IRAK inhibitors and method for making and using

1. A compound, having a formula

and/or a salt thereof, wherein:

at least one of R 1 and R 2 is heteroaryl, and the remaining R 1 or R 2 is H, alkyl, or haloalkyl;

R 3 is H, aliphatic, heteroaliphatic, heterocyclyl, amide, aromatic, or araliphatic;

R 4 is H or alkyl;

R 5 is H or alkyl; and

each R 6 independently is H, alkyl, haloalkyl, halogen, alkyl phosphate or alkylphosphonate.

2. The compound of claim 1 , wherein R 1 is heteroaryl and R 2 is H.

3. The compound of claim 1 , wherein at least one of R 1 and R 2 is nitrogen-containing heteroaryl.

4. The compound of claim 1 , wherein at least one of R 1 and R 2 is 6-membered heteroaryl.

5. The compound of claim 1 , wherein R 3 is R a , R b ,R a substituted with 1, 2, or 3 R b , R a substituted with R b and R c , R a substituted with R c , —(CR a R a ) n —R a , —(CH 2 ) n —R a , —(CR a R a ) n —R b , —(CH 2 ) n —R b , —[(CH 2 ) m —O—] n —R a , —[(CH 2 ) m —O—] n —[R a substituted with 1, 2 or 3 R b ], or —(CH 2 ) m —O—(CH 2 ) m —O—R a wherein each m and n independently are 1, 2 or 3;

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

where Y and Z independently are —CH 2 , —CHR b , O or NR d ;

R b is independently for each occurrence —OH, —CF 3 , —OR c , —NR d R d , or halogen;

R c is independently for each occurrence C 1-6 alkyl, C 3-6 heteroalicyclyl, C 1-6 alkyl substituted with 1, 2 or 3 R e , C 3-6 cycloalkyl substituted with 1, 2 or 3 R e , or C 3-6 heteroalicyclyl 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 , 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 R 70 ; and

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

6. The compound of claim 5 , wherein each R 6 independently is H, halogen, alkyl, or R a substituted with —OP(O)(R f ) 2 , and R f is independently for each occurrence —OR a , —O − M + where each M + independently is an alkali metal ion or an ammonium ion.

7. The compound of claim 1 , wherein the compound, and/or salt thereof, has a formula

R 7 is H, alkyl, alkyl phosphate or alkylphosphonate; and

each of R 8 and R 9 is independently H, alkyl, haloalkyl, halogen.

8. The compound of claim 7 , wherein one of R 8 and R 9 is H and the other of R 8 and R 9 is H or F.

9. The compound of claim 7 , wherein R 7 is H.

10. The compound of claim 7 , wherein R 7 is CH 2 OP(═O)(OR′) 2 , and each OR′ independently is OH, —Oalkyl, or —O − M + where M + is a positive counter ion.

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

each of Z 1 , Z 2 , Z 3 and Z 4 independently is N or CR 10 , where at least one of Z 1 , Z 2 , Z 3 and Z 4 is N; and

each R 10 independently is H, halogen, or aliphatic.

12. The compound of claim 11 , wherein the compound, and/or a salt thereof, has a formula

R 7 is H, alkyl, alkyl phosphate or alkylphosphonate; and

each of R 8 and R 9 is independently H, alkyl, haloalkyl, halogen.

13. The compound of claim 12 , wherein the compound, and/or salt thereof, has a formula selected from

and

R 11 , R 12 , R 13 , and R 14 , if present, are independently H, halogen, or alkyl.

14. The compound of claim 13 , wherein the compound has a formula

15. The compound of claim 14 , wherein R 11 , R 12 , R 13 , and R 14 independently is H, F, CF 3 , or CF 2 .

16. The compound of claim 15 , wherein R 2 , R 4 and R 5 are H.

17. The compound of claim 16 , wherein R 3 is H, alkyl, cycloalkyl, heteroaliphatic, or heterocycloaliphatic.

18. The compound of claim 16 , wherein R 3 is C 1-6 alkyl, tetrahydropyran, unsubstituted heteroaliphatic, heteroaliphatic substituted with halogen, unsubstituted cyclobutyl, cyclobutyl substituted with OH, alkoxy, or heterocycloaliphatic, unsubstituted cyclohexyl, or cyclohexyl substituted with —OH, alkoxy or heterocycloaliphatic.

19. A compound, selected from:

I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-2: N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-3: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-4: N-(3-(6-(difluoromethyl)pyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-5: N-(3-(6-(difluoromethyl)pyridin-2-yl)-1-((1R,4r)-4-((2R,6S)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-6: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-4-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-7: N-(3-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-8: sodium (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;

I-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-10: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-12: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;

I-13: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-14: N-(5-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-15: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-16: di-tert-butyl ((4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl) phosphate;

I-17: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;

I-18: sodium (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;

I-19: 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-20: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-21: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-22: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-23: N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-24: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-25: N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-26: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,3r)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-27: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-28: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3,5,6-trifluoropyridin-2-yl)-1H-pyrazol-4-y1)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-29: N-(3-(4,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-30: N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-31: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-32: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-33: N-(1-((1r,3r)-3-morpholinocyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-34: N-(1-((1s,3s)-3-morpholinocyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-35: 2-(3-fluoro-1H-pyrazol-4-yl)-N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrazin-2-y1)-1H-pyrazol-4-yl)oxazole-4-carboxamide formic acid salt;

I-36: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-(4-methylpiperazin-l-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-37: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-y1)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;

I-38: N-(1-((1s,3s)-3-hydroxycyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide; or

I-39: 2-(3-fluoro-1H-pyrazol-4-yl)-N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrazin-2-y1)-1H-pyrazol-4-yl)oxazole-4-carboxamide.

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

21. The composition of claim 20 , further comprising an additional therapeutic agent.