Heteroaromatic NMDA receptor modulators and uses thereof
Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated modulate the NMDA receptor.
1. A method for treating a neuropsychiatric disorder selected from schizophrenia, depression, an autism spectrum disorder, and Rett syndrome in a subject comprising administering to said subject a therapeutically effective amount of a compound represented by Formula I
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
rings A and B are a fused [5,6] or [6,6] heteroaromatic system;
Q is N or CR 6 ;
T is N or CR 6 ; and
y is 0 or 1 wherein
when y is 1, U 1 and U 2 are C; W and V are each independently selected from CR 6 ; one of Y and X is CR 3 and one of Y and X is CR 6 ; and
when y is 0:
X is CR 3 or NR 33 ;
W is selected from the group consisting of CR 6 , N or S;
V is selected from the group consisting of N, NR 7 , CR 6 , S and O;
U 1 and U 2 may each be C or N; wherein when one of U 1 and U 2 is N the other is C; and
when Q is CR 6 , T is N, W is CR 6 and X is CR 3 ; V is not S;
L 1 is a bond or C 1-4 alkylene optionally interrupted by O, and optionally substituted on a carbon not bound to the ring nitrogen with one, two, or three substituents each independently selected from the group consisting of halogen, OH, cyano and —NR a R b ;
R 1 and R 2 , together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclic ring optionally substituted on a carbon by one, two or more substituents each selected from the group consisting of halogen, cyano, oxo, hydroxyl and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by one, two or three halogens;
R 3 is phenyl, thiophenyl, pyrimidinyl, pyrazinyl or pyridinyl, each optionally substituted by one or two substituents each independently selected from the group consisting of halogen and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by one, two or three halogens;
R 33 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl and C 3-6 cycloalkyl, wherein R 33 is optionally substituted with one, two or three substituents each independently selected from the group consisting of C 1-4 alkyl, halogen, hydroxyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, C 1-6 alkylcarbonyl, R a R b N—SO 2 —, NR a R b , C(O)OH, C 1-4 alkoxycarbonyl, and NR a R b carbonyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 — and C 1-6 alkylcarbonyl may be optionally substituted by one or more substituents each selected from the group consisting of halogen, hydroxyl, cyano, and NR a R b ;
R 6 is independently selected for each occurrence from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C(O)OH, C(O)H, —C(═NH)—NR a R c , phenyl, pyridinyl and pyrimidinyl, wherein said C 1-4 alkyl for R 6 is optionally substituted by one or two substituents each selected from the group consisting of —NR a R b , C 1-4 alkoxy, halogen, cyano, hydroxyl, C(O)H, and ═NR a , and wherein said phenyl for R 6 is optionally substituted by one or two substituents each selected from the group consisting of NR a R b , C 1-4 alkoxy, halogen, cyano, hydroxyl, C(O)H, and ═NR a ;
R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl and C 3-6 cycloalkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, hydroxyl, C 1-4 alkoxy (optionally substituted by halogen or —Si(R s ) 0-3 (wherein R s is H or C 1-6 alkyl)), cyano, —Si(R s ) 0-3 (wherein R s is H or C 1-6 alkyl), —O—Si(R s ) 0-3 (wherein R s is H or C 1-6 alkyl), and NR a R b ;
R c is selected from the group consisting of hydrogen, C 1-3 alkyl, and hydroxyl; and
R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen, C 1-4 alkylcarbonyl, —C(O)—O—C 1-4 alkyl, C 3-6 cycloalkyl and C 1-3 alkyl; wherein C 1-3 alkyl and C 3-6 cycloalkyl may optionally be substituted on a carbon not bound to the nitrogen by one or more substituents each selected from the group consisting of fluorine, cyano, oxo and hydroxyl; or
R a and R b , together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N; and wherein the 4-6 membered heterocyclic ring may optionally be substituted on a carbon not bound to the nitrogen by one or more substituents selected from the group consisting of fluorine, methyl, cyano, oxo and hydroxyl.
2. The method of claim 1 , wherein the fused [5,6] or [6,6] heteroaromatic system is selected from the group consisting of:
3. The method of claim 1 , wherein the rings A and B are a fused [5,6] heteroaromatic system.
4. The method of claim 1 , wherein the rings A and B are a fused [5,6] heteroaromatic system selected from the group consisting of:
5. The method of claim 1 , wherein the rings A and B represent the following fused [5,6] heteroaromatic system:
6. The method of claim 1 , wherein L 1 is —CH 2 —.
7. The method of claim 1 , wherein R 3 is phenyl, optionally substituted by one or two substituents each independently selected from the group consisting of Cl, F, Br, and CF 3 .
8. The method of claim 1 , wherein the compound is represented by:
wherein
U 1 and U 2 may each be C or N; wherein when one of U 1 and U 2 is N the other is C;
T is N or CR 6 ;
R 66 and R 67 are each independently selected from the group consisting of halogen and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by one, two, three substituents selected from halogen, hydroxyl, cyano and NR a R b ; and
V is selected from the group consisting of N, NR 7 , CR 66 and S.
9. The method of claim 8 , wherein U 1 is N and U 2 is C.
10. The method of claim 1 , wherein V is NR 7 .
11. The method of claim 1 , wherein U 1 is C and U 2 is N.
12. The method of claim 1 , wherein V is N.
13. The method of claim 8 , wherein the compound is represented by:
wherein V is NR 7 or S.
14. The method of claim 13 , wherein R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, pyridyl, and phenyl; wherein C 1-6 alkyl is optionally substituted by one or more substituents each selected from the group consisting of halogen, hydroxyl, and C 1-4 alkoxy.
