Substituted quinoxalines and quinoxalinones as PDE-10 inhibitors
Provided herein are compounds of formula A-L-B, and pharmaceutically acceptable salts and stereoisomers thereof, wherein A is R 1 and R 2 together with the carbon atoms to which they are attached form a 1,2-phenylene ring optionally substituted with one or more R 11 ; L is —C(R 6 ) 2 —C(R 6 ) 2 —; B is a heteroaromatic group defined herein; and -A 1 -A 2 - , A 3 , R 11 and R 6 are defined herein. Also disclosed are methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. In one embodiment, the compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and metabolic disorders, including, but not limited to, e.g., neurological disorders, psychosis, schizophrenia, obesity, and diabetes.
1. A compound of formula (I):
A-L-B (I),
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
L is —C(R 6 ) 2 —C(R 6 ) 2 —;
A is
B is
-A 1 -A 2 - is —NR 7 —C(═O)— or —N═CR 8 —;
A 3 is N;
A 4 is NR 5 or O;
A 5 is CR 5 or N;
A 6 is CR 5 ;
R 1 and R 2 together with the carbon atoms to which they are attached form a 1,2-phenylene ring optionally substituted with one or more R 11 ;
R 3 and R 4 are each independently (i) hydrogen, cyano, or halo; or (ii) (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )aminoalkyl, (C 1 C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxy, amino, imino, amido, or thiol, each of which is optionally substituted with one or more R 11 ; or (iii) R 3 and R 4 together with the atoms to which they are attached form a ring optionally substituted with one or more R 11 ;
R 5 is (i) hydrogen, cyano, or halo; or (ii) (C 1 -C 10 )alkyl, (C 2 C 10 )alkenyl, (C1-C 10 )alkoxy, (C 1 -C 10 )aminoalkyl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxy, amino, imino, amido, or thiol, each of which is optionally substituted with one or more R 11 ; or (iii) R 4 and R 5 together with the atoms to which they are attached form a ring optionally substituted with one or more R 11 ;
R 19 is (i) hydrogen, cyano, or halo; or (ii) (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C1-C 10 )alkoxy, (C 1 -C 10 )aminoalkyl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxy, amino, imino, amido, or thiol, each of which is optionally substituted with one or more R 11 ;
R 20 is (i) hydrogen; or (ii) (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, each of which is optionally substituted with one or more R 11 ;
each occurrence of R 6 is independently hydrogen, halo, or (C 1 -C 6 )alkyl optionally substituted with one or more halo;
R 7 is hydrogen or (C 1 -C 6 )alkyl optionally substituted with one or more halo;
R 8 is (i) hydrogen, cyano, or halo; or (ii) (C 1 -C 10 ) alkyl, (C 2 -C 10 )alkenyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )aminoalkyl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 ) cycloalkyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, (3 to 12 membered) heterocyclyl, hydroxy, amino, imino, amido, or thiol, each of which is optionally substituted with one or more R 11 ;
each occurrence of R 11 is independently hydrogen, halogen, cyano, ═O, —OR 13 , —NR 13 R 14 , —N(R 13 )C(O)R 14 , —C(O)NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —S(O) 2 NR 13 R 14 , (C 1 -C 10 )alkyl optionally substituted with one or more R 12 , (C 1 -C 10 )heteroalkyl optionally substituted with one or more R 12 , (C 3 -C 10 )cycloalkyl optionally substituted with one or more R 12 , (C 7 -C 12 )aralkyl optionally substituted with one or more R 12 , (C 3 -C 12 )heteroaralkyl optionally substituted with one or more R 12 , (6 to 10 membered)aryl optionally substituted with one or more R 12 ,(5 to 10 membered)heteroaryl optionally substituted with one or more R 12 , or (3 to 12 membered)heterocyclyl optionally substituted with one or more R 12 ;
each occurrence of R 12 is independently hydrogen, (C 1 -C 6 )alkyl optionally substituted with one or more R 13 , (C 3 -C 6 )cycloalkyl optionally substituted with one or more R 13 , halogen, cyano, ═O, —OR 13 , —NR 13 R 14, —N(R 13 )C(O)R 14 ,—C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , or —S(O) 2 NR 13 R 14 ; and
each occurrence of R 13 and R 14 is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 ) heteroalkyl, (C 3 -C 6 )cycloalkyl, (C 7 -C 10 )aralkyl; (C 3 -C 12 )heteroaralkyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, or (3 to 12 membered)heterocyclyl; or R 13 and R 14 together may form a 3 to 10 membered ring.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, having formula (I-A):
3. The compound of claim 2 , wherein
k is 0, 1, 2, 3, or 4;
each occurrence of G is independently CH or N; and
J is O, S, NH or CH 2 .
