Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
View Patent ↗Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
1. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is a 5- to 14-membered heteroaryl containing 1-3 heteroatoms;
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 6 alkenyl; wherein said alkyl, cycloalkyl or alkenyl is optionally substituted with one to three substituents each independently selected from the group consisting of fluoro, hydroxy and C 1 -C 6 alkoxy;
A is a C 3 -C 6 cycloalkyl or a 4- to 10-membered heterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of halogen and C 1 -C 6 alkyl;
R 2a and R 2b for each occurrence is independently hydrogen, fluoro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 8 bicycloalkyl, C 2 -C 6 alkynyl or phenyl; wherein said alkyl, alkenyl, cycloalkyl, bicycloalkyl, alkynyl or phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, C 1 -C 3 alkyl and fluoro; or R 2a and R 2b together with the carbon to which they are bonded form a 3- to 5-membered cycloalkyl optionally substituted with one to three of R 8 ;
R 3 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(C(R 10 ) 2 ) t —(C 3 -C 6 cycloalkyl), —(C(R 10 ) 2 ) t -(4- to 10-membered heterocycloalkyl), —(C(R 10 ) 2 )t—( C6 6 -C 10 aryl), —(C(R 10 ) 2 ) t -(5- to 10-membered heteroaryl) or —(C(R 10 ) 2 ) t —OR 12 ; wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to five of R 11 ;
R 4a and R 4b are each independently hydrogen, or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro;
R 5a and R 5b for each occurrence are each independently hydrogen, or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro;
R 6 , R 7 and R 8 are each independently hydrogen, —CF 3 , cyano, halogen, C 1 -C 6 alkyl, or —OR 9 ; provided that R 6 and R 7 cannot both be —OH;
R 9 is hydrogen, or C 1 -C 6 alkyl; wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro;
each R 10 is independently hydrogen, halogen, cyano, C 1 -C 6 alkyl, or —SF 5 ; wherein said alkyl is optionally substituted with one to three fluoro;
each R 11 is independently hydrogen, halogen, —SF 5 , —Si(CH 3 ) 3 , OR 12 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C(R 10 ) 2 ) t —(C 3 -C 6 cycloalkyl), —(C(R 10 ) 2 ) t —(C 6 -C 10 aryl) or —(C(R 10 ) 2 ) t -(5- to 10-membered heteroaryl) wherein said —Si(CH 3 ) 3 , alkyl, alkenyl alkynyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to five substituents each independently selected from the group consisting of halogen and —CF 3 ;
each R 12 is hydrogen, C 1 -C 6 alkyl, —(C(R 13 ) 2 ) n —(C 3 -C 6 cycloalkyl), —(C(R 13 ) 2 ) n -(4- to 10-membered heterocycloalkyl), —(C(R 13 ) 2 ) n —(C 6 -C 10 aryl), or —(C(R 13 ) 2 ) n -(5- to 10-membered heteroaryl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to five of R 14 ;
each R 13 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, —CF 3 , or —OCF 3 ;
R 14 is independently hydrogen, —CF 3 , cyano, halogen or C 1-6 alkyl; wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of hydroxy, cyano and fluoro;
each t or n is an integer independently selected from 0, 1, 2 or 3;
each z is 1; and
each y is an integer independently selected from 0, 1, 2, 3 or 4.
2. The method according to claim 1 , wherein A is dihydroisoxazolyl, tetrahydrofuranyl or tetrahydropyranyl, or a pharmaceutically acceptable salt thereof.
3. The method according to claim 2 , wherein A is tetrahydrofuranyl, or a pharmaceutically acceptable salt thereof.
4. The method according to claim 2 , wherein A is tetrahydropyranyl, or a pharmaceutically acceptable salt thereof.
5. The method according to claim 4 , wherein R 3 is —(C(R 10 ) 2 ) t —(C 6 -C 10 aryl) or —(C(R 10 ) 2 ) t —OR 12 ; and t is 0 or 1, or a pharmaceutically acceptable salt thereof.
6. The method according to claim 5 , wherein R 3 is —(C(R 10 ) 2 ) t —(C 6 -C 10 aryl); t is 0; and said aryl is phenyl optionally substituted with one to three R 11 , wherein R 11 is selected from the group consisting of fluoro, chloro, —SF 5 , OR 12 , C 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl; wherein said alkyl or said cycloalkyl is optionally and independently substituted with one to three substituents selected from the group consisting of halogen and —CF 3 or a pharmaceutically acceptable salt thereof.
