Pyrazolo [1,5-A]pyrimidine adenosine A
View Patent ↗Compounds having the structural formula I are disclosed, wherein A is alkylene, or optionally substituted arylene, cycloalkylene or heteroaryldiyl; X is —C(O)— or —S(O) 2 —; R 1 is alkyl or cycloalkyl; R 2 is hydrogen, halo or —CN; R 3 is hydrogen or alkyl; R 4 is hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl-, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted by alkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl; or R 3 and R 4 , form an optionally substituted 5-7 membered ring, said ring optionally comprising an additional heteroatom ring member; R 7 is alkyl, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkyl, halo, morpholinyl, optionally substituted piperazinyl, or optionally substituted azacycloalkyl. Also disclosed is the use of the compounds in the treatment of Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, pharmaceutical compositions comprising them and kits comprising the components of the combinations.
1. A compound represented by the structural formula I
or a pharmaceutically acceptable salt thereof, wherein:
A is alkylene, R 16 -arylene, R 16 -cycloalkylene or R 16 -heteroaryldiyl;
X is —C(O)— or —S(O) 2 —;
R 1 is alkyl or cycloalkyl;
R 2 is hydrogen, halo or —CN;
R 3 is hydrogen or alkyl;
R 4 is hydrogen, alkyl, alkoxy, hydroxyalkyl, -alkyl-NR 14 R 15 , cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted by alkyl, R 8 -arylalkyl or R 8 -heteroarylalkyl;
or R 3 and R 4 together with the nitrogen to which they are attached, form a 5-7 membered ring, said ring optionally comprising an additional heteroatom ring member selected from the group consisting of —O—, —S— and —N(R 17 )—, said ring being optionally substituted by alkyl, hydroxyalkyl, R 8 -arylalkyl, R 8 -heteroarylalkyl, —N(R 9 )—C(O)alkyl, —CO 2 -alkyl, —C(O)NR 10 R 11 or heterocycloalkyl;
or R 3 and R 4 together with the nitrogen to which they are attached, form the group
R 7 is alkyl, R 12 -phenyl, R 12 -heteroaryl, cycloalkyl, halo, morpholinyl,
n is 1 or 2;
R 8 is 1-3 substituents independently selected from the group consisting of hydrogen, alkyl, halo, alkoxy, —CO 2 H, —CO 2 -alkyl, —CF 3 , —CN, —CO 2 NR 14 R 15 , —SO 2 -alkyl,
—SO 2 NR 14 R 15 and —NR 14 R 15 ;
R 9 is hydrogen or alkyl;
R 10 and R 11 are independently selected from the group consisting of alkyl and cycloalkyl; or R 10 and R 11 form a C 4 -C 5 alkylene chain and together with the nitrogen to which they are attached, form a 5- or 6-membered ring;
R 12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, halo, alkoxy, —CO 2 H, —CO 2 -alkyl, —CF 3 , —CN, —CO 2 NR 14 R 15 , —SO 2 -alkyl, —SO 2 NR 14 R 15 and —NR 14 R 15 ;
R 13 is H, OH, hydroxyalkyl or alkyl;
R 14 and R 15 are independently selected form the group consisting of hydrogen, alkyl and cycloalkyl;
R 16 is 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, halo, OH and alkoxy; and
R 17 is hydrogen, alkyl, cycloalkyl or R 8 -arylalkyl.
2. A compound of claim 1 wherein R 1 is methyl or cyclopropyl.
3. A compound of claim 1 wherein A is R 16 -arylene.
4. A compound of claim 3 wherein A is phenylene.
5. A compound of claim 1 wherein R 7 is R 12 -phenyl, pyridyl or
6. A compound of claim 5 wherein R 7 is
7. A compound of claim 1 wherein X is —S(O) 2 — and R 7 is 2-pyridyl.
8. A compound of claim 1 wherein X is —C(O)— and R 7 is 2-, 3- or 4-pyridyl.
9. A compound of claim 1 wherein X is —S(O) 2 —, R 1 is methyl, and R 2 is CN, Cl or Br.
10. A compound of claim 1 wherein X is —S(O) 2 —, R 1 is cyclopropyl, and R 2 is H.
11. A compound represented by the structural formula I
or a pharmaceutically acceptable salt thereof, wherein:
A is alkylene, R 16 -arylene, R 16 -cycloalkylene or R 16 -heteroaryldiyl;
R 1 is alkyl or cycloalkyl;
R 2 is hydrogen, halo or —CN;
X is —S(O) 2 —;
—NR 3 R 4 is selected from the group consisting of
R 7 is alkyl, R 12 -phenyl, R 12 -heteroaryl, cycloalkyl, halo, morpholinyl,
n is 1 or 2;
R 9 is hydrogen or alkyl;
R 12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, halo, alkoxy, —CO 2 H, —CO 2 -alkyl, —CF 3 , —ON, —CO 2 NR 14 R 15 , —SO 2 -alkyl, —SO 2 NR 14 R 15 and —NR 14 R 15 ;
R 13 is H, OH, hydroxyalkyl or alkyl;
R 14 and R 15 are independently selected form the group consisting of hydrogen, alkyl and cycloalkyl; and
R 16 is 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, halo, OH and alkoxy.
12. A compound of claim 1 wherein X is —C(O)— and —NR 3 R 4 is selected from the group consisting of:
13. A compound represented by the structural formula I
or a pharmaceutically acceptable salt thereof, wherein X is —S(O) 2 —, A is phenylene, R 1 is methyl, R 2 is Br, R 7 is phenyl or
and —NR 3 R 4 is
14. A compound of claim 1 wherein X is —C(O)—, A is phenylene, R 1 is cyclopropyl, R 2 is hydrogen, R 7 is phenyl or
and —NR 3 R 4 is
15. A compound of claim 1 wherein X is —C(O)—, A is phenylene, R 1 is methyl, R 2 is hydrogen, R 7 is phenyl or
and —NR 3 R 4 is
16. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 11 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 13 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 16 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.