IP Library Granted Patent US 8,269,019
Granted Patent B2
US 8,269,019 · App. 13/044,678 · Granted Sep 18, 2012

Inhibitors

Assignee: Probiodrug AG
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Quick Facts
Patent No.
US 8,269,019
App. No.
13/044,678
Granted
Sep 18, 2012
Kind
B2
Abstract

Novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.

Claims (116)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof wherein:

R 1 represents —C 1-6 alkyl, -aryl, —C 1-6 alkylaryl, -cycloalkyl, —C 1-6 alkylcycloalkyl, -heteroaryl, —C 1-6 alkylheteroaryl, -heterocyclyl, —C 1-6 alkylheterocyclyl, -cycloalkyl substituted by phenyl, -cycloalkyl substituted by phenoxy, -phenyl substituted by cycloalkyl, -phenyl substituted by phenoxy, -phenyl substituted by phenyl, heterocyclyl substituted by phenyl, heteroaryl substituted by phenyl, phenyl substituted by heterocyclyl, phenyl substituted by heteroaryl, phenyl substituted by —O-cycloalkyl or phenyl substituted by-cycloalkyl -heterocyclyl;

and in which any of aforesaid aryl, cycloalkyl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SOC 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, —SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl) and —C(O)NH(C 3-10 cycloalkyl);

R 2 represents —C 1-6 alkyl, C 1-6 haloalkyl, -aryl, —C 1-6 alkylaryl, -cycloalkyl, —C 1-6 alkylcycloalkyl, -heteroaryl, —C 1-6 alkylheteroaryl, -heterocyclyl or —C 1-6 alkylheterocyclyl;

and in which any of aforesaid aryl, heteroaryl or heterocyclyl groups may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SOC 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, —SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl) and —C(O)NH(C 3-10 cycloalkyl);

R 3 represents C 1-6 alkyl or C 1-6 haloalkyl;

n represents an integer selected from 0 to 3; and

R a represents C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SOC 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, —SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl) and —C(O)NH(C 3-10 cycloalkyl).

2. A compound according to claim 1 , wherein

R 1 represents —C 1-6 alkyl, -aryl, -cycloalkyl, -heteroaryl, -heterocyclyl, -cycloalkyl substituted by phenyl, -cycloalkyl substituted by phenoxy, -phenyl substituted by cycloalkyl, -phenyl substituted by phenoxy, -phenyl substituted by phenyl, heterocyclyl substituted by phenyl, heteroaryl substituted by phenyl, phenyl substituted by heterocyclyl, phenyl substituted by heteroaryl, phenyl substituted by —O-cycloalkyl or phenyl substituted by -cycloalkyl-heterocyclyl; and

any of aforesaid aryl, cycloalkyl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SOC 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, —SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynloxy-, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)NH 2 —C(O) NH(C 1-4 alkyl) and —C(O)NH(C 3-10 cycloalkyl).

3. A compound according to claim 2 , wherein R 1 represents —C 1-6 alkyl, -aryl, -cycloalkyl, -heteroaryl, -cycloalkyl substituted by phenyl, -cycloalkyl substituted by phenoxy, -phenyl substituted by cycloalkyl, -phenyl substituted by phenyl, heterocyclyl substituted by phenyl, phenyl substituted by heterocyclyl, phenyl substituted by —O-cycloalkyl or phenyl substituted by -cycloalkyl-heterocyclyl any of aforesaid aryl, cycloalkyl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SOC 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, —SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 olkyl)(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl) and —C(O)NH(C 3-10 cycloalkyl).

4. A compound according to claim 3 , wherein R 1 represents —C 1-6 alkyl, -aryl, -cycloalkyl, -heteroaryl, -phenyl substituted by phenyl, phenyl substituted by heterocyclyl or phenyl substituted by —O-cycloalkyl, wherein said phenyl group is optionally substituted by one or more halogen groups, wherein said heterocyclyl group is optionally substituted by one or more C 1-6 alkyl groups, and wherein said cycloalkyl group is optionally substituted by one or more halogen groups.

5. A compound according to claim 4 , wherein R 1 represents phenyl optionally substituted by one or more halogen groups.

6. A compound according to claim 1 , wherein

R 2 represents —C 1-6 alkyl, C 1-6 haloalkyl, -aryl, -cycloalkyl, -heteroaryl or-heterocyclyl; and

any of aforesaid aryl, heteroaryl or heterocvclvl groups may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SOC 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, —SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl) and —C(O)NH(C 3-10 cycloalkyl).

