
thiol,
amino, and
C 1 -C 6 linear and branched alkyl groups,
wherein when R 5 is absent, Q is a bridgehead atom.
2. 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 chosen from:
(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 0, 1, 2, 3, and 4;
(vi) n is chosen from 0, 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 and R 4 are independently 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, and C 1 -C 6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C 1 -C 6 linear and branched alkoxy groups,
or R 3 and R 4 , 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,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups, oxo, and C 3 -C 6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkyl groups,
amide groups optionally substituted with one to four groups independently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with one to four groups independently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C 1 -C 6 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 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 or two 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; and
(xii) R 5 is hydrogen.
3. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Q is CR 5 .
4. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 1 is independently chosen from halogen groups and C 1 -C 6 linear, branched, and cyclic haloalkyl groups.
5. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 1 is independently chosen from fluoro and CF 3 .
6. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 2 is independently chosen from halogen groups.
7. The compound, salt, or deuterated derivative according to claim 1 , wherein each R 2 is fluoro.
8. The compound, salt, or deuterated derivative according to claim 1 , wherein m is 2.
9. The compound, salt, or deuterated derivative according to claim 1 , wherein n is 1.
10. The compound, salt, or deuterated derivative according to claim 1 , wherein X is chosen from divalent C 1 -C 8 linear, branched, and cyclic alkyl groups, wherein the divalent alkyl groups are optionally substituted with one to four groups chosen from:
C 1 -C 6 alkyl groups,
aryl groups,
heteroaryl groups,
halogen groups,
hydroxy, and
amino.
11. The compound, salt, or deuterated derivative according to claim 1 , wherein X is chosen from —CH 2 — and —CH 2 —CH 2 —.
12. The compound, salt, or deuterated derivative according to claim 1 , wherein Y is chosen from divalent amino, divalent oxygen, divalent C 1 -C 8 linear, branched, and cyclic alkyl groups, and divalent C 1 -C 8 linear, branched, and cyclic aminoalkyl groups, wherein the divalent alkyl groups and divalent aminoalkyl 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,
oxo, and
hydroxy,
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.
13. The compound, salt, or deuterated derivative according to claim 1 , wherein Y is chosen from
14. The compound, salt, or deuterated derivative according to claim 1 , wherein o is 0 or 1.
15. The compound, salt, or deuterated derivative according to claim 1 , wherein p is 0 or 1.
16. The compound, salt, or deuterated derivative according to claim 1 , wherein R 3 is hydrogen, and R 4 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,
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,
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, and C 1 -C 6 linear and branched alkyl groups optionally substituted with one to three groups independently from hydroxy, halogen groups, and C 1 -C 6 linear and branched alkoxy groups.
17. The compound, salt, or deuterated derivative according to claim 1 , wherein R 3 and R 4 , 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,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with one to four groups independently chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups, oxo, and C 3 -C 6 cyclic alkyl groups optionally substituted with one or two groups independently chosen from hydroxy and C 1 -C 6 linear and branched alkyl groups,
amide groups optionally substituted with one to four groups indepedently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with one to four groups indepedently chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with one to four groups independently chosen from oxo, C 1 -C 6 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 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 or two 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.
18. The compound, salt, or deuterated derivative according to claim 1 , wherein R 5 is independently chosen from hydrogen, fluoro, and methyl.
19. The compound, salt, or deuterated derivative according to claim 2 , wherein the compound is selected from compounds of Formula (V-a) and (V-b):
pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein R 1 , R 2 , R 3 , R 4 , Y, and p are as defined in claim 2 .
20. A compound chosen from compounds of Formula (Ia):
pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:
(i) 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;
(ii) 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;
(iii) m is chosen from 0, 1, 2, 3, and 4;
(iv) n is chosen from 0, 1, 2,3 4, and 5;
(v) 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 at least one group chosen from
C 1 -C 6 alkyl groups,
aryl groups,
heteroaryl groups,
halogen groups,
hydroxy, and
amino;
(vi) Y is chosen from 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 at least one group chosen from
C 1 -C 6 alkyl groups,
aryl groups,
heteroaryl groups,
halogen groups,
hydroxy, and
amino;
(vii) o is chosen from 0, 1, 2, 3, and 4;
(viii) p is chosen from 0, 1, 2, 3, and 4;
(ix) R 3 and R 4 are independently chosen from
hydrogen,
C 1 -C 6 linear and branched alkylsulfonyl groups,
C 1 -C 6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and amido groups,
heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
heteroaryl groups optionally substituted with at least one group chosen from C 1 -C 6 linear alkyl groups, and
C 1 -C 6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from:
amino groups,
hydroxy,
cyano,
carboxylic acid,
halogen groups,
amido groups optionally substituted with one or two groups 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 chosen from halogen groups and hydroxy,
C 1 -C 6 linear and branched alkynyl groups,
C 1 -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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups 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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, or R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group chosen from
hydroxy,
oxo,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups,
amide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups and heterocyclic groups,
4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups; and
(vi) each R 5 is independently chosen from
hydrogen,
halogen groups,
hydroxy,
thiol,
amino, and
C 1 -C 6 linear and branched alkyl groups.
