Piperazine derivatives as MAGL inhibitors
The invention provides new heterocyclic compounds having the general Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X, Y 1 and Y 2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is C—H or N;
Y 1 is selected from the group consisting of C—H, C—F, C-alkyl, C-haloalkyl, and N;
Y 2 is selected from the group consisting of C—H, C-halogen, C-alkyl, and C-haloalkyl;
R 1 is selected from the group consisting of:
i. aryl,
ii. substituted aryl,
iii. heteroaryl,
iv. substituted heteroaryl,
v. heterocyclyl,
vi. substituted heterocyclyl,
vii. cycloalkyl, and
viii. substituted cycloalkyl;
wherein each of said substituted aryl, substituted heteroaryl, substituted heterocyclyl, and substituted cycloalkyl is independently substituted with one or more substituents selected from the group consisting of aminoalkyl, amino, haloalkylaryl, cycloalkyl, cycloalkylaryl, aryl-alkenyl, haloaryl-alkenyl, cyano(haloaryl), haloarylsulfonyl, alkyl(hydroxyheterocyclyl), alkyl(haloheterocyclyl), arylalkoxyalkylheteroaryl, hydroxyalkynyl, haloalkylaryl-alkoxyalkyl, haloalkylheteroaryl, haloalkylheterocyclyl, alkylheteroaryl, arylcycloalkyl, hydroxyalkylheterocyclyl, alkylsulfanyl, alkoxyheterocyclyl, cycloalkylheteroaryl, alkylcycloalkylheteroaryl, haloalkylcycloalkylheteroaryl, alkoxyalkylheteroaryl, alkoxyalkylheterocyclyl, alkoxyalkylaryl, cycloalkylalkoxy, arylalkoxy, aryloxyalkyl, haloaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, aryloxy, haloalkylaryloxy, halogen, heterocyclyl, hydroxyheterocyclyl, heterocyclylalkyl, heteroaryl, aryl, aryl-C(O)—, haloaryl, haloheteroaryl, halocycloalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkoxyaryl, hydroxyalkoxyheteroaryl, alkoxy, alkyl, haloalkyl, cyano, cyanoaryl, cyanoheteroaryl, cyanocycloalkyl, cyanoalkylaryl, arylheterocyclyl, alkoxy-(haloalkyl)aryl, alkylaryl, arylalkoxy-(alkyl)aryl, haloaryloxy, hydroxyalkylaryl, hydroxyalkylheteroaryl, alkenyloxy, pentafluoro-lambda6-sulfanyl, heteroarylalkyl, heteroarylalkoxy, haloheteroarylalkoxy, alkoxyaryl, alkoxyheteroaryl, (arylalkoxy)aryl, (arylalkoxy)heteroaryl, carbamoylaryl, alkyl-(alkoxy)aryl, haloalkoxyaryl, haloalkoxyheteroaryl, alkylheterocyclyl, haloheterocyclyl, alkylhaloaryl, haloalkylhaloaryl, and haloarylalkoxy;
wherein said aminoalkyl is substituted on the nitrogen atom with one or two substituents independently selected from the group consisting of H, alkyl, cycloalkyl, alkanoyl, arylalkyl, and haloalkylarylalkyl; and
wherein said amino is substituted on the nitrogen atom with one or two substituents independently selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, haloarylalkyl, haloalkoxyarylalkyl, benzyl and benzyl substituted with a substituent selected from the group consisting of halogen, alkyl, and haloalkyl; and
R 2 is selected from the group consisting of hydrogen and alkyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C—H.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is selected from the group consisting of C—H, C—F, and N.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is C—H.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is selected from the group consisting of C—H and C-halogen.
7. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein said C-halogen is C—F or C—Cl.
