Tetrahydro-benzoazepine glycosidase inhibitors
Compounds of formula (I′), wherein A, R 1 , R 2 , T 1 , T 2 , T 3 , T 4 , L, W, Z, R′″, m 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 1 and R 2 are independently 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; or
one of R 1 and R 2 is H, while the other 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; or
R 1 and R 2 may both be H, if A is:
Z is H, OR 3 , OCF 3 , Hal, or a straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OR 3 ;
T 1 , T 2 , T 3 and T 4 are independently CR′″ or N;
L is a single bond, O, NR 3′ , CH 2 , OCH 2 , CH 2 CH 2 , CONR 3′ , CONR 3′ CH 2 , NR 3′ CO, NR 3′ COCH 2 , SO 2 NR 3′ , NR 3′ SO 2 , CONR 3′ CH 2 , CH 2 CONR 3′ , SO 2 NR 3′ CH 2 , CH 2 SO 2 NR 3′ , CH 2 NR 3′ CO, NR 3′ SO 2 CH 2 , CH 2 NR 3′ SO 2 , CH 2 O, S(O)(NR 3′ ), NS(O)R 3′ ,
m and n are 0, 1, or 2, wherein m+n is 2;
A is:
X is N or CR′″;
X a is N, NR 3 , C, or CR′″;
X b is N or C;
Y is O, S, SO, or SO 2 ;
R′ and R″ are independently H, Hal, or straight chain or branched alkyl having 1 to 12 carbon atoms;
R′″ and R″″ are independently H, Hal, 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′ ), NS(O)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′″ and R″″ are independently
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;
W is Q or R;
Q is:
H,
Z 1 is S, O, or NR 3 ;
Z 2 and Z 3 are independently CR 5 , CR 6 , or N;
Z 4 is N, CH, CON, or COCH;
Z 5 is O, NR 8 , CHR 5 , SO 2 , S(O)(NR 3′ ), NS(O)R 3′ ,
Z 6 is CH 2 , CO, S(O)(NR 3′ ), NS(O)R 3′ ,
Z 7 is C(R 3′ ) 2 , S, O, or NR 3′ ;
s is 0 or 1;
T is N, CH, or CR 7 ;
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;
R, R 5 , R 6 and R 7 are independently H, Hal, CN, OH, NR 3 R 4 , NO 2 , 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′ ), NS(O)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 3 , Het, Ar, Cyc,
or R, R 5 , R 6 and R 7 are independently Ar, Het, Cyc,
R 8 is H or 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 SO, SO 2 , S(O)(NR 3′ ), NS(O)R 3′ , CO, COO, OCO, CONR 3 , NR 3 CO,
and further wherein 1 to 5 hydrogen atoms may be replaced by CN, OR 3 , SR 3 , Hal, NR 3 R 4 , NO 2 ,
or R 8 is:
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 5 , 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 5 , 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 5 , Hal, and OH; and
t and q are independently 0, 1, 2, or 3, with t+q≥1,
or a solvate, salt, tautomer, enantiomer, racemate, stereoisomer thereof, including mixtures thereof in all ratios, or a compound of formula I wherein one or more H atoms are replaced by D (deuterium).
2. A compound selected from the group of formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih:
wherein A, W, L, T 1 , T 2 , T 3 , T 4 , R′″, m and n have the meaning given in claim 1 and wherein R 1 and R 2 are independently 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.
3. A mixture comprising compounds of formulae Ia and Ic or a mixture comprising compounds of formulae Ib and Id or a mixture comprising compounds of formulae Ie and If or a mixture comprising compounds of formulae Ig and Ih according to claim 2 , having identical groups A, W, L, R 1 , R 2 , T 1 , T 2 , T 3 , T 4 , R′″, m and n, in equal or unequal amounts.
4. A compound of formula (I′) according to claim 1 , wherein R 1 is methyl and R 2 is H; or R 1 and R 2 are both methyl.
5. A compound of formula (I′) according to claim 1 , wherein A is:
wherein R 3 , X, R′, R″ and R′″ have the meaning given in claim 1 .
6. A compound of formula (I′) according to claim 1 , wherein the group Q is
wherein X, R′″, R 3 , T, Z 5 , Z 6 , R 5 , R 6 , R 7 , and R 8 have the meaning given in claim 1 .
7. A compound of formula (I′) according to claim 1 , wherein R, R 5 , R 6 , R 7 are independently selected from H, CN, SO 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 CH 2 CH 2 OH, SO 2 CH 2 CH 2 OCH 3 , S(O)(NR 3′ )CH 3 , S(O)(NR 3′ )CH 2 CH 3 , S(O)(NR 3′ )CH 2 CH 2 OH, S(O)(NR 3′ )CH 2 CH 2 OCH 3 , NS(O)R 3′ CH 3 , NS(O)R 3′ CH 2 CH 3 , NS(O)R 3′ CH 2 CH 2 OH, NS(O)R 3′ CH 2 CH 2 OCH 3 , Hal, NR 3 R 4 , NO 2 , phenyl, benzyl, CH 2 -pyridyl, O-phenyl, O-pyridyl, O-pyrimidinyl, O-benzyl, 2-,3- or 4-hydroxy or methoxyphenyl, alkyl, alkoxy (Oalkyl), hydroxyalkylene, alkoxyalkylene, COOH, COOalkyl, CONHalkyl, CONH 2 , CON(CH 3 ) 2 , NHCOalkyl, NHCOCH 3 , NHCOphenyl, NHCOpyridyl, NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCOCH 2 CH 2 OH, CO—N-morpholinyl, CON(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , CO-1-piperidinyl, CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl, CH 2 —N-morpholinyl, CH 2 N(H)COCH 3 , CH 2 N(CH 3 )COCH 3 , CH 2 NH 2 , NH 2 , CH(OH)CH 3 , CH(OR 3 )CH 3 ,
wherein t+q is 2 or 3,
and Z 7 , R 3′ , R 3 and R 4 have the meaning given in claim 1 .
8. A compound of formula (I′) according to claim 1 , wherein L is a single bond or O.
9. A compound of formula (I′) according to claim 1 , wherein m and n are both 1.
10. A compound according to claim 1 , wherein the compound is:
No
Structure
1
4
7
10
11
12
13
14
15
16
17
18
19
20
23
24
25
26
28
29
30
31
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
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
116
117
120
121
122
123
124
125
126
127
128
129
130
131
132
133
or a solvate, salt, tautomer, enantiomer, racemate, or stereoisomer thereof, including mixtures thereof in all ratios.
11. A pharmaceutical composition comprising as an active ingredient a compound of formula (I′) as recited in 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.