Substituted 2-imino-1,3-thiazolidin-4-ones as N-arachidonoylethanolamine cellular uptake inhibitors

1. A compound of formula (1):

wherein:

R 1 is selected from formula (2e) or formula (2e′):

wherein:

D is C 1 -C 4 -alkyl;

T is independently selected from —CH 2 —, —NH—, —S—, —O—, —CH(CH 3 )— or —C(CH 3 ) 2 —;

each Z 1 is independently selected from —F, —Cl, —Br, —I, —CN, —R a , —OR a , —(CH 2 ) r OR a , —SR a , —(CH 2 ) r SR a or —N(R a ) 2 ;

each R a is independently selected from H, an unsubstituted C 1 -C 8 -alkyl, an unsubstituted C 2 -C 8 -alkenyl or an unsubstituted C 2 -C 8 -alkynyl;

r is 1, 2, 3 or 4; and

n is 0, 1, 2 or 3;

R 2 is selected from an unsubstituted cycloalkyl, a substituted or unsubstituted aryl, an unsubstituted saturated heterocyclyl, or a substituted or unsubstituted heteroaryl;

wherein:

the substituted aryl or the substituted heteroaryl is substituted by at least one Z 2 ;

each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R b , —OR b , —(CH 2 ) r OR b , —SR b , —(CH 2 ) r SR b or —N(R b ) 2 ;

each R b is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

r is 1, 2, 3 or 4; or

R 2 is formula -L-Ar;

wherein:

L is an alkyl, an alkenyl or an alkynyl; and

Ar is a substituted or unsubstituted C 6 -aryl or a substituted or unsubstituted C 5 -C 6 -heteroaryl;

wherein:

the substituted C 6 -aryl or substituted C 5 -C 6 -heteroaryl is substituted by at least one Z 2 ;

each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R b , —OR b , —(CH 2 ) r OR b , —SR b , —(CH 2 ) r SR b or —N(R b ) 2 ;

each R b is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

r is 1, 2, 3 or 4; and

R 3 is selected from an unsubstituted alkyl, an unsubstituted alkoxy, an unsubstituted alkenyl, an unsubstituted alkynyl, an unsubstituted cycloalkyl, an unsubstituted saturated heterocyclyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

wherein:

the substituted aryl or substituted heteroaryl is substituted by at least one Z 3 ;

each Z 3 is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;

each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

r is 1, 2, 3 or 4; or

R 3 is formula -D-Ar;

wherein:

D is an alkyl, an alkenyl or an alkynyl; and

Ar is a substituted or unsubstituted C 6 -aryl or a substituted or unsubstituted C 5 -C 6 -heteroaryl;

wherein:

the substituted C 6 -aryl or substituted C 5 -C 6 -heteroaryl is substituted by at least one Z 3 ;

each Z 3 is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;

each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

r is 1, 2, 3 or 4.

2. The compound according to claim 1 , wherein each Z 1 is independently selected from —F, —Cl, —Br, —I, —CN, —R a , —OR a or —(CH 2 ) r OR a .

3. The compound according to claim 1 , wherein R 2 is formula -L-Ar.

4. The compound according to claim 1 , wherein R 2 is formula -L-Ar, wherein formula -L-Ar is formula (4a) or formula (4b):

wherein o is 0, 1, 2, 3, 4 or 5; or

wherein o is 1, 2, 3, 4 or 5.

5. The compound according to claim 4 , wherein each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R b , —OR b , —CH 2 OR b or —N(R b ) 2 .

6. The compound according to claim 1 , wherein:

R 3 is selected from an unsubstituted alkyl, an unsubstituted alkenyl, an unsubstituted alkynyl, an unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or

R 3 is formula -D-Ar.

7. The compound according to claim 1 , wherein:

R 3 is an unsubstituted C 3 -C 10 -cycloalkyl; or

R 3 is formula -D-Ar.

8. The compound according to claim 1 , wherein R 3 is formula -D-Ar, wherein formula -D-Ar is formula (5a) or formula (5b):

wherein p is 0, 1, 2, 3, 4 or 5; or

wherein p is 1, 2, 3, 4 or 5.

9. A method for inhibiting N-arachidonoylethanolamine uptake in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

10. The method according to claim 9 , wherein the subject has a disorder selected from the group consisting of a psychiatric disorder, a neurological disorder and neuroinflammation.

11. A compound of formula (1):

wherein:

R 1 is formula (6a):

wherein:

M is alkyl, alkenyl or alkynyl;

each Z 10 is independently selected from —CN, —OR e or —CH 2 OR e ;

each R e is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

l is 0, 1, 2 or 3; or

R 1 is formula (6b):

wherein:

each Z 10 is independently selected from —CN, —OR e or —CH 2 OR e ;

each R e is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

l is 1, 2 or 3; or

R 1 is selected from an unsubstituted saturated heterocyclyl or a substituted or unsubstituted heteroaryl;

wherein:

the substituted heteroaryl is substituted by at least one substituent;

each substituent is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;

each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

r is 1, 2, 3 or 4;

R 2 is an unsubstituted alkyl, an unsubstituted alkoxy, an unsubstituted alkenyl, an unsubstituted alkynyl, an unsubstituted cycloalkyl, an unsubstituted saturated heterocyclyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

wherein:

the substituted aryl or substituted heteroaryl is substituted by at least one substituent;

each substituent is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;

each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

r is 1, 2, 3 or 4; or

R 2 is formula -L-Ar;

wherein:

L is an alkyl, an alkenyl or an alkynyl; and

Ar is a substituted or unsubstituted C 6 -aryl or a substituted or unsubstituted C 5 -C 6 -heteroaryl;

wherein:

the substituted C 6 -aryl or substituted C 5 -C 6 -heteroaryl is substituted by at least one Z 2 ;

each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;

each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and

r is 1, 2, 3 or 4; and

R 3 is an unsubstituted cycloalkyl.

12. The compound according to claim 11 , wherein R 1 is formula (6b):

13. The compound according to claim 11 , wherein:

R 2 is selected from an unsubstituted alkyl, an unsubstituted alkenyl, an unsubstituted alkynyl, an unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or

R 2 is formula -L-Ar.

14. The compound according to claim 11 , wherein the substituted aryl or substituted heteroaryl is substituted by at least one substituent independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d or —CH 2 OR d .

15. The compound according to claim 11 , wherein R 2 is formula -L-Ar.

16. The compound according to claim 11 , wherein R 2 is formula -L-Ar, wherein formula -L-Ar is formula (4a) or formula (4b):

wherein o is 0, 1, 2, 3, 4 or 5; or

wherein o is 1, 2, 3, 4 or 5.

17. The compound according to claim 16 , wherein each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —CH 2 OR d or —N(R d ) 2 .

18. A method for inhibiting N-arachidonoylethanolamine uptake in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 2 .

19. The method according to claim 17 , wherein the subject has a disorder selected from the group consisting of a psychiatric disorder, a neurological disorder and neuroinflammation.