Phosphodiesterase inhibitors and uses thereof
The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.
1. A compound of formula (V):
wherein:
A is O or N;
X is —(CH 2 ) n , C(O), S(O), or S(O) 2 ;
R l is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 5 is hydrogen or —OR 6 ;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R l0 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; and n is 1, 2,or 3,
or a pharmaceutically acceptable salt or tautomer thereof.
2. The compound of claim 1 , wherein A is N.
3. The compound of claim 1 , wherein R 5 is hydrogen.
4. The compound of claim 1 , wherein R 5 is —OCH 3 .
5. The compound of claim 1 , wherein the compound is of formula (V-1):
wherein:
R l is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R l0 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
6. The compound of claim 5 , wherein R 6 is CH 3 .
7. The compound of claim 1 , wherein the compound is of formula (V-1a):
wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
8. The compound of claim 1 , wherein R 2 is CH 2 —OH.
9. The compound of claim 1 , wherein R 3 is H.
10. The compound of claim 1 , wherein R 3 is a halogen.
11. The compound of claim 1 , wherein R 3 is chlorine.
12. The compound of claim 1 , wherein R 4 is —CN.
13. The compound of claim 1 , wherein R 4 is a halogen.
14. The compound of claim 1 , wherein R 4 is fluorine.
15. The compound of claim 1 , wherein the compound is of formula (V-1a1):
wherein:
R l is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8- membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R l0 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
16. The compound of claim 1 , wherein R 1 is C 3 -C 8 cycloalkyl or —NR 7 R 8 .
17. The compound of claim 1 , wherein R 1 is —NR 7 R 8 .
18. The compound of claim 1 , wherein R 1 is —NR 7 R 8 , and wherein R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl,or —NR 9 R 10 ; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8- membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with O, NR 9 or N —C(O)R 9 .
19. The compound of claim 1 , wherein R 1 is —SR 7 .
20. The compound of claim 1 , wherein R 1 is —S—(C 1 -C 6 )-alkyl.
21. The compound of claim 1 , wherein R 1 is C 3 -C 8 cycloalkyl.
22. The compound of claim 1 , wherein R 1 is cyclopropyl.
23. The compound of claim 1 , wherein R 1 is dimethylamino.
24. The compound of claim 1 , wherein the compound is
25. The compound of claim 1 , wherein the compound is