Sulfone compounds and pharmaceutical compositions thereof, and their therapeutic applications
Provided herein are sulfone compounds, for example, a compound of Formula A, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.
1 . A method of inhibiting the production of amyloid β in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound chosen from compounds of Formula I(a) and pharmaceutically acceptable salts thereof:
wherein, in Formula I(a):
X is —SO 2 —;
Y is —CH 2 — or —NH—;
R 3 and R 5 are independently chosen from hydrogen, —NR 1a S(O) 2 R 1d , —C(R A )—, optionally substituted C 1-6 alkyl, and optionally substituted C 1-6 alkoxy, with the proviso that if R 3 or R 5 is optionally substituted C 1-6 alkyl or optionally substituted C 1-6 alkoxy, the substituent(s) are fluoro;
R A is —S(O) 2 R 1a ; and
R 1a , R 1d , R 2 , R 4 , and R 6 are independently chosen from hydrogen and C 1-6 alkyl.
2 . The method of claim 1 , wherein the amyloid β is amyloid β40 or amyloid β42.
3 . The method according to claim 1 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is substituted C 1-6 alkyl.
4 . The method according to claim 1 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is trifluoromethyl.
5 . The method according to claim 1 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are C 1-6 alkoxy.
6 . The method according to claim 1 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are methoxy.
7 . The method according to claim 1 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is substituted C 1-6 alkyl.
8 . The method according to claim 1 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is trifluoromethyl.
9 . The method according to claim 1 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are C 1-6 alkoxy.
10 . The method according to claim 1 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are methoxy.
11 . The method according to claim 1 , wherein:
Y is —NH—;
R 2 is —NR 1a S(O) 2 R 1d ; and
R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen.
12 . The method according to claim 1 , comprising administering a composition comprising a compound of Formula I(a) and at least one pharmaceutically acceptable excipient to said subject.
13 . A method of inhibiting the production of amyloid β in a cell, the method comprising contacting said cell with an effective amount of a compound chosen from compounds of Formula I(a) and pharmaceutically acceptable salts thereof:
wherein, in Formula I(a):
X is —SO 2 —;
Y is —CH 2 — or —NH—;
R 3 and R 5 are independently chosen from hydrogen, —NR 1a S(O) 2 R 1d , —C(R A )—, optionally substituted C 1-6 alkyl, and optionally substituted C 1-6 alkoxy, with the proviso that if R 3 or R 5 is optionally substituted C 1-6 alkyl or optionally substituted C 1-6 alkoxy, the substituent(s) are fluoro;
R A is —S(O) 2 R 1a ; and
R 1a , R 1d , R 2 , R 4 , and R 6 are independently chosen from hydrogen and C 1-6 alkyl.
14 . The method of claim 13 , wherein the amyloid β is amyloid β36, amyloid β37, amyloid β38, amyloid β39, amyloid β40, amyloid β41, amyloid β42, amyloid β 43, amyloid β44, amyloid β45, amyloid β46, amyloid β47, amyloid β48, amyloid β49, amyloid β50, amyloid β51, amyloid β52, or a combination of two or more thereof.
15 . The method according to claim 13 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is substituted C 1-6 alkyl.
16 . The method according to claim 13 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is trifluoromethyl.
17 . The method according to claim 13 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are C 1-6 alkoxy.
18 . The method according to claim 13 , wherein:
Y is —CH 2 —;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are methoxy.
19 . The method according to claim 13 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is substituted C 1-6 alkyl.
20 . The method according to claim 13 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
one of R 3 and R 5 is trifluoromethyl.
21 . The method according to claim 13 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are C 1-6 alkoxy.
22 . The method according to claim 13 , wherein:
Y is —NH—;
R 2 , R 4 , and R 6 are independently chosen from hydrogen and methyl; and
R 3 and R 5 are methoxy.
23 . The method according to claim 13 , wherein:
Y is —NH—;
R 2 is —NR 1a S(O) 2 R 1d ; and
R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen.