Amide compounds and method for making and using

1. A method for inhibiting IRAK in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a composition comprising the compound according to formula 1

or a salt thereof, wherein: ring A is heterocyclyl; R 1 is H, aliphatic, or heteroaliphatic; R 2 is H, aliphatic, heteroaliphatic, or heterocyclyl; each of Z 1 , Z 2 , Z 3 , and Z 4 , independently is N or CR 3 , wherein at least one of Z 1 , Z 2 , Z 3 , and Z4 is N; each R 3 independently is H, aliphatic, or heteroaliphatic; and R 4 is halogen, heterocycloaliphatic, aromatic, —O-aromatic, or —NH-aromatic.

2. The method of claim 1 , wherein ring A is pyridinyl, pyrazinyl, pyrrolidinyl, piperidinyl, or morpholino.

3. The method of claim 1 , wherein ring A is

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

and each of R 8 , R 9 , R 10 and R 11 independently is H, aliphatic, halogen, heterocycloaliphatic, alkoxy, or —O-heterocycloaliphatic.

5. The method of claim 4 , wherein each of R 8 , R 9 , R 10 and R 11 independently is H, halogen, 3- to 6-membered heterocycloaliphatic, alkoxy, or —O-(3- to 6-membered heterocycloaliphatic).

6. The method of claim 5 , wherein:

R 8 is H or halogen;

R 9 and R 11 are H;

R 10 is H, F, morpholino, N-methylpiperidin-1-yl, methoxy, 2-hydroxy-2-methylpropoxy, or —O-oxetanyl; or

a combination thereof.

7. The method of claim 4 , wherein the compound has a formula

8. The method of claim 1 , wherein:

R 1 is H or C 1-6 alkyl;

R 2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, cyclobutyl substituted with alkoxy and/or hydroxy, cyclohexyl, cyclohexyl substituted with alkoxy and/or hydroxy, unsubstituted C 1-6 alkyl, or C 1-6 alkyl substituted with —OH, amino, alkoxy, or heterocycloaliphatic;

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

R 4 is halogen, heterocycloaliphatic, aryl, heteroaryl, —NH-heteroaryl, or —O-heteroaryl;

Z 1 is N;

or a combination thereof.

9. The method of claim 1 , wherein R 2 is H, CH 3 ,

10. The method of claim 1 , wherein:

Z 1 is N, and Z 2 , Z 3 , and Z 4 are CR 3 ;

Z 1 and Z 2 are N, and Z 3 and Z 4 are CR 3 ;

Z 1 and Z 3 are N, and Z 2 and Z 4 are CR 3 ;

Z 1 and Z 4 are N, and Z 2 and Z 3 are CR 3 ; or

Z 3 is N, and Z 1 , Z 2 , and Z 4 are CR 3 .

11. The method of claim 10 , wherein R 4 is Br, 5- to 10-membered heteroaryl, 3- to 6-membered heterocycloaliphatic, 6- to 10-membered aryl, —NH-(5- to 10-membered heteroaryl), or —O-(5- to 10-membered heteroaryl).

12. The method of claim 10 , wherein R 4 is pyridinyl, pyrimidinyl, pyrazolyl, —NH-pyrazolyl, pyrrolyl, —O-pyridinyl, —NH-pyridinyl, indolyl, furanyl, —NH-benzopyrazolyl, pyrrolopyridinyl, phenyl, tetrahydropyridinyl, piperidinyl, or 2-oxo-1,2-dihydropyridinyl.

13. The method of claim 10 , wherein R 4 is Br,

where y is 0, 1 or 2, and each R p independently is R a , R b , R a substituted with R b , or R a substituted with R c ;

R a is independently for each occurrence H, D, C 1-6 alkyl, C 3-6 cycloalkyl, C 5-10 aromatic, or C 3-6 heterocycloaliphatic;

R b is independently for each occurrence —OH, —CF 3 , —CN, —OR c , —SO 2 R c , —NR d R d , —N(H)SO 2 R c , —C(O)OH, —N(H)C(O)R c , —C(O)OR c , —C(O)NR d R d , ═O, or halogen;

R c is independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heteroalicyclyl, aralkyl, C 1-6 alkyl substituted with 1, 2 or 3 R e , C 5-10 aromatic, C 5-10 aromatic substituted with 1, 2 or 3 R e ;

R d is independently for each occurrence H, C 1-6 alkyl optionally substituted with 1, 2 or 3 R e C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R e , C 3-6 heteroalicyclyl optionally substituted with 1, 2 or 3 R e , C 5-10 aromatic optionally substituted with 1, 2 or 3 R a or R b , or two R d groups together with the nitrogen bound thereto form a C 3-6 heteroalicyclyl moiety optionally substituted with C 1-6 alkyl and optionally interrupted with one or two —O— or —N(R g ) wherein R g is H, C 1-10 aliphatic, heteroaliphatic, or cycloaliphatic; and

R e is independently for each occurrence halogen, C 1-6 alkyl, C 3-6 cycloalkyl, or —OR a .