8. The compound according to claim 1 , a pharmaceutically acceptable salt thereof, wherein Y 2 is C—H.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 2 are C—H, and X is N.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
i. aryl substituted with one or more substituents selected from the group consisting of aminoalkyl, amino, haloalkylaryl, cycloalkyl, haloaryl-alkenyl, hydroxyalkynyl, haloalkylaryl-alkoxyalkyl, haloalkylaryloxy, haloalkylheteroaryl, alkylheteroaryl, arylcycloalkyl, cycloalkylheteroaryl, cycloalkylalkoxy, arylalkoxy, aryloxy, halogen, heterocyclyl, haloheterocyclyl, hydroxyalkylheterocyclyl, hydroxyalkylheteroaryl, arylalkoxyalkylheteroaryl, haloalkylheterocyclyl, haloaryloxyalkyl, alkoxyalkylheterocyclyl, heteroaryl, haloheteroarylalkoxy, aryl, haloaryl, haloalkoxy, alkoxy, alkyl, haloalkyl, cyano, cyanoaryl, cyanocycloalkyl, cyanoalkylaryl, arylheterocyclyl, alkoxy-(haloalkyl)aryl, arylalkoxy-(alkyl)aryl, haloaryloxy, hydroxyalkylaryl, alkenyloxy, pentafluoro-lambda6-sulfanyl, heteroarylalkyl, alkoxyaryl, (arylalkoxy)aryl, carbamoylaryl, alkyl-(alkoxy)aryl, haloalkoxyaryl, alkylheterocyclyl, alkylcycloalkylheteroaryl, and haloarylalkoxy,
wherein said aminoalkyl is substituted on the nitrogen atom with one or two substituents independently selected from the group consisting of alkanoyl, arylalkyl and haloalkylarylalkyl; and
wherein said amino is substituted on the nitrogen atom with one or two substituents independently selected from the group consisting of alkyl, haloarylalkyl and haloalkoxyarylalkyl;
ii. heteroaryl substituted with one or more substituents selected from the group consisting of alkylsulfanyl, heteroaryl, cycloalkyl, haloaryl, cyano(haloaryl), heterocyclyl, alkoxyheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, alkyl(hydroxyheterocyclyl), alkyl(haloheterocyclyl), alkylheteroaryl, hydroxyalkylheterocyclyl, aryl, alkyl, haloalkyl, cyano, cyanoaryl, halogen, arylalkoxy, alkoxy, dialkylamino, haloheterocyclyl, haloalkylhaloaryl, aryloxyalkyl, alkylaryl, heteroarylalkoxy, and haloalkylaryl;
iii. heteroaryl;
iv. cycloalkyl, substituted once with alkylheteroaryl; and
v. heterocyclyl, substituted once with haloarylsulfonyl or haloarylalkyl.
11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
i. heteroaryl substituted with one or more substituents selected from the group consisting of aryl, alkylaryl, haloaryl, cyano(haloaryl), heterocyclyl, haloheterocyclyl, alkyl(haloheterocyclyl), alkylheterocyclyl, hydroxyalkylheterocyclyl, cycloalkyl, cyano, alkyl and haloalkyl; and
ii. aryl substituted with one or more substituents selected from the group consisting of heterocyclyl, hydroxyalkylheterocyclyl, haloalkylaryl, haloalkylheteroaryl, haloheteroarylalkoxy, haloaryloxyalkyl, arylheterocyclyl, alkylheteroaryl, haloarylalkoxy, halogen, haloalkyl, alkyl, heteroaryl, haloalkoxy, haloalkoxyaryl, hydroxyalkylaryl, alkoxy-(haloalkyl)aryl, alkylheterocyclyl, cycloalkylheteroaryl, alkylcycloalkylheteroaryl and aminoalkyl;
wherein said aminoalkyl is substituted on the nitrogen atom with two substituents independently selected from the group consisting of alkanoyl and haloalkylarylalkyl.
12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
i. monocyclic heteroaryl substituted with one or more alkylaryl substituents;
ii. bicyclic heteroaryl substituted with one or more substituents selected from the group consisting of aryl, haloaryl, cyano(haloaryl), heterocyclyl, haloheterocyclyl, alkyl(haloheterocyclyl), alkylheterocyclyl, hydroxyalkylheterocyclyl, cycloalkyl, cyano, alkyl, and haloalkyl; and
iii. monocyclic aryl substituted with one or more substituents selected from the group consisting of heterocyclyl, hydroxyalkylheterocyclyl, haloalkylaryl, haloalkylheteroaryl, haloheteroarylalkoxy, haloaryloxyalkyl, arylheterocyclyl, alkylheteroaryl, haloarylalkoxy, halogen, haloalkyl, alkyl, heteroaryl, haloalkoxy, haloalkoxyaryl, hydroxyalkylaryl, alkoxy-(haloalkyl)aryl, alkylheterocyclyl, cycloalkylheteroaryl, alkylcycloalkylheteroaryl, and aminoalkyl;
wherein said aminoalkyl is substituted on the nitrogen atom with two substituents independently selected from the group consisting of alkanoyl and haloalkylarylalkyl.
