Bicyclic heteroaryl kinase inhibitors and methods of use
Provided are compounds having an inhibitory effect on kinases including Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions that are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders that comprise the inhibition of Mixed Lineage Kinases.
1. A compound of structural Formula VI
or a salt thereof, wherein:
Y 3 is chosen from a bond, lower alkyl, lower carboxyl, and lower heteroalkyl;
Y 4 is chosen from O, S, C(O), SO, SO 2 , NH, N(CH 3 ), CH 2 , CHF, CF 2 , CH(CH 3 ), C(CH 3 ) 2 , CH 2 O—, and —CH 2 N—; and
R 2 is chosen from phenyl and 6-membered monocyclic heteroaryl, either of which is optionally substituted with one or more substituents chosen from deuterium, halogen, hydroxy, lower amino, lower amido, C 1 -C 3 alkoxy, and C 1 -C 3 alkyl;
R 3 is chosen from cycloalkyl, aryl, heteroaryl, bicyclic heteroaryl, any of which is optionally substituted with one or more substituents chosen from deuterium, halogen, hydroxy, lower amino, lower amido, lower carboxyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, (O), (S), cyano, haloalkyl, phenyl, cycloalkyl, heteroaryl, and cycloheteroalkyl;
R 14 is chosen from lower heteroalkyl, lower heterocycloalkyl, and lower heteroaryl, any of which is optionally substituted with one or more substituents chosen from deuterium, halogen, hydroxy, lower amino, lower amido, lower carboxyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, (O), (S), haloalkyl, phenyl, benzyl, and lower cycloalkyl.
2. The compound of claim 1 , wherein R 2 is phenyl optionally substituted with one or more substituents chosen from halogen, hydroxy, lower amino, lower amido, C 1 -C 3 alkoxy, and C 1 -C 3 alkyl.
3. The compound of claim 1 , wherein Y 4 is O, S, C(O), N or CH 2 .
4. The compound of claim 1 , wherein R 14 is a monocyclic heterocycloalkyl optionally substituted with one or more substituents chosen from halogen, hydroxy, lower amino, lower amido, lower carboxyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, (O), (S), haloalkyl, phenyl, benzyl, and tower cycloalkyl.
5. The compound of claim 1 , wherein R 14 is piperazinyl or morpholino, optionally substituted with one or more substituents chosen from halogen, hydroxy, lower amino, lower amido, lower carboxyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, (O), (S), haloalkyl, phenyl, benzyl, and lower cycloalkyl.
6. The compound of claim 1 , wherein R 2 is substituted with 0 to 3 substituents R 15 , which each R 15 is independently chosen from fluorine, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NS(O) 2 CH 3 , methoxy, and methyl.
7. The compound of claim 1 , wherein Y 3 is a bond or CH 2 .
8. The compound of claim 1 , wherein R 3 is phenyl or 5/6-fused bicyclic heteroaryl, either of which is optionally substituted with one or more substituents chosen from halogen, hydroxy, cyano, lower amino, lower amido, lower phenylamido, lower phenylalkylamido, lower heterocycloalkyl, lower heterocycloalkyl, lower alkyl heterocycloalkyl, C 1 -C 3 alkoxy, and C 1 -C 3 alkyl.
9. The compound of claim 1 , wherein R 3 is chosen from benzothiazolyl, pyrrolopyridinyl, indanyl, cyclopropyl, cyclopentyl, phenyl, pyridinyl, pyrimidinyl, and indolyl, any of which is optionally substituted with one or more substituents chosen from fluorine, chlorine, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , C(O)NH 2 , C(O)NHCH 3 , morpholino, piperazinyl, methylpiperazinyl, acetamido, methylacetamido, methylpropionamido, phenylacetamidomethylene, benzamidomethylene, phenylpropanamidomethylene, methoxy, and methyl.
10. The compound of claim 1 , wherein R 3 is phenyl optionally substituted with one or more substituents chosen from hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, halogen, lower amino, lower carboxyl, and cyano.
11. The compound of claim 1 , wherein R 2 , R 3 , or R 14 is substituted with deuterium, fluorine, or methyl.
12. The compound of claim 1 , wherein R 3 is chosen from indanyl, indolyl, indazolyl, indolinonyl, benzothiophenyl, quinolinyl, pyrrolopyrazinyl, and pyrrolopyridinyl, any of which is optionally substituted with one or more substituents chosen from hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, halogen, lower amino, and lower carboxyl.
13. The compound of claim 1 , wherein R 3 is indanyl optionally substituted at a carbon atom with one or more substituents chosen from deuterium, halogen, and lower alkyl.
14. The compound of claim 1 , wherein R 3 is indanyl or phenyl optionally substituted with one or more substituents chosen from hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, halogen, lower amino, and lower carboxyl.
15. The compound of claim 1 , wherein the compound is chosen from
Com-
pound
no.
Structure
224
225
226
227
228
229
230
231
232
233
235
236
237
and
238
16. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier.
17. A method of inhibition of MLK comprising contacting MLK with a compound of claim 1 .
18. The method of claim 17 , wherein said MLK is MLK3.
19. The method of claim 17 , wherein said inhibition is selective over other kinases.