US 12,234,218 B2
Heterocyclic compounds as modulators of mGluR7
Guillaume Duvey, Thyez (FR); and Sylvain Celanire, Reignier-Esery (FR)
Assigned to PRAGMA Therapeutics, Archamps (FR)
Filed by PRAGMA Therapeutics, Archamps (FR)
Filed on Jul. 6, 2022, as Appl. No. 17/810,922.
Application 17/810,922 is a continuation of application No. 16/650,817, granted, now 11,414,395, previously published as PCT/EP2018/076080, filed on Sep. 26, 2018.
Claims priority of application No. 17306269 (EP), filed on Sep. 26, 2017.
Prior Publication US 2022/0363664 A1, Nov. 17, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/14 (2006.01); A61K 31/502 (2006.01); C07D 401/04 (2006.01); C07D 403/04 (2006.01); C07D 413/14 (2006.01); C07D 417/04 (2006.01)
CPC C07D 401/04 (2013.01) [C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 413/14 (2013.01); C07D 417/04 (2013.01); C07B 2200/07 (2013.01)] 15 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
wherein:
G is N,
E is CR8,
Y is CR9,
R1, R2, R3, R4, R5, R6, R8 and R9, identical or different, are each independently selected from hydrogen, halogen, —CN, —CF3—C(═O)R10, —C(═O)OR10, —C(═O)NR10R11, —OR10, —OC(═O)R10, —OC(═O)NR10R11, —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR10R11, —NR10R11, —NR10C(═O)R11, —NR10C(═O) OR11, —NR10S(O)2R11, or an optionally substituted radical chosen among: —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C3-C7)cycloalkyl, —(C1-C6)alkylene-(C3-C7)cycloalkyl, or —(C1-C6)cyanoalkyl,
wherein any two radicals R1 and R2, R3 and R4, and R5 and R6 may be taken together to form an oxo (═O),
wherein R10 and R11, identical or different, are each independently selected from hydrogen, an optionally substituted radical chosen among: —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C1-C6)cyanoalkyl, —(C3-C7)cycloalkyl or —(C1-C6)alkylene-(C3-C7)cycloalkyl,
wherein optionally any two radicals selected from R1, R2, R3, R4, R5, R6, R9, R10 and R11 may be taken together to form an optionally substituted 3 to 10-membered non-aromatic carbocyclic or heterocyclic ring or a 5 to 10-membered aromatic heterocyclic ring,
n is 1,
Ar1 represents an aryl or heteroaryl chosen among:

OG Complex Work Unit Chemistry
wherein m is the number of substituents A on the cycle and is an integer equal to 0, 1, 2, 3, 4 or 5;
Ar2 represents an aryl or heteroaryl chosen among:

OG Complex Work Unit Chemistry
wherein p is the number of substituents B on the cycle and is an integer equal to 0, 1, 2, 3, 4 or 5;
wherein A and B, identical or different, are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OH, —NH2, —CF3, an optionally substituted radical selected from the group of —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C3-C7)cycloalkyl, —(C1-C6)alkylene-(C3-C7)cycloalkyl, —(C3-C8)cycloalkenyl, —(C1-C6)cyanoalkyl, —(C1-C6)alkylene-heteroaryl, —(C1-C6)alkylene-aryl, —(C1-C6)alkylene-heterocycle, aryl, heteroaryl, heterocycle, —OR13, —(C1-C6)alkylene-OR13, —O—(C2-C6)alkylene-OR13, —NR13(C2-C6)alkylene-OR14, —(C2-C6)alkenylene-OR13, —(C2-C6)alkynylene-OR13, —NR13R14, —(C1-C6)alkylene-NR13R14, —O—(C2-C6)alkylene-NR13R14, —NR13—(C2-C6)alkylene-NR14R15, —(C2-C6)alkenylene-NR13R14, —(C2-C6)alkynylene-NR13R14, —SR13, —(C1-C6)alkylene-SR13, —O—(C2-C6)alkylene-SR13, —NR13—(C2-C6)alkylene-SR14, —S(═O)—R13, —(C1-C6)alkylene-S(═O)—R13, —O—(C1-C6)alkylene-S(═O)—R13, —NR13—(C1-C6)alkylene-S(═O)—R14, —S(═O)2—R13, —(C1-C6)alkylene-S(═O)2—R13, —O—(C1-C6)alkylene-S(═O)2—R13, —NR13—(C1-C6)alkylene-S(═O)2—R14, —S(═O)2NR13R14, —(C1-C6)alkylene-S(═O)2NR13R14, —O—(C1-C6)alkylene-S(═O)2NR13R14, —NR13—(C1-C6)alkylene-S(═O)2NR14R15, —NR13—S(═O)2R14, —(C1-C6)alkylene-NR13—S(═O)2R14, —O—(C2-C6)alkylene-NR13—S(═O)2R14, —NR13—(C2-C6)alkylene-NR14—S(═O)2R15, —C(═O)—NR13R14, —(C1-C6)alkylene-C(═O)—NR13R14, —O—(C1-C6)alkylene-C(═O)—NR13R14, —NR13—(C1-C6)alkylene-C(═O)—NR14R15, —NR13C(═O)—R14, —(C1-C6)alkylene-NR13C(═O)—R14, —O—(C2-C6)alkylene-NR13C(═O)—R14, —NR13—(C2-C6)alkylene-NR14C(═O)—R15, —C(═O)—R13, —(C1-C6)alkylene-C(═O)—R13, —O—(C1-C6)alkylene-C(═O)—R13, —NR13—(C1-C6)alkylene-C(═O)—R14, —C(═O)—OR13, —(C1-C6)alkylene-C(═O)—OR13, —O—(C1-C6)alkylene-C(═O)—OR13, —NR13—(C1-C6)alkylene-C(═O)—OR14, —OC(═O)—R13, —(C1-C6)alkylene-OC(═O)—R13, —O—(C2-C6)alkylene-OC(═O)—R13, —NR13—(C2-C6)alkylene-OC(═O)—R14, —NR13—C(═O)—NR14R15, —(C1-C6)alkylene-NR13—C(═O)—NR14R15, —O—(C2-C6)alkylene-NR13—C(═O)—NR14R15, —NR13—(C2-C6)alkylene-NR14—C(═O)—NR15R16, —NR13—C(═O)—OR14, —(C1-C6)alkylene-NR13—C(═O)—OR14, —O—(C2-C6)alkylene-NR13—C(═O)—OR14, —NR13—(C2-C6)alkylene-NR14—C(═O)—OR15, —O—C(═O)—NR13R14, —(C1-C6)alkylene-O—C(═O)—NR13R14, —O—(C2-C6)alkylene-O—C(═O)—NR13R14, —NR13—(C2-C6)alkylene-O—C(═O)—NR14R15, —C(═O)—(C1-C6)alkylene-NR13R14, —(C1-C6)alkylene-C(═O)—(C1-C6)alkylene-NR13R14, —C(═O)—(C1-C6)alkylene-OR13, —(C1-C6)alkylene-C(═O)—(C1-C6)alkylene-OR13, —NR13—C(═S)—NR14R15, —(C1-C6)alkylene-NR13—C(═S)—NR14R15, —NR13_C(═NR14)—NR15R16 or —(C1-C6)alkylene-NR13—C(═NR14)—NR15R16;
wherein R13, R14, R15 and R16 are each independently selected from hydrogen, an optionally substituted-(C1-C6)haloalkyl, —(C1-C6)alkyl, —(C1-C6)cyanoalkyl, —(C3-C7)cycloalkyl, —(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, —(C1-C6)alkylene-heteroaryl, —(C1-C6)alkylene-heterocycle and —(C1-C6)alkylene-aryl;
wherein optionally any two radicals selected from R13, R14, R15 or R16 may be taken together to form a 3 to 10-membered carbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 radicals independently selected from halogen, cyano, nitro, hydroxyl, amino, —(C1-C6)alkyl, —O—(C1-C6)alkyl and —N—((C1-C6)alkyl)2;
wherein any two radicals A and any two radicals B may be combined with the intervening atoms to form a 3 to 10-membered carbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 radicals independently selected from halogen, —CN, hydroxyl, amino, —(C1-C6)alkyl, —O—(C1-C6)alkyl and —N—((C1-C6)alkyl)2;
wherein the term “heteroaryl” or “aromatic heterocyclic ring”, unless otherwise defined, refers to a 5 to 10-membered monocyclic or bicyclic unsaturated aromatic ring system containing from 1 to 3 heteroatoms selected independently from N, O and S;
wherein the term “heterocycle” or “non-aromatic heterocyclic ring”, unless otherwise defined, refers to a 5 to 10-membered monocyclic or bicyclic saturated or partially saturated ring system containing from 1 to 3 heteroatoms selected independently from N, O and S;
wherein the term “optionally substituted”, unless otherwise defined, refers to an optional substitution with one or more substituents selected from (C1-C6)alkyl, hydroxy, (C1-C6)alkylene-OH, (C1-C6)alkylene-O—(C1-C6)alkyl, mercapto, aryl, heteroaryl, heterocycle, (C1-C6)alkylene-aryl, (C1-C6)alkylene-heterocycle, (C1-C6)alkylene-(C3-C7)cycloalkyl, (C1-C6)alkylene-heteroaryl, halogen, trifluoroalkyl, trifluoroalkoxy, cyano, cyanoalkyl, nitro, amino, carboxyl, carboxamide, —NH—C(═O)O—(C1-C6)alkyl, —S(═O)2—NH2, —C(O)O—(C1-C6)alkyl, and —S(═O)—(C1-C6)alkyl;
or an N-oxide form thereof, a pharmaceutically acceptable salt or solvate thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.