Aromatic heterocyclic derivatives and pharmaceutical applications thereof
Provided herein are aromatic heterocyclic derivatives or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof used for treating Alzheimer's disease. Also provided herein are pharmaceutical compositions containing such compounds, and use of such compounds or pharmaceutical compositions thereof for managing or treating 5-HT 6 receptor-mediated diseases, especially in the manufacture of a medicament for managing or treating Alzheimer's disease.
1. A compound having Formula (I), or a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,
wherein
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
A is CR 3 or N;
X is CR 1 ;
Y is CR 4 or N;
each R 1 is independently H, D, F, Cl, Br, I, —CN, —NO 2 , —OH, —NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, —C(═O)NR 6 R 6a , —C(═O)R 6b , —C(═O)OR 6c , R 6 R 6a N—S(═O) 2 —, R 6b S(═O) 2 —, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl or 5- to 12-membered heteroaryl;
R 2 is —CN, —OH, —NR 6 R 6a , —C(═O)—(C 1-6 alkyl), —C(═O)NR 6 R 6a , R 6 R 6a N—S(═O) 2 —, hydroxy-substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxy or (C 6-10 aryl)-(C 1-6 alkylene)-;
R 3 is H, D, F, Cl, Br, I, —CN, —NO 2 , —OH, —NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carboxy-substituted C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —C(═O)NR 6 R 6a , —C(═O)R 6b , C 3-8 cycloalkyl or C 6-10 aryl;
each R 4 is independently H, D, F, Cl, Br, I, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl or C 6-10 aryl;
R 5 is 3- to 12-membered heterocyclyl, C 5-8 cycloalkyl, 5- to 12-membered heteroaryl, (3- to 12-membered heterocyclyl)-NH—, (3- to 12-membered heterocyclyl)-(C 1-3 alkylene)-, (3- to 12-membered heterocyclyl)-O— or (3- to 12-membered heterocyclyl)-S—, and wherein optionally each of 3- to 12-membered heterocyclyl, C 5-8 cycloalkyl, 5- to 12-membered heteroaryl, (3- to 12-membered heterocyclyl)-NH—, (3- to 12-membered heterocyclyl)-(C 1-3 alkylene)-, (3- to 12-membered heterocyclyl)-O— and (3- to 12-membered heterocyclyl)-S— is independently substituted with 1, 2, 3 or 4 R 7 ;
each R 6 , R 6a , R 6b and R 6c is independently H, D, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl or 5- to 12-membered heteroaryl; or R 6 and R 6a , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3- to 8-membered ring; and
each R 7 is independently H, D, F, Cl, Br, I, —CN, —C(═O)NR 6 R 6a , —C(═O)R 6b , —C(═O)OR 6c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl or (5- to 12-membered heteroaryl)-(C 1-6 alkylene)-.
2. The compound according to claim 1 , wherein R 5 is 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-NH—, (5- to 6-membered heterocyclyl)-CH 2 —, (5- to 6-membered heterocyclyl)-CH(CH 3 )—, (5- to 6-membered heterocyclyl)-O— or (5- to 6-membered heterocyclyl)-S—, and wherein optionally each of 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-NH—, (5- to 6-membered heterocyclyl)-CH 2 —, (5- to 6-membered heterocyclyl)-CH(CH 3 )—, (5- to 6-membered heterocyclyl)-O— and (5- to 6-membered heterocyclyl)-S— is independently substituted with 1, 2, 3 or 4 R 7 .
3. The compound according to claim 1 having Formula (II), or a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,
wherein
Q is CH or N;
M is —NR 7 — or —O—; and
L 1 is a bond, —NH—, —CH 2 —, —O— or —S—.
4. The compound according to claim 1 , wherein each R 1 is independently H, D, F, Cl, Br, I, —CN, —NO 2 , —OH, —NH 2 , methyl, ethyl, —CHF 2 or —CF 3 .
5. The compound according to claim 1 , wherein R 2 is —CN, —OH, —NH 2 , —C(═O)—(C 1-4 alkyl), hydroxy-substituted C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkoxy or phenyl-(C 1-4 alkylene)-.
6. The compound according to claim 5 , wherein R 2 is —CN, —OH, —NH 2 , —C(═O)CH 3 , —C(═O)CH 2 CH 3 , —C(═O)CH 2 CH 2 CH 3 , —C(═O)CH 2 (CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 Br, —CHBr 2 , —CBr 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CHFCF 3 , —CF 2 CHF 2 , —CF 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CF 2 CHF 2 or ethoxy.
7. The compound according to claim 1 , wherein each R 4 is independently H, D, F, Cl, Br, I, —CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl or C 6-10 aryl.
8. The compound according to claim 7 , wherein each R 4 is independently H, D, F, Cl, Br, I, —CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CHFCF 3 , —CF 2 CHF 2 , —CF 2 CF 3 , methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, —OCHF 2 , —OCF 3 or —OCH 2 CF 3 .
9. The compound according to claim 1 , wherein each R 7 is independently H, D, F, Cl, Br, I, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl.
10. The compound according to claim 9 , wherein each R 7 is independently H, D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, thietanyl, pyrrolidyl or tetrahydrofuryl.
11. The compound according to claim 1 having one of the following structures, or a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,
12. A pharmaceutical composition comprising the compound according to claim 1 , and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
13. The pharmaceutical composition according to claim 12 further comprising an additional therapeutic agent used for treating Alzheimer's disease, neuropathy or a combination thereof.
14. The pharmaceutical composition according to claim 13 , wherein the additional therapeutic agent is donepezil, nalmefene, risperidone, Vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, RVT-101, naluzaton, idalopirdine, tacrine, rivastigmine, galantamine, memantine, mirtazapine, venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or a combination thereof.
15. A method for treating or lessening a 5-HT 6 receptor-mediated disease in a subject, comprising administering to the subject in need of such treatment a therapeutically effective amount of the compound according to claim 1 , wherein the 5-HT 6 receptor-mediated disease is obesity, anxiety, manic depression, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease.
16. A method for treating or lessening a 5-HT 6 receptor-mediated disease in a subject, comprising administering to the subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition according to claim 12 , wherein the 5-HT 6 receptor-mediated disease is obesity, anxiety, manic depression, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease.