Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors
Provided are compounds having an inhibitory effect on Mixed Lineage Kinases. The compounds include substituted pyrrolo [ 2,3 b]pyridines having Formula IX 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 which are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders which comprise the inhibition of Mixed Lineage Kinases.
1. A compound having Formula (IX):
or a pharmaceutically acceptable salt thereof, wherein:
Y 3 is chosen from a bond or CH 2 ;
R 3 is chosen from lower cycloalkyl and bicyclic heteroaryl, any of which are unsubstituted or substituted with one or more substituents chosen from halogen, hydroxy, lower amino, lower amido, lower phenylamido, lower phenylalkylamido, lower heterocycloalkyl, and lower alkylheterocycloalkyl;
the moiety R 14 —Y 4 —R 2 is chosen from
wherein
u is 0, 1, or 2;
wherein each R 15 is independently chosen from halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, lower amino, lower amido, lower sulfonamido, and lower sulfonyl,
Y 4 is —CH 2 —; and
wherein R 14 is chosen from lower cycloalkyl and lower heterocycloalkyl, any of which are unsubstituted or substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carboxy, lower alkylcarbonyl, lower carboxyester, lower carboxamido, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, sulfonate, or sulfonic acid.
2. The compound as recited in claim 1 , wherein Y 3 is a bond.
3. The compound as recited in claim 1 , wherein R 3 is chosen from benzothiazolyl, pyrrolopyridinyl, and indolyl, any of which is optionally substituted.
4. The compound as recited in claim 1 , wherein R 3 is substituted with one or more substituents chosen from 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, and phenylpropanamidomethylene.
5. The compound as recited in claim 1 , wherein Y 3 is CH 2 and R 3 is lower cycloalkyl optionally substitute with one or more substituents chosen from halogen, hydroxyl, lower amino, lower amino, lower phenylamido, lower pdenylalkylamido, lower heterocycloalkyl, and lower alkylheterocycloalky.
6. The compound as recited in claim 1 , wherein
u is 1 or 2; and
each R 15 is independently chosen from fluorine, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NHS(O) 2 CH 3 , methoxy, and methyl.
7. The compound as recited in claim 1 , wherein u is 0.
8. The compound as recited in claim 1 , wherein
R 3 is optionally substituted 5/6-fused bicyclic heteroaryl; and
R 14 is substituted or unsubstituted monocyclic heterocycloalkyl.
9. The compound as recited in claim 1 , wherein R 14 is substituted or unsubstituted lower heterocycloalkyl.
10. The compound as recited in claim 1 , wherein R 14 is substituted or unsubstituted piperazinyl.
11. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.
12. A method of inhibiting mixed lineage kinase-3 activity in a patient, comprising the step of administering to said patient a therapeutically effective amount of a compound as recited in claim 1 .
13. The method as recited in claim 12 , wherein the patient has depression, bipolar disorder, or post-traumatic stress disorder.
14. The method as recited in claim 12 , wherein the patient has traumatic brain injury.
15. The method as recited in claim 12 , wherein the patient has Alzheimer's disease, Parkinson's disease, or human immunodeficiency virus associated neurocognitive disorder.
16. The method as recited in claim 12 wherein the patient has a neurologic disorder of hearing or vision.
17. The method as recited in claim 12 , wherein said disorder is chosen from ototoxicity, hearing loss, acute injury to the inner ear, acoustic trauma, and injury resulting from blast noise.