Phosphodiesterase inhibitors and uses thereof
The invention provides for novel benzonaphthyridine derivatives and compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the compounds are phosphodiesterase inhibitors. The invention further provides for methods for inhibition of phosphodiesterase comprising contacting phosphodiesterase with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. The invention further provides for methods for treatment of neurodegenerative diseases, increasing memory or long term potentiation with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the phosphodiesterase is PDE5.
1. A compound of formula (I),
or a pharmaceutically acceptable salt or tautomer thereof,
wherein
A is O or NR 4 ;
B is CR 16 or N;
V is a bond or C(O);
W is a bond;
X is —(C 1 -C 3 )-alkyl, C(O), S, S(O), S(O) 2 or (C 1 -C 3 )-alkyl substituted with at least one D;
Y is NR 5 or O;
Z is CR 2 or N;
R 1 is halogen or —(C 1 -C 6 )-haloalkyl;
R 2 is —OR 6 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 4 is hydrogen or —(C 1 -C 3 )-alkyl;
R 5 is hydrogen, —(C 1 -C 3 )-alkyl, —(C 3 -C 5 )-cycloalkyl, —C(O)R 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , or —S(O) 2 R 7 ;
R 6 is hydrogen, —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-haloalkyl, or —(C 3 -C 8 )-cycloalkyl;
R 7 is independently hydrogen, —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-haloalkyl, or aryl;
R 14 is hydrogen, halogen or —(C 1 -C 6 )-haloalkyl;
R 15 is hydrogen, —OR 17 , —OH or halogen;
R 16 is hydrogen, —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-haloalkyl, —(C 3 -C 8 )-cycloalkyl, heterocycle, —OR 17 , —OH or halogen;
R 17 is hydrogen, —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-haloalkyl, or —(C 3 -C 8 )-cycloalkyl; and
m and n are each 0, 1, 2, or 3, provided that the sum of m+n is an integer from 1.
2. The compound of claim 1 , having formula (Ia):
3. The compound of claim 1 , having formula (Ib):
4. The compound of claim 1 , having formula (Ic):
5. The compound of claim 1 , wherein X is —(C 1 -C 3 )-alkyl.
6. The compound of claim 1 , wherein X is —(C 1 -C 3 )-alkyl substituted with at least one D.
7. The compound of claim 1 , wherein
A is NR 4 ;
V is a bond or C(O);
W is a bond;
X is (C 1 -C 3 )-alkyl or —(C 1 -C 3 )-alkyl substituted with at least one D;
Y is NR 5 ;
R 1 is halogen or —(C 1 -C 3 )-haloalkyl;
R 2 is —OR 6 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 5 is hydrogen, —(C 1 -C 3 )-alkyl, —(C 3 -C 5 )-cycloalkyl, or —C(O)R 7 ;
R 6 is —(C 1 -C 3 )-alkyl or —(C 1 -C 3 )-haloalkyl;
R 7 is —(C 1 -C 3 )-alkyl;
R 16 is hydrogen or —(C 1 -C 3 )-alkyl;
m and n are independently 0, 1 or 2, provided that the sum of m+n is an integer from 2-3.
8. The compound of claim 1 , wherein
A is NH;
V is a bond or C(O);
W is a bond;
X is —(C 1 -C 3 )-alkyl or —(C 1 -C 3 )-alkyl substituted with at least one D;
Y is NR 5 ;
R 1 is halogen;
R 2 is —OR 6 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 5 is hydrogen, —(C 1 -C 3 )-alkyl, or —C(O)R 7 ;
R 6 is —(C 1 -C 3 )-alkyl;
R 7 is —(C 1 -C 3 )-alkyl;
R 16 is hydrogen or —(C 1 -C 3 )-alkyl;
m is 0 or 1; and
n is 2.
9. The compound of claim 1 , wherein
A is NH;
V is a bond or C(O);
W is a bond;
X is —CH 2 — or —CD 2 ;
Y is NR 5 ;
R 1 is halogen;
R 2 is —OCH 3 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 5 is hydrogen, —(C 1 -C 3 )-alkyl, or —C(O)CH 3 ;
R 16 is hydrogen or —(C 1 -C 3 )-alkyl;
m is 0 or 1; and
n is 2.