14. The method of claim 13 , wherein each R p independently is —CH 3 , —OCH 3 , —NH 2 , —CF 3 , F, —CN,

15. The method of claim 7 , wherein:

R 1 is H;

R 2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, cyclobutyl substituted with alkoxy and/or hydroxy, cyclohexyl, cyclohexyl substituted with alkoxy and/or hydroxy, unsubstituted C 1-6 alkyl, or C 1-6 alkyl substituted with —OH, amino, alkoxy, or heterocycloaliphatic;

R 4 is Br; unsubstituted pyridinyl; pyridinyl substituted with C 1-6 alkyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, —CN, alkoxy, —O-heterocycloaliphatic, —NH-heterocycloaliphatic, halogen, sulfonamide, —O-benzyl, carboxyl, sulfonyl, —NH-cycloalkyl, or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C 1-6 alkyl; unsubstituted —NH-pyrazolyl; —NH-pyrazolyl substituted with C 1-6 alkyl, or heteroaryl; pyrrolyl; unsubstituted —O-pyridinyl; —O-pyridinyl substituted with amino; —NH-pyridinyl substituted with C 1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; indolyl substituted with alkoxy; furanyl; —NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C 1-6 alkyl, alkoxy, —CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl;

R 8 is H or F;

R 9 and R 11 are H; and

R 10 is H, F, morpholino, N-methylpiperidinyl, methoxy, 2-hydroxy-2-methylpropoxy, or —O-oxetanyl.

16. The method of claim 15 , wherein

each of R 8 , R 9 , R 10 and R 11 is H;

R 8 , R 9 , and R 11 are H and R 10 is 3- to 6-membered morpholino or N-methylpiperidinyl, methoxy, 2-hydroxy-2-methylpropoxy, or —O-oxetanyl; or

R 8 and R 10 are F, and R 9 and R 11 are H.

17. The method of claim 1 , having a formula

or a salt thereof, wherein:

ring A is heterocyclic;

R 1 is H;

R 2 is H, alkyl or heterocyclic;

R 4 is halogen, heterocycloaliphatic, aromatic, —O-aromatic, or —NH-aromatic; and

each of R 5 , R 6 , and R 7 independently is H or alkyl.

18. The method of claim 1 , wherein the subject has a disease or condition selected from the group consisting of an auto-immune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multi-organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection and immune regulatory disorder or a combination thereof.

19. A method for inhibiting IRAK in a subject, comprising administering to a subject in need thereof an effective amount of a compound selected from:

I-1: 6-bromo-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-2: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-3: 5′-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-4: 5′-cyano-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-5: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(pyrimidin-5-yl)picolinamide;

I-6: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-5-yl)picolinamide;

I-7: 6-(3-methyl-1H-pyrazol-5-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-8: 6-(1-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-9: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-10: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrol-2-yl)picolinamide;

I-11: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrol-3-yl)picolinamide;

I-12: 5′-methyl-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-13: 5′-cyclopropyl-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-14: 5′-(2-hydroxypropan-2-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-15: 2′-methyl-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-16: 6′-methyl-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-17: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridine]-6-carboxamide;

I-18: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2′-(trifluoromethyl)-[2,4′-bipyridine]-6-carboxamide;

I-19: 5′-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-20: 6′-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-21: 2′-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-22: 5′-isopropoxy-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-23: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-((tetrahydro-2H-pyran-4-yl)oxy)-[2,3′-bipyridine]-6-carboxamide;

I-24: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(2,2,2-trifluoroethoxy)-[2,3′-bipyridine]-6-carboxamide;

I-25: 5′-amino-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-26: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(methylamino)-[2,3′-bipyridine]-6-carboxamide;

I-27: 5′-(cyclopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-28: 5′-(isopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-29: 5′-(tert-butylamino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-30: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-((tetrahydro-2H-pyran-4-yl)amino)-[2,3′-bipyridine]-6-carboxamide;

I-31: 5′-((2-methoxyethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-32: 5′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-33: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-((2,2,2-trifluoroethyl)amino)-[2,3′-bipyridine]-6-carboxamide;

I-34: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(methylsulfonamido)-[2,3′-bipyridine]-6-carboxamide;

I-35: 5′-(dimethylamino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-36: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(pyrrolidin-1-yl)-[2,3′-bipyridine]-6-carboxamide;

I-37: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-morpholino-[2,3′-bipyridine]-6-carboxamide;

I-38: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(4-methylpiperazin-1-yl)-[2,3′-bipyridine]-6-carboxamide;

I-39: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(methylsulfonyl)-[2,3′-bipyridine]-6-carboxamide;

