Pyrazine derivatives and use as PI3K inhibitors
The present invention is related to pyrazine derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung injuries.
1. A compound according to Formula (I),
wherein:
A is nitrogen and B, D and E are carbon; or A, B and E are carbon and D is nitrogen;
R l is H, halogen, nitro, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl;
R 2 is H, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl;
R 3 is H, halo, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted heteroaryl;
R 4 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl C 1 -C 6 -alkyl, optionally substituted heteroaryl C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 cycloalkyl optionally substituted C 1 -C 6 -alkyl, optionally substituted heterocycloalkyl C 1 -C 6 -alkyl, optionally substituted aryl C 2 -C 6 -alkenyl or optionally substituted heteroaryl C 2 -C 6 -alkenyl;
n is an integer selected from 0, 1, 2, 3 and 4;
an optionally substituted group is substituted with from 1 to 5 substituent's selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 1 -Co-alkyl heterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, aryl, carbamate, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro;
with the first proviso that when R 4 is thiophenyl, it is not selected from the group consisting of: unsubstituted thiophenyl, unsubstituted chloro-5-thiophenyl and unsubstituted bromo-5thiophenyl; with the second proviso that when R 4 is a phenyl, it is a mono-substituted phenyl that is not selected from the group consisting of: p-bromo phenyl; p-methoxy phenyl; p- ethoxy phenyl; o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro phenyl; o-CF3- phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and p-amino phenyl; or it is a multi-substituted phenyl, that is not an unsubstituted bi-substituted phenyl selected from the group consisting of:
m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-, p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl; m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro phenyl and o-ethoxy m-bromo phenyl;
with the final proviso that wherein R 4 is a 1,4 benzodioxin it is a substituted benzodioxin;
or an optically active form or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 1 is H or halogen.
3. The compound according to claim 1 , wherein R 2 is methyl or substituted methyl.
4. The compound according to claim 1 , wherein R 3 is H, alkoxy or substituted alkoxy.
5. The compound according to claim 1 , wherein R 3 is halo, optionally substituted aryl or optionally substituted heteroaryl.
6. The compound according to claim 1 , wherein R 4 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl C 1 -C 6 -alkyl or optionally substituted heteroaryl C 1 -C 6 -alkyl.
7. The compound according to claim 1 , wherein R 4 is optionally substituted aryl or optionally substituted heteroaryl.
8. The compound according to claim 1 , wherein R 1 is H or halogen; R 2 is substituted methyl; and R 3 is H or substituted alkoxy.
9. The compound according to claim 1 , wherein R 1 is H or halogen; R 2 is methyl; R 3 is H or alkoxy.
10. The compound according to claim 1 ,
wherein:
A, B and E are carbon and D is nitrogen;
R 1 is H, halogen, nitro, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl;
R 2 is H, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl;
R 3 is H, halo, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted heteroaryl;
R 4 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl C 1 -C 6 -alkyl, optionally substituted heteroaryl C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 cycloalkyl optionally substituted C 1 -C 6 -alkyl, optionally substituted heterocycloalkyl C 1 -C 6 -alkyl, optionally substituted aryl C 2 -C 6 -alkenyl or optionally substituted heteroaryl C 2 -C 6 -alkenyl;
n is an integer selected from 0, 1, 2, 3 and 4;
an optionally substituted group is substituted with from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, aryl, carbamate, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro;
with the first proviso that when R 4 is thiophenyl, it is not selected from the group consisting of: unsubstituted thiophenyl, unsubstituted chloro-5-thiophenyl and unsubstituted bromo-5-thiophenyl; with the second proviso that when R 4 is a phenyl, it is a mono-substituted phenyl that is not selected from the group consisting of: p-bromo phenyl; p-methoxy phenyl; p- ethoxy phenyl; o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro phenyl; o-CF3- phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and p-amino phenyl; or it is a multi-substituted phenyl, that is not an unsubstituted bi-substituted phenyl selected from the group consisting of: m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-, p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl; m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro phenyl and o-ethoxy m-bromo phenyl;
with the final proviso that wherein R 4 is a 1,4 benzodioxin it is a substituted benzodioxin;
or an optically active form or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 10 , wherein R 1 is H or halogen.
12. The compound according to claim 10 , wherein R 2 is methyl or substituted methyl.
13. The compound according to claim 10 , wherein R 3 is H, alkoxy or substituted alkoxy.
14. The compound according to claim 10 , wherein R 3 is halo, optionally substituted aryl or optionally substituted heteroaryl.
15. The compound according to claim 10 , wherein R 4 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl C 1 -C 6 -alkyl or optionally substituted heteroaryl C 1 -C 6 -alkyl.
16. The compound according to claim 10 , wherein R 4 is optionally substituted aryl or optionally substituted heteroaryl.
17. The compound according to claim 10 , wherein R 1 is H or halogen; R 2 is substituted methyl; and R 3 is H or substituted alkoxy.
18. The compound according to claim 10 , wherein R 1 is H or halogen; R 2 is methyl; R 3 is H or alkoxy.
19. The compound according to claim 1 , wherein:
A is nitrogen and B, D and E are carbon;
R 1 is H, halogen, nitro, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl;
R 2 is H, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl;
R 3 is H, halo, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted heteroaryl;
R 4 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl C 1 -C 6 -alkyl, optionally substituted heteroaryl C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 cycloalkyl optionally substituted C 1 -C 6 -alkyl, optionally substituted heterocycloalkyl C 1 -C 6 -alkyl, optionally substituted aryl C 2 -C 6 -alkenyl or optionally substituted heteroaryl C 2 -C 6 -alkenyl;
n is an integer selected from 0, 1, 2, 3 and 4;
an optionally substituted group is substituted with from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, aryl, carbamate, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro;
with the first proviso that when R 4 is thiophenyl, it is not selected from the group consisting of: unsubstituted thiophenyl, unsubstituted chloro-5-thiophenyl and unsubstituted bromo-5-thiophenyl; with the second proviso that when R 4 is a phenyl, it is a mono-substituted phenyl that is not selected from the group consisting of: p-bromo phenyl; p-methoxy phenyl; p- ethoxy phenyl; o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro phenyl; o-CF3- phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and p-amino phenyl; or it is a multi-substituted phenyl, that is not an unsubstituted bi-substituted phenyl selected from the group consisting of:
m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-, p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl; m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro phenyl and o-ethoxy m-bromo phenyl;
with the final proviso that wherein R 4 is a 1,4 benzodioxin it is a substituted benzodioxin;
or an optically active form or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 19 , wherein R 1 is H or halogen.
21. The compound according to claim 19 , wherein R 2 is methyl or substituted methyl.
22. The compound according to claim 19 , wherein R 3 is H, alkoxy or substituted alkoxy.
23. The compound according to claim 19 , wherein R 3 is halo, optionally substituted aryl or optionally substituted heteroaryl.
24. The compound according to claim 19 , wherein R 4 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl C 1 -C 6 -alkyl or optionally substituted heteroaryl C 1 -C 6 -alkyl.
25. The compound according to claim 19 , wherein R 4 is optionally substituted aryl or optionally substituted heteroaryl.
26. The compound according to claim 19 , wherein R 1 is H or halogen; R 2 is substituted methyl; and R 3 is H or substituted alkoxy.
27. The compound according to claim 19 , wherein R 1 is H or halogen; R 2 is methyl; R 3 is H or alkoxy.
28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and the compound according to claim 1 .