Spiro compounds as glycosidase inhibitors
Compounds of formula (I), wherein A, R, L, Z, Q 1 , Q 2 and n have the meaning according to the claims, can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
1. A compound of formula (I)
wherein
R is a straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH;
L is NR 3′ or N(CH 2 ) n Z;
Q 1 is CH 2 or CO;
Q 2 is CH 2 or CO;
n is 0, 1, or 2;
A is:
X is N or CR′″;
X a is N, NR 3 , C, or CR′″;
X b is N or C;
Z 1 is S, O, NR 3 ;
Y is O, S, SO, or SO 2 ;
R′, R″ are, independently H, Hal, or straight chain or branched alkyl having 1 to 12 carbon atoms;
R′″, R″″ are, independently, H, Hal, CF 3 , OCF 3 , NR 3 R 4 , CHR 3 R 4 , OR 3 , CN or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , S(O)(NR 3′ ), N(SO)R 3′ , CO, COO, OCO, CONR 3 , NR 3 CO,
and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , NO 2 :
or R′″, R″″ are, independently:
Z 7 is C(R 3′ ) 2 , S, O, or NR 3′ ;
R 3 and R 4 are, independently, H, or a straight chain or branched alkyl group having 1 to 12 carbon atoms;
R 3a is a straight chain or branched alkyl group having 1 to 12 carbon atoms;
s is 0 or 1;
R 3′ is H, or a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from SO 2 , CO, and O, and wherein 1 to 5 hydrogen atoms may be replaced by Hal;
Z is Ar, Het, Cyc,
Hal is F, Cl, Br, or I;
Het is a saturated, unsaturated or aromatic ring, being monocyclic or bicyclic or fused bicyclic and having 3 to 8 members and containing 1 to 4 heteroatoms selected from N, O, and S, which may be substituted by 1 to 3 substituents selected from R′″, Hal, and OR 3 ;
Ar is a 6-membered carbocyclic aromatic ring or a fused or non-fused bicyclic aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R′″, OR 3 , and Hal;
Cyc is a saturated or an unsaturated carbocyclic ring having from 3 to 8 carbon atoms which is optionally substituted by 1 to 3 substituents independently selected from R′″, Hal, and OH;
t and q are, independently, 0, 1, 2, or 3, with t+q≥1;
or a pharmaceutically acceptable salt, tautomer, enantiomer, racemate, stereoisomer, compound of formula (I) wherein one or more H atoms are replaced by D (deuterium), or any mixture thereof in any ratio.
2. A compound selected from the group consisting of formula Ia, Ib, Ie, If, Ig, and Ih:
wherein A, R, L, Q 1 , Q 2 , Z and n have the meaning given in claim 1 .
3. A mixture comprising: (i) compounds of formula Ia and Ib of claim 2 ; (ii) compounds of formula Ie and If of claim 2 ; or (iii) compounds of formula Ig and Ih of claim 2 ; having identical groups A, R, L, Q 1 , Q 2 , Z and n; wherein the two compounds are present in the mixture in equal or unequal amounts.
4. The compound of claim 1 , wherein R is methyl.
5. The compound of claim 1 , wherein A is:
wherein R 3 , X, R′, R″ and R′″ have the meaning given in claim 1 .
6. The compound of claim 1 , wherein Z is selected from the group consisting of:
wherein X, R 3 and R′″ have the meaning given in claim 1 .
7. The compound of claim 1 , wherein R′″ is H, CH 3 , Hal, CN, OCF 3 , CF 3 , or SO 2 CH 3 .
8. The compound of claim 1 , wherein Q 2 is CO.
9. The compound of claim 1 , wherein n is 0 or 1.
10. The compound of claim 1 , wherein the compound is:
No.
Structure
4
5
8
9
10
11
12
13
22
23
24
30
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
70
74
75
76
77
or a pharmaceutically acceptable salt, tautomer, enantiomer, racemate, or stereoisomer thereof, including mixtures thereof in all ratios.
11. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 together with pharmaceutically tolerable adjuvants and/or excipients.
12. The pharmaceutical composition of claim 11 , further comprising one or more additional active ingredients.
13. A compound, wherein the compound is:
No.
Structure
1
2
3
6
7
or a pharmaceutically acceptable salt, tautomer, enantiomer, racemate, or stereoisomer thereof, including mixtures thereof in all ratios.
14. A pharmaceutical composition comprising as active ingredient a compound according to claim 13 together with pharmaceutically tolerable adjuvants and/or excipients.
15. The pharmaceutical composition of claim 14 , further comprising one or more additional active ingredients.