Thienopyrimidinone 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 represented by Formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
n is 1;
R 1 is selected from the group consisting of halogen, hydroxyl, NR a R b , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy; wherein C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NR a R b ;
R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, NR a R b , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy; wherein C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NR a R b ; or
R 1 and R 2 , together with the carbon to which they are attached form:
a 4-6 membered saturated heterocyclic ring having one or two heteroatoms selected from the group consisting of O, S(O) w (wherein w is 0, 1 or 2) and NR a ; or
a 3-6 membered saturated carbocyclic ring;
wherein the heterocyclic ring may optionally be substituted on carbon by one, two or more substituents each selected from the group consisting of phenyl (optionally substituted by one, two or three halogens), C 3 -C 6 cycloalkyl (optionally substituted by one, two or three halogens), C 1-6 alkoxy (optionally substituted by one, two or three halogens), C 1-6 alkyl (optionally substituted by one, two or three halogens), and oxo; and on a carbon that is not bound to a heteroatom, by halogen, cyano, —NR a R b and hydroxyl; and
the carbocyclic ring may optionally be substituted by one, two or more substituents each selected from the group consisting of: phenyl (optionally substituted by one, two or three halogens), C 3 -C 6 cycloalkyl (optionally substituted by one, two or three halogens), C 1-6 alkoxy (optionally substituted by one, two or three halogens), C 1-6 alkyl (optionally substituted by one, two or three halogens), oxo, halogen, cyano, —NR a R b and hydroxyl;
R 3 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl and C 3-6 cycloalkyl; wherein R 3 may optionally be substituted with one, two or three substituents each independently selected from C 1-4 alkyl, halogen, hydroxyl, cyano, 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, NR a R b N—SO 2 —, NR a R b , C(O)OH, C 1-4 alkoxycarbonyl, and NR a R b carbonyl; and wherein C 1-4 alkyl, C 1-4 alkoxy, 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 independently selected from halogen, hydroxyl, cyano, and NR a R b ;
R 66 and R 67 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl (optionally substituted by one, two, three substituents selected from halogen, hydroxyl, cyano and NR a R b ), and phenyl (optionally substituted by one, two or three halogens); and
R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; 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.
2. The compound of claim 1 , wherein R 1 is selected from the group consisting of halogen, C 1-3 alkyl, and C 1-3 alkoxy; wherein C 1-3 alkyl and C 1-3 alkoxy may optionally be substituted by one, two or three halogens; and R 2 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, and C 1-3 alkoxy; wherein C 1-3 alkyl and C 1-3 alkoxy may optionally be substituted by one, two or three halogens.
3. The compound of claim 2 , wherein R 1 is selected from the group consisting of fluorine, C 1-3 alkyl and methoxy; wherein C 1-3 alkyl may optionally be substituted by one, two or three fluorine atoms; and R 2 is selected from the group consisting of hydrogen, fluorine, C 1-3 alkyl and methoxy; wherein C 1-3 alkyl may optionally be substituted by one, two or three fluorine atoms.
4. The compound of claim 1 , wherein R 3 is selected from the group consisting of phenyl and heteroaryl; wherein R 3 may optionally be substituted with one, two or three substituents each independently selected from the group consisting of C 1-4 alkyl, halogen, hydroxyl, cyano, C 1-6 alkoxy, C 2-6 alkynyl, 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 1-4 alkyl, C 1-4 alkoxy, 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 independently selected from halogen, hydroxyl, cyano, and NR a R b .
5. The compound of claim 4 , wherein R 3 is phenyl, 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 (optionally substituted by one, two or three halogens).
6. The compound of claim 5 , wherein R 3 is phenyl, optionally substituted by one, two or three substituents each independently selected from the group consisting of fluorine, chlorine, bromine, CF 3 , and C 1-4 alkyl.
7. The compound of claim 6 , wherein the compound is represented by:
wherein
R 33 is selected from the group consisting of fluorine, chlorine, CF 3 and methyl; and wherein q is 0, 1, 2 or 3.
8. The compound of claim 7 , wherein R 66 and R 67 are each independently selected from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one, two, or three halogens.
9. The compound of claim 8 , wherein R 66 and R 67 are each independently selected from the group consisting of hydrogen, methyl, and CF 3 .
