RIP1 inhibitory compounds and methods for making and using the same
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, having a formula
wherein R 2 is R a ;
R a is independently for each occurrence H, D, C 1 alkyl, substituted or non-substituted C 2-10 aliphatic, substituted or non-substituted C 1-10 haloaliphatic, substituted or non-substituted C 5-10 aromatic, or substituted or non-substituted C 3-6 heterocyclic;
linker is CH 2 or R a , provided that R a is not H or D;
R 6 is R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , or —C(O)NR d R d ;
R c is independently for each occurrence substituted or non-substituted C 1-10 alkyl, substituted or non-substituted C 2-10 alkenyl, substituted or non-substituted C 2-10 alkynyl, or substituted or non-substituted C 3-6 cycloalkyl;
R d is independently for each occurrence H; substituted or non-substituted C 1-6 alkyl; substituted or non-substituted C 3-6 cycloalkyl; substituted or non-substituted C 3-6 heterocyclic; substituted or non-substituted C 5-10 aryl; substituted or non-substituted C 5-10 heteroaryl; or two R d groups together with the nitrogen bound thereto provide a substituted or non-substituted C 3-9 heterocyclic group, or a substituted or non-substituted C 5-10 heteroaryl;
R e is independently for each occurrence halogen, substituted or non-substituted C 1-6 alkyl, substituted or non-substituted C 2-10 alkenyl, substituted or non-substituted C 2-10 alkynyl, substituted or non-substituted C 1-6 haloalkyl, substituted or non-substituted C 3-6 cycloalkyl, substituted or non-substituted C 5-10 heteroaryl, or —OR a ;
R f is independently for each occurrence R a , R b , or R c , or two R f groups together with the carbon atom bound thereto provide a substituted or non-substituted C 3-6 cycloalkyl group or a substituted or non-substituted C 3-10 heterocyclic group;
m is 1 to 4; and
PG is an amine protecting group.
2. The compound of claim 1 , wherein PG is a 9-fluorenylmethoxycarbonyl group, a t-butyloxycarbonyl group, a trityl group, an allyloxycarbonyl group, or a benzyloxycarbonyl group.
3. The compound of claim 1 , wherein the linker is CH 2 or a substituted or non-substituted C 2 , C 3 , or C 4 aliphatic group.
4. The compound of claim 3 , wherein the substituted or non-substituted C 2 aliphatic group comprises a substituted or non-substituted alkyne and wherein R 6 is —C(R f ) 3 , wherein one R f is R e and each other R f independently for each occurrence is substituted or non-substituted C 1-4 alkyl.
5. The compound of claim 4 , wherein R e is —OR a , wherein R a is H.
6. The compound of claim 4 , wherein the substituted or non-substituted C 1-4 alkyl is methyl.
7. The compound of claim 1 , wherein the linker is a substituted or non-substituted alkyne and wherein R 6 is —C(R f ) 3 , wherein one R f is OR a wherein R a is H, and the remaining two R f groups together with the carbon atom bound thereto provide an oxetane.
8. The compound of claim 1 , wherein the linker is a substituted or non-substituted alkyne and wherein R 6 is —C(R f ) 3 , wherein one R f is OR a wherein R a is H, and the remaining two R f groups together with the carbon atom bound thereto provide a tetrahydropyran.
9. The compound of claim 1 , wherein the linker-R 6 group is selected from
10. The compound of claim 1 , wherein the compound is
11. A compound, having a formula
or a salt thereof, wherein:
R 2 is R a ;
R a is independently for each occurrence H, D, C 1 alkyl, substituted or non-substituted C 2-10 aliphatic, substituted or non-substituted C 1-10 haloaliphatic, or substituted or non-substituted C 3-6 heterocyclic;
linker is CH 2 or R a , provided that R a is not H or D;
R 6 is R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , or —C(O)NR d R d ;
R c is independently for each occurrence substituted or non-substituted C 1-10 alkyl, substituted or non-substituted C 2-10 alkenyl, substituted or non-substituted C 2-10 alkynyl, or substituted or non-substituted C 3-6 cycloalkyl;
R d is independently for each occurrence H; substituted or non-substituted C 1-6 alkyl; substituted or non-substituted C 3-6 cycloalkyl; substituted or non-substituted C 3-6 heterocyclic; substituted or non-substituted C 5-10 aryl; substituted or non-substituted C 5-10 heteroaryl; or two R d groups together with the nitrogen bound thereto provide a substituted or non-substituted C 3-9 heterocyclic group, or a substituted or non-substituted C 5-10 heteroaryl;
R e is independently for each occurrence halogen, substituted or non-substituted C 1-6 alkyl, substituted or non-substituted C 2-10 alkenyl, substituted or non-substituted C 2-10 alkynyl, substituted or non-substituted C 1-6 haloalkyl, substituted or non-substituted C 3-6 cycloalkyl, substituted or non-substituted C 5-10 heteroaryl, or —OR a ;
R f is independently for each occurrence R a , R b , or R c , or two R f groups together with the carbon atom bound thereto provide a substituted or non-substituted C 3-6 cycloalkyl group or a substituted or non-substituted C 3-10 heterocyclic group;
m is 1 to 4.
12. The compound of claim 11 , wherein the linker is CH 2 , or a substituted or non-substituted C 2 , C 3 , or C 4 aliphatic group.
13. The compound of claim 12 , wherein the substituted or non-substituted C 2 aliphatic group comprises a substituted or non-substituted alkyne and wherein R 6 is —C(R f ) 3 , wherein one R f is R e and each other R f independently for each occurrence is C 1-4 alkyl.
14. The compound of claim 13 , wherein R e is —OR a , wherein R a is H.
15. The compound of claim 13 , wherein the C 1-4 alkyl is methyl.
16. The compound of claim 11 , wherein the linker-R 6 group is selected from
17. The compound of claim 11 , wherein the compound is selected from
or an HCl salt thereof.