IRAK inhibitors and method for making and using

1. A method for treating a disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a compound, or a composition comprising the 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,

wherein the disease or condition comprises gout, gout flares, pseudogout, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, dermatomyositis, ichthyosis vulgaris, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, dermatitis, atopic dermatitis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, lupus, psoriasis, psoriatic arthritis, osteoarthritis, pyoderma, Waldenström's macroglobulinemia, myelodysplastic syndrome, alcoholic liver disease, alcoholic cirrhosis, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, sclerosing cholangitis, adult onset Still's disease, periodic fever syndrome, hyperimmunoglobulinemia d syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, uveitis, Behcet's disease, dermatomyositis, vasculitis or systemic juvenile idiopathic arthritis.

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

3. The method of claim 1 , wherein:

at least one of R 1 and R 2 is nitrogen-containing heteroaryl;

at least one of R 1 and R 2 is 6-membered heteroaryl; or

at least one of R 1 and R 2 is 6-membered nitrogen-containing heteroaryl.

4. The method 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 .

5. The method of claim 4 , 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.

6. The method 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.

7. The method of claim 6 , wherein one of R 8 and R 9 is H and the other of R 8 and R 9 is H or F.

8. The method of claim 6 , wherein R 7 is H.

9. The method of claim 6 , wherein R 7 is CH 2 OP(═O)(OR′) 2 , and each OR′ independently is OH, —O-alkyl, or —O − M + where M + is a positive counter ion.

10. The method 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.

11. The method of claim 10 , wherein the compound, and/or salt thereof, has a formula selected from

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

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

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

12. The method of claim 11 , wherein the compound has a formula

and

each of R 11 , R 12 , R 13 , and R 14 independently is H, F, CF 3 , or CF 2 .

13. The method of claim 12 , wherein R 2 , R 4 and R 5 are H.

14. The method of claim 13 , wherein R 3 is H, alkyl, cycloalkyl, heteroaliphatic, or heterocycloaliphatic.

15. The method of claim 13 , 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.

16. The method of claim 1 , wherein the compound is 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-yl)-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-yl)-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-1-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-yl)-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-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide.

17. The method of claim 1 , wherein the disease or condition is selected from aplastic anemia, psoriasis, primary biliary cirrhosis, pyoderma, sclerosing cholangitis, systemic juvenile idiopathic arthritis or a combination thereof.

18. The method of claim 1 , wherein the disease is dermatitis.

19. The method of claim 1 , wherein the disease is pustular psoriasis.

20. The method of claim 1 , wherein the disease is myelodysplastic syndrome.

21. The method of claim 1 , wherein the disease is Waldenström's macroglobulinemia.