7. The method according to claim 5 , wherein R 3 is —(C(R 10 ) 2 ) t —OR 12 ; t is 0; and R 12 is selected from phenyl, naphthyl or dihydroindenyl; wherein said phenyl, naphthyl or dihydroindenyl is optionally and independently substituted with one to three R 14 selected from the group consisting of fluoro, chloro, and C 1 -C 3 alkyl; wherein said alkyl may be independently substituted with one to three halogen, or a pharmaceutically acceptable salt thereof.
8. The method according to claim 1 wherein R 3 is —(C(R 10 ) 2 ) t -(5- to 10-membered heteroaryl); t is 0; and said heteroaryl is thiophenyl optionally substituted with one to three R 11 , wherein R 11 is selected from the group consisting of fluoro, chloro and, —CF 3 or a pharmaceutically acceptable salt thereof.
9. The method according to claim 1 , wherein X is imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl or pyridyl; and R 1 is C 1 -C 6 alkyl, or a pharmaceutically acceptable salt thereof.
10. The method according to claim 1 , wherein X is imidazolyl; and R 1 is methyl, or a pharmaceutically acceptable salt thereof.
11. The method according to claim 1 , wherein R 4a and R 4b are independently hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
12. The method according to claim 1 , wherein R 5a , R 5b , R 6 , and R 7 are independently hydrogen, or a pharmaceutically acceptable salt thereof.
13. The method according to claim 1 , wherein y is 0 or 1; and R 2a and R 2b are independently hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
14. The method according to claim 1 , wherein A is cyclobutyl, cyclopentyl, or cyclohexyl, or a pharmaceutically acceptable salt thereof.
15. The method according to claim 1 , wherein the subject is a human.
16. The method according to claim 1 , wherein said compound is:
7-(4-methyl-1H-imidazol-1-yl)-2-[(1S)-1-{(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-[(1S)-1-{(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{(1S)-1-[(2S,5R)-5-(4-chloro-3,5-difluorophenyl)tetrahydrofuran-2-yl]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-[(1S)-1-{(2S,5R)-5-[4,5-difluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-[(1S)-1-{(2S,5R)-5-[4-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-[(1S)-1-{(2S,5R)-5-[4-chloro-5-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; or
2-[(1S)-1-{(2S,5R)-5-[4-chloro-3-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
17. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of a compound of Formula Id, or a pharmaceutically acceptable salt thereof:
wherein:
R 2 is hydrogen or methyl; R 3 is —(C(R 10 ) 2 ) t —(C 6 -C 10 aryl) or —(C(R 10 ) 2 ) t —(5- to 10-membered heteroaryl), wherein said aryl or heteroaryl is optionally substituted with one to three R 11 independently selected from the group consisting of fluoro, chloro, methyl, —CF 3 , —SF 5 , —OCH 3 , —OCF 3 , —CF 2 (CH 3 ) and —OCHF 2 ; R 10 is independently hydrogen, halogen, cyano, C 1 -C 6 alkyl, or —SF 5 ; wherein said alkyl is optionally substituted with one to three fluoro; and t is 0 or 1.
18. The method according to claim 17 , or a pharmaceutically acceptable salt thereof, wherein t is 0; and R 3 is phenyl optionally substituted with one to three R 11 independently selected from the group consisting of fluoro, chloro, —CF 3 , —SF 5 , —OCH 3 , —OCF 3 , —CF 2 (CH 3 ) and —OCHF 2 .
19. The method according to claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 3 is thiophenyl optionally substituted with one to three R 11 independently selected from the group consisting of fluoro, chloro, —CF 3 , —SF 5 , —OCH 3 , —OCF 3 , —CF 2 (CH 3 ) and —OCHF 2 .
20. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4-chloro-5-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
21. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydro-furan-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
22. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of 2-{(1S)-1-[(2S,5R)-5-(4-chloro-3,5-difluorophenyl)tetrahydrofuran-2-yl]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
23. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]-tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
24. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
25. A method of reducing the production of amyloid beta proteins in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4,5-difluoro-2-(trifluoromethyl)phenyl]-tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
26. A method for treating Alzheimer's disease in a subject, comprising:
administering to said subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is a 5- to 14-membered heteroaryl containing 1-3 heteroatoms;
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 6 alkenyl; wherein said alkyl, cycloalkyl or alkenyl is optionally substituted with one to three substituents each independently selected from the group consisting of fluoro, hydroxy and C 1 -C 6 alkoxy;
A is a C 3 -C 6 cycloalkyl or a 4- to 10-membered heterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of halogen and C 1 -C 6 alkyl;
R 2a and R 2b for each occurrence is independently hydrogen, fluoro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 8 bicycloalkyl, C 2 -C 6 alkynyl or phenyl; wherein said alkyl, alkenyl, cycloalkyl, bicycloalkyl, alkynyl or phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, C 1 -C 3 alkyl and fluoro; or R 2a and R 2b together with the carbon to which they are bonded form a 3- to 5-membered cycloalkyl optionally substituted with one to three of R 8 ;
R 3 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(C(R 10 ) 2 ) t —(C 3 -C 6 cycloalkyl), —(C(R 10 ) 2 ) t -(4- to 10-membered heterocycloalkyl), —(C(R 10 ) 2 ) t —(C 6 -C 10 aryl), —(C(R 10 ) 2 ) t -(5- to 10-membered heteroaryl) or —(C(R 10 ) 2 ) t —OR 12 ; wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to five of R 11 ;
R 4a and R 4b are each independently hydrogen, or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro;
R 5a and R 5b for each occurrence are each independently hydrogen, or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro;
R 6 , R 7 and R 8 are each independently hydrogen, —CF 3 , cyano, halogen, C 1 -C 6 alkyl, or —OR; provided that R 6 and R 7 cannot both be —OH;
R 9 is hydrogen, or C 1 -C 6 alkyl; wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro;
each R 10 is independently hydrogen, halogen, cyano, C 1 -C 6 alkyl, or —SF 5 ; wherein said alkyl is optionally substituted with one to three fluoro;
each R 11 is independently hydrogen, halogen, —SF 5 , —Si(CH 3 ) 3 , OR 12 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl,C 2 -C 6 alkynyl, —(C(R 10 ) 2 ) t —(C 3 -C 6 cycloalkyl), —(C(R 10 ) 2 ) t —(C 6 -C 10 aryl) or —(C(R 10 ) 2 ) t -(5-to 10-membered heteroaryl) wherein said —Si(CH 3 ) 3 , alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to five substituents each independently selected from the group consisting of halogen and —CF 3 ;
each R 12 is hydrogen, C 1 -C 6 alkyl, —(C(R 13 ) 2 ) n —(C 3 -C 6 cycloalkyl), —(C(R 13 ) 2 ) n -(4- to 10-membered heterocycloalkyl), —(C(R 13 ) 2 ) n —(C 6 -C 10 aryl), or —(C(R 13 ) 2 ) n -(5- to 10-membered heteroaryl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to five of R 14 ;
each R 13 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, —CF 3 , or —OCF 3 ;
R 14 is independently hydrogen, —CF 3 , cyano, halogen or C 1-6 alkyl; wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of hydroxy, cyano and fluoro;
each t or n is an integer independently selected from 0, 1, 2 or 3;
each z is 1; and
each y is an integer independently selected from 0, 1, 2, 3 or 4.
27. A method for treating Alzheimer's disease in a subject, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4-chloro-5-fluoro-2-(trifluoromethyl)phenyl]-tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
28. A method for treating Alzheimer's disease in a subject, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
29. A method for treating Alzheimer's disease in a subject, comprising:
administering to said subject a therapeutically effective amount of 2-{(1S)-1-[(2S,5R)-5-(4-chloro-3,5-difluorophenyl)tetrahydrofuran-2-yl]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
30. A method for treating Alzheimer's disease in a subject, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[3, 5-difluoro-4-(trifluoromethyl)phenyl]-tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
31. A method for treating Alzheimer's disease in a subject, comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
32. A method for treating Alzheimer's disease in a subject comprising:
administering to said subject a therapeutically effective amount of 2-[(1S)-1-{(2S,5R)-5-[4 ,5-difluoro-2-(trifluoromethyl)phenyl]-tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.