Substituted dihydrobenzofuran glycosidase inhibitors

1. A compound of formula (I)

wherein

R is straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH;

W is CH or N;

X is N or CR′″;

R′, R″ denote each independently H, Hal or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein at least one of R′ and R″ is different from H;

R′″ denotes 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′ ), 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 or NO 2 or by one of the following groups:

 or R′″ denotes one of the following groups:

R 3 , R 4 denote each independently H or a straight chain or branched alkyl group having 1 to 12 carbon atoms;

Q denotes one of the following groups:

Y is N or CR′″;

Z 1 is S, O, NR 3 ;

Z 2 , Z 3 independently denote CR 5 or N;

Z 4 is N, CH, CON, COCH;

Z 5 is NR 8 , CHR 5 , S(O)(NR 3′ ), N(SO)R 3′ ,

Z 6 is CH 2 , CO, SO 2 , S(O)(NR 3′ ), N(SO)R 3′ ,

Z 7 is C(R 3′ ) 2 , S, O, NR 3′ ;

s denotes 0 or 1;

T is N, CH or CR 7 ;

R 3′ denotes 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, O and wherein 1 to 5 hydrogen atoms may be replaced by Hal;

R 5 , R 6 , R 7 independently denote H, Hal, 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′ ), 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 3 , Het, Ar, Cyc, or by one of the following groups:

 or R 5 , R 6 , R 7 denote Ar, Het or Cyc or one of the following groups:

R 8 denotes 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′ ), N(SO)R 3′ , CO, COO, OCO, CONR 3 , NR 3 CO, and

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 by one of the following groups:

 or R 8 denote one of the following groups:

Hal denotes F, Cl, Br or I;

Het denotes 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 denotes a 6-membered carbocyclic aromatic ring or a fused or non-fused bicylic aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R 5 , OR 3 and Hal;

Cyc denotes 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 or Hal or OH;

m and n denote independently from one another 0, 1, 2 or 3,

t and q denote independently from one another 0, 1, 2 or 3, with t+q≥1;

and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms are replaced by D (deuterium).

2. A compound chosen from the group consisting of formula Ia and Ib:

wherein R, R′, R″, X, W, Q, n and m have the meaning given in claim 1 .

3. A mixture comprising compounds Ia and Ib according to claim 2 , having identical groups R, R′, R″, X, W, Q, n and m in equal or unequal amounts.

4. A compound of formula I according to claim 1 , wherein R is methyl and/or W is N.

5. A compound of formula I according to claim 1 , wherein the groups X denote both simultaneously CH.

6. A compound of formula I according to claim 1 , wherein Q denotes one of the following groups:

wherein T, Y, Z 5 , Z 6 , R′″, 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 5 , R 6 , R 7 are independently selected from H, 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 , N(SO)R 3 ′CH 3 , N(SO)R 3 ′CH 2 CH 3 , N(SO)R 3 ′CH 2 CH 2 OH, N(SO)R 3 ′CH 2 CH 2 OCH 3 , Hal, NR 3 R 4 , NO 2 , phenyl, 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, alkoxy (Oalkyl), hydroxyalkylen, alkoxyalkylen, COOH, COOalkyl, CONHalkyl, CONH 2 , CON(CH 3 ) 2 , NHCOalkyl, 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 and a group

wherein t+q is 2 or 3, Z 7 , R 3 , R 4 and R 3 ′ have the meaning given in claim 1 .

8. A compound of formula Ic

wherein R, R′, W, Q, n and m have the meaning given in claim 1 .

9. A compound of formula I according to claim 1 , wherein m and n simultaneously denote 1.

10. A compound according to claim 1 , selected from the following group:

Configuration

No

Structure

specification

1

Racemic

2

Racemic

3

Racemic

4

Racemic

5

Racemic

6

Racemic

7

Racemic

8

Racemic

9

Synthesized from (R)-propane-1,2- diol

10

Synthesized from (R)-propane-1,2- diol

11

Chiral SFC Method A: 1st eluting compound

12

Chiral SFC Method A: 2nd eluting compound

13

Chiral SFC Method A: 1st eluting compound

14

Synthesized from (S)-propane-1,2- diol

15

Synthesized from (S)-propane-1,2- diol

16

Chiral SFC Method B: 1st eluting compound

17

Chiral SFC Method B: 2nd eluting compound

18

Chiral SFC Method C: 1st eluting compound

19

Synthesized from (R)-propane-1,2- diol

20

Synthesized from (R)-propane-1,2- diol

21

Synthesized from (R)-propane-1,2- diol

and/or and pharmaceutically usable derivatives, solvates, salts, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios.

11. A compound of formula (I) according to claim 1 for use as a medicament.

12. A compound of formula (I) according to claim 1 and pharmaceutically usable derivatives, solvates, salts, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios for use in a treatment of a condition selected from neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke.

13. A compound for use in a treatment of a condition according to claim 12 , wherein the condition is selected from the group of one or more tauopathies and Alzheimer's disease, Dementia, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain disease, Behavioural variant frontomeporal dmenetia (BvFTD), Bluit disease, Chronic traumatic encephalopathy, Corticobasal degeneration (CBP), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobar degeneration (FTLD), Ganglioglioma, Gangliocytoma, Gerstmann-Straussler-Scheinker disease, Globular glia tauopathy, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), Lead encephalopathy, Lipofuscinosis, Meningioangiomatosis, Multiple system atrophy, Myotonic dystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick's disease (PiD), Parkinson's disease dementia, Postencephalitic parkinsonism (PEP), Primary progressive aphasia, Prion diseases (including Creutzfeldt-Jakob Disease (GJD), Progressive nonfluent aphasia, Variant Creutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, Kuru, Progressive supercortical gliosis, Progressive supranuclear palsy (PSP), Semantic dementia, Steele-Richardson-Olszewski syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, Tuberous sclerosis, Huntington's disease and Parkinson's disease, preferably one or more tauopathies and Alzheimer's disease.

14. A method for treating a tauopathy, wherein a compound defined in claim 1 is administered to a mammal in need of such treatment.

15. A method for inhibiting a glycosidase, wherein a system expressing the glycosidase is contacted with a compound as defined in claim 1 under in-vitro conditions such that the glycosidase is inhibited.

16. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 together with pharmaceutically tolerable adjuvants and/or excipients, optionally in combination with one or more further active ingredients.