7. A compound according to claim 6 , wherein R 2 represents —C 1-6 alkyl, C 1-6 haloalkyl or -aryl; and

the aryl group may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C 1-6 thioalkyl, —SOC 1-4 alkyl, —SO 2 C 1-4 alkyl, C 1-6 alkoxy-, —O—C 3-8 cycloalkyl, C 3-8 cycloalkyl, —SO 2 C 3-8 cycloalkyl, —SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, —C(O) C 1-6 alkyl, —C(O)OC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH 2 —NHC 1-4 alkyl, —N(C 1-4 alkyl)(C 1-4 alkyl), —C(O)N(C 1-4 alkyl)(C 1-4 alkyl), —-C(O)NH 2 , —C(O)NH(C 1-4 alkyl) and —C(O)NH(C 3-10 cycloalkyl).

8. A compound according to claim 7 , wherein R 2 represents —C 1-6 alkyl or -aryl.

9. A compound according to claim 7 , wherein R 2 represents methyl, ethyl, propyl, isopropyl, trifluoromethyl or phenyl optionally substituted by one or more halogen groups.

10. A compound according to claim 9 , wherein R 2 represents methyl or unsubstituted phenyl.

11. A compound according to claim 1 , wherein R 3 represents C 1-6 alkyl.

12. A compound according to claim 1 , wherein R 3 represents C 1-6 haloalkyl.

13. A compound according to claim 1 , wherein n represents 0.

14. A compound or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers, selected from the group consisting of:

1-(1H-Benzo[d]imidazol-6- yl)-5-cyclohexyl-3-methoxy- 4-methyl-1H-pyrrol-2(5H)- one;

1-(1H-Benzo[d]imidazol-6- yl)-5-isopropyl-3-methoxy-4- methyl-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-5-(2,6-difluorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-5-(2,4,5-trifluorophenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-5-(2,3,5-trifluorophenyl)- 3-methoxy-4-phenyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(5-bromo-2- fluorophenyl)-3-methoxy-4- methyl-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2-chloro-3,6- difluorophenyl)-3-methoxy- 4-methyl-1H-pyrrol-2(5H)- one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(R)-1-(1H-Benzo[d]imidazol- 6-yl)-5-(2,3-difluorophenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(S)-1-(1H-Benzo[d]imidazol- 6-yl)-5-(2,3-difluorophenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-4-ethyl-5-(2,3- difluorophenyl)-3-methoxy- 1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-propyl-1H-pyrrol- 2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-4- isopropyl-3-methoxy-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-4-(trifluoromethyl)-5-(2,3- difluorophenyl)-3-methoxy- 1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-phenyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-4- (4-fluorophenyl)-3-methoxy- 1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-dichlorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(R)-1-(1H-Benzo[d]imidazol- 5-yl)-5-(2,3-dichlorophenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(S)-1-(1H-Benzo[d]imidazol- 5-yl)-5-(2,3-dichlorophenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5-(4- morpholinophenyl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (biphen-4-yl)-1H-pyrrol- 2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5-(4- (piperidin-1-yl)phenyl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(4- (cyclohexyloxy)phenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-3-methoxy-4-phenyl-5- (quinolin-3-yl)-1H-pyrrol- 2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(4-cyclohexylphenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-benzo[d]imidazol-6- yl)-5-(4-(4,4- difluorocyclohexyl)phenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(4-(tetrahydro-2H- pyran-4-yl)phenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5-(4- (1-methylpiperidin-4- yl)phenyl)-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5-(4-(4- morpholinocyclohexyl)- phenyl)-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5-(4- phenoxycyclohexyl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5-(1- phenylpiperidin-4-yl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5-(4- phenylcyclohexyl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-3-ethoxy-5-(2,3- difluorophenyl)-4-methyl- 1H-pyrrol-2(5H)-one;

3-(2,2,3,3- Tetrafluoropropoxy)-1-(1H- benzo[d]imidazol-5-yl)-5- (2,3-difluoro-phenyl)-4- methyl-1H-pyrrol-2(5H)-one; and

3-(2,2,2-Trifluoroethoxy)-1- (1H-benzo[d]imidazol-5-yl)- 5-(2,3-difluorophenyl)-4- methyl-1H-pyrrol-2(5H)-one.

15. A compound according to claim 1 , which is 1-(1H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound according to claim 1 , optionally in combination with one or more therapeutically acceptable diluents or carriers.

17. The pharmaceutical composition of claim 16 , which comprises additionally at least one compound, selected from the group consisting of neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

18. The pharmaceutical composition of claim 16 , which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCI, inhibitors of inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.

19. A method of treatment of:

(i) a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome and Huntington's disease; or

(ii) a disease selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis;

the method comprising administering to a subject an effective amount of a compound according to claim 1 , optionally in combination with one or more therapeutically acceptable diluents or carriers.

20. A process for preparation of a compound of formula (I) according to claim 1 , which comprises:

(a) preparing a compound of formula (I) from a compound of formula (II)

wherein R a , n, R 1 and R 2 are as defined in claim 1 ;

(b) interconversion of compounds of formula (I); and/or

(c) deprotecting a compound of formula (I) which is protected.

21. A pharmaceutical composition according to claim 16 , wherein the compound is selected from the group consisting of:

1-(1H-Benzo[d]imidazol-6- yl)-5-cyclohexyl-3-methoxy- 4-methyl-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-isopropyl-3-methoxy- 4-methyl-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-5-(2,6-difluorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-5-(2,4,5-trifluorophenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-5-(2,3,5-trifluorophenyl)- 3-methoxy-4-phenyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(5-bromo-2- fluorophenyl)-3-methoxy-4- methyl-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2-chloro-3,6- difluorophenyl)-3-methoxy- 4-methyl-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(R)-1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(S)-1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-4-ethyl-5-(2,3- difluorophenyl)-3-methoxy- 1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-propyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-4- isopropyl-3-methoxy-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-4-(trifluoromethyl)-5- (2,3-difluorophenyl)-3- methoxy-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-3- methoxy-4-phenyl-1H- pyrrol-2(5H)-one

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-difluorophenyl)-4- (4-fluorophenyl)-3-methoxy- 1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(2,3-dichlorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(R)-1-(1H-Benzo[d]imidazol-5- yl)-5-(2,3-dichlorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

(S)-1-(1H-Benzo[d]imidazol-5- yl)-5-(2,3-dichlorophenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (4-morpholinophenyl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (biphen-4-yl)-1H-pyrrol- 2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (4-(piperidin-1-yl)phenyl)- 1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(4-(cyclohexyloxy)- phenyl)-3-methoxy-4-methyl- 1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-3-methoxy-4-phenyl-5- (quinolin-3-yl)-1H-pyrrol- 2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(4-cyclohexylphenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-benzo[d]imidazol-6- yl)-5-(4-(4,4- difluorocyclohexyl)phenyl)- 3-methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-5-(4-(tetrahydro-2H- pyran-4-yl)phenyl)-3- methoxy-4-methyl-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (4-(1-methylpiperidin-4- yl)phenyl)-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (4-(4-morpholinocyclohexyl)- phenyl)-1H-pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (4-phenoxycyclohexyl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (1-phenylpiperidin-4-yl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-6- yl)-3-methoxy-4-methyl-5- (4-phenylcyclohexyl)-1H- pyrrol-2(5H)-one;

1-(1H-Benzo[d]imidazol-5- yl)-3-ethoxy-5-(2,3- difluorophenyl)-4-methyl- 1H-pyrrol-2(5H)-one;

3-(2,2,3,3- Tetrafluoropropoxy)-1-(1H- benzo[d]imidazol-5-yl)-5- (2,3-difluoro-phenyl)-4- methyl-1H-pyrrol-2(5H)- one; and

3-(2,2,2-Trifluoroethoxy)-1- (1H-benzo[d]imidazol-5-yl)- 5-(2,3-difluorophenyl)-4- methyl-1H-pyrrol-2(5H)- one.

22. A compound according to claim 5 , wherein R 1 represents 2,3-difluorophenyl.

23. A compound according to claim 11 , wherein R 3 represents methyl.

24. A compound according to claim 12 , wherein R 3 represents 2,2,2-trifluoroethyl or 2,2,3,3-tetrafluoropropyl.

25. A method of treatment according to claim 19 , wherein the disease is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome and Huntington's disease.

26. A method of treatment according to claim 19 , wherein the disease is selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.

Assignments (3)
CHANGE OF NAME Recorded Oct 27, 2021
From: PROBIODRUG AG
To: VIVORYON THERAPEUTICS AG
Reel/Frame 057928/0117 →
CHANGE OF NAME Recorded Oct 27, 2021
From: VIVORYON THERAPEUTICS AG
To: VIVORYON THERAPEUTICS N.V.
Reel/Frame 058250/0641 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 13, 2011
From: HEISER, ULRICH; GAERTNER, ULF-TORSTEN; DEMUTH, HANS-ULRICH
To: PROBIODRUG AG
Reel/Frame 026276/0531 →
Continuity (2)
Provisional Application 61312339 · Mar 10, 2010
Related Publication 20110224254A1 · Sep 15, 2011