13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
i. benzoxazolyl substituted with 1 or 2 substituents selected from the group consisting of methyl, CF 3 , phenyl, chlorophenyl, cyano-chlorophenyl, 2-azaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, difluoro-2-azaspiro[3.3]heptanyl, 3-fluoro-3-methyl-pyrrolidinyl, 3-(1-hydroxy-1-methyl-ethyl)pyrrolidinyl, fluorophenyl, piperidinyl, cyclohexyl, methylpyrrolidinyl and CN;
ii. indolyl substituted once with phenyl or fluorophenyl;
iii. indazolyl substituted once with fluorophenyl;
iv. phenyl substituted with 1 or 2 substituents selected from the group consisting of Cl, F, methyl, CF 3 , pyrrolidinyl, hydroxyethylpyrrolidinyl, dimethylpyrrolidinyl, diethylpyrrolidinyl, imidazolyl, dimethylpiperidinyl, trifluoromethylpyridyl, substituted phenyl, phenylcyclopropyl, substituted oxadiazolyl, chlorophenylmethoxy, 2,3-dihydroindolyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, (chloropyridyl)methoxy, (chlorophenoxy)methyl, azepanyl, 2,3-dihydropyrrolo[2,3-b]pyridin-1-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl and aminoethyl;
wherein said substituted phenyl is substituted with 1 or 2 substituents independently selected from the group consisting of CF 3 , methoxy, trifluoromethoxy, and hydroxymethyl;
said substituted oxadiazolyl is substituted once with propan-2-yl, trifluoroethyl, 2-fluoro-1,1-dimethyl-ethyl, tert-butyl, cyclopropyl or 1-methylcyclopropyl; and
said aminoethyl is substituted on the nitrogen atom with acetyl and trifluoromethylbenzyl; and
v. pyridyl substituted once with tert-butylphenyl.
14. The compound according claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
wherein the wavy line indicates the point of attachment of R 1 to the rest of Formula (I).
15. The compound according to claim 1 , a pharmaceutically acceptable salt thereof, wherein R 1 is:
i. heteroaryl substituted with one or more substituents selected from the group consisting of aryl, haloaryl, haloalkylaryl, heterocyclyl, haloheterocyclyl, and dialkylamino; or
ii. aryl substituted with one or more substituents selected from the group consisting of alkylheteroaryl and heterocyclyl.
16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
i. bicyclic heteroaryl substituted with one or more substituents selected from the group consisting of aryl, haloaryl, haloalkylaryl, heterocyclyl, haloheterocyclyl, and dialkylamino; or
ii. monocyclic aryl substituted with one or more substituents selected from the group consisting of alkylheteroaryl and heterocyclyl.
17. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
i. benzoxazolyl substituted with 1 or 2 substituents selected from the group consisting of:
phenyl, chlorophenyl, trifluoromethylphenyl, morpholinyl, 2-azaspiro[3.4]octanyl, difluoro-2-azaspiro[3.3]heptanyl and methyl(propyl)amino; and
ii. phenyl substituted with 1 substituent selected from the group consisting of substituted oxadiazolyl, 2-azaspiro[3.4]octanyl and 6-azaspiro[3.4]octan-yl, wherein:
said substituted oxadiazolyl is substituted once with 2,2-dimethylpropyl or tert-butyl.
18. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
wherein a wavy line indicates the point of attachment of R 1 to the rest of Formula (I).
19. The compound according claim 1 , a pharmaceutically acceptable salt thereof, wherein R 2 is H.
20. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—H or N;
Y′ is selected from the group consisting of C—H, C—F and N;
Y 2 is selected from the group consisting of C—H and C-halogen;
R 1 is selected from the group consisting of:
i. aryl substituted with one or more substituents selected from the group consisting of aminoalkyl, amino, haloalkylaryl, cycloalkyl, haloaryl-alkenyl, alkylcycloalkylheteroaryl, hydroxyalkynyl, haloalkylaryl-alkoxyalkyl, haloalkylaryloxy, haloalkylheteroaryl, alkylheteroaryl, arylcycloalkyl, cycloalkylheteroaryl, cycloalkylalkoxy, arylalkoxy, aryloxy, halogen, heterocyclyl, haloheterocyclyl, hydroxyalkylheterocyclyl, hydroxyalkylheteroaryl, arylalkoxyalkylheteroaryl, haloalkylheterocyclyl, haloaryloxyalkyl, alkoxyalkylheterocyclyl, heteroaryl, haloheteroarylalkoxy, aryl, haloaryl, haloalkoxy, alkoxy, alkyl, haloalkyl, cyano, cyanoaryl, cyanocycloalkyl, cyanoalkylaryl, arylheterocyclyl, alkoxy-(haloalkyl)aryl, arylalkoxy-(alkyl)aryl, haloaryloxy, hydroxyalkylaryl, alkenyloxy, pentafluoro-lambda6-sulfanyl, heteroarylalkyl, alkoxyaryl, (arylalkoxy)aryl, carbamoylaryl, alkyl-(alkoxy)aryl, haloalkoxyaryl, alkylheterocyclyl, and haloarylalkoxy;
wherein said aminoalkyl is substituted on the nitrogen atom with one or two substituents independently selected from the group consisting of alkanoyl, arylalkyl and haloalkylarylalkyl; and
wherein said amino is substituted on the nitrogen atom with one or two substituents independently selected from the group consisting of alkyl, haloarylalkyl and haloalkoxyarylalkyl;
ii. heteroaryl substituted with one or more substituents selected from the group consisting of alkylsulfanyl, heteroaryl, cycloalkyl, haloaryl, cyano(haloaryl), heterocyclyl, alkoxyheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, alkyl(hydroxyheterocyclyl), alkyl(haloheterocyclyl), alkylheteroaryl, hydroxyalkylheterocyclyl, aryl, alkyl, haloalkyl, cyano, cyanoaryl, halogen, arylalkoxy, alkoxy, dialkylamino, haloheterocyclyl, haloalkylhaloaryl, aryloxyalkyl, alkylaryl, heteroarylalkoxy, and haloalkylaryl;
iii. heteroaryl;
iv. cycloalkyl substituted once with alkylheteroaryl; and
v. heterocyclyl substituted once with haloarylsulfonyl or haloarylalkyl; and
R 2 is selected from the group consisting of hydrogen and alkyl.
21. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—H or N;
Y 1 is selected from the group consisting of C—H and C—F;
Y 2 is selected from the group consisting of C—H and C-halogen;
R 1 is selected from the group consisting of:
i. heteroaryl substituted with one or more substituents selected from the group consisting of aryl, alkylaryl, haloaryl, cyano(haloaryl), heterocyclyl, haloheterocyclyl, hydroxyalkylheterocyclyl, alkylheterocyclyl, alkyl(haloheterocyclyl), cycloalkyl, cyano, alkyl, and haloalkyl; and
ii. aryl substituted with one or more substituents selected from the group consisting of heterocyclyl, hydroxyalkylheterocyclyl, haloalkylaryl, haloalkylheteroaryl, haloheteroarylalkoxy, haloaryloxyalkyl, arylheterocyclyl, alkylheteroaryl, haloarylalkoxy, halogen, haloalkyl, alkyl, heteroaryl, haloalkoxy, haloalkoxyaryl, hydroxyalkylaryl, alkoxy-(haloalkyl)aryl, alkylheterocyclyl, cycloalkylheteroaryl, alkylcycloalkylheteroaryl, and aminoalkyl;
wherein said aminoalkyl is substituted on the nitrogen atom with two substituents independently selected from the group consisting of alkanoyl and haloalkylarylalkyl; and
R 2 is selected from the group consisting of hydrogen and alkyl.
22. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Y 1 and Y 2 are each C—H;
R 1 is selected from the group consisting of:
i. heteroaryl substituted with one or more substituents selected from the group consisting of aryl, haloaryl, haloalkylaryl, heterocyclyl, haloheterocyclyl, and dialkylamino; and
ii. aryl substituted with one or more substituents selected from the group consisting of alkylheteroaryl and heterocyclyl; and
R 2 is hydrogen.
23. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—H or N;
Y 1 is selected from the group consisting of C—H and C—F;
Y 2 is selected from the group consisting of C—H, C—Cl, and C—F;
R 1 is selected from the group consisting of:
i. benzoxazolyl substituted with 1 or 2 substituents selected from the group consisting of methyl, CF 3 , phenyl, chlorophenyl, cyano-chlorophenyl, 2-azaspiro[3.3]heptanyl, difluoro-2-azaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 3-fluoro-3-methyl-pyrrolidinyl, 3-(1-hydroxy-1-methyl-ethyl)pyrrolidinyl, fluorophenyl, piperidinyl, cyclohexyl, methylpyrrolidinyl, and CN;
ii. indolyl substituted once with phenyl or fluorophenyl;
iii. indazolyl substituted once with fluorophenyl;
iv. phenyl substituted with 1 or 2 substituents selected from the group consisting of Cl, F, methyl, CF 3 , pyrrolidinyl, hydroxyethylpyrrolidinyl, dimethylpyrrolidinyl, diethylpyrrolidinyl, imidazolyl, dimethylpiperidinyl, trifluoromethylpyridyl, substituted phenyl, phenylcyclopropyl, substituted oxadiazolyl, chlorophenylmethoxy, 2,3-dihydroindolyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, (chloropyridyl)methoxy, (chlorophenoxy)methyl, azepanyl, 2,3-dihydropyrrolo[2,3-b]pyridin-1-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl, and aminoethyl;
wherein said substituted phenyl is substituted with 1 or 2 substituents independently selected from the group consisting of CF 3 , methoxy, trifluoromethoxy, and hydroxymethyl;
said substituted oxadiazolyl is substituted once with propan-2-yl, trifluoroethyl, 2-fluoro-1,1-dimethyl-ethyl, tert-butyl, cyclopropyl, or 1-methylcyclopropyl; and
said aminoethyl is substituted on the nitrogen atom with acetyl and trifluoromethylbenzyl; and
v. pyridyl substituted once with tert-butylphenyl; and
R 2 is selected from the group consisting of hydrogen and alkyl.
24. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Y 1 and Y 2 are both C—H;
R 1 is selected from the group consisting of:
i. benzoxazolyl substituted with 1 or 2 substituents selected from the group consisting of phenyl, chlorophenyl, trifluoromethylphenyl, morpholinyl, 2-azaspiro[3.4]octanyl, difluoro-2-azaspiro[3.3]heptanyl and methyl(propyl)amino; and
ii. phenyl substituted with 1 substituent selected from the group consisting of substituted oxadiazolyl, 2-azaspiro[3.4]octanyl, and 6-azaspiro[3.4]octan-yl, wherein said substituted oxadiazolyl is substituted once with 2,2-dimethylpropyl or tert-butyl; and
R 2 is hydrogen.
25. A compound, selected from the group consisting of:
N-[2-[4-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]phenyl]ethyl]-N-methyl]acetamide;
2-[4-[4-[(E)-2-(3-fluorophenyl)ethenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Phenoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Phenoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(Trifluoromethoxy)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-(Trifluoromethoxy)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1,3-benzoxazole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(1H-Indole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[1-(4-Fluorophenyl)indole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Pyrrolidin-1-ylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(2-Iodophenyl)methylamino]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Phenylmethoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-methylamino]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-(Cyclopentylmethoxy)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Phenylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Trifluoromethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Phenyl-1,2-oxazole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Chloro-4-pyrrolidin-1-ylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
N-benzyl-N-[2-[4-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]phenyl]ethyl]acetamide;
2-[4-[3-(Trifluoromethyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1H-indole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
(Rac, cis)-2-[4-[4-[2-phenylcyclopropyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
(Rac, trans)-2-[4-[4-[2-phenylcyclopropyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Bromo-5-(trifluoromethoxy)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Prop-2-enoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Methylpropyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-Propan-2-yl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Methyl-1-phenylbenzimidazole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3,5-Bis(trifluoromethyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[2-methoxy]ethyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-tert-Butyl-3-methoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(Pentafluoro-λ6-sulfanyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[1-(4-Fluorophenyl)indazole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2,5-Dimethylpyrrol-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(Quinoline-7-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Bromo-4-(trifluoromethoxy)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(Benzimidazol-1-ylmethyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(1,3-Thiazol-2-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(4-Methylpyrazol-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Methylpyrazol-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(6-Methoxy-1-benzofuran-2-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[5-(2,3-Dihydro-1H-inden-5-yloxymethyl)furan-2-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(1,5-Diphenylpyrazole-3-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1H-benzimidazole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Fluorophenyl)-1H-indole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Trifluoromethyl)phenyl]benzoyl]piperazin-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one;
2-[4-(2-Phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one;
2-[4-[1-(4-Fluorophenyl)pyrrolo[2,3-b]pyridine-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Piperidin-1-ylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[1-(4-Fluorophenyl)benzimidazole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Piperidin-1-yl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
3-Methyl-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]quinazolin-4-one;
2-[4-[4-[5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[4-(Trifluoromethyl)pyrazol-1-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Trifluoromethyl)pyrazol-1-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Fluorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Chlorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[3-(Trifluoromethyl)phenyl]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Phenylmethoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(Diethylamino)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-[(3-Chlorophenyl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-4-[(3-chlorophenyl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(2,2-Dimethylpropyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[tert-Butyl(methyl)amino]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2,3-Dihydroindol-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(Azetidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Chloro-4-pyrrolidin-1-ylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]-3-(trifluoromethyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]-3-methylbenzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Pyrrolidin-1-ylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-tert-Butyl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]-3-(1H-imidazol-2-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[(3-Chlorophenyl)methoxy]-5-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]benzonitrile;
2-[4-(4-Cyclohexylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Cyclohexyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(4-Oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]phenyl]benzonitrile;
2-[4-(1-Butyl-2-methylbenzimidazole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3,5-Bis(trifluoromethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Trifluoromethoxy)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[1-Propan-2-yl-2-(trifluoromethyl)benzimidazole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[5-[3-(Trifluoromethyl)phenyl]pyridine-3-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3,4-Difluorophenyl)-2-fluorobenzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Methoxy-5-methylphenyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Methyl-1-benzofuran-2-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-[2-(Hydroxymethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Hydroxymethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Bromo-5-propan-2-yloxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-5-[4-(hydroxymethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-Chloro-3-(2-methylpropoxy)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Bromo-5-ethoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-Fluoro-3-[2-(hydroxymethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Fluoro-4-[3-(trifluoromethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-[2-(Trifluoromethoxy)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[6-(Trifluoromethyl)quinoline-3-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4,6-Dimethyl-1H-indole-2-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
