Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors

1. A compound having Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein:

Y 3 is chosen from a bond, lower alkyl, lower carboxy, and lower heteroalkyl;

R 3 is chosen from phenol and bicyclic heteroaryl, any of which are unsubstituted or substituted with one or more substituents chosen from hydroxy, lower amino, lower amido, lower phenylamido, lower phenylalkylamido, lower heterocycloalkyl, lower alkylheterocycloalkyl;

the moiety R 14 —Y 4 —R 2 is chosen from

wherein

u is 0, 1, 2, or 3;

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 chosen from CHF, CF 2 , —CH 2 —, —CH 2 O—, and —CH 2 N—; and

wherein R 14 is chosen from lower cycloalkyl, lower heterocycloalkyl, phenyl, and lower heteroaryl, 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 R 3 is chosen from benzothiazolyl, pyrrolopyridinyl, and indolyl, any of which may be optionally substituted.

3. The compound as recited in claim 2 , 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.

4. The compound as recited in claim 1 , wherein

Y 3 is a bond;

Y 4 is chosen from CH 2 , CHF, and CF 2 ;

R 3 is optionally substituted 5/6-fused bicyclic heteroaryl;

and R 14 is substituted or unsubstituted monocyclic lower heterocycloalkyl.

5. The compound as recited in claim 4 , wherein R 14 is substituted or unsubstituted piperazinyl.

6. The compound as recited in claim 4 , wherein said compound is 3-(1H-indol-5-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine.

7. The compound as recited in claim 1 , wherein Y 3 is chosen from a bond and lower alkyl.

8. The compound as recited in claim 1 , wherein

u is 1, 2, or 3; 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.

9. The compound as recited in claim 1 , wherein

Y 4 is —(CH 2 )—;

u is 0, 1, or 2; and

if present, 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.

10. The compound as recited in claim 1 , wherein Y 3 is chosen from a bond and methyl and wherein R 14 is substituted or unsubstituted lower heterocycloalkyl.

11. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.

13. 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 .

14. The method as recited in claim 13 wherein the patient has a neurologic disorder of hearing or vision.

15. The method as recited in claim 14 wherein said disorder is chosen from ototoxicity, hearing loss, acute injury to the inner ear, acoustic trauma, and injury resulting from blast noise.

16. The method as recited in claim 13 , wherein the patient has depression, bipolar disorder, or post-traumatic stress disorder.

17. The method as recited in claim 13 wherein the patient has a traumatic brain injury.

18. The method as recited in claim 13 wherein the patient has Alzheimer's disease, Parkinson's disease, or human immunodeficiency virus associated neurocognitive disorder.

19. The method of claim 13 , comprising administering to said patient a therapeutically effective amount of the compound of claim 4 .

20. A compound selected from the group consisting of:

5-(3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)pyridin-2-amine;

3-(1H-indol-5-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine;

3-(1H-indol-5-yl)-5-(3-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine;

1-(4-{4-[3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzyl}piperazin-1-yl)ethanone;

4-{4-[3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzyl}-1-methyl-piperazin-2-one;

4-{4-[3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzyl}piperazin-2-one;

4-{3-[3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzyl}-1-methyl-piperazin-2-one; and

4-{4-[3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzyl}piperazine-1-carboxylic acid tert-butyl ester,

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the compound of claim 20 and a pharmaceutically acceptable carrier.