10. The compound of claim 1 , wherein
V and W are each a bond;
X is —(C 1 -C 3 )-alkyl or —(C 1 -C 3 )-alkyl substituted with at least one D;
Y is NR 5 ; and
m and n are each 0, 1 or 2, provided that the sum of m+n is an integer from 2-3.
11. The compound of claim 1 , wherein
A is NH;
V is C(O);
W is a bond;
X is CH 2 or CD 2 ;
Y is NR 5 ;
R 1 is halogen or —(C 1 -C 3 )-haloalkyl;
R 2 is —OR 6 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 5 is hydrogen, —(C 1 -C 3 )-alkyl, or C(O)R 7 ;
R 6 is hydrogen, —(C 1 -C 3 )-alkyl, or —(C 1 -C 3 )-haloalkyl;
R 7 is hydrogen or —(C 1 -C 3 )-alkyl;
R 16 is hydrogen, —(C 1 -C 3 )-alkyl, —(C 1 -C 3 )-haloalkyl, or —(C 3 -C 5 )-cycloalkyl;
m is 0 or 1; and
n is 2.
12. The compound of claim 1 , wherein
A is NH;
V is C(O);
W is a bond;
X is CH 2 or CD 2 ;
Y is NR 5 ;
R 1 is halogen;
R 2 is —OCH 3 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 5 is hydrogen, —(C 1 -C 3 )-alkyl, or C(O)R 7 ;
R 7 is —(C 1 -C 3 )-alkyl;
R 16 is hydrogen or —(C 1 -C 3 )-alkyl; m is 0; and
n is 2.
13. The compound of claim 1 , wherein A is NH;
V and W are each a bond;
X is CH 2 or CD 2 ;
Y is NR 5 ;
R 1 is halogen or —(C 1 -C 3 )-haloalkyl;
R 2 is —OR 6 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 5 is hydrogen, —(C 1 -C 3 )-alkyl, or C(O)R 7 ;
R 6 is hydrogen, —(C 1 -C 2 )-alkyl, or —(C 1 -C 2 )-haloalkyl;
R 7 is —(C 1 -C 3 )-alkyl;
R 16 is hydrogen, —(C 1 -C 3 )-alkyl, —(C 1 -C 3 )-haloalkyl, or —(C 3 -C 5 )-cycloalkyl;
m is 0 or 1; and
n is 2.
14. The compound of claim 1 , wherein
A is NH;
V and W are each a bond;
X is CH 2 or CD 2 ;
Y is NR 5 ;
R 1 is chlorine;
R 2 is —OCH 3 ;
R 3 is —CN;
R 5 is hydrogen or —(C 1 -C 3 )-alkyl;
R 16 is hydrogen or —(C 1 -C 3 )-alkyl;
m is 1; and
n is 2.
15. The compound of claim 1 , wherein
A is NH;
V and W are each a bond;
X is CH 2 or CD 2 ;
Y is NC(O)CH 3 ;
R 1 is halogen;
R 2 is —OCH 3 ;
R 3 is hydrogen, —OMe, —CF 3 , —CN or halogen;
R 16 is hydrogen;
m is 1; and
n is 2.
16. The compound of claim 1 , wherein the compound is:
wherein R 3 is —OMe, —CF 3 , or —CN or a pharmaceutically acceptable salt or tautomer thereof.
17. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt or tautomer thereof.
18. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt or tautomer thereof.
19. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt or tautomer thereof.
20. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
21. A method of treating neurodegenerative disease in a subject in need thereof comprising administration of a therapeutically effective amount of a compound of claim 1 to said subject.
22. The method of claim 21 , wherein the disease is Alzheimer's Disease.
23. A method of increasing long-term potentiation in a subject comprising administration of a therapeutically effective amount of a compound of claim 1 to said subject.
24. A method of improving memory in a subject comprising administration of a therapeutically effective amount of a compound of claim 1 to said subject.
25. The method of claim 24 , wherein the subject has a neurodegenerative disease.
26. The method of claim 25 , wherein the neurodegenerative disease is Alzheimer's Disease.