Substituted quinoxalines and quinoxalinones as PDE-10 inhibitors

摘要

Provided herein are compounds of formula A-L-B, and pharmaceutically acceptable salts and stereoisomers thereof, wherein A is;
R1 and R2 together with the carbon atoms to which they are attached form a 1,2-phenylene ring optionally substituted with one or more R11; L is —C(R6)2—C(R6)2—; B is a heteroaromatic group defined herein; and -A1-A2- , A3, R11 and R6 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.

主权项

1. A compound of formula (I):
A-L-B  (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is —C(R6)2—C(R6)2 —; A is B is -A1-A2- is —NR7—C(═O)— or —N═CR8—; A3 is N; A4 is NR5 or O; A5 is CR5 or N; A6 is CR5; R1 and R2 together with the carbon atoms to which they are attached form a 1,2-phenylene ring optionally substituted with one or more R11; R3 and R4 are each independently (i) hydrogen, cyano, or halo; or (ii) (C1-C10)alkyl, (C2-C10)alkenyl, (C1-C10)alkoxy, (C1-C10)aminoalkyl, (C1C10)heteroalkyl, (C3-C10)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 R11; or (iii) R3 and R4 together with the atoms to which they are attached form a ring optionally substituted with one or more R11; R5 is (i) hydrogen, cyano, or halo; or (ii) (C1-C10)alkyl, (C2C10)alkenyl, (C1-C10)alkoxy, (C1-C10)aminoalkyl, (C1-C10)heteroalkyl, (C3-C10)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 R11; or (iii) R4 and R5 together with the atoms to which they are attached form a ring optionally substituted with one or more R11; R19 is (i) hydrogen, cyano, or halo; or (ii) (C1-C10)alkyl, (C2-C10)alkenyl, (C1-C10)alkoxy, (C1-C 10)aminoalkyl, (C1-C10)heteroalkyl, (C3-C10)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 R11; R20is (i) hydrogen; or (ii) (C1-C10)alkyl, (C2-C10)alkenyl, (C1-C10)heteroalkyl, (C3-C10)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 R11; each occurrence of R6 is independently hydrogen, halo, or (C1-C6)alkyl optionally substituted with one or more halo; R7 is hydrogen or (C1-C6)alkyl optionally substituted with one or more halo; R8 is (i) hydrogen, cyano, or halo; or (ii) (C1-C10) alkyl, (C2-C10)alkenyl, (C1-C10)alkoxy, (C1-C10)aminoalkyl, (C1-C10)heteroalkyl, (C3-C10) 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 R11; each occurrence of R11 is independently hydrogen, halogen, cyano, ═O, —OR13, —NR13R14, —N(R13)C(O)R14, —C(O)NR13R14, —C(O)R13, —C(O)OR13, —SR13, —S(O)R13, —S(O)2R13, —S(O)2NR13R14, (C1-C10)alkyl optionally substituted with one or more R12, (C1-C10)heteroalkyl optionally substituted with one or more R12, (C3-C10)cycloalkyl optionally substituted with one or more R12, (C7-C12)aralkyl optionally substituted with one or more R12, (C3-C12)heteroaralkyl optionally substituted with one or more R12, (6 to 10 membered)aryl optionally substituted with one or more R12,(5 to 10 membered)heteroaryl optionally substituted with one or more R12, or (3 to 12 membered)heterocyclyl optionally substituted with one or more R12; each occurrence of R12 is independently hydrogen, (C1-C6)alkyl optionally substituted with one or more R13, (C3-C6)cycloalkyl optionally substituted with one or more R13, halogen, cyano, ═O, —OR13, —NR13R14, —N(R13)C(O)R14,—C(O)R13, —C(O)OR13, —OC(O)R13, —SR13, —S(O)R13, —S(O)2R13, or —S(O)2NR13R14; and each occurrence of R13 and R14 is independently hydrogen, (C1-C6)alkyl, (C1-C6) heteroalkyl, (C3-C6)cycloalkyl, (C7-C10)aralkyl; (C3-C12)heteroaralkyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, or (3 to 12 membered)heterocyclyl; or R13 and R14 together may form a 3 to 10 membered ring.