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 inhibit a RIP1 kinase in vivo or ex vivo, and also may treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.
1. A method, comprising contacting a receptor-interacting protein-1 (RIP1) kinase in a subject with a compound, a pharmaceutically acceptable salt thereof, or both the compound and the pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising the compound and/or the pharmaceutically acceptable salt thereof, and wherein the compound has a formula
or a pharmaceutically acceptable salt thereof, wherein:
ring B is 5-membered heteroaryl;
L is a C 1-10 aliphatic linker;
R 1 is R a or R b wherein at least one R 1 is R b ;
each of R 2 and R 3 independently are R a ;
each R 4 and each R 5 independently are R a or R b ;
R a is independently for each occurrence H, D, C 1-10 aliphatic, or C 1-10 cycloaliphatic;
R b is independently for each occurrence halogen or —NR d R d wherein two R d groups together with the nitrogen bound thereto provide a C 3-10 heterocyclic group optionally substituted with one or more R e or R g ;
R e is independently for each occurrence —OR a , —N(R a ) 2 , 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 the Rb group to which the two R e groups are bound;
R g is independently for each occurrence halogen, C 1-10 aliphatic-C 5-10 aromatic, or ═O
m is 1 to 4;
n is 0, 1 or 2; and
p is 0, 1, 2, 3, 4, or 5,
wherein the subject has a disease involving a receptor-interacting protein-1 (RIP1) kinase, wherein the diseases involving a receptor-interacting protein-1 (RIP1) kinase is ankylosing spondylitis, rheumatoid arthritis, atopic dermatitis, psoriasis, or any combination thereof.
2. The method of claim 1 , wherein the disease involving the RIP′ kinase is ankylosing spondylitis.
3. The method of claim 1 , wherein the disease involving the RIP1 kinase is rheumatoid arthritis.
4. The method of claim 1 , wherein the disease involving the RIP′ kinase is atopic dermatitis.
5. The method of claim 1 , wherein the disease involving the RIP1 kinase is psoriasis.
6. The method of claim 1 , wherein the compound has a structure satisfying a formula
7. The method 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.
8. The method of claim 1 , wherein ring B is a triazole selected from
or an oxazole selected from
9. The method of claim 1 , wherein R 5 is R a , wherein R a is C 1 -C 4 aliphatic, and/or wherein R 2 is R a wherein R a is C 1 -C 4 aliphatic and R 3 is R a , wherein R a is hydrogen.
10. The method of claim 1 , wherein R 1 is R b wherein R b is —NR d R d wherein two R d groups together with the nitrogen bound thereto provide a C 3-10 heterocyclic group comprising two R e groups that join together to provide a second C 3-10 heterocyclic group.
11. The method of claim 10 , wherein the second C 3-10 heterocyclic formed by the two R e groups and the C 3-10 heterocyclic formed by the two R d groups of R b provide a spirocyclic group or a bicyclic group.
12. The method of claim 11 , wherein the spirocyclic group comprises greater than 7 total atoms in the spirocyclic system.
13. The method of claim 10 , wherein the C 3-10 heterocyclic formed by the two R e groups and the C 3-10 heterocyclic formed by the two R d groups of R b provide a bicyclic group and the bicyclic group comprises two or more heteroatoms in the bicyclic group.
14. The method of claim 13 , wherein the bicyclic group is a fused bicyclic group or a bridged bicyclic group and wherein the bicyclic group is attached to the compound through a nitrogen atom of the bicyclic group.
15. The method of claim 1 , wherein R 1 is
wherein each n independently is an integer ranging from 0 to 2.
16. The method of claim 1 , wherein the compound is selected from
17. The method of claim 1 , wherein the compound is
18. The method of claim 1 , wherein the compound is