21. A compound chosen from compounds of Formula (II):
pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:
(i) 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;
(ii) 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;
(iii) m is chosen from 0, 1, 2, 3, and 4;
(iv) n is chosen from 0, 1, 2, 3, 4, and 5;
(v) R 3 and R 4 are independently chosen from
hydrogen,
C 1 -C 6 linear and branched alkylsulfonyl groups,
C 1 -C 6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and amido groups,
heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
heteroaryl groups optionally substituted with at least one group chosen from C 1 -C 6 linear alkyl groups, and
C 1 -C 6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from:
amino groups,
hydroxy,
cyano,
carboxylic acid,
halogen groups,
amido groups optionally substituted with one or two groups 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 chosen from halogen groups and hydroxy,
C 1 -C 6 linear and branched alkynyl groups,
C 1 -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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups 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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, or R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group chosen from
hydroxy,
oxo,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups,
amide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups and heterocyclic groups,
4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups; and
(vi) each R 5 is independently chosen from
hydrogen,
halogen groups,
hydroxy,
thiol,
amino, and
C 1 -C 6 linear and branched alkyl groups,
halogen groups, and
methyl;
(iii) m is 0, 1 or 2; and
(iv) n is 1 or 2.
22. A compound chosen from compounds of Formula (IIIa)
compounds of Formula (IIIb):
pharmaceutically acceptable salts of any of the foregoing, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:
(i) 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;
(ii) 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;
(iii) m is chosen from 0, 1, 2, 3, and 4;
(iv) n is chosen from 0, 1, 2, 3, 4, and 5;
(v) R 3 and R 4 are independently chosen from:
hydrogen,
C 1 -C 6 linear and branched alkylsulfonyl groups,
C 1 -C 6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and amido groups,
heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
heteroaryl groups optionally substituted with at least one group chosen from C 1 -C 6 linear alkyl groups, and
C 1 -C 6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from:
amino groups,
hydroxy,
cyano,
carboxylic acid,
halogen groups,
amido groups optionally substituted with one or two groups 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 chosen from halogen groups and hydroxy,
C 1 -C 6 linear and branched alkynyl groups,
C 1 -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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups 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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
or R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group chosen from:
hydroxy,
oxo,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups,
amide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups and heterocyclic groups,
4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups; and
(vi) each R 5 is independently chosen from
hydrogen,
halogen groups,
hydroxy,
thiol,
amino, and
C 1 -C 6 linear and branched alkyl groups.
23. A compound chosen from compounds of Formula (IV):
pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein:
(i) each R 1 and R 2 is independently chosen from:
fluoro,
chloro,
bromo,
cyano,
methyl,
cyclopropyl,
ethyl,
hydroxypropyl,
isopropyl,
propen-2-yl,
dihydrofuran,
furan, and
methoxy;
(ii) R 3 and R 4 are independently chosen from:
hydrogen,
C 1 -C 6 linear and branched alkylsulfonyl groups,
C 1 -C 6 cyclic alkyl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and amido groups,
heterocyclic groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
aryl groups optionally substituted with at least one group chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups,
heteroaryl groups optionally substituted with at least one group chosen from C 1 -C 6 linear alkyl groups, and
C 1 -C 6 linear and branched alkyl groups, wherein the alkyl groups are optionally substituted with at least one group chosen from:
amino groups,
hydroxy,
cyano,
carboxylic acid,
halogen groups,
amido groups optionally substituted with one or two groups 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 chosen from halogen groups and hydroxy,
C 1 -C 6 linear and branched alkynyl groups,
C 1 -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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups 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 chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, or R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 4- to 10-membered heterocyclyl group optionally substituted with at least one group chosen from
hydroxy,
oxo,
C 1 -C 6 linear, branched, and cyclic alkyl groups optionally substituted with at least one groups chosen from hydroxy, amino groups, C 1 -C 6 linear, branched, and cyclic alkoxy groups,
amide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
carboxamide groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups,
C 1 -C 6 linear, branched, and cyclic alkoxy groups optionally substituted with at least one group chosen from C 1 -C 6 linear, branched, and cyclic alkyl groups and heterocyclic groups,
4- to 10-membered heterocyclyl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl groups optionally substituted with one or two groups chosen from halogen groups, hydroxy, C 1 -C 6 linear and branched alkyl groups optionally substituted with one or two groups chosen from hydroxy and C 1 -C 6 linear and branched alkoxy groups; and
(iii) each R 5 is independently chosen from:
hydrogen,
halogen groups,
hydroxy,
thiol,
amino, and
C 1 -C 6 linear and branched alkyl groups.
24. A compound chosen from
pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.
25. A compound chosen from
pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.
26. A pharmaceutical composition comprising the compound, salt, or deuterated derivative according to claim 1 and a pharmaceutically acceptable carrier.
27. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, salt, or deuterated derivative according to claim 1 or a pharmaceutical composition according to claim 26 .
28. The method according to claim 27 , wherein the APOL1 mediated kidney disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.
29. The method according to claim 27 , wherein the APOL1 mediated kidney disease is associated with APOL1 genetic alleles chosen from homozygous G1: S342G:I384M and homozygous G2:N388del:Y389del.
30. The method according to claim 27 , wherein the APOL1 mediated kidney disease is associated with compound heterozygous G1: S342G:I384M and G2: N388del:Y389del APOL1 genetic alleles.
31. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, salt, or deuterated derivative according to claim 1 or a pharmaceutical composition according to claim 26 .
32. The method according to claim 31 , wherein the APOL1 is associated with APOL1 genetic alleles chosen from homozygous G1: S342G:I384M and homozygous G2: N388del:Y389del.
33. The method according to claim 31 , wherein the APOL1 is associated with compound heterozygous G1: S342G:I384M and G2: N388del:Y389del APOL1 genetic alleles.