15. A method of treating cognitive impairment associated with schizophrenia or Phelan-McDermid Syndrome comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula I
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
rings A and B are a fused [5,6] or [6,6] heteroaromatic system;
Q is N or CR 6 ;
T is N or CR 6 ; and
y is 0 or 1 wherein
when y is 1, U 1 and U 2 are C; W and V are each independently selected from CR 6 ; one of Y and X is CR 3 and one of Y and X is CR 6 ; and
when y is 0:
X is CR 3 or NR 33 ;
W is selected from the group consisting of CR 6 , N or S;
V is selected from the group consisting of N, NR 7 , CR 6 , S and O;
U 1 and U 2 may each be C or N; wherein when one of U 1 and U 2 is N the other is C; and
when Q is CR 6 , T is N, W is CR 6 and X is CR 3 ; V is not S;
L 1 is a bond or C 1-4 alkylene optionally interrupted by O, and optionally substituted on a carbon not bound to the ring nitrogen with one, two, or three substituents each independently selected from the group consisting of halogen, OH, cyano and —NR a R b ;
R 1 and R 2 , together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclic ring optionally substituted on a carbon by one, two or more substituents each selected from the group consisting of halogen, cyano, oxo, hydroxyl and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by one, two or three halogens;
R 3 is phenyl, thiophenyl, pyrimidinyl, pyrazinyl or pyridinyl, each optionally substituted by one or two substituents each independently selected from the group consisting of halogen and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by one, two or three halogens;
R 33 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl and C 3-6 cycloalkyl, wherein R 33 is optionally substituted with one, two or three substituents each independently selected from the group consisting of C 1-4 alkyl, halogen, hydroxyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, C 1-6 alkylcarbonyl, R a R b N—SO 2 —, NR a R b , C(O)OH, C 1-4 alkoxycarbonyl, and NR a R b carbonyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 — and C 1-6 alkylcarbonyl may be optionally substituted by one or more substituents each selected from the group consisting of halogen, hydroxyl, cyano, and NR a R b ;
R 6 is independently selected for each occurrence from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C(O)OH, C(O)H, —C(═NH)—NR a R c , phenyl, pyridinyl and pyrimidinyl, wherein said C 1-4 alkyl for R 6 is optionally substituted by one or two substituents each selected from the group consisting of —NR a R b , C 1-4 alkoxy, halogen, cyano, hydroxyl, C(O)H, and ═NR a , and wherein said phenyl for R 6 is optionally substituted by one or two substituents each selected from the group consisting of NR a R b , C 1-4 alkoxy, halogen, cyano, hydroxyl, C(O)H, and ═NR a ;
R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl and C 3-6 cycloalkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, hydroxyl, C 1-4 alkoxy (optionally substituted by halogen or —Si(R s ) 0-3 (wherein R s is H or C 1-6 alkyl)), cyano, —Si(R s ) 0-3 (wherein R s is H or C 1-6 alkyl), —O—Si(R s ) 0-3 (wherein R s is H or C 1-6 alkyl), and NR a R b ;
R c is selected from the group consisting of hydrogen, C 1-3 alkyl, and hydroxyl; and
R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen, C 1-4 alkylcarbonyl, —C(O)—O—C 1-4 alkyl, C 3-6 cycloalkyl and C 1-3 alkyl; wherein C 1-3 alkyl and C 3-6 cycloalkyl may optionally be substituted on a carbon not bound to the nitrogen by one or more substituents each selected from the group consisting of fluorine, cyano, oxo and hydroxyl; or
R a and R b , together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N; and wherein the 4-6 membered heterocyclic ring may optionally be substituted on a carbon not bound to the nitrogen by one or more substituents selected from the group consisting of fluorine, methyl, cyano, oxo and hydroxyl.
16. The method of claim 15 , wherein the fused [5,6] or [6,6] heteroaromatic system is selected from the group consisting of:
17. The method of claim 15 , wherein the rings A and B are a fused [5,6] heteroaromatic system.
18. The method of claim 15 , wherein the rings A and B are a fused [5,6] heteroaromatic system selected from the group consisting of:
19. The method of claim 15 , wherein the rings A and B represent the following fused [5,6] heteroaromatic system:
20. The method of claim 15 , wherein L 1 is —CH 2 —.
21. The method of claim 15 , wherein R 3 is phenyl, optionally substituted by one or two substituents each independently selected from the group consisting of Cl, F, Br, and CF 3 .
22. The method of claim 15 , wherein the compound is represented by:
wherein
U 1 and U 2 may each be C or N; wherein when one of U 1 and U 2 is N the other is C;
T is N or CR 6 ;
R 66 and R 67 are each independently selected from the group consisting of halogen and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by one, two, three substituents selected from halogen, hydroxyl, cyano and NR a R b ; and
V is selected from the group consisting of N, NR 7 , CR 66 and S.
23. The method of claim 22 , wherein U 1 is N and U 2 is C.
24. The method of claim 15 , wherein V is NR 7 .
25. The method of claim 15 , wherein U 1 is C and U 2 is N.
26. The method of claim 15 , wherein V is N.
27. The method of claim 22 , wherein the compound is represented by:
wherein V is NR 7 or S.
28. The method of claim 27 , wherein R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, pyridyl, and phenyl; wherein C 1-6 alkyl is optionally substituted by one or more substituents each selected from the group consisting of halogen, hydroxyl, and C 1-4 alkoxy.