Compounds and methods useful for stabilizing phenylalanine hydroxylase mutations
The disclosure relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein, m, R 1 -R 5 , R 5A , and L are defined herein. These compounds are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2;
R 1 is
x is 0 to 5;
each R a independently is halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R 2 is C 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl,
R 3 is H or C 1-6 alkyl;
R 4 is H or C 1-6 alkyl;
or R 3 and R 4 , together with the atom to which they are attached, form a C 3-6 cycloalkyl;
R 5 is H or D;
R 5A is H or D;
L is a bond, carbonyl, optionally substituted C 1-6 alkylene, optionally substituted C 1-6 alkylenecarbonyl, optionally substituted C 2-6 alkenylenecarbonyl, optionally substituted C 1-6 haloalkylenecarbonyl, or optionally substituted —C(O)NR b (C 1-6 alkylene)-, wherein the carbon atom of the carbonyl group is connected to N in Formula I;
R b is H or C 1-6 alkyl;
W is S or NR 15 ;
W 1 is S, O, or NR 15 ;
R 10 , R 11 , R 12 , R 13 , and R 14 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxy(alkylene), C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 haloalkoxy(alkylene), C 2-6 alkenyl, CN, halo, (CR v R x ) p NR y R z , C(O)NR y2 R z2 , optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), optionally substituted aryl, or optionally substituted heteroaryl;
R v and R x are independently H or C 1-6 alkyl;
R y and R z are independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy(alkylene), or C(O)OC 1-6 alkyl;
R y2 and R z2 are independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
p is 0, 1, 2, or 3; and
R 15 is H or C 1-6 alkyl.
2 . The compound of claim 1 , wherein the compound is of Formula I-A-1:
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , wherein the compound is of Formula I-B-1:
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , wherein the compound is of Formula I-C-1:
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein L is a bond, —C(O)—, —C(O)CH 2 —, or —C(O)CF 2 —.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R a is F, Br, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, CF 3 , CHF 2 , OCF 3 , OCHF 2 , or cyclopropyl.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 3-8 cycloalkyl, optionally substituted with one or more of halo, C 1-6 alkyl, C 1-6 haloalkyl, or OH.
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl,
12 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is aryl, optionally substituted with one or more of halo or C 1-6 alkoxy.
13 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
14 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 10 , R 11 , R 12 , R 13 , and R 14 are each H.
15 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
wherein:
R 10 , R 11 , R 12 , R 13 and R 14 are independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxy(alkylene), optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), optionally substituted heteroaryl, or (CR v R x ) p NR y R z ;
R v and R x are, independently, H or C 1-6 alkyl;
R y and R z are, independently, H, C 1-6 alkyl, C 3-6 cycloalkyl, or C(O)OC 1-6 alkyl; and
p is 0, 1, 2, or 3.
16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is substituted with one or more of halo, C 1-6 haloalkyl, or C 1-6 alkyl.
17 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 10 , R 11 , R 13 , and R 14 are each hydrogen.
18 . The compound of claim 8 , wherein the compound is an S-enantiomer, or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
20 . A method for stabilizing a mutant PAH protein, comprising contacting the protein with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21 . The method of claim 20 , wherein the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation.
22 . The method of claim 20 , wherein the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.
23 . The method of claim 20 , wherein the mutant PAH protein contains at least one R408W mutation.
24 . A method for reducing blood phenylalanine concentration in a subject suffering from phenylketonuria comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
25 . The method of claim 24 , wherein the blood phenylalanine concentration is reduced to a concentration less than or equal to about 600 μM.
26 . The method of claim 25 , wherein the blood phenylalanine concentration is reduced to a concentration less than or equal to about 360 μM.
27 . The method of claim 24 , wherein the subject has a blood phenylalanine concentration greater than about 600 μM prior to administration of the compound.
28 . The method of claim 24 , wherein the subject has a blood phenylalanine concentration greater than about 1200 μM prior to administration of the compound.
29 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:
30 . A pharmaceutical composition comprising a compound of claim 29 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
31 . A method for stabilizing a mutant PAH protein, comprising contacting the protein with a compound of claim 29 , or a pharmaceutically acceptable salt thereof.
32 . The method of claim 31 , wherein the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation.
33 . The method of claim 31 , wherein the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.
34 . The method of claim 31 , wherein the mutant PAH protein contains at least one R408W mutation.
35 . A method for reducing blood phenylalanine concentration in a subject suffering from phenylketonuria comprising administering a compound of claim 29 , or a pharmaceutically acceptable salt thereof.
36 . The method of claim 35 , wherein the blood phenylalanine concentration is reduced to a concentration less than or equal to about 600 μM.
37 . The method of claim 36 , wherein the blood phenylalanine concentration is reduced to a concentration less than or equal to about 360 μM.
38 . The method of claim 35 , wherein the subject has a blood phenylalanine concentration greater than about 600 μM prior to administration of the compound.
39 . The method of claim 35 , wherein the subject has a blood phenylalanine concentration greater than about 1200 μM prior to administration of the compound.