10. A compound represented by Formula II:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, hydroxyl, NR a R b , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy; wherein C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NR a R b ;
R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, NR a R b , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy; wherein C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 3-6 cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NR a R b ;
R 3 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl and C 3-6 cycloalkyl; wherein R 3 may optionally be substituted with one, two or three substituents each independently selected from C 1-4 alkyl, halogen, hydroxyl, cyano, 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—S 2 —, NR a R b , C(O)OH, C 1-4 alkoxycarbonyl, and NR a R b carbonyl; and wherein C 1-4 alkyl, C 1-4 alkoxy, 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 independently selected from halogen, hydroxyl, cyano, and NR a R b ;
R 66 and R 67 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl (optionally substituted by one, two, three substituents selected from halogen, hydroxyl, cyano and NR a R b ), and phenyl (optionally substituted by one, two or three halogens); and
R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; 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.
11. The compound of claim 10 , wherein R 1 is selected from the group consisting of halogen, C 1-3 alkyl, and C 1-3 alkoxy; wherein C 1-3 alkyl and C 1-3 alkoxy may optionally be substituted by one, two or three halogens; and R 2 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, and C 1-3 alkoxy; wherein C 1-3 alkyl and C 1-3 alkoxy may optionally be substituted by one, two or three halogens.
12. The compound of claim 11 , wherein R 1 is selected from the group consisting of hydrogen, fluorine, C 1-3 alkyl and methoxy; wherein C 1-3 alkyl may optionally be substituted by one, two or three fluorine atoms; and R 2 is selected from the group consisting of hydrogen, fluorine, C 1-3 alkyl and methoxy; wherein C 1-3 alkyl may optionally be substituted by one, two or three fluorine atoms.
13. The compound of claim 10 , wherein R 3 is selected from the group consisting of phenyl and heteroaryl; wherein R 3 may optionally be substituted with one, two or three substituents each independently selected from the group consisting of C 1-4 alkyl, halogen, hydroxyl, cyano, 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 1-4 alkyl, C 1-4 alkoxy, 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 independently selected from halogen, hydroxyl, cyano, and NR a R b .
14. The compound of claim 13 , wherein R 3 is phenyl, 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 (optionally substituted by one, two or three halogens).
15. The compound of claim 14 , wherein R 3 is phenyl, optionally substituted by one, two or three substituents each independently selected from the group consisting of fluorine, chlorine, bromine, CF 3 , and C 1-4 alkyl.
16. The compound of claim 15 , wherein the compound is represented by:
wherein
R 33 is selected from the group consisting of fluorine, chlorine, CF 3 and methyl; and wherein q is 0, 1, 2 or 3.
17. The compound of claim 10 , wherein R 66 and R 67 are each independently selected from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one, two, or three halogens.
18. The compound of claim 17 , wherein R 66 and R 67 are each independently selected from the group consisting of hydrogen, methyl, and CF 3 .
19. A compound selected from the group consisting of: 5-(3,4-dichlorophenyl)-3-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(3-chloro-4-fluorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3 -d]pyrimidin-4-one; 5-(3 -chloro-4-fluorophenyl)-3 -{2-[3 -fluoro-3 -(fluoromethyl)azetidin-1-yl]-2oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(3-chloro-4-fluorophenyl)-3-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(3,4-dichlorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(3,4-dichlorophenyl)-3{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-3H,4H-thieno [2,3-d]pyrimidin-4-one; 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(3-chloro-4-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)--oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-6-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one; 3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-(4-methylphenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one; 3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-(4-fluorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one; 3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-[4-(trifluoromethyl)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 3-[2-(azetidin-1-yl)-2-oxoethyl]-6-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one; 6-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno [2,3 -d]pyrimidin-4-one; 5-(4-chlorophenyl)-3-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2-oxoethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one; 5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one; and 3-[2-(azetidin-1-yl)-2-oxoethyl]-5-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one; or a pharmaceutically acceptable salt or stereoisomer of any of the foregoing.
20. A pharmaceutically acceptable composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutically acceptable excipient.
21. A method of treating a patient suffering from a neuropsychiatric disorder comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof to the patient.
22. The method of claim 21 , wherein the neuropsychiatric disorder is selected from schizophrenia, depression, an autism spectrum disorder, and Rett syndrome.