GPR52 modulators and methods of use
The present disclosure relates to compounds of Formula (I) that modulate the activity of G-protein coupled receptor 52 (GPR52), pharmaceutically acceptable salts of compounds of Formula (I), and pharmaceutical compositions thereof. Compounds, pharmaceutical salts of compounds, and pharmaceutical compositions of the present disclosure are directed to methods useful in the treatment or prophylaxis of a neurological disease or disorder and conditions related thereto.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X, Y 1 and Y 2 are independently N (nitrogen) or CH;
Z is N or CR 1 , where at least one of Z, X, Y 1 and Y 2 is N (nitrogen);
Z 1 is
Z 2 is
Q 1 is N (nitrogen) or CR 4 ;
Q 2 is N (nitrogen) or CR 5 ;
R 1 is hydrogen, halogen, C 1 -C 6 alkyl or haloC 1 -C 6 alkyl;
R 2 is hydrogen, halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, or —OR A ;
R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl;
i) R 4 , R 5 , R 6 , and R 7 , are independently hydrogen, halogen, —(CH 2 ) n —CN, nitro, haloC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, —NHC(═O)R B , —OR B , —S(O) m R B , —(CH 2 ) m C(═O)R B , —S(O) p N(R B R C ), or C 1 -C 6 alkyl optionally substituted with hydroxyl; or
ii) R 4 and R 5 , together with the carbon atoms to which they are attached, form a 6 membered aryl group, a 5-6 membered heteroaryl group optionally substituted with C 1 -C 6 alkyl, a 5-6 membered cycloalkyl group optionally substituted with ═O, or a 5-6 membered heterocyclyl group, and R 6 and R 7 are independently hydrogen, halogen, —(CH 2 ) n —CN, nitro, C 1 -C 6 alkyl optionally substituted with hydroxyl, haloC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, —NHC(═O)R B , —OR B , —S(O) m R B , —(CH 2 ) m C(═O)R B or —S(O) p N(R B R C ); or
iii) R 5 and R 6 , together with the carbon atoms to which they are attached, form a 6 membered aryl group, a 5-6 membered heteroaryl group optionally substituted with C 1 -C 6 alkyl, a 5-6 membered cycloalkyl group optionally substituted with ═O, or a 5-6 membered heterocyclyl group, and R 4 and R 7 , are independently hydrogen, halogen, —(CH 2 ) n —CN, nitro, C 1 -C 6 alkyl optionally substituted with hydroxyl, haloC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, —NHC(═O)R B , —OR B , —S(O) m R B , —(CH 2 ) m C(═O)R B or —S(O) p N(R B R C ); or
iv) R 6 and R 7 , together with the carbon atoms to which they are attached, form a 6 membered aryl group, a 5-6 membered heteroaryl group optionally substituted with C 1 -C 6 alkyl, a 5-6 membered cycloalkyl group optionally substituted with ═O, or a 5-6 membered heterocyclyl group, and R 4 and R 5 , are independently hydrogen, halogen, —(CH 2 ) n —CN, nitro, C 1 -C 6 alkyl optionally substituted with hydroxyl, haloC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, —NHC(═O)R B , —OR B , —S(O) m R B , —(CH 2 ) m C(═O)R B or —S(O) p N(R B R C );
one of R 8 and R 9 is —(CH 2 ) n C(═O)N(R E R F ) and the other of R 8 and R 9 is hydrogen, halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, —C(═O)R D , or —OR E ; or
R 8 and R 9 together with the carbon atom to which they are attached, form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group optionally substituted with ═O, with the proviso that the heterocyclic group formed is not a 1,3-dioxolanyl ring when Y 1 and Z are each N and X and Y 2 are each CH;
R 10 is hydrogen, halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, —C(═O)R D , or —OR E ;
each R A , R B , R C , is independently hydrogen, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl;
each R D is independently hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, —NH 2 , or —NH(CH 2 ) q OH;
each R E , and R F , is independently hydrogen, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl; or
R E and R F , together with the nitrogen atom to which they are attached, form a 5-6 membered heterocyclyl group;
each m is independently 0, 1, 2 or 3;
each n is independently 0, 1, 2 or 3;
each p is independently 1 or 2; and
each q is independently 2, 3 or 4.
2. The compound of claim 1 , wherein X, Y 1 and Y 2 are CH and Z is N (nitrogen), or Z, Y 1 and Y 2 are CH and X is N (nitrogen), or X, Y 1 and Z are CH and Y 2 is N (nitrogen).
3. The compound of claim 1 , wherein X and Y 1 are each N or wherein X and Y 1 are each CH.
4. The compound of claim 1 , wherein R 2 and R 3 are each hydrogen.
5. The compound of claim 1 , wherein Z 2 is
6. The compound of claim 1 , wherein Z 2 is
7. The compound of claim 1 , wherein Q 1 is CR 4 and R 4 is hydrogen; and R 7 is hydrogen.
8. The compound of claim 1 , wherein Q 2 is CR 5 and R 5 is halogen, —(CH 2 ) n —CN, C 1 -C 3 alkyl, haloC 1 -C 3 alkyl, —OR B or —S(O) m R B .
9. The compound of claim 1 , wherein Q 2 is CR 5 and R 5 is unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by hydroxyl.
10. The compound of claim 1 , wherein R 6 is halogen, haloC 1 -C 6 alkyl, —(CH 2 ) n —CN, unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by hydroxyl or nitro.
11. The compound of claim 1 , wherein R 6 is hydrogen.
12. The compound of claim 1 , wherein R 5 is —NHC(═O)R B , —OR B , —S(O) m R B , or —S(O) p N(R B R C ).
13. The compound of claim 1 , wherein R 6 is —NHC(═O)R B , —OR B , —S(O) m R B , or —S(O) p N(R B R C ).
14. The compound of claim 1 , wherein Z 1 is
15. The compound of claim 1 , wherein Z 1 is
16. The compound of claim 1 , wherein R 8 is hydrogen, halogen, C 1 -C 6 alkyl or haloC 1 -C 6 alkyl; or wherein R 8 is —OR E , —C(═O)R D , or —(CH 2 ) n C(═O)N(R E R F ).
17. The compound of claim 1 , wherein R 9 is hydrogen, halogen, C 1 -C 6 alkyl or haloC 1 -C 6 alkyl; or wherein R 9 is —OR E , —C(═O)R D , or —(CH 2 ) n C(═O)N(R E R F ).
18. The compound of claim 1 , wherein Z 2 is
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more excipients.
20. A method of treating a neurological disorder, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof; wherein the neurological disorder is selected from the group consisting of:
schizophrenia, cognitive impairment, a panic disorder, a phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's Disease, Lewy Body Dementia, bipolar disorder, ADHD, Tourette's syndrome, an extrapyramidal or movement disorder, a motor disorder, a hyperkinetic movement disorder, a psychotic disorder, catatonia, a mood disorder, a depressive disorder, an anxiety disorder, obsessive-compulsive disorder (OCD), an autism spectrum disorder, a prolactin-related disorder, a neurocognitive disorder, a trauma- or stressor-related disorder; a disruptive, impulse-control, or conduct disorder, a sleep-wake disorder, a substance-related disorder, an addictive disorder, a behavioral disorder, hypofrontality, an abnormality in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway, decreased activity in the striatum, cortical dysfunction, neurocognitive dysfunction and the cognitive deficits associated with schizophrenia; dyskinesias, dystonia, chorea, levodopa induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease.
21. The compound of claim 1 , wherein the compound is selected from the group consisting of: