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

1. A method for inhibiting mixed lineage kinase-3 activity in a patient, comprising administering to said patient a therapeutically effective amount of 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, each of which are unsubstituted or substituted with one or more substituents chosen from 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, 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, each of which are unsubstituted or substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carboxy, lower alkylcarbonyl, lower carboxyester, lower carboxamido, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, mercapto, lower alkylthio, lower haloalkylthio, sulfonate, or sulfonic acid.

2. The method of claim 1 , wherein the patient suffers from a disease selected from the group consisting of non-alcoholic steatohepatitis and multiple sclerosis.

3. The method of claim 1 , wherein R 3 is chosen from benzothiazolyl, pyrrolopyridinyl, and indolyl, each of which may be unsubstituted or substituted.

4. The method of claim 3 , 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 method of claim 1 , wherein Y 3 is chosen from a bond and lower alkyl.

6. The method of claim 1 , wherein Y 3 is chosen from a bond and methyl and wherein R 14 is unsubstituted or substituted lower heterocycloalkyl.

7. The method of claim 1 , wherein

u is 1, 2, or 3; and

each R 15 is independently chosen from fluoro, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NHS(O) 2 CH 3 , methoxy, and methyl.

8. The method of claim 1 , wherein

Y 4 is —CH 2 —;

u is 0, 1, or 2; and

if present, each R 15 is independently chosen from fluoro, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NHS(O) 2 CH 3 , methoxy, and methyl.

9. The method of claim 1 , wherein

Y 3 is a bond;

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

R 3 is unsubstituted or substituted 5/6-fused bicyclic heteroaryl; and

R 14 is unsubstituted or substituted lower heterocycloalkyl.

10. The method of claim 9 , wherein R 14 is unsubstituted or substituted piperazinyl.

11. The method of claim 1 , wherein the compound is selected from the group consisting of:

(5-(3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)pyridine-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]pyridine-5-yl]-benzyl}-piperazin-1-yl)-ethanone);

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

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

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

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

12. The method of claim 1 , wherein the compound is 3-(1H-indol-5-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine.

13. A method for inhibiting mixed lineage kinase-3 activity in a patient, comprising administering to said patient a therapeutically effective amount of 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, each 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, of which are unsubstituted or substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carboxy, lower alkylcarbonyl, lower carboxyester, lower carboxamido, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, mercapto, lower alkylthio, lower haloalkylthio, sulfonate, or sulfonic acid.

14. The method of claim 13 , wherein the patient suffers from a disease selected from the group consisting of non-alcoholic steatohepatitis and multiple sclerosis.

15. The method of claim 13 , wherein R 3 is chosen from benzothiazolyl, pyrrolopyridinyl, and indolyl, each of which is unsubstituted or substituted.

16. The method of claim 13 , 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.

17. The method of claim 13 , wherein Y 3 is a bond.

18. The method of claim 13 , wherein Y 3 is —CH 2 — and R 3 is lower cycloalkyl, 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.

19. The method of claim 13 , wherein

R 3 is unsubstituted or substituted 5/6-fused bicyclic heteroaryl; and

R 14 is unsubstituted or substituted lower heterocycloalkyl.

20. The method of claim 13 , wherein R 14 is unsubstituted or substituted lower heterocycloalkyl.

21. The method of claim 13 , wherein R 14 is unsubstituted or substituted piperazinyl.

22. The method of claim 13 , wherein u is 0.

23. The method of claim 13 , wherein

u is 1 or 2; and

each R 15 is independently chosen from fluoro, hydroxy, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NHS(O) 2 CH 3 , methoxy, and methyl.