RIP1K inhibitors
Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.
1. A compound according to Formula I
wherein ring B is 5-membered or 6-membered heteroaryl;
X is CH 2 or O;
L is a heteroatom or R a , provided that R a is not hydrogen;
Z is C 1-10 aliphatic (such as C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl); aryl or heteroaryl, each optionally substituted with one or more R 5 group;
R 1 is independently for each occurrence —NR d R d wherein the two R d groups together with the nitrogen bound thereto provide a C 3-10 heterocyclic group; —C≡CH, or a -linker-R 6 group, wherein the linker is a divalent C 1-10 aliphatic moiety (such as C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl) or C 1-10 cycloaliphatic moiety, and R 6 is R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ; C 5-10 aromatic, or C 3-6 heterocyclic, each linker optionally substituted with one or more halo, R a , or both;
R 2 and R 3 independently are R a ;
R 4 and R 5 independently are, for each occurrence, R e ;
R a is independently for each occurrence hydrogen, C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic, or C 3-6 heterocyclic;
R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR e R e , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , or —C(O)NR e R e
R c is independently for each occurrence C 1-10 alkyl (optionally substituted with 1, 2 or 3 R e ), C 2-10 alkenyl (optionally substituted with 1, 2 or 3 R e ), C 2-10 alkynyl (optionally substituted with 1, 2 or 3 R e ), C 3-6 cycloalkyl (optionally substituted with 1, 2 or 3 R e ), or C 5-10 aromatic (optionally substituted with 1, 2 or 3 R e );
R d is C 1-9 aliphatic optionally substituted with 1, 2, or 3 R a , R b and/or R e groups;
R e is independently for each occurrence oxo (═O), —OR a , N(R a ) 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, or two R e groups join together to provide a C 3-10 heterocyclic group with a nitrogen to which the two R e groups are bound;
m is 1 to 4; and
n is 0, 1 or 2.
2. A method for inhibiting a RIP kinase, comprising contacting the kinase with a compound according to claim 1 .
3. The compound of claim 1 , wherein ring B is 5-membered or 6-membered heteroaryl.
4. The compound of claim 1 , wherein ring B is a 5-membered heteroaryl.
5. The compound of claim 4 , wherein ring B is a triazole, a diazole, an oxazole or an oxadiazole.
6. The compound of claim 1 , wherein ring B is pyrazolyl, and the —N(R 3 )C(O)— moiety is attached to ring B at a ring nitrogen atom on ring B.
7. The compound of claim 1 , wherein ring B is 6-membered heteroaryl.
8. The compound of claim 7 , wherein ring B is pyridinyl.
9. The compound of claim 1 , wherein R 2 is C 1-6 alkyl.
10. The compound of claim 1 , wherein R 2 is methyl.
11. The compound of claim 10 , wherein R 2 is CD 3 .
12. The compound of claim 1 , wherein R 3 is H.
13. The compound of claim 1 , wherein n is 0.
14. The compound of claim 1 , wherein n is 1.
15. The compound of claim 1 , wherein at least one R 4 is C 1-6 alkyl.
16. The compound of claim 1 , wherein at least one R 4 is fluoro.
17. The compound of claim 14 , wherein R 4 is C 1-6 alkyl or fluoro.
18. The compound of claim 1 , wherein X is O.
19. The compound of claim 1 , wherein X is —CH 2 —.
20. The compound of claim 1 , wherein L is a heteroatom.
21. The compound of claim 13 , wherein L is O.
22. The compound of claim 1 , wherein L is C 1-6 alkyl.
23. The compound of claim 1 , having Formula II
24. The compound of claim 1 , having Formula IIA
25. The compound of claim 1 , having Formula IIB, IIC, IID or IIE
wherein each W is independently N or O.
26. The compound of claim 1 , having Formula IIF, IIG, IIH
27. The compound of claim 1 , having Formula IIK
28. The compound of claim 1 , wherein m is 1.
29. The compound of claim 1 , wherein at least one R 1 is halogen.
30. The compound of claim 1 , wherein at least one R 1 is -linker-R 6 .
31. The compound of claim 29 , wherein at least one R 1 is 8- to 12-membered spiroheterocyclyl, C 1-10 alkyl or a C 2-10 alkyne.
32. The compound of claim 1 , wherein at least one R 1 is selected from the following:
33. The compound of claim 1 , wherein at least one R 1 is
34. The compound of claim 1 , wherein at least one R 1 is selected from
35. The compound of claim 1 , wherein at least one R 1 is selected from
36. The compound of claim 1 , having the formula
37. The compound of claim 1 , having the formula