IRAK inhibitors and method for making and using
Disclosed embodiments concern interleukin receptor associated kinases (IRAK) inhibitors, such as oxazole compounds, and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.
1. A compound, having a formula 1
or a salt thereof, wherein:
at least one of R 1 and R 2 is a nitrogen-containing heteroaryl, and the remaining R 1 or R 2 is H, alkyl, haloalkyl, nitro, cyano, amide, amino, hydroxyl, carboxyl, carboxyl ester, or acyl;
R 3 is H, aliphatic, heteroaliphatic, heterocyclyl, amide, aromatic, or araliphatic;
R 4 is H, aliphatic, heteroaliphatic, or one of R 1 or R 2 together with R 4 , and together with the atoms to which they are attached, form a heterocyclic ring;
R 5 is H or alkyl; and
ring A is a heterocyclic ring.
2. The compound of claim 1 , wherein the compound has a structure according to Formula 2
or a salt thereof.
3. The compound of claim 1 , wherein one of R 1 and R 2 is pyridinyl, pyrimidinyl or pyrazinyl, and the other of R 1 and R 2 is H.
4. The compound of claim 1 , wherein the compound has a structure according to Formula 5
or a salt thereof, wherein:
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.
5. The compound of claim 1 , wherein ring A is pyrazolyl.
6. The compound of claim 1 , wherein R 3 is H, alkyl, cycloalkyl, heteroaliphatic, or heterocycloaliphatic.
7. 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 a , 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 .
8. The compound of claim 1 , wherein the compound has a structure according to Formula 7
or a salt thereof, wherein:
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;
each R 6 independently is H, aliphatic, heteroaliphatic, aryl, —O-aliphatic, araliphatic, heterocyclyl, sulfonyl, halogen, nitro, OH, haloalkyl, carboxyl ester, cyano, acyl, amino, alkyl phosphate or alkylphosphonate; and
each R 10 independently is H, halogen, or aliphatic.
9. The compound of claim 8 , wherein Z 1 is N, and none or one of Z 2 , Z 3 and Z 4 is N.
10. The compound of claim 8 , wherein Z 1 and Z 2 are N, and Z 3 and Z 4 are CR 10 .
11. The compound of claim 8 , wherein Z 1 and Z 3 are N, and Z 2 and Z 4 are CR 10 .
12. The compound of claim 8 , wherein Z 1 and Z 4 are N, and Z 2 and Z 3 are CR 10 .
13. The compound of claim 8 , 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.
14. A composition, comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
15. A method for treating a disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 , or a composition comprising the compound.
16. A method for inhibiting IRAK in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a composition comprising the compound.
17. The method of claim 16 , wherein the IRAK protein is in a subject, and the method comprising administering the compound to the subject.