# US 10,500,205 B2 · Thienopyrimidinone NMDA receptor modulators and uses thereof

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- Number: US 10,500,205 B2
- Document ID: US10500205B2
- Status: Granted
- Kind: B2
- Application number: 16/060,294
- Filed: 2016-12-09
- Published: 2018-12-27
- Granted: 2019-12-10
- Earliest claimed: 2015-12-09
- Assignees: Cadent Therapeutics, Inc.
- Applicants: Cadent Therapeutics, Inc.
- Inventors: David R. Anderson; Robert A. Volkmann; Frank S. Menniti; Christopher Fanger
- Web page: https://patentgrep.com/patent/US10500205B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 495/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of halogen, C1-3alkyl, and C1-3alkoxy; wherein C1-3alkyl and C1-3alkoxy may optionally be substituted by one, two or three halogens; and R2 is selected from the group consisting of hydrogen, halogen, C1-3alkyl, and C1-3alkoxy; wherein C1-3alkyl and C1-3alkoxy may optionally be substituted by one, two or three halogens.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R1 is selected from the group consisting of fluorine, C1-3alkyl and methoxy; wherein C1-3alkyl may optionally be substituted by one, two or three fluorine atoms; and R2 is selected from the group consisting of hydrogen, fluorine, C1-3alkyl and methoxy; wherein C1-3alkyl may optionally be substituted by one, two or three fluorine atoms.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R3 is selected from the group consisting of phenyl and heteroaryl; wherein R3 may optionally be substituted with one, two or three substituents each independently selected from the group consisting of C1-4alkyl, halogen, hydroxyl, cyano, C1-6alkoxy, C2-6alkynyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, C1-6alkylcarbonyl, RaRbN—SO2—, NRaRb, C(O)OH, C1-4alkoxycarbonyl, and NRaRbcarbonyl; 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.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R3 is phenyl, pyrimidinyl, pyrazinyl or pyridinyl, each optionally substituted by one or two substituents each independently selected from the group consisting of halogen and C1-3alkyl (optionally substituted by one, two or three halogens).

### Claim 6 (depends on 5)

The compound of claim 5, wherein R3 is phenyl, optionally substituted by one, two or three substituents each independently selected from the group consisting of fluorine, chlorine, bromine, CF3, and C1-4alkyl.

### Claim 7 (depends on 6)

The compound of claim 6, wherein the compound is represented by:
wherein
R33 is selected from the group consisting of fluorine, chlorine, CF3 and methyl; and wherein q is 0, 1, 2 or 3.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R66 and R67 are each independently selected from the group consisting of hydrogen and C1-3alkyl; wherein C1-3alkyl may optionally be substituted by one, two, or three halogens.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R66 and R67 are each independently selected from the group consisting of hydrogen, methyl, and CF3.

### Claim 10

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.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R1 is selected from the group consisting of halogen, C1-3alkyl, and C1-3alkoxy; wherein C1-3alkyl and C1-3alkoxy may optionally be substituted by one, two or three halogens; and R2 is selected from the group consisting of hydrogen, halogen, C1-3alkyl, and C1-3alkoxy; wherein C1-3alkyl and C1-3alkoxy may optionally be substituted by one, two or three halogens.

### Claim 12 (depends on 11)

The compound of claim 11, wherein R1 is selected from the group consisting of hydrogen, fluorine, C1-3alkyl and methoxy; wherein C1-3alkyl may optionally be substituted by one, two or three fluorine atoms; and R2 is selected from the group consisting of hydrogen, fluorine, C1-3alkyl and methoxy; wherein C1-3alkyl may optionally be substituted by one, two or three fluorine atoms.

### Claim 13 (depends on 10)

The compound of claim 10, wherein R3 is selected from the group consisting of phenyl and heteroaryl; wherein R3 may optionally be substituted with one, two or three substituents each independently selected from the group consisting of C1-4alkyl, halogen, hydroxyl, cyano, C1-4alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, C1-6alkylcarbonyl, RaRbN—SO2—, NRaRb, C(O)OH, C1-4alkoxycarbonyl, and NRaRbcarbonyl; 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.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R3 is phenyl, pyrimidinyl, pyrazinyl or pyridinyl, each optionally substituted by one or two substituents each independently selected from the group consisting of halogen and C1-3alkyl (optionally substituted by one, two or three halogens).

### Claim 15 (depends on 14)

The compound of claim 14, wherein R3 is phenyl, optionally substituted by one, two or three substituents each independently selected from the group consisting of fluorine, chlorine, bromine, CF3, and C1-4 alkyl.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the compound is represented by:
wherein
R33 is selected from the group consisting of fluorine, chlorine, CF3 and methyl; and wherein q is 0, 1, 2 or 3.

### Claim 17 (depends on 10)

The compound of claim 10, wherein R66 and R67 are each independently selected from the group consisting of hydrogen and C1-3alkyl; wherein C1-3alkyl may optionally be substituted by one, two, or three halogens.

### Claim 18 (depends on 17)

The compound of claim 17, wherein R66 and R67 are each independently selected from the group consisting of hydrogen, methyl, and CF3.

### Claim 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.

### Claim 20 (depends on 1)

A pharmaceutically acceptable composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 1)

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.

### Claim 22 (depends on 21)

The method of claim 21, wherein the neuropsychiatric disorder is selected from schizophrenia, depression, an autism spectrum disorder, and Rett syndrome.