Bicyclic derivatives as GABAA A5 receptor modulators

Patent metadata

Field	Value
Publication number	US-12370182-B2
Application number	US-201917279654-A
Country	US
Kind code	B2
Filing date	Sep 27, 2019
Priority date	Sep 28, 2018
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

The present invention provides compounds of formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof having affinity and selectivity for the gamma-aminobutyric acid A receptor subunit alpha 5 and act as GABA A α5 negative allosteric modulators, thereby useful in the treatment or prevention of diseases related to the GABA A α5 receptor, process for the preparation thereof, pharmaceutical compositions comprising them alone or in combination with one or more other active ingredients and their use as medicaments.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is represented by

R 1 is hydrogen or halogen,
n and m are each independently 1 or 2,
R 2 is hydrogen; C 1-4 alkyl optionally and independently substituted with one or more halogen, C 1-4 alkoxy, —S(O) 2 -C 1-4 alkyl, or R 3 ; NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 ; or R 4 and R 5 are taken together with the N to which they are attached to form a heterocycle, and
R 3 , R 6 and R 7 are optionally substituted carbocycle, heterocycle or heteroaryl; and
pharmaceutically acceptable salts, geometric isomers, stereoisomers, enantiomers, racemates, diastereomers, biologically active metabolites, prodrugs, solvates, hydrates, and polymorphs thereof.

2. The compound according to claim 1 having formula (I-a),

wherein
R 1 is hydrogen or halogen,
n and m are each independently 1 or 2,
R 2 is hydrogen; C 1-4 alkyl optionally and independently substituted with one or more halogen, C 1-4 alkoxy, —S(O) 2 -C 1-4 alkyl, or R 3 ; NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 ; or R 4 and R 5 are taken together with the N to which they are attached to form a heterocycle, and
R 3 , R 6 and R 7 are optionally substituted carbocycle, heterocycle or heteroaryl.

3. The compound according to claim 1 having formula (I-b),

wherein
R 1 is hydrogen or halogen,
n and m are each independently 1 or 2,
R 2 is hydrogen; C 1-4 alkyl optionally and independently substituted with one or more halogen, C 1-4 alkoxy, —S(O) 2 -C 1-4 alkyl, or R 3 ; NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 ; or R 4 and R 5 are taken together with the N to which they are attached to form a heterocycle, and
R 3 , R 6 and R 7 are optionally substituted carbocycle, heterocycle or heteroaryl.

4. The compound according to claim 1 having formula (I-c),

wherein
R 1 is hydrogen or halogen,
n and m are each independently 1 or 2,
R 2 is hydrogen; C 1-4 alkyl optionally and independently substituted with one or more halogen, C 1-4 alkoxy, —S(O) 2 -C 1-4 alkyl, or R 3 ; NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 ; or R 4 and R 5 are taken together with the N to which they are attached to form a heterocycle, and
R 3 , R 6 and R 7 are optionally substituted carbocycle, heterocycle or heteroaryl.

5. The compound according to claim 1 , wherein
R 1 is halogen,
n is 1 and m is 2,
R 2 is C 1-4 alkyl optionally and independently substituted with C 1-4 alkoxy, or —S(O) 2 -C 1-4 alkyl;
NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 ; or R 4 and R 5 are taken together with the N to which they are attached to form a monocyclic heterocycle, and
R 3 , R 6 and R 7 are optionally substituted C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 6-10 -aryl, C 3-10 heterocycle comprising 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, or C 5-10 heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.

6. The compound according to claim 1 , wherein
R 1 is halogen,
n is 1 and m is 2,
R 2 is C 1-4 alkyl optionally and independently substituted with C 1-4 alkoxy, or —S(O) 2 -C 1-4 alkyl;
NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 ; or R 4 and R 5 are taken together with the N to which they are attached to form a monocyclic heterocycle, and
R 3 , R 6 and R 7 are optionally substituted C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 6-10 -aryl, C 3-10 heterocycle comprising 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, or C 5-10 heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.

7. The compound according to claim 1 , wherein
R 1 is halogen,
n and m are 1, R 2 is C 1-4 alkyl optionally and independently substituted with C 1-4 alkoxy, or —S(O) 2 -C 1-4 alkyl;
NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 ; or R 4 and R 5 are taken together with the N to which they are attached to form a monocyclic heterocycle, and
R 6 and R 7 are optionally substituted C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 6-10 -aryl, C 3-10 heterocycle comprising 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, or C 5-10 heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.

8. The compound according to claim 1 , wherein
R 1 is fluorine, bromine or chlorine,
R 2 is C 1-3 alkyl, C 1-4 alkoxy C 1-3 alkyl, C 1-3 alkyl-S(O) 2 -C 1-3 alkyl, NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-4 alkyl or R 7 , and
R 6 and R 7 are C 3-6 cycloalkyl, C 6-10 aryl, C 4-6 heterocycle comprising 1 or 2 ring heteroatoms independently selected from N, O and S, or C 5-6 heteroaryl comprising 1 or 2 ring heteroatoms independently selected from N and O, wherein R 6 and R 7 are optionally substituted with C 1-4 alkyl, C 1-4 alkoxy, halogen, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyl or oxo.

9. The compound according to claim 1 , wherein
R 1 is fluorine or chlorine,
R 2 is C 1-4 alkoxyC 1-3 alkyl, methylsulfonylmethane, ethylsulfonylmethane, NR 4 R 5 or R 6 ,
R 4 and R 5 are each independently hydrogen, C 1-3 alkyl or R 7 , and
R 6 and R 7 are cyclopropyl, cyclobutyl, cyclohexane, phenyl, oxetane, tetrahydrofuran, tetrahydropyran, thiane, pyrrolidine, piperidine, pyridine, isoxazole, pyrrole, or morpholine, wherein R 6 and R 7 are optionally substituted with C 1-4 alkyl, C 1-4 alkoxy, halogen, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyl or oxo.

10. The compound according to claim 1 selected from the group consisting of:
1-[2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]ethanone,
2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-6-(oxolane-3-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine,
2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-6-(1,2-oxazole-5-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine,
6-cyclobutanecarbonyl-2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-5,6,7,8-tetrahydro-1,6-naphthyridine,
6-cyclopropanecarbonyl-2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-5,6,7,8-tetrahydro-1,6-naphthyridine,
4-(2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-1lambda6-thiane-1,1-dione,
2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-6-(oxolane-2-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine,
1-(2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)-2-methanesulfonylethan-1-one,
2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-6-(oxane-4-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine,
2-{[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy}-6-(5-methyl-1,2-oxazole-3-carbonyl)-5,6,7,8-tetrah

Assignees

• Richter Gedeon Nyrt

Inventors

• Szabó György
• Túrós György István
• Éliás Olivér
• Károlyi Benedek Imre
• Erdélyi Péter
• Kapus Gábor

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title