Metabotropic glutamate receptor positive allosteric modulators (pams) and uses thereof

Patent metadata

Field	Value
Publication number	US-2025179000-A1
Application number	US-202218723093-A
Country	US
Kind code	A1
Filing date	Dec 22, 2022
Priority date	Dec 23, 2021
Publication date	Jun 5, 2025
Grant date	—

Abstract

Provided herein are small molecule active metabotropic glutamate subtype-2 and -3 receptor positive allosteric modulators (PAMS), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

First claim

What is claimed is:

1 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (I):

wherein:
R 1 is substituted or unsubstituted C 2 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
X 1 is absent, —O—, —NR 5 —, —S—, —S(═O)—, or —S(═O) 2 —;
X 2 is —O—, —NR 6 —, —S—, —S(═O)—, or —S(═O) 2 —;
R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R 4 , —S(═O) 2 R 4 , or —C(═O)OR 3 ;
L 1 is substituted C 4 alkylene, substituted or unsubstituted C 5 -C 10 alkylene, substituted or unsubstituted C 2 -C 10 alkenylene, substituted or unsubstituted C 2 -C 10 alkynylene, -L 3 -X 3 -L 4 -, or -L 5 -X 4 -L 6 -;
L 3 and L 4 are each independently substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 2 -C 6 alkenylene, or optionally substituted or unsubstituted C 2 -C 6 alkynylene;
X 3 is —C(R′) 2 —, —C(R 9 )═C(R 9 )—, —C≡C—, —O—, —NR 7 —, —S—, —S(═O)—, or —S(═O) 2 —;
L 5 and L 6 are each —C(D) 2 - and X 4 is substituted or unsubstituted C 1 -C 4 alkylene;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R 4 , —S(═O) 2 R 4 , or —C(═O)OR 3 ;
each R 8 is independently D, halogen, —OH, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl;
or two R 8 are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl;
each R 9 is independently hydrogen, D, halogen, —OH, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl;
L 2 is absent or C 1 -C 6 alkylene;
Q is —C(═O)OH, —C(═O)OR 4 , —C(═O)NHOR 3 , —C(═O)NHCN, —C(═O)NR 3 R 3 , —C(═O)NHS(═O) 2 R 4 , —C(═O)R 4 , —S(═O) 2 NR 3 R 3 , —S(═O) 2 NHC(═O)R 4 , —NHC(═O)NHS(═O) 2 R 4 ,

each R 2 is independently halogen, nitro, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted cycloalkyl;
n is 0, 1, 2, 3, or 4;
Y is —OH, —OR 4 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted cycloalkyl;
Z is —OH, —OR 4 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted cycloalkyl;
each R 3 is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
or two R 3 taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C 2 -C 8 heterocycloalkyl;
each R 4 is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted cycloalkyl substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is —OH.

3 . (canceled)

4 . (canceled)

5 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: Z is substituted or unsubstituted C 1 -C 6 alkyl.

6 . The compound of claim 5 , or a pharmaceutically acceptable salt or solvate, wherein: Z is methyl.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: L 2 is C 1 -C 6 alkylene.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: L 2 is absent.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is —C(═O)OH, —C(═O)OR 4 , —C(═O)NHOR 3 , —C(═O)NR 3 R 3 , —C(═O)NHS(═O) 2 R 4 , —C(═O)R 4 , —S(═O) 2 NR 3 R 3 , —S(═O) 2 NHC(═O)R 4 ,

and
wherein each R 3 and R 4 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is —C(═O)OH or —C(═O)OR 4 ; and wherein R 4 is methyl or ethyl.

11 . (canceled)

12 . (canceled)

13 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is unsubstituted C 2 -C 6 alkyl.

14 . (canceled)

15 . (canceled)

16 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: each R 2 is independently halogen, nitro, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl; and wherein R 4 is substituted or unsubstituted C 1 -C 6 alkyl.

17 .- 25 . (canceled)

26 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 is —O—.

27 .- 29 . (canceled)

30 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: X 2 is —O—.

31 . (canceled)

32 . (canceled)

33 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: L 1 is substituted C 4 alkylene, substituted or unsubstituted C 5 -C 10 alkylene, substituted or unsubstituted C 2 -C 10 alkenylene, or substituted or unsubstituted C 2 -C 10 alkynylene.

34 .- 51 . (canceled)

52 . The compound of any claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (I) has the structure of Formula (Ia), or a pharmaceutically acceptable salt, or solvate thereof:

wherein:
L 3 and L 4 are each independently C 1 -C 4 alkylene;
X 3 is —C(R 8 ) 2 , —C(R 9 )═C(R 9 )—, —C≡C—, —O—, —NR 7 —, —S—, —S(═O)—, or —S(═O) 2 —;
each R 8 is independently D, halogen, —OH, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl;
or two R 8 are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl;
each R 9 is independently hydrogen, D, halogen, —OH, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl.

53 - 126 . (cance

Assignees

• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Cosford Nicholas David Peter
• Sheffler Douglas J
• Raveendra-Panickar Dhanya

Classifications

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title