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 the formula
wherein
X is selected from CH 2 , O, S, S(O), S(O) 2 and NR a ;
R a is for each occurrence selected from hydrogen, C 1-6 alkyl and C 1-6 acyl;
Y 1 , Y 2 and Y 3 are independently selected from the group consisting of N, N(R a ), O, C(R b ) 1-2 and C═O;
R b is selected from hydrogen, C 1-6 alkyl and halo;
Z is C(R c ) or NR c ;
R c is a C 1-4 unsaturated carbon chain optionally substituted with one or more R 1 groups, optionally interrupted by 1 or 2 heteroatoms selected from O, N and S;
R z is N, CH or C(R 1 ) and together with ZR c and the carbon to which they are bound form a 5- or 6-membered heteroaryl or 6-membered aryl ring substituted with m R 1 groups;
R 1 is a linker-R 6 group, wherein the linker is a bond, (C1-C4) alkanyl, (C2-C4) alkenyl or (C2-C4) alkynyl, optionally substituted by one or more R b and R 6 is R e , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R 2 is R a ;
ring B is 5-10-membered heteroaryl;
R 3 is, for each occurrence, independently selected from R b and OR a ;
L is O, NR a or alkylene;
W is 5-10 membered aryl or heteroaryl optionally substituted by p R 4 ;
R 4 is for each occurrence selected from R b and OR a ;
R d is for each occurrence independently selected from hydrogen, C 1-6 alkyl, aralkyl, C 5-10 aryl or heteroaryl, or two R d together with a nitrogen to which they are both attached form a C 3-10 heterocyclic group optionally substituted by one or more R e ;
R e is independently for each occurrence halo, —OR d , —SR d , —S(O) 2 R d , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR a , or —C(O)NR d R d ;
R f is independently for each occurrence R a , R b , or R e , or two R f groups together with the carbon atom bound thereto provide a C 3-6 cycloalkyl group or a C 3-10 heterocyclic group each optionally substituted with one or more R e ;
m is 1, 2, 3, or 4;
n is 0, 1 or 2; and
p is 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1 , having the formula
3. The compound of claim 1 , having the formula
4. The compound of claim 1 , having the formula
5. The compound of claim 1 , having the formula
wherein Z 1 is selected from C and N; and
Z 2 , Z 3 and Z 4 independently are selected from O, S, S(O) 2 , CH, N, N(R a ) and CR 1 .
6. The compound of claim 1 , having the formula
wherein Z 1 is C or N and Z 3 is O, S, N or N(R a ).
7. A compound according to the formula
wherein
X is selected from CH 2 , O, S, S(O), S(O) 2 and NR a ;
R a is for each occurrence selected from hydrogen, C 1-6 alkyl and C 1-6 acyl;
Y 1 , Y 2 and Y 3 are independently selected from the group consisting of N, N(R a ), O, C(R b ) 1-2 and C═O;
R b is selected from hydrogen, C 1-6 alkyl and halo;
Z is C(R c ) or NR c ;
R c is a C 1-4 unsaturated carbon chain optionally substituted with one or more R 1 groups, optionally interrupted by 1 or 2 heteroatoms selected from O, N and S;
R z is N, CH or C(R 1 ) and together with ZR c and the carbon to which they are bound form a 5 or 6 membered heteroaryl or 6-membered aryl ring is substituted with m R 1 groups;
R 1 is halo or a linker-R 6 group, wherein the linker is a bond, (C1-C4) alkanyl, (C2-C4) alkenyl or (C2-C4) alkynyl, optionally substituted by one or more R b and R 6 is R e , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R 2 is R a ;
ring B is 5-10-membered heteroaryl;
R 3 is, for each occurrence, independently selected from R b and OR a ;
L is O, NR a or alkylene;
W is 5-10 membered aryl or heteroaryl optionally substituted by p R 4 ;
R 4 is for each occurrence selected from R b and OR a ;
R d is for each occurrence independently selected from hydrogen, C 1-6 alkyl, aralkyl, C 5-10 aryl or heteroaryl, or two R d together with a nitrogen to which they are both attached form a C 3-10 heterocyclic group optionally substituted by one or more R e ;
R e is independently for each occurrence halo, —OR d , —SR d , —S(O) 2 R d , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR a , or —C(O)NR d R d ;
R f is independently for each occurrence R a , R b , or R e , or two R f groups together with the carbon atom bound thereto provide a C 3-6 cycloalkyl group or a C 3-10 heterocyclic group each optionally substituted with one or more R e ;
m is 1, 2, 3, or 4;
n is 0, 1 or 2; and
p is 0, 1, 2, 3, 4, or 5.
8. The compound according to claim 1 , wherein X is O.
9. The compound according to claim 1 , wherein Y 1 is N.
10. The compound according to claim 1 , wherein Y 1 , Y 2 and Y 3 are each N.
11. The compound according to claim 1 , wherein Y 2 is O.
12. The compound according to claim 1 , wherein Y 3 is C═O.
13. The compound according to claim 1 , wherein Y 1 , Y 2 and Y 3 are each C(R b ) 1-2 .
14. The compound of claim 13 , wherein at least one R b of Y 1 , Y 2 and Y 3 is halo.
15. The compound according to claim 1 , wherein at least one R 1 is a linker-R 6 group.
16. The compound according to claim 1 , wherein W is
17. The compound according to claim 1 , wherein W is pyridyl.
18. The compound according to claim 1 , wherein the B ring has the formula
19. The compound according to claim 1 , wherein the compound is present in a salt form.