4. The compound of claim 3 , wherein R 3 is (i) hydrogen; or (ii) (C 1 -C 10 )alkyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl, each of which is optionally substituted with one or more R 11 .
5. The compound of claim 3 , wherein R 4 is (i) hydrogen; or (ii) (C 1 -C 10 )alkyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl, each of which is optionally substituted with one or more R 11 .
6. The compound of claim 3 , wherein R 5 is (i) hydrogen; or (ii) (C 1 -C 10 )alkyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl, each of which is optionally substituted with one or more R 11 .
7. The compound of claim 3 , wherein each occurrence of R 11 is independently (i) hydrogen; or (ii) (C 1 -C 10 )alkyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl, each of which is optionally substituted with one or more R 12 .
8. The compound of claim 2 , wherein A 4 is NR 5 ; and R 5 is (i) hydrogen; or (ii) (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered) aryl, (5 to 10 membered) heteroaryl, or (3 to 12 membered)heterocyclyl, each of which is optionally substituted with one or more R 11 ; or (iii) R 4 and R 5 together with the atoms to which they are attached form a ring optionally substituted with one or more R 11 .
9. The compound of claim 8 , wherein R 5 is H or CH 3 .
10. The compound of claim 2 , wherein
each occurrence of R 15 is independently: hydrogen, halo, cyano, —OR 13 , —NR 13 R 14 , —N(R 13 )C(O)R 14 , —C(O)NR 13 R 14 , —C(O)R 13 , —OC(O)R 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —S(O) 2 NR 13 R 14 , (C 1 -C 10 )alkyl optionally substituted with one or more R 12 , (C 1 -C 10 )heteroalkyl optionally substituted with one or more R 12 , (C 3 -C 10 )cycloalkyl optionally substituted with one or more R 12 , (C 7 -C 12 )aralkyl optionally substituted with one or more R 12 , (C 3 -C 12 )heteroaralkyl optionally substituted with one or more R 12 , (6 to 10 membered)aryl optionally substituted with one or more R 12 , (5 to 10 membered)heteroaryl optionally substituted with one or more R 12 , or (3 to 12 membered)heterocyclyl optionally substituted with one or more R 12 ; and
m is 0,1,2,3, or 4.
11. The compound of claim 10 , wherein R 8 is H or CH 3 .
12. The compound of claim 10 , wherein the compound is:
13. The compound of claim 2 , wherein
14. The compound of claim 2 , wherein the compound is:
15. The compound of claim 1 , wherein
B is
A 5 is CR 5 ;
R 3 and R 4 together with the atoms to which they are attached form an optionally substituted ring.
16. The compound of claim 15 , wherein R 5 is H or CH 3 .
17. The compound of claim 15 , wherein the compound is:
18. The compound of claim 1 , wherein
B is
wherein each R 11 may be the same or different.
19. The compound of claim 18 , wherein the compound is:
20. The compound of claim 1 , having formula (I-B):
D-L-E (I-B),
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
L is —(CH 2 ) 2 —;
D is
E is:
each Y is independently N or CR;
each Z is independently N or C;
provided that D contains 1, 2, 3, or 4 nitrogen ring atoms;
each occurrence of R is independently hydrogen, halo, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, aryl, or heteroaryl;
each occurrence of R 21 , R 22 , R 23 , and R 24 is independently hydrogen, halo, cyano, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )aminoalkyl, (C 1 -C 6 )hydroxyalkyl, CH 2 CN, CH 2 C(O)NH 2 , (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or alkyl-heterocycloalkyl; and
R 25 is hydrogen, halo, cyano, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, CH 2 CN, CH 2 C(O)NH 2 , (C 7 -C 12 )aralkyl, or alkyl-heterocycloalkyl.
21. The compound of claim 20 , wherein the compound is:
22. The compound of claim 1 , wherein L is —CH 2 —CH 2 —.
23. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
24. A method of inhibiting phosphodiesterase-10A activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
25. A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is: