BCAT modulation
This disclosure relates to, in part, the treatment of an organic acidemia in a subject in need thereof via administration of a therapeutically effective amount of compounds that inhibit BCAT2. The disclosure also relates to, in part, methods for identifying a candidate compound for treatment of organic acidemias such as maple syrup urinary disease, methylmalonic acidemia, propionic acidemia and isovaleric acidemia.
1 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein
Z is CH 2 , CF 2 , O, or a bond;
each of J 1 , J 2 , J 3 , and J 4 is independently CH or N;
X 1 is N or CR 5A ;
X 2 is N or CR 5B ;
R 1 is —NR 3 SO 2 R 4 , —NR 3 C(O)R 4 , or —C(O)(CH 2 ) m NR 3 R 4 ;
R 2 is —NR 6 R 7 , C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one, two, or three substituents R 2′ independently selected from halo, —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)NR 6 R 7 , —C(O)R 6 , —NR 6 R 7 , —NR 6 C(O)R 7 , —OH, —S-(haloC 1 -C 6 alkyl), C 6 -C 10 aryl, and 5-10 membered heterocyclyl; or two R 2′ substituents together with the atoms to which they are attached form a five-membered heterocyclyl or C 3 -C 8 cycloalkyl, each optionally substituted with halo;
R 3 is H or methyl;
R 4 is phenyl, thiophene, oxazole, isoxazole, thiazole, furan, pyrrole, or C 2 -C 6 alkenyl, wherein each phenyl, thiophene, oxazole, isoxazole, thiazole, furan, or pyrrole is optionally substituted with one, two, or three substituents R 4′ independently selected from halo, —CN, —NO 2 , C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, —(CH 2 ) q NR 8 C(O)R 9 , —C(O)NR 8 R 9 , —C(O)OR 9 , —C(O)R 9 , and 5-10 membered heterocyclyl;
R 5A is F;
R 5B is H, halo, —CN, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(CH 2 ), OH, —C(O)NR 8 R 9 , —NR 8 COR 9 , 5-10 membered heteroaryl, —C(O)R 8 , or —C(O)OR 8 ;
or R 5A and R 5B together with the atoms to which they are attached form a six-membered heterocyclyl ring optionally substituted with oxo;
R 6 and R 7 are independently H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl;
each R 8 is independently H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl;
each R 9 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
m is 0;
q is 0 or 1; and
r is 0 or 1.
2 . The compound of claim 1 , wherein each of J 2 , J 3 , and J 4 is CH; X 1 is CR 5A , and X 2 is CR 5B .
3 . The compound of claim 1 , wherein R 1 is —NR 3 C(O)R 4 or —C(O)(CH 2 ) m NR 3 R 4 .
4 . The compound of claim 3 , wherein R 4 is phenyl thiophene, oxazole, isoxazole, thiazole, furan, or pyrrole, each optionally substituted with one, two, or three substituents R 4′ .
5 . The compound of claim 4 , wherein R 4 is phenyl, thiophene, oxazole, isoxazole, thiazole, furan, or pyrrole, each of which is optionally substituted with one, two, or three substituents R 4′ , wherein each R 4′ is independently selected from the group consisting of —F, —Cl, —Br, —CN, —NO 2 , —CF 3 , —CH 3 , —CH(CH 3 ) 2 , —C(O)CH 3 , —C(O)OCH 3 , phenyl, cyclopropyl, and morpholinyl.
6 . The compound of claim 1 , wherein R 2 is C 6 -C 10 aryl or 5-10 membered heteroaryl, each optionally substituted with one, two, or three substituents R 2′ .
7 . The compound of claim 6 , wherein R 2 is selected from the group consisting of phenyl, pyridine, pyrimidine, pyridazine, pyrazine, imidazole, and thiophene, each of which is optionally substituted with one, two, or three substituents R 2′ , wherein each R 2′ is independently selected from the group consisting of —F, —Cl, —Br, —CN, NO 2 , —CH 3 , —CF 2 H, —C═CH, —C(O)H, —CONH 2 , —C(O)NHCH 3 , —OH, —OCH 3 , —OCF 3 , —SCF 3 , —NH 2 , —NHC(O)CH 3 , and morpholine.
8 . The compound of claim 1 , wherein X 2 is CR 5B and R 5B is —C(O)NR 8 R 9 .
9 . The compound of claim 1 , wherein X 2 is CR 5B and R 5B is halo, —CN, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(CH 2 ) r OH, —NR 8 COR 9 , 5-10 membered heteroaryl, —C(O)R 8 , or —C(O)OR 8 .
