Benzazole compounds and methods for making and using the compounds

1. A compound having a formula

or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof, wherein:

X is O;

Y is O and Z is CR 9 ; or

Y is S and Z is N;

Het-1 is pyrazolyl;

R 1 and R 2 independently are H, aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, or together with the nitrogen to which they are attached, form a heterocyclic ring;

R 3 , R 4 , R 5 , R 6 and R 9 independently are H, aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl;

R 7 is H, aliphatic, heteroaliphatic, heterocyclyl, aryl or araliphatic;

each R 8 independently is aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl; and

m is from 0 to 3.

2. The compound of claim 1 , wherein Het-1 is selected from

and

R 10 is selected from H, aliphatic, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl.

3. The compound of claim 1 , wherein

is selected from

4. The compound of claim 2 , wherein:

each R 8 independently is selected from halo, C 1-6 haloalkyl, C 1-6 alkyl, —OC 1-6 alkyl, amino or —CH 2 OP(O)(OR 24 ) 2 ; and

each R 24 independently is H, C 1-6 alkyl or a counterion forming a pharmaceutically acceptable base addition salt with the phosphate moiety.

5. The compound of claim 4 , wherein at least one R 8 is —NH 2 , —CH 3 , CF 3 , —CF 2 H or —CH 2 CF 3 .

6. The compound of claim 1 , wherein the compound has a formula

7. The compound of claim 1 , wherein the compound has formula selected from

and

R 10 is selected from H, aliphatic, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl.

8. The compound of claim 1 , wherein the compound has a formula selected from

R 10 is H, aliphatic, aryl or heterocyclyl; and

R 11 , R 12 , and R 13 independently are H, aliphatic, halogen, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, or haloalkyl.

9. The compound of claim 8 , wherein the compound has a formula selected from

10. The compound of claim 8 , wherein the compound has a formula selected from

11. The compound of claim 1 , wherein R 5 is amino, aryl or heteroaryl.

12. The compound of claim 11 , wherein R 5 is amino having a formula —NRR wherein each R independently is aliphatic, or both R groups together with the nitrogen attached thereto form a heterocyclic ring.

13. The compound of claim 12 , wherein R 5 is a cyclic amino selected from

14. The compound of claim 11 , wherein R 5 is

15. The compound of claim 1 , wherein R 1 and R 2 independently are H, aliphatic, heteroaliphatic, or together with the nitrogen attached thereto forms a heteroaliphatic ring.

16. The compound of claim 15 , wherein R 1 is H or alkyl, and R 2 is aliphatic or heteroaliphatic.

17. The compound of claim 1 , wherein R 1 and R 2 , together with the nitrogen attached thereto, are selected from

R a is aliphatic, haloalkyl or acyl;

n is 1 or 2; and

p is 0, 1 or 2.

18. The compound of claim 17 , wherein:

R a is CH 3 , CF 3 , CF 2 H, or R b C(O)—; and

R b is aliphatic or haloalkyl.

19. A compound selected from

I-3: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-4: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;

I-7: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-8: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;

I-12: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-13: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;

I-16: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-17: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;

I-20: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-21: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;

I-23: N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-25: N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-27: N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-29: N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-31: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-32: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;

I-35: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-36: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;

I-38: N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-40: N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-42: N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-44: N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-46: N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-47: N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-48: N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-49: N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-50: N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-51: N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-52: N-(2-((2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-53: N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-54: N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-55: N-(2-((2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or combination thereof.

20. A composition, comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.

21. The compound of claim 1 , wherein the compound has a formula

22. The compound of claim 1 , wherein R 3 , R 4 , R 6 and R 7 are H.

23. The compound of claim 19 , wherein the compound has an activity in an LPS induced IL23p19 assay performed in THP-1 cells primed with IFNγ of from greater than zero to 20 μM.

24. An IRAK inhibitor compound having a formula

or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof, and an activity in an LPS induced IL23p19 assay performed in THP-1 cells primed with IFNγ of from greater than zero to 20 μM;

wherein:

X is O;

Y is O and Z is CR 9 ; or

Y is S and Z is N;

Het-1 is pyrazolyl;

R 1 and R 2 independently are H, aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, or together with the nitrogen to which they are attached, form a heterocyclic ring;

R 3 , R 4 , R 6 and R 9 are H;

R 5 is H, aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O— heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl;

R 7 is H, aliphatic, heteroaliphatic, heterocyclyl, aryl or araliphatic;

each R 8 independently is aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl; and

m is from 0 to 3.