RIP1 inhibitory compounds and methods for making and using the same

1. A compound, having a formula

or a pharmaceutically acceptable salt thereof, wherein:

ring B is substituted or non-substituted 5-membered heteroaryl;

L is a substituted or non-substituted 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 halogen, R a or R b ;

R a is independently for each occurrence H, D, substituted or non-substituted C 1-10 aliphatic, or substituted or non-substituted C 1-10 cycloaliphatic;

R b is independently for each occurrence —NR d R d wherein two R d groups together with the nitrogen bound thereto provide a non-aromatic C 3-10 heterocyclic group that is non-substituted or substituted with one or more R e groups and/or one or more R 9 groups, wherein R e is independently for each occurrence —OR a , N(R a ) 2 , substituted or non-substituted C 1-6 alkyl, substituted or non-substituted C 1-6 haloalkyl, substituted or non-substituted C 1-6 heteroalkyl, substituted or non-substituted C 3-6 cycloalkyl, or two R e groups join together to provide a substituted or non-substituted C 3-10 heterocyclic group with the R b group to which the two R e groups are bound; and R 9 is halogen, substituted or non-substituted 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.

2. The compound of claim 1 , wherein the compound has a structure satisfying a formula

3. 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.

4. The compound of claim 1 , wherein ring B is a triazole selected from

or an oxazole selected from

5. The compound of claim 1 , wherein R 5 is R a , wherein R a is substituted or non-substituted C 1 -C 4 aliphatic, or R 5 is halogen; and/or wherein R 2 is R a wherein R a is substituted or non-substituted C 1 -C 4 aliphatic and R 3 is R a , wherein R a is hydrogen.

6. The compound 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 substituted or non-substituted non-aromatic C 3-10 heterocyclic group comprising two R e groups that join together to provide a second substituted or non-substituted C 3-10 heterocyclic group.

7. The compound of claim 6 , wherein the second substituted or non-substituted C 3-10 heterocyclic group formed by the two R e groups and the substituted or non-substituted non-aromatic C 3-10 heterocyclic formed by the two R d groups of R b provide a substituted or non-substituted spirocyclic group or a substituted or non-substituted bicyclic group.

8. The compound of claim 7 , wherein the substituted or non-substituted spirocyclic group comprises at least two rings, wherein a first ring and a second ring of the spirocyclic group have a different number of carbon atoms, a different number of heteroatoms, or both and wherein each ring of the spirocyclic group comprises a heteroatom in the ring.

9. The compound of claim 8 , wherein the substituted or non-substituted spirocyclic group comprises at least one oxygen atom and at least one nitrogen atom.

10. The compound of claim 7 , wherein the substituted or non-substituted spirocyclic group comprises a first ring and a second ring, wherein the first ring is coupled to a carbon atom of the compound and has 3 to 7 atoms, and wherein the second ring has 3 to 7 atoms.

11. The compound of claim 7 , wherein the substituted or non-substituted spirocyclic group comprises greater than 7 total atoms in the substituted or non-substituted spirocyclic group.

12. The compound of claim 7 , wherein the substituted or non-substituted C 3-10 heterocyclic formed by the two R e groups and the substituted or non-substituted non-aromatic C 3-10 heterocyclic formed by the two R d groups of R b provide a substituted or non-substituted bicyclic group comprising two or more heteroatoms in the substituted or non-substituted bicyclic group.

13. The compound of claim 12 , wherein the substituted or non-substituted bicyclic group is a fused substituted or non-substituted bicyclic group or a bridged substituted or non-substituted bicyclic group and wherein the substituted or non-substituted bicyclic group is attached to the compound through a nitrogen atom of the substituted or non-substituted bicyclic group.

14. A compound, having a formula

or a pharmaceutically acceptable salt thereof, wherein:

ring B is substituted or non-substituted 5-membered heteroaryl;

L is a substituted or non-substituted C 1-10 aliphatic linker;

each of R 2 and R 3 independently are R a ;

each R 4 and each R 5 independently are halogen, R a , or R b ;

R a is independently for each occurrence H, D, substituted or non-substituted C 1-10 aliphatic, or substituted or non-substituted C 1-10 cycloaliphatic;

R b is independently for each occurrence —NR d R d wherein (i) each R d independently is R a or R e ; or (ii) two R d groups together with the nitrogen bound thereto provide a substituted or non-substituted C 3-10 heterocyclic group;

R e is independently for each occurrence —OR a , —N(R a ) 2 , substituted or non-substituted C 1-6 alkyl, substituted or non-substituted C 1-6 haloalkyl, substituted or non-substituted C 1-6 heteroalkyl, substituted or non-substituted C 3-6 cycloalkyl, or two R e groups join together to provide a substituted or non-substituted C 3-10 heterocyclic group with the R b group to which the two R e groups are bound;

m is 1 to 4;

n is 0, 1 or 2;

p is 0, 1, 2, 3, 4, or 5; and

each R 1 independently for each occurrence is

wherein each n′ independently is an integer ranging from 0 to 4; and each R 6 independently is selected from hydrogen, substituted or non-substituted aliphatic, substituted or non-substituted aromatic, or substituted or non-substituted heteroaliphatic.

15. The compound of claim 14 , wherein the compound is selected from

16. The compound of claim 1 , wherein the compound is

17. A method for making the compound of claim 1 , comprising:

coupling a starting material having a Formula A with an R 1 -containing reagent having a formula R 1 —H, by combining the starting material and the R 1 -containing reagent with a transition metal catalyst, a ligand component, and a solvent to form an R 1 -functionalized product;

deprotecting an amine group of the R 1 -functionalized product to provide an amine compound; and

forming an amide bond between the amine compound and an acid-containing coupling partner;

wherein Formula A is

the R 1 -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 .

18. The method of claim 17 , wherein the amide bond is formed by coupling the amine compound and the acid-containing coupling partner in the presence of propylphosphonic anhydride and diisopropylethylamine.