10 . The compound of claim 9 wherein X 2 is CR 5B and R 5B is —NR 8 COR 9 or —C(O)OR 8 .
11 . The compound of claim 1 , wherein X 2 is CR 5B and R 5B is —CF 3 , —COCH 3 , —CH 2 OH, —CN, or tetrazole.
12 . The compound of claim 1 , having a structure of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein
each J 3 and J 4 is independently CH or N;
X 1 is N or CR 5A ;
X 2 is N or CR 5B ;
wherein one, two, three, or four of J 3 , J 4 , X 1 , and X 2 is N;
R 2 is C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one, two, or three substituents R 2′ independently selected from halo, —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)NR 6 R 7 , —C(O)R 6 , —NR 6 R 7 , —NR 6 C(O)R 7 , —OH, —S-(haloC 1 -C 6 alkyl), C 6 -C 10 aryl, and 5-10 membered heterocyclyl; or two R 2′ substituents together with the atoms to which they are attached form a five-membered heterocyclyl or C 3 -C 8 cycloalkyl, each optionally substituted with halo; and
R 4 is phenyl, thiophene, oxazole, isoxazole, thiazole, furan, pyrrole, or C 2 -C 6 alkenyl, wherein each phenyl, thiophene, oxazole, isoxazole, thiazole, furan, or pyrrole is optionally substituted with one, two, or three substituents R 4′ independently selected from halo, —CN, —NO 2 , C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, —(CH 2 ) q NR 8 C(O)R 9 , —C(O)NR 8 R 9 , —C(O)OR 9 , —C(O)R 9 , and 5-10 membered heterocyclyl.
13 . The compound of claim 12 , wherein R 2 is phenyl optionally substituted with one, two, or three substituents R 2′ independently selected from halo, —CN, —NO 2 , and C 1 -C 6 alkyl.
14 . The compound of claim 12 , wherein R 2 is thiophene, oxazole, isoxazole, thiazole, furan, or pyrrole optionally substituted with one, two, or three substituents R 2′ independently selected from halo, —CN, —NO 2 , and C 1 -C 6 alkyl.
15 . The compound of claim 12 , wherein R 4 is thiophene optionally substituted with halo or phenyl.
16 . The compound of claim 12 , wherein
X 2 is CR 5B ;
R 5B is H, halo, —C(O)NR 8 R 9 , —NR 8 COR 9 , or —C(O)OR 8 ; and
R 8 and R 9 are each independently H or C 1 -C 6 alkyl.
17 . The compound of claim 1 , having a structure of Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is —NR 3 C(O)R 4 or —C(O)(CH 2 ) m NR 3 R 4 ; and
R 2 is —NR 6 R 7 , C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, wherein each aryl or heteroaryl is substituted with one, two, or three substituents R 2′ independently selected from halo, —CN, —NO 2 , C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)NR 6 R 7 , —C(O)R 6 , —NR 6 R 7 , —NR 6 C(O)R 7 , —OH, C 6 -C 10 aryl, and 5-10 membered heterocyclyl; or two R 2′ substituents together with the atoms to which they are attached form a five-membered heterocyclyl or C 3 -C 8 cycloalkyl, each optionally substituted with halo.
18 . The compound of claim 1 , having a structure of Formula (V), or a pharmaceutically acceptable salt thereof:
wherein
R 1 is —NR 3 SO 2 R 4 , —NR 3 C(O)R 4 , or —C(O)(CH 2 ) m NR 3 R 4 ;
R 2 is —NR 6 R 7 , C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one, two, or three substituents R 2′ independently selected from halo, —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)NR 6 R 7 , —C(O)R 6 , —NR 6 R 7 , —NR 6 C(O)R 7 , —OH, —S-(haloC 1 -C 6 alkyl), C 6 -C 10 aryl, and 5-10 membered heterocyclyl; or two R 2′ substituents together with the atoms to which they are attached form a five-membered heterocyclyl or C 3 -C 8 cycloalkyl, each optionally substituted with halo;
R 5A is F;
R 5B is H, halo, —CN, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(CH 2 ), OH, —C(O)NR 8 R 9 , —NR 8 COR 9 , 5-10 membered heteroaryl, —C(O)R 8 , or —C(O)OR 8 ; and
or R 5A and R 5B together with the atoms to which they are attached form a six-membered heterocyclyl ring optionally substituted with oxo.
19 . The compound of claim 1 , having a structure of Formula (VI) or a pharmaceutically acceptable salt thereof:
20 . The compound of claim 1 , having a structure of Formula (VII), or a pharmaceutically acceptable salt thereof:
21 . A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of: