Functionalized lactams as modulators of the 5-hydroxytryptamine receptor 7 and their method of use

Patent metadata

Field	Value
Publication number	US-12559494-B2
Application number	US-201917054468-A
Country	US
Kind code	B2
Filing date	May 10, 2019
Priority date	May 11, 2018
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

Pharmaceutical compositions of the invention comprise functionalized lactam derivatives of formula (I) having a disease-modifying action in the treatment of diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, wherein A is selected from a group consisting of:

First claim

What is claimed is:

1 . A compound having a structure according to Formula (XLIIIb):

or a pharmaceutically acceptable salt thereof, wherein:
R 3 is phenyl or substituted phenyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, cyano, C 1-6 alkoxy, C 1-6 linear alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, and heterocyclyl;
R 7 is selected from the group consisting of H, COR 8 , CO 2 R 9 , and SO 2 R 10c ;
R 8 is selected from the group consisting of H, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
R 9 is selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
R 10c is C 1-6 linear alkyl or C 3-7 branched alkyl; and
n is 1, 2, 3, or 4.

2 . A compound having a structure according to Formula (II),

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each C 1-6 linear alkyl;
R 3 is phenyl or substituted phenyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, cyano, C 1-6 alkoxy, C 1-6 linear alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, and heterocyclyl; and
n is 1, 2, 3, or 4.

3 . The compound of claim 1 , having the Formula (XLIV):

Formula (XLV):

or a pharmaceutically acceptable salt thereof.

4 . A composition comprising an effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, optionally further comprising at least one excipient.

5 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is ethyl and/or n is 2.

6 . The compound of claim 2 , wherein R 3 is selected from the group consisting of hydroxylphenyl, fluorophenyl, chlorophenyl, bromophenyl, cyanophenyl, tolyl, methoxylphenyl, difluorophenyl, dichlorophenyl, chloro-fluorophenyl, dimethylphenyl, trifluoromethylphenyl, di(trifluoromethyl)phenyl.

7 . The compound of claim 2 , wherein R 3 is selected from the group consisting of 4-hydroxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-chlorophenyl, 4-cyanophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-isopropylphenyl, 4-trifluoromethylphenyl, 2-morpholinophenyl, and 4-methyl-2-morpholinophenyl.

8 . The compound of claim 7 , wherein R 3 is 4-fluorophenyl.

9 . The compound of claim 1 , wherein R 8 , R 9 , or R 10 is C 1-6 linear alkyl.

10 . The compound of claim 9 , wherein R 7 is COR 8 .

11 . The compound of claim 9 , wherein R 7 is CO 2 R 9 .

12 . The compound of claim 9 , wherein R 7 is SO 2 R 10C .

13 . The compound of claim 1 , wherein R 3 is selected from the group consisting of 4-hydroxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-chlorophenyl, 4-cyanophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methyphenyl, 2-isopropylphenyl, 4-trifluoromethyphenyl, 2-morpholinophenyl, and 4-methyl-2-morpholinophenyl.

14 . The compound of claim 13 , wherein R 3 is 4-fluorophenyl.

15 . The compound of claim 2 , wherein the compound is selected from the compounds described in Table 1:

TABLE 1

Entry
R 1
R 2
n
R 3

1
Methyl
Methyl
1
Phenyl

2
Methyl
Methyl
2
Phenyl

3
Methyl
Methyl
3
Phenyl

4
Methyl
Methyl
4
Phenyl

5
Methyl
Methyl
1
4-OH-Phenyl

6
Methyl
Methyl
2
4-OH-Phenyl

7
Methyl
Methyl
3
4-OH-Phenyl

8
Methyl
Methyl
4
4-OH-Phenyl

9
Methyl
Methyl
1
3-OH-Phenyl

10
Methyl
Methyl
2
3-OH-Phenyl

11
Methyl
Methyl
3
3-OH-Phenyl

12
Methyl
Methyl
4
3-OH-Phenyl

13
Methyl
Methyl
1
2-OH-Phenyl

14
Methyl
Methyl
2
2-OH-Phenyl

15
Methyl
Methyl
3
2-OH-Phenyl

16
Methyl
Methyl
4
2-OH-Phenyl

17
Methyl
Methyl
1
4-OMe-Phenyl

18
Methyl
Methyl
2
4-OMe-Phenyl

19
Methyl
Methyl
3
4-OMe-Phenyl

20
Methyl
Methyl
4
4-OMe-Phenyl

21
Methyl
Methyl
1
3-OMe-Phenyl

22
Methyl
Methyl
2
3-OMe-Phenyl

23
Methyl
Methyl
3
3-OMe-Phenyl

Assignees

• Univ Temple
• Praeventix Llc

Inventors

• Canney Daniel J
• Blass Benjamin E
• Blattner Kevin M
• Pippin Douglas A

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D209/96

  Spiro-condensed ring systems · CPC title

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• C07D401/12

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