Sulfonamide derivatives and pharmaceutical applications thereof

1. A compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof,

wherein

k is 0,1,2 or 3;

m is 0, 1, 2, 3 or 4;

n is 1, 2, 3 or 4;

each X is independently CH or N, and at most two X are N;

each Y is independently CH or N;

each R 1 and R 3 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 3-8 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkenylthio, R 9a R 9 N—C 1-6 alkyl, —C(=O)R 9b , —C(=O)OR 9c , —C(=O)NR 9 R 9a , R 9 R 9a N—S(=O) 2 -, R 9b S(=O) 2 -, R 9b S(=O)-C 1-6 alkyl, R 9 R 9a N—C(=O)-C 1-6 alkyl, C 6-10 aryl, C 6-10 arylamino, 5- to 12-membered heteroaryl, (C 3-8 cycloalkyl)-(C 1-6 alkyl)-, (3- to 12-membered heterocyclyl)-(C 1-6 alkyl)-, (C 6-10 aryl)-(C 1-6 alkyl)-, (5- to 12-membered heteroaryl)-(C 1-6 alkyl)- or 3- to 12-membered heterocyclyl;

each R 2 is independently F, Cl, Br, I, —CN, —OH, —NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; or two adjacent R 2 , together with the carbon atoms to which they are attached, form a substituted or unsubstituted 5- to 7-membered carbocyclic ring, 5- to 7-membered heterocyclic ring, benzene ring or 5- to 6-membered heteroaromatic ring;

R 4 is H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C(=O)R 9b , —C(=O)NR 9 R 9a , C 2-6 alkenyl or C 2-6 alkynyl;

each of R 5 , R 6 , R 7 and R 8 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, 3- to 12-memerbered heterocyclyl, C 3-8 cycloalkyl, —C(=O)R 9b or —C(=O)NR 9 R 9a ;

or R 5 and R 6 , or R 7 and R 8 , together with the carbon atom to which they are attached, independently form a substituted or unsubstituted 3- to 8-membered carbocyclic ring or 3- to 8-membered heterocyclic ring;

R 10 is 3- to 12-membered heterocyclyl, C 3-8 cycloalkyl, or 5- to 12-membered heteroaryl, and wherein optionally each of 3- to 12-membered heterocyclyl, C 3-8 cycloalkyl, and 5- to 12-membered heteroaryl is independently substituted with 1, 2, 3 or 4 substitutents independently selected from H, D, F, Cl, Br, I, —CN, oxo (=O), —C(=O)R 9b , —C(=O)OR 9c , —C(=O)NR 9 R 9a , C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 6-10 aryl)-(C 1-6 alkyl)- or (5- to 12-membered heteroaryl)-(C 1-6 alkyl)-; and

each R 9 , R 9a , R 9b and R 9c is independently H, D, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 6-10 aryl, 3- to 12-membered heterocyclyl, C 3-8 cycloalkyl, (C 6-10 aryl)-(C 1-6 alkyl)-, C 6-10 aryloxy, 3- to 12-memebered heterocyclyloxy, C 3-8 cycloalkoxy, C 6-10 arylamino, 3- to 12-membered heterocyclylamino, C 3-8 cycloalkylamino or 5- to 12-membered heteroaryl; or R 9 and R 9a , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3- to 8-membered ring.

2. The compound according to claim 1 , wherein R 10 is 3- to 8-membered heterocyclyl, and wherein optionally the heterocyclyl is independently substituted with 1, 2, 3 or 4 substitutents independently selected from H, D, F, Cl, Br, I, —CN, oxo (=O), —C(=O)R 9b , —C(=O)OR 9c , —C(=O)NR 9 R 9a , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, (C 6-10 aryl)-(C 1-4 alkyl)- or (5- to 12-membered heteroaryl)-(C 1-4 alkyl)-; and

each of R 9 , R 9a , R 9b and R 9c is independently H, D, —OH or C 1-4 alkyl.

3. The compound according to claim 1 having Formula (II), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof,

wherein

Q is CH, N or N→O;

M is —NR 11 — or —O—; and

R 11 is H, D, C 1-6 alkyl or C 1-6 haloalkyl.

4. The compound according to claim 1 , wherein each R 1 and R 3 is independently H, D, F, Cl, Br, I, —CN, —OH, —NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 3- to 8-membered heterocyclyl, 5- to 9-membered heteroaryl or C 6-10 aryl.

5. The compound according to claim 1 , wherein each R 2 is independently F, Cl, Br, I, —CN, —OH, —NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; or two adjacent R 2 , together with the carbon atoms to which they are attached, form a substituted or unsubstituted benzene ring or 5- to 6-membered heteroaromatic ring.

6. The compound according to claim 1 , wherein each of R 5 , R 6 , R 7 and R 8 is independently H, D, F, Cl, Br, I, —CN, —NO 2 , —OH, —NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3-6 cycloalkyl;

or R 5 and R 6 , or R 7 and R 8 , together with the carbon atom to which they are attached, independently form a substituted or unsubstituted 3- to 6-membered carbocyclic ring.

7. The compound according to claim 4 , wherein each R 1 and R 3 is independently H, D, F, Cl, Br, I, —CN, —OH, —NH 2 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophen-yl or 1,4-dioxanyl.

8. The compound according to claim 5 , wherein each R 2 is independently F, Cl, Br, I, —CN, —OH, —NH 2 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy, cyclopropyl, cyclobutyl or fluorine-substituted C 1-4 alkoxy; or two adjacent R 2 , together with the carbon atoms to which they are attached, form a substituted or unsubstituted benzene ring.

9. The compound according to claim 3 , wherein each of R 4 and R 11 is independently H, D, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or tert-butyl.

10. The compound according to claim 6 , wherein each of R 5 , R 6 , R 7 and R 8 is independently H, D, F, Cl, Br, I, —OH, —NH 2 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, cyclopropyl or cyclobutyl;

or R 5 and R 6 , or R 7 and R 8 , together with the carbon atom to which they are attached, independently form a cyclopropane, cyclobutane, cyclopentane or cyclohexane.

11. A compound having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, 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, wherein the additional therapeutic agent is used as a medicament 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, SB-742457, 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 5-HT 6 receptor-mediated disease, comprising administering to a subject a therapeutically effective amount of the compound according to claim 1 , wherein the 5-HT 6 receptor-mediated disease is Alzheimer's disease, neuropathy or a combination thereof.

16. A method for treating or lessening 5-HT 6 receptor-mediated disease, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition according to claim 12 , wherein the 5-HT 6 receptor-mediated disease is Alzheimer's disease, neuropathy or a combination thereof.