N,N-dimethyl-4-[2-methyl-4-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]phenyl]benzamide;
2-[4-[2-(4-tert-Butylphenyl)pyridine-4-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Chlorophenoxy)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-tert-Butyl-5-chlorobenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Phenylmethoxyphenyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-(2-Methyl-6-phenylmethoxyphenyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[4-Methoxy-3-(trifluoromethyl)phenyl]-3-methylbenzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(7-Phenylmethoxy-1H-indole-3-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2,6-Difluorophenyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(1-Cyclopropylbenzimidazole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(6-tert-Butyl-1H-indole-2-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Chloro-3-ethoxybenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(4,4-Dimethylpiperidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[5-(Trifluoromethyl)imidazo[1,2-a]pyridine-2-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
4-[2-Fluoro-5-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]phenyl]-N,N-dimethylbenzamide;
2-[4-[3-(3,5-Difluorophenyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3,4-Dichlorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-Chlorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Azabicyclo[2.2.1]heptan-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Azaspiro[3.3]heptan-2-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(Azepan-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-[1,3]oxazolo[4,5-b]pyridine-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Cyclopropyl-1H-1,2,4-triazol-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
6-[4-(4-Oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]-2-phenyl-1,3-benzoxazole-4-carbonitrile;
2-[4-[4-(3,4-Dichlorophenyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(6-Pyrrolidin-1-ylpyridine-3-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-[5-(2,2-Dimethylpropyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Azaspiro[3.4]octan-2-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-Ethyl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Methyl-1,3-thiazol-4-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3,4-Difluorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[4-(Trifluoromethyl)phenyl]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-Fluorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
6-Fluoro-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
7-Fluoro-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Bromo-3-fluorobenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(5-Pyrrolidin-1-ylpyridine-2-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Fluoro-4-[5-(trifluoromethyl)pyridin-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Methyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-Phenyl-4-(trifluoromethyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Bromo-3-methylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Morpholin-4-yl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2,3-Dihydropyrrolo[2,3-b]pyridin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Phenylpyrrolidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Pyridin-2-yl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(2,2,2-Trifluoroethyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[3-[4-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]phenyl]phenyl]acetonitrile;
2-[4-[3-Fluoro-4-[3-(trifluoromethoxy)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Methyl-4-[3-(trifluoromethoxy)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Ethoxyphenyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
6-Chloro-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[2-methylamino]ethyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
1-[4-[4-(4-Oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]phenyl]cyclopentane-1-carbonitrile;
2-[4-(4-Morpholin-4-yl-2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(2-Azaspiro[3.4]octan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(7,7-Difluoro-2-azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[Methyl(propyl)amino]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
N-[2-[4-[4-(1-oxo-2H-isoquinolin-3-yl)piperazine-1-carbonyl]phenyl]ethyl]-N-methyl]acetamide;
2-[4-[2-(Oxan-4-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Pyridin-4-yl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Pyridin-3-yl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
3-[6-[4-(4-Oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]-1,3-benzoxazol-2-yl]benzonitrile;
2-[4-(2-Methylsulfanyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Pyrrolidin-1-yl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-Methoxypiperidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-Hydroxypiperidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Methylpyrrolidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(6-Azaspiro[3.4]octan-6-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3,3-Difluoropyrrolidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(1-Hydroxyethyl)pyrrolidin-1-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[4-(Trifluoromethyl)piperidin-1-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-Azaspiro[2.4]heptan-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-4-[(4-chloropyridin-2-yl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-4-[(2-chloropyridin-4-yl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(3-Phenylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-4-[(6-chloropyridin-2-yl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-[3-(Trifluoromethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Trifluoromethyl)phenoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(2,2,2-Trifluoroethyl)-1,2,4-oxadiazol-5-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2,5-Dimethylpyrrolidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(4,4-Difluoropiperidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-4-[(3-Chlorophenoxy)methyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1,3-benzothiazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(Oxolan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Methoxymethyl)pyrrolidin-1-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(2,2,2-Trifluoroethyl)-1,3-benzoxazole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-[1-(fluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-Methyl-4-(1H-pyrazol-4-ylmethoxy)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(1-Fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-Chloro-4-[6-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]-1,3-benzoxazol-2-yl]benzonitrile;
2-[4-[4-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentane-1-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-(3-Chlorophenyl)sulfonyl-3,9-diazaspiro[5.5]undecane-9-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-tert-Butyl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-6-chloro-3H-quinazolin-4-one;
2-[4-[4-(3,3-Dimethylpyrrolidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(1-Methylpyrrol-3-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(1-Hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(8-Oxa-2-azaspiro[4.5]decan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Methoxypyrrolidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(2-Azaspiro[3.4]octan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3-methylquinazolin-4-one;
2-[4-[2-(2-Azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(6-Hydroxy-2-azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Hydroxy-3-methylpyrrolidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Fluoro-3-methylpyrrolidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(6-Azaspiro[3.4]octan-6-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3-methylquinazolin-4-one;
2-[4-[2-(6-Azaspiro[3.4]octan-6-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(2-Methyl-1-phenylmethoxypropan-2-yl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Hydroxy-3-methylbut-1-ynyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3,3-Diethylpyrrolidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-Chlorophenyl)sulfonyl-2,7-diazaspiro[4.4]nonane-7-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Chlorophenyl)sulfonyl-2,7-diazaspiro[4.4]nonane-7-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one; and
2-[4-[7-[(3-Chlorophenyl)methyl]-2,7-diazaspiro[4.4]nonane-2-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 25 , selected from the group consisting of:
2-[4-(2-Phenyl-1,3-benzoxazole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[1-(4-Fluorophenyl)indole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Pyrrolidin-1-ylbenzoyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Trifluoromethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1H-indole-5-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
(Rac, trans)-2-[4-[4-[2-phenylcyclopropyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-Propan-2-yl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[1-(4-Fluorophenyl)indazole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Fluorophenyl)-1H-indole-5-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Piperidin-1-yl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
3-Methyl-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]quinazolin-4-one;
2-[4-[3-Chloro-4-[(3-chlorophenyl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2,3-Dihydroindol-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]-3-(trifluoromethyl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]-3-methylbenzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[(3-Chlorophenyl)methoxy]-3-(1H-imidazol-2-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Cyclohexyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(Trifluoromethoxy)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-5-[4-(hydroxymethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Fluoro-4-[3-(trifluoromethyl)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-tert-Butylphenyl)pyridine-4-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[4-Methoxy-3-(trifluoromethyl)phenyl]-3-methylbenzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(4,4-Dimethylpiperidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3,4-Dichlorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-Chlorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Azaspiro[3.3]heptan-2-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(Azepan-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
6-[4-(4-Oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]-2-phenyl-1,3-benzoxazole-4-carbonitrile;
2-[4-[2-(3,4-Difluorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(4-Fluorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
6-Fluoro-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
7-Fluoro-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Fluoro-4-[5-(trifluoromethyl)pyridin-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Methyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-Phenyl-4-(trifluoromethyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2,3-Dihydropyrrolo[2,3-b]pyridin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(2,2,2-Trifluoroethyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Fluoro-4-[3-(trifluoromethoxy)phenyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
6-Chloro-2-[4-(2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
N-[2-[4-[4-(1-oxo-2H-isoquinolin-3-yl)piperazine-1-carbonyl]phenyl]ethyl]-N-methyl]acetamide;
2-[4-[2-(3-Methylpyrrolidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[3-(1-Hydroxyethyl)pyrrolidin-1-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-Azaspiro[2.4]heptan-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-4-[(4-chloropyridin-2-yl)methoxy]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-Chloro-4-[(3-Chlorophenoxy)methyl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(2-Phenyl-1,3-benzothiazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(1-Methylcyclopropyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(1-Fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-Chloro-4-[6-[4-(4-oxo-3H-quinazolin-2-yl)piperazine-1-carbonyl]-1,3-benzoxazol-2-yl]benzonitrile;
2-[4-[4-(5-tert-Butyl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-6-chloro-3H-quinazolin-4-one;
2-[4-[4-(3,3-Dimethylpyrrolidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(2-Azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(3-Fluoro-3-methylpyrrolidin-1-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(6-Azaspiro[3.4]octan-6-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3,3-Diethylpyrrolidin-1-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one; and
2-[4-[2-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 25 , selected from the group consisting of:
2-[4-[2-(3-Chlorophenyl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[3-(Trifluoromethyl)phenyl]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-[5-(2,2-Dimethylpropyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(5-tert-Butyl-1,2,4-oxadiazol-3-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[3-[5-(2,2-Dimethylpropyl)-1,2,4-oxadiazol-3-yl]benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(2-Azaspiro[3.4]octan-2-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-(4-Morpholin-4-yl-2-phenyl-1,3-benzoxazole-6-carbonyl)piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(2-Azaspiro[3.4]octan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-(7,7-Difluoro-2-azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[2-[Methyl(propyl)amino]-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(6-Azaspiro[3.4]octan-6-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one;
2-[4-[4-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)benzoyl]piperazin-1-yl]-3H-quinazolin-4-one; and
2-[4-[2-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-1,3-benzoxazole-6-carbonyl]piperazin-1-yl]-3H-quinazolin-4-one;
or a pharmaceutically acceptable salt thereof.
28. A process of manufacturing a compound according claim 1 , or a pharmaceutically acceptable salt thereof, the process comprising:
a) reacting an amine 1, wherein R 2 , X, Y 1 and Y 2 are as defined for Formula (I),
with an acid 2, wherein R 1 is as defined for Formula (I),
or
b) reacting an amine 1, wherein R 2 , X, Y 1 and Y 2 are as defined for Formula (I),
with an acid chloride 2a, wherein R 1 is as defined for Formula (I),
or
c) reacting a compound of formula 3, wherein R 2 , X, Y 1 and Y 2 are as defined for Formula (I),
with a piperazine derivative 4, wherein R 1 is as defined for Formula (I),
to form said compound of Formula (I), or a pharmaceutically acceptable salt thereof.
29. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is manufactured according to a process comprising:
a) reacting an amine 1, wherein R 2 , X, Y 1 and Y 2 are as defined for Formula (I),
with an acid 2, wherein R 1 is as defined for Formula (I),
or
b) reacting an amine 1, wherein R 2 , X, Y 1 and Y 2 are as defined for Formula (I),
with an acid chloride 2a, wherein R 1 is as defined for Formula (I),
or
c) reacting a compound of formula 3, wherein R 2 , X, Y 1 and Y 2 are as defined for Formula (I),
with a piperazine derivative 4, wherein R 1 is as defined for Formula (I),
to form said compound of Formula (I), or a pharmaceutically acceptable salt thereof.
30. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound or pharmaceutically acceptable salt thereof has an IC 50 for monoacylglycerol lipase below 10 μM as measured in an assay comprising the steps of:
a) providing a solution of the compound or pharmaceutically acceptable salt thereof in DMSO;
b) providing a solution of monoacylglycerol lipase (recombinant wild-type) in assay buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid);
c) adding 1 μL of compound solution from step a) to 19 μL of monoacylglycerol lipase solution from step b);
d) shaking the mixture for 1 min at 2000 rpm;
e) incubating for 15 min at RT;
f) adding 20 μL of a solution of 4-nitrophenlyacetate in assay buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid, 6% EtOH);
g) shaking the mixture for 1 min at 2000 rpm;
h) incubating for 5 min at RT;
i) measuring the absorbance of the mixture at 405 nm a first time;
j) incubating a further 80 min at RT;
k) measuring the absorbance of the mixture at 405 nm a second time;
l) subtracting the absorbance measured under i) from the absorbance measured under k) and calculating the slope of absorbance;
wherein:
i) the concentration of the compound or pharmaceutically acceptable salt thereof in the assay after step f) is in the range of 25 μM to 1.7 nM;
ii) the concentration of monoacylglycerol lipase in the assay after step f) is 1 nM;
iii) the concentration of 4-nitrophenylacetate in the assay after step f) is 300 μM; and
iv) steps a) to 1) are repeated for at least 3 times, each time with a different concentration of the compound or pharmaceutically acceptable salt thereof in the assay.
31. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
32. A pharmaceutical composition, comprising a compound of claim 25 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
33. A method for inhibiting monoacylglycerol lipase in a mammal, the method comprising administering to the mammal an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
34. A method for inhibiting monoacylglycerol lipase in a mammal, the method comprising administering to the mammal an effective amount of a compound of claim 25 , or a pharmaceutically acceptable salt thereof.
35. A method for the treatment of a condition in a mammal, wherein the condition is neuroinflammation, a neurodegenerative disease, pain, cancer, or a mental disorder, or any combination thereof, the method comprising administering to the mammal an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
36. A method for the treatment of a condition in a mammal, wherein the condition is neuroinflammation, a neurodegenerative disease, pain, cancer, or a mental disorder, or any combination thereof, the method comprising administering to the mammal an effective amount of a compound of claim 25 , or a pharmaceutically acceptable salt thereof.
37. A method for the treatment of a condition in a mammal, wherein the condition is multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer, or pain, or any combination thereof, the method comprising administering to the mammal an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
38. A method for the treatment of a condition in a mammal, wherein the condition is multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer, or pain, or any combination thereof, the method comprising administering to the mammal an effective amount of a compound of claim 25 , or a pharmaceutically acceptable salt thereof.