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US 10,500,205 B2Granted
Thienopyrimidinone NMDA receptor modulators and uses thereof
AssigneeCadent Therapeutics, Inc.
InventorsDavid R. Anderson, Robert A. Volkmann, Frank S. Menniti, Christopher Fanger
Life of this patent
Estimating the term…
Abstract
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.
Claims22
A compound represented by Formula I:
- or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
- n is 1;
- R1 is selected from the group consisting of halogen, hydroxyl, NRaRb, C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy;
- wherein C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NRaRb;
- R2 is selected from the group consisting of hydrogen, halogen, hydroxyl, NRaRb, C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy;
- wherein C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NRaRb;
- or
- R1 and R2, 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 NRa;
- 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), C3-C6cycloalkyl (optionally substituted by one, two or three halogens), C1-6alkoxy (optionally substituted by one, two or three halogens), C1-6alkyl (optionally substituted by one, two or three halogens), and oxo;
- and on a carbon that is not bound to a heteroatom, by halogen, cyano, —NRaRb 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), C3-C6cycloalkyl (optionally substituted by one, two or three halogens), C1-6alkoxy (optionally substituted by one, two or three halogens), C1-6alkyl (optionally substituted by one, two or three halogens), oxo, halogen, cyano, —NRaRb and hydroxyl;
- R3 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl and C3-6cycloalkyl;
- wherein R3 may optionally be substituted with one, two or three substituents each independently selected from C1-4alkyl, halogen, hydroxyl, cyano, C1-4alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, C1-6alkylcarbonyl, NRaRbN—SO2—, NRaRb, C(O)OH, C1-4alkoxycarbonyl, and NRaRbcarbonyl;
- and wherein C1-4alkyl, C1-4alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, and C1-6alkylcarbonyl may be optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, cyano, and NRaRb;
- R66 and R67 are each independently selected from the group consisting of hydrogen, halogen, C1-4alkyl (optionally substituted by one, two, three substituents selected from halogen, hydroxyl, cyano and NRaRb), and phenyl (optionally substituted by one, two or three halogens);
- and
- Ra and Rb are independently selected, for each occurrence, from the group consisting of hydrogen and C1-3alkyl;
- or Ra and Rb, 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.
20 more elements
A compound represented by Formula II:
- or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
- R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, NRaRb, C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy;
- wherein C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NRaRb;
- R2 is selected from the group consisting of hydrogen, halogen, hydroxyl, NRaRb, C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy;
- wherein C1-4 alkyl, C3-6cycloalkyl, C1-4alkoxy, and C3-6cycloalkoxy may be optionally substituted with one, two or three substituents each independently selected from halogen, hydroxyl, cyano, and NRaRb;
- R3 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl and C3-6cycloalkyl;
- wherein R3 may optionally be substituted with one, two or three substituents each independently selected from C1-4alkyl, halogen, hydroxyl, cyano, C1-4alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, C1-6alkylcarbonyl, RaRbN—S2—, NRaRb, C(O)OH, C1-4alkoxycarbonyl, and NRaRbcarbonyl;
- and wherein C1-4alkyl, C1-4alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, and C1-6alkylcarbonyl may be optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, cyano, and NRaRb;
- R66 and R67 are each independently selected from the group consisting of hydrogen, halogen, C1-4alkyl (optionally substituted by one, two, three substituents selected from halogen, hydroxyl, cyano and NRaRb), and phenyl (optionally substituted by one, two or three halogens);
- and
- Ra and Rb are independently selected, for each occurrence, from the group consisting of hydrogen and C1-3alkyl;
- or Ra and Rb, 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.
9 more elements
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.
19 more elements
Dependencies are inferred from the claim text.