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
or a pharmaceutically acceptable salt thereof, wherein:
ring B is substituted or non-substituted 5-membered or 6-membered heteroaryl;
L is a heteroatom, CH 2 , or R a , provided that R a is not H or D;
Z is substituted or non-substituted C 1-10 aliphatic or
R 1 is —C≡CH, or a -linker-R 6 group, wherein the linker is CH 2 or R a , provided that R a is not H or D, and R 6 is R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R 2 and R 3 independently are R a ;
R 4 and R 5 independently are R e ;
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;
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 e , 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;
n is 0, 1 or 2; and
p is 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein the compound has a formula
3. The compound claim 1 , wherein the compound has a structure satisfying a formula
wherein L is oxygen or CH 2 .
4. The compound of claim 1 , wherein ring B has a structure satisfying a formula
wherein at least one W is nitrogen, and each remaining W independently is selected from carbon, CH, oxygen, sulfur, nitrogen, or NH.
5. The compound of claim 1 , wherein ring B is a diazole, a triazole, an oxadiazole, an oxazole, or a pyridinyl.
6. The compound of claim 5 , wherein the triazole is
the diazole is
the oxadiazole is
the oxazole is
7. The compound of claim 1 , wherein R 5 is R e , wherein R e is halogen or methyl.
8. The compound of claim 1 , wherein the linker of the linker-R 6 group is CH 2 , or non-substituted C 2 , C 3 , or C 4 aliphatic group.
9. The compound of claim 8 , 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.
10. The compound of claim 9 , wherein R e is —OR a , wherein R a is H.
11. The compound of claim 9 , wherein the substituted or non-substituted C 1-4 alkyl is methyl.
12. The compound of claim 9 , wherein ring B is
13. The compound of claim 1 , wherein R 1 is
14. A compound selected from:
15. A compound selected from:
16. A method for making the compound of claim 1 , comprising:
coupling a starting material having a Formula A with an R 1 -containing reagent, by combining the starting material and the R 1 -containing reagent, wherein R 1 comprises a linker-R 6 group, with a transition metal catalyst, a base, and a solvent to form a functionalized product;
deprotecting an amine group of the functionalized product to provide an amine compound; and
forming an amide bond between the amine compound and an acid-containing coupling partner to provide an amide-containing compound;
wherein Formula A is
the functionalized product has a structure satisfying Formula B
and the acid-containing coupling partner has a structure satisfying Formula C
and wherein
X is a halogen or a triflate;
PG is an amine protecting group;
and each of ring B, L, R 1 , R 2 , R 4 , R 5 , m, n, and p are as recited for claim 1 .
17. The compound of claim 1 , wherein the linker of the linker-R 6 group is R a wherein R a is a substituted or non-substituted C 2 alkyl, alkenyl, or alkynyl group; a substituted or non-substituted C 3 alkyl group; a substituted or non-substituted C 3 aliphatic group comprising a substituted or non-substituted alkenyl or alkynyl group; a substituted or non-substituted C 4 alkyl group; or a substituted or non-substituted C 4 aliphatic group comprising a substituted or non-substituted alkenyl or alkynyl group.