I-40: N6-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-5′,6-dicarboxamide;

I-41: N6-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-2′,6-dicarboxamide;

I-42: 2′-cyano-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-43: 6′-amino-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-44: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;

I-45: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)picolinamide;

I-46: 6-(1H-indol-5-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-47: 6-(1H-indol-6-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-48: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-phenylpicolinamide;

I-49: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(m-tolyl)picolinamide;

I-50: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(p-tolyl)picolinamide;

I-51: 6-(3-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-52: 6-(4-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-53: 6-(3-cyanophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-54: 6-(4-cyanophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-55: 6-(3-fluorophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-56: 6-(4-fluorophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-57: 6-(3-aminophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-58: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(3-(methylamino)phenyl)picolinamide;

I-59: 6-(3-(dimethylamino)phenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-60: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(3-(methylsulfonamido)phenyl)picolinamide;

I-61: tert-butyl 6-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate;

I-62: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-6-carboxamide;

I-63: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(piperidin-4-yl)picolinamide;

I-64: tert-butyl 6-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)-5′,6′-dihydro-[2,3′-bipyridine]-1′(2′H)-carboxylate;

I-65: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-1′,2′,5′,6′-tetrahydro-[2,3′-bipyridine]-6-carboxamide;

I-66: 6-bromo-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)picolinamide;

I-67: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-5-yl)picolinamide;

I-68: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-69: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-70: 5′-isopropoxy-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-71: 5′-(isopropylamino)-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-72: N-(1-methyl-3-(pyrrolidin-1-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-73: N-(1-methyl-3-(piperidin-1-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-74: N-(1-methyl-3-morpholino-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-75: 5′-methyl-N-(1-methyl-3-(pyrrolidin-1-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-76: 5′-methyl-N-(1-methyl-3-(piperidin-1-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-77: 5′-methyl-N-(1-methyl-3-morpholino-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-78: 6-(3-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-79: 6-bromo-N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-80: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-81: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-82: 6-bromo-N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-83: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-84: 5′-methyl-N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-85: 6-bromo-N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-86: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-87: 5′-methyl-N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-88: N-(1-(2-hydroxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-89: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(pyridin-4-yloxy)picolinamide;

I-90: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-91: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2′-oxo-1′,2′-dihydro-[2,4′-bipyridine]-6-carboxamide;

I-92: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6′-oxo-1′,6′-dihydro-[2,3′-bipyridine]-6-carboxamide;

I-93: N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-5′-(2,2,2-trifluoroethoxy)-[2,3′-bipyridine]-6-carboxamide;

I-94: N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-95: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-96: 2′-methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-97: 6′-amino-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-98: 6′-acetamido-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-99: 2′-methoxy-N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-100: N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-101: N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-102: 6′-acetamido-N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-103: 2′-(benzyloxy)-N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-104: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-105: N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-5′-(2,2,2-trifluoroethoxy)-[2,3′-bipyridine]-6-carboxamide formate;

I-106: N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide formate;

I-107: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide formate;

I-108: N-(1-(2-hydroxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide formate;

I-109: 5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)nicotinamide;

I-110: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[3,4′-bipyridine]-5-carboxamide;

I-111: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[3,3′-bipyridine]-5-carboxamide;

I-112: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-113: 6-bromo-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-114: 5′-methyl-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-115: 5′-(methylsulfonamido)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-116: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-117: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide;

I-118: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)amino)pyrimidine-2-carboxamide;

I-119: sodium (methyl sulfonyl)(6-((1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)-[2,3′-bipyridin]-5′-yl)amide;

I-120: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(5-methylpyridin-3-yl)pyrimidine-2-carboxamide;

I-121: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(5-methylpyridin-3-yl)pyrazine-2-carboxamide;

I-122: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazine-2-carboxamide;

I-123: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)pyrazine-2-carboxamide;

I-124: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrimidine-2-carboxamide;

I-125: N-(1-(1,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-126: N-(1-(1,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-127: N-(1-(1,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-128: 4-((1H-pyrazol-3-yl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidine-2-carboxamide;

I-129: 4-((3-methyl-1H-pyrazol-4-yl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidine-2-carboxamide;

I-130: 5′-isopropoxy-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-131: 5′-fluoro-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-132: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridine]-6-carboxamide;

I-133: N6-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-5′,6-dicarboxamide;

I-134: 6-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-135: 6-((1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)-[2,3′-bipyridine]-5′-carboxylic acid;

I-136: 6-(3-methyl-1H-pyrazol-5-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-137: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)pyrimidine-4-carboxamide;

I-138: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-3-yl)pyrimidine-4-carboxamide;

I-139: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(pyridin-4-yloxy)picolinamide formate;

I-140: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide formate;

I-141: 2′-methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide formate;

I-142: 6′-amino-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide formate;

