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 to modulate the NMDA receptor.
1. A compound of the Formula Im:
Ring A is optionally substituted phenyl or 5-7 membered heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of N, S, and O, and p is 0, 1, 2 or 3;
R C is selected from the group consisting of cyano, hydrogen, halogen, S(C 1-6 )alkyl, S(O)(C 1-6 )alkyl, SO 2 (C 1-6 )alkyl, C(O)NR a R b , —C(O)OH, —C(O)O(C 1-6 )alkyl, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl and heteroaryl (optionally substituted by C 1-4 alkyl or halogen);
R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, —C(O)OH, —C(O)OC 1-6 alkyl, (C 3-6 )cycloalkyl and phenyl (optionally substituted by one, two or three substituents each selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, —C(O)OH, —C(O)OC 1-6 alkyl and NR a R b );
t is 0, 1 or 2;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —CO 2 H, —CO 2 C 1-6 alkyl, —CO 2 NR a R b , NR a R b , C 3-6 cycloalkyl and phenyl (optionally substituted by one or two substituents each selected from halogen and methyl); or when q or m is two, each of said R 3 or R 4 may be taken together with the carbon to which they are attached to form a 3-5 membered carbocyclic ring, methylene group or a 4-5 membered heterocyclic ring having at least one heteroatom, wherein one or more carbon atoms of said C 3-6 cycloalkyl may be optionally replaced by N or O;
m is one or two;
wherein when R 3 or R 4 is bound to a carbon adjacent to a ring nitrogen, R 3 or R 4 must be other than halogen, hydroxyl or C 1-6 alkoxy;
R 5 independently for each occurrence is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, OH, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heteroaryl, phenyl, —NR a R b , —C(O)OH, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, (NR a R b )carbonyl-, C 1-6 alkyl-S(O) w — (where w is 0, 1 or 2), and R a R b N—SO w — (where w is 0, 1 or 2); wherein heteroaryl and phenyl may optionally be substituted by one, two or three substituents each selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, and —NR a R b ; wherein one or more carbon atoms of said C 3-6 cycloalkyl may be optionally replaced by N or O;
or two R 5 , together with two adjacent carbons on ring A to which they are attached, form a 5-7 membered unsaturated, partially unsaturated or saturated carbocyclic or heterocyclic ring;
wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl wherever they occur may be optionally independently substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, C 3-6 cycloalkyl (wherein one or more ring carbon atoms is replaced by N, O or S), heteroaryl, phenyl, CF 3 , NR a R b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-S—, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl-S—, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, (NR a R b )carbonyl-, and C 1-6 alkylcarbonyl-(NR a R b )—;
R a and R b are independently selected, for each occurrence, from the group consisting of: hydrogen, C 1-4 alkylcarbonyl, C 1-6 alkoxycarbonyl, cyclopropyl, and C 1-3 alkyl; wherein C 1-3 alkyl 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 (optionally substituted by one or two methyl groups); 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 each selected from the group consisting of fluorine, methyl, cyano, oxo and hydroxyl;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein said ring A is 5-7 membered heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of N, S, and O.
3. The compound according claim 1 , wherein ring A is pyridinyl, pyrimidinyl or pyridazinyl.
4. The compound according to claim 1 , wherein R 5 is independently for each occurrence selected from the group consisting of hydrogen, halogen, methoxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, t-butyl, t-butyloxy, t-butylthio, pyridinyl (optionally substituted by halogen), and phenyl (optionally substituted by halogen).
5. The compound according to claim 1 , wherein R 5 is t-butyl.
6. The compound according to claim 1 , wherein R c is —CN.
7. The compound according to claim 1 , wherein p is 1.
8. The compound according to claim 1 , wherein R 4 is selected from the group consisting of hydrogen, C 1-4 alkyl, and phenyl.
9. The compound according to claim 1 , wherein R 4 is hydrogen.
10. The compound according to claim 1 , wherein R 1 is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-6 )cycloalkyl and phenyl (optionally substituted by one or two substituents each selected from halogen or methyl), tis 0, 1 or 2.
11. The compound according to claim 1 , wherein R 1 is hydrogen.
12. The compound according to claim 1 , wherein one of said R 3 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —CO 2 H, —CO 2 C 1-6 alkyl, —CO 2 NR a R b , NR a R b , C 3-6 cycloalkyl and phenyl; wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl wherever they occur may be optionally independently substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, C 3-6 cycloalkyl (wherein one or more ring carbon atoms is replaced by N, O or S), heteroaryl, phenyl, CF 3 , NR a R b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-S—, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl-S—, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, (NR a R b )carbonyl-, and C 1-6 alkylcarbonyl-(NR a R b )—.
13. The compound according to claim 1 , wherein R 3 are each independently selected from the group consisting of hydrogen, fluoro, methoxy, methyl, hydroxyl, C 1-6 alkoxymethyl, hydroxymethyl, aminomethyl, amidomethyl, carbamoylmethyl, and fluoromethyl.
14. A pharmaceutically acceptable composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
15. A method of treating a patient suffering from a neuropsychiatric disorder comprising administering a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the patient.
16. The method according to claim 15 , wherein the neuropsychiatric disorder is selected from schizophrenia, depression, an autism spectrum disorder, and Rett syndrome.
17. The compound according to claim 1 , wherein the compound is
8-(6-(tert-butyl)pyridin-3-yl)-6-oxo-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]oxazine-7-carbonitrile;
or a pharmaceutically acceptable salt thereof.