Kinase inhibitors and methods for making and using

1. A compound, having a formula 1

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

Het-1 is a 5- or 6-membered heteroaryl comprising at least one carbon atom and at least one heteroatom selected from N, O or S;

R 1 is H or alkyl;

R 2 is —N(R c ) 2 ;

each R 3 independently is C 1-6 alkyl, C 1-3 haloalkyl, or halo;

m is 0, 1 or 2;

each R 4 independently is C 1-6 alkyl;

k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

A is N or CR h ;

R h is H, R 3 or the

 moiety;

R 5 is H, aliphatic, phosphonooxyalkyl, phosphonoalkyl, or acyl;

each of R 6 and R 7 independently is H, aliphatic, or halo;

X is O or NR 9 ;

R 9 is R a , C(O)C 1-6 aliphatic, C(O)N(R c ) 2 , or CO 2 R a ;

Y is N or CH;

Linker is a bond, —(C(R 10 ) 2 ) n —, —(C(R 10 ) 2 ) n —O—, —C(O)—(C(R 10 ) 2 ) p —, or —(C(R 10 ) 2 ) p —N(R a )—;

each R 10 independently is R a or R b ;

n is 1, 2, 3, 4, 5, or 6;

p is 0, 1, or 2;

R a is independently for each occurrence H, D, C 1-6 alkyl, or C 3-6 cycloalkyl;

R b is independently for each occurrence —OH, —OR a , or halo; and

R c is independently for each occurrence R a , or two R c groups together with the nitrogen bound thereto form a C 3-7 heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents selected from C 1-6 alkyl, C 1-3 haloalkyl, —OH, or halo, and optionally interrupted with one or two additional heteroatoms selected from O, —N(R g )—, or S, where R g is R a , —C(O)R a , —C(O)OR a or —C(O)N(R a ) 2 ; or

the compound is selected from

I-39: N-(2-methoxy-5-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-40: N-(2-methoxy-5-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; or

I-41: N-(2-methoxy-5-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide.

2. The compound of claim 1 , wherein Het-1 is pyridinyl, furanyl or thiazolyl.

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

4. The compound of claim 1 , wherein R 1 is H.

5. The compound of claim 1 , wherein:

R 2 has a formula

Z is a bond, O, —NR a , —NC(O)R a , or C(R 8 ) 2 ; and

each R 8 independently is H, C 1-6 alkyl, C 1-3 haloalkyl, —OH, or halo.

6. The compound of claim 5 , wherein each R 8 independently is H, —OH, C 1-3 alkyl, or halo.

7. The compound of claim 5 , wherein Z is a bond, O, or C(R 8 ) 2 .

8. The compound of claim 5 , wherein R 2 is

9. The compound of claim 1 , wherein m is 1 or 2 and each R 3 independently is F, Cl, Br, or I.

10. The compound of claim 9 , wherein m is 1 or 2 and each R 3 independently is F.

11. The compound of claim 1 , wherein m is 1.

12. The compound of claim 1 , wherein m is 0.

13. The compound of claim 1 , wherein k is 0.

14. The compound of claim 1 , wherein each of R 6 and R 7 independently is H, halo, or C 1-6 alkyl.

15. The compound of claim 1 , wherein R 5 is H, C 1-6 alkyl, —CH 2 OP(O)(R d ) 2 , —CH 2 P(O)(R d ) 2 , or acyl, where each R d is independently for each occurrence —OR a , —O − M + where each M + independently is an alkali metal ion selected from K + , Na + , Li + or an ammonium ion selected from + NH 4 or + N(R a ) 4 , or —O − [M 2+ ] 0.5 where M 2+ is an alkaline metal earth ion selected from Mg 2+ , Ca 2+ or Ba 2+ .

16. The compound of claim 15 , wherein R 5 is H, C 1-6 alkyl, or —CH 2 OP(O)(R d ) 2 .

17. The compound of claim 16 , wherein R 5 is H.

18. The compound of claim 1 , wherein R 6 is H, R 7 is H, or both R 6 and R 7 are H.

19. The compound of claim 1 , wherein R 9 is H or C 1-6 alkyl.

20. The compound of claim 1 , wherein the

moiety is

21. The compound of claim 1 , wherein Linker is a bond, —CH 2 —, —C(O)—, —C(O)—CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 N(CH 3 )—, —CH 2 CH 2 N(H)—, —CH 2 CH 2 O—, or —CH 2 CF 2 —.

22. The compound of claim 1 , wherein the

moiety is

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

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

24. The compound of claim 1 , wherein the

moiety is para to R 2 .

25. The compound of claim 1 , wherein the

moiety is para to the amide.

26. The compound of claim 1 , wherein m is 1 and R 3 is para to the amide.

27. The compound of claim 1 , wherein m is 1 and R 3 is para to R 2 .

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

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

29. The compound of claim 28 , wherein the

moiety is para to the amide.

30. The compound of claim 28 , wherein the compound has a formula

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

31. The compound of claim 1 , wherein the

moiety is

32. The compound of claim 1 , the compound having a structure according to formula 2

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

Het-1 is pyridinyl, furanyl or thiazolyl;

R 2 is —N(R c ) 2 ;

each R 3 independently is halo;

m is 0 or 1;

each of R 5 , R 6 and R 7 is H;

A is N or CR h ;

R h is H, R 3 or the

 moiety;

X is O or NR 9 ;

R 9 is R a ;

Y is N or CH;

Linker is a bond, —(C(R 10 ) 2 ) n —, —(C(R 10 ) 2 ) n —O—, —C(O)—(C(R 10 ) 2 ) p —, or —(C(R 10 ) 2 ) p —N(R a )—;

each R 10 independently is R a or R b ;

n is 1 or 2; and

p is 0 or 1.

33. The compound of claim 32 , wherein the compound has a general formula selected from

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

34. A compound selected from:

I-1: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-2: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-3: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-4: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-5: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-6: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-7: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-8: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-9: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-10: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-11: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-12: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-13: N-(2,4-dimorpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-14: N-(2,4-dimorpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-15: N-(2,4-dimorpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-16: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-17: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-18: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-19: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-20: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-21: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-22: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-23: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-24: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-25: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-26: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-27: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-28: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-29: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-30: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-31: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-32: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-33: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-34: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-35: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-36: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-37: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-38: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-39: N-(2-methoxy-5-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-40: N-(2-methoxy-5-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-41: N-(2-methoxy-5-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-42: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-43: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-44: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-45: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-46: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-47: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-48: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-49: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-50: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-51: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-52: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-53: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-54: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-55: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-56: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-57: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-58: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-59: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-60: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-61: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-62: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-63: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-64: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-65: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-66: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-67: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-68: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-69: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-70: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-71: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carb oxamide;

I-72: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-73: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-74: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; or

I-75: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide.

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

36. The composition of claim 35 , further comprising an additional therapeutic agent selected from an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral, anticancer, antifungal, or a combination thereof.

37. A method of inhibiting an IRAK protein in a subject with rheumatoid arthritis, comprising administering to the subject an effective amount of a compound according to claim 1 .