I-143: 6′-acetamido-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide formate;

I-144: 3′-fluoro-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide formate;

I-145: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-3′-methyl-[2,4′-bipyridine]-6-carboxamide formate;

I-146: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2′-methyl-[2,4′-bipyridine]-6-carboxamide formate;

I-147: 6-(6-methoxy-1H-indol-2-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide formate;

I-148: 6-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide formate;

I-149: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide formate;

I-150: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide formate;

I-151: 6-(furan-3-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide 2,2,2-trifluoroacetate;

I-152: 6-(furan-2-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide 2,2,2-trifluoroacetate;

I-153: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide formate;

I-154: 6-((1H-indazol-5-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide formate;

I-155: 6-((2H-indazol-5-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide formate;

I-156: 6-((2-aminopyridin-4-yl)oxy)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide formate;

I-157: 6-((2,5-dimethylpyridin-4-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide formate;

I-158: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-((6-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)picolinamide formate;

I-159: 2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide formate;

I-160: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide 2,2,2-trifluoroacetate;

I-161: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2′-((2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide formate;

I-162: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide formate;

I-163: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide formate;

I-164: 5′-methyl-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-165: 6-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinamide;

I-166: 6-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinamide;

I-167: N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-168: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-169: N-(1-(3-methoxypropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-170: 5′-methyl-N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-171: N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-172: N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide;

I-173: 5′-methyl-N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-174: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-175: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide;

I-176: 5′-methyl-N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide dihydrochloride;

I-177: 5′-methyl-N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide dihydrochloride;

I-178: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-179: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-180: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide;

I-181: 5′-methyl-N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide;

I-182: N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-183: N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide;

I-184: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-185: 3′-fluoro-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-186: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-3′-methyl-[2,4′-bipyridine]-6-carboxamide;

I-187: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2′-methyl-[2,4′-bipyridine]-6-carboxamide;

I-188: 6-(6-methoxy-1H-indol-2-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-189: 6-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-190: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-191: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide;

I-192: 6-(furan-3-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-193: 6-(furan-2-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-193: 6-(furan-2-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-194: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-195: 6-((1H-indazol-5-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-196: 6-((2H-indazol-5-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-197: 6-((2-aminopyridin-4-yl)oxy)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-198: 6-((2,5-dimethylpyridin-4-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-199: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-((6-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)picolinamide;

I-200: 2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-201: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide;

I-202: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2′-((2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide;

I-203: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-204: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-205: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-206: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-5′-methyl-[2,3′-bipyridine]-6-carboxamide;

I-207: N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide; or

I-208: 5′-methyl-N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide.

20. A method for inhibiting an IRAK protein, comprising contacting the IRAK protein with an effective amount of a compound according to formula 1

or a salt thereof, wherein:

ring A is heterocyclyl;

R 1 is H, aliphatic, or heteroaliphatic;

R 2 is H, aliphatic, heteroaliphatic, or heterocyclyl;

each of Z 1 , Z 2 , Z 3 , and Z 4 , independently is N or CR 3 , wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;

each R 3 independently is H, aliphatic, or heteroaliphatic; and

R 4 is halogen, heterocycloaliphatic, aromatic, —O-aromatic, or —NH-aromatic.

21. The method of claim 20 , wherein the IRAK protein is in a subject.

22. The method of claim 21 , wherein the method is a method for treating a disease or condition for which an IRAK inhibitor is indicated.

23. The method of claim 22 , wherein the disease or condition is an auto-immune disease, inflammatory disorder, cardiovascular disease, cancer, ischemic condition, immune regulatory disorder or a combination thereof.

24. The method of claim 23 , wherein the disorder is an inflammatory skin disease, psoriasis, primary biliary cirrhosis, sclerosing cholangitis, or systemic juvenile idiopathic arthritis.

25. The method of claim 18 , wherein the disease or condition is an auto-immune disease or inflammatory disorder.

26. The method of claim 18 , wherein the cancer is breast cancer, lung cancer, melanoma, leukemia, large B-cell lymphoma, Waldenström's macroglobulinemia, myelodysplastic syndromes, Kaposi's sarcoma, or a combination thereof.

27. The method of claim 25 , wherein the disorder comprises transplant or tissue rejection, a graft-versus-host disease, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, postinfectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Sjögren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia, alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma, Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis, cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, carcinogenesis, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, non-alcoholic steatohepatitis (NASH), hepatic failure, fulminant hepatic failure, late-onset hepatic failure, “acute-on-chronic” liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, senile dementia, Parkinson's disease, trauma, chronic bacterial infection, or a combination thereof.

28. The method of claim 25 , wherein the disorder is an inflammatory skin disease, psoriasis, primary biliary cirrhosis, sclerosing cholangitis, or systemic juvenile idiopathic arthritis.