# US 12,006,328 B2 · Thieno[2,3-d]pyrimidin-4-one derivatives as NMDAR modulators and uses related thereto

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- Number: US 12,006,328 B2
- Document ID: US12006328B2
- Status: Granted
- Kind: B2
- Application number: 15/528,087
- Filed: 2015-11-18
- Published: 2017-11-02
- Granted: 2024-06-11
- Earliest claimed: 2014-11-18
- Assignees: Emory University
- Applicants: Emory University
- Inventors: Stephen F. Traynelis; Lanny S. Liebeskind; Dennis C. Liotta; Ethel C. Garnier-Amblard; PavanKumar Reddy Gangireddy
- Web page: https://patentgrep.com/patent/US12006328B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The disclosure relates thieno[2,3-d]pyrimidin-4-one derivatives as modulators of NMDA receptors and uses related thereto. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising compounds disclosed herein or pharmaceutically acceptable salts or prodrugs thereof. In certain embodiments, the compositions disclosed herein are used for managing conditions related to cognition, typically prevention or treatment of neurological conditions related to the NMDA receptor.

## Claims

### Claim 1

A compound of Formula I,
or a salt thereof, wherein:
X is S;
Y is S, O, or NH;
Z is S, O, NH, or CH2;
W is O, S, or NH;
R1 is pyrrolidin-1-yl or azetidin-1-yl, substituted with one or more, the same or different, R5,
R2 is phenyl or six-membered heteroaryl, substituted with one or more, the same or different, R5, having at least one R5 substituent at the 3- or 5-position relative to the ring atom of R2 that connects to the rest of Formula I, wherein the ring atom of R2 that connects to the rest of Formula I corresponds to the 1-position;
R3 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R5;
R4 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R7; and
R7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethyl carbamoyl, N,N-dimethylcarbamoyl, N,N-diethyl carbamoyl, N-methyl-N-ethyl carb amoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen, alkyl, or methyl, R4 is hydrogen, Z is CH2, and W is O.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is pyrrolidin-1-yl substituted with one or more, the same or different, R5.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, in the form of a tablet, capsule, pill, gel, solid formulation comprising a saccharide, polysaccharide, or fatty acid, a pH buffered solution, or a solution containing an alcohol or oil.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R2 has an R5 substituent at the 4-position relative to the ring atom in R2 that connects to the rest of Formula I.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R2 is phenyl substituted with one or more, the same or different, R5, having at least one R5 substituent at the 3- or 5-position relative to the ring atom of R2 that connects to the rest of Formula I and an R5 substituent at the 4-position relative to the ring atom in R2 that connects to the rest of Formula I.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R2 is phenyl substituted with one or more, the same or different, R5, having at least one R5 substituent at the 3- or 5-position relative to the ring atom of R2 that connects to the rest of Formula I.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1 is azetidin-1-yl substituted with one or more, the same or different, R5.

### Claim 10

A compound of Formula IB,
or a salt thereof, wherein:
n is 1 or 2;
R1 is 5-membered heterocyclyl or azetidin-1-yl, optionally substituted with one or more, the same or different, R5;
R3 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R5;
R4 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6 ;
R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R7 ;
R7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-m ethyl sulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R9, R11, R12, and R13 are each individually and independently selected from the group consisting of hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R9, R11, R12, and R13 , are, each individually and independently, optionally substituted with one or more, the same or different, R15;
R10 is selected from the group consisting of halogen, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R15;
R15 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R15 is optionally substituted with one or more, the same or different, R6;
R16 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R16 is optionally substituted with one or more, the same or different, R17 ; and
R17 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methyl carb am oyl, N-ethyl carb am oyl, N,N-dimethyl carb amoyl, N,N-diethyl carbamoyl, N-methyl-N-ethyl carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein the R1 is 5-membered heterocyclyl, optionally substituted with one or more, the same or different, R5.

### Claim 12 (depends on 11)

The compound of claim 11, wherein the R1 is pyrrolidin-1-yl, optionally substituted with one or more, the same or different, R5.

### Claim 13 (depends on 10)

The compound of claim 10, wherein the R1 is azetidin-1-yl, optionally substituted with one or more, the same or different, R5.

### Claim 14 (depends on 10)

The compound of claim 10, wherein R10 is halogen.

### Claim 15 (depends on 10)

The compound of claim 10, wherein R11 is halogen.

### Claim 16 (depends on 10)

The compound of claim 10, wherein R9 is hydrogen.

### Claim 17 (depends on 10)

The compound of claim 10, wherein R12 is hydrogen.

### Claim 18 (depends on 10)

The compound of claim 10, wherein R13 is hydrogen.

### Claim 19

A compound of Formula ID,
or a salt thereof, wherein:
n is 1 or 2;
R3 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl. alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R5;
R4 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6.
R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R7;
R7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R9, R11, R12, and R13 are each individually and independently selected from the group consisting of hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R9, R11, R12, and R13, are, each individually and independently, optionally substituted with one or more, the same or different, R15;
R10 is selected from the group consisting of halogen, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkanoyl, alkylthio, alkylamino, aminoalkyl, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R15;
R15 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R15 is optionally substituted with one or more, the same or different, R16;
R16 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R16 is optionally substituted with one or more, the same or different, R17, and
R17 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R18, R19, R20, R21, R22, R23, R24, and R25, are each individually and independently selected from the group consisting of hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R18, R19, R20, R21, R22, R23, R24, and R25, are, each individually and independently, optionally substituted with one or more, the same or different, R26;
R26 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R26 is optionally substituted with one or more, the same or different, R27;
and R27 is halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R27 is optionally substituted with one or more, the same or different, R28 ; and
and R27 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

### Claim 20

A compound selected from the group consisting of:
5-(3-iodophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3-chlorophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3-bromophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3-bromophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3-trifluoromethylphenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3-nitrophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3,5-dibromophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3,5-difluorophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3,5-diiodophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3,5-bis(trifluoromethyl)phenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
5-(3,4-dibromophenyl)-6-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;
and salts thereof.

### Claim 21 (depends on 1)

The compound of claim 1, wherein R4 is hydrogen.

### Claim 22 (depends on 1)

The compound of claim 1, wherein Y is O.

### Claim 23 (depends on 1)

The compound of claim 1, wherein Z is CH2.

### Claim 24 (depends on 1)

The compound of claim 1, wherein W is O.

### Claim 25 (depends on 7)

The compound of claim 7, wherein the R5 substituent at the 4-position relative to the ring atom of R2 that connects to the rest of Formula I is halogen.

### Claim 26 (depends on 8)

The compound of claim 8, wherein the at least one R5 substituent at the 3- or 5-position relative to the ring atom of R2 that connects to the rest of Formula I is halogen.