RIP1K inhibitors

1. A method for treating a disease in a subject, comprising administering to the subject

(i) a therapeutically effective amount of a compound of Formula I; or

(ii) a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable excipient;

wherein the subject has, or is suspected of having or developing, the disease, wherein the disease is a disease involving a receptor-interacting protein-1 (RIP1) kinase, wherein the disease involving a receptor-interacting protein-1 (RIP1) kinase is amyotrophic lateral sclerosis (ALS), type I diabetes, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, asthma, or leukemia;

wherein the compound of Formula I is

wherein

ring B is a 5-membered or 6-membered heteroaryl;

X is CH 2 or O;

L is a heteroatom or R a , provided that R a is not hydrogen;

Z is C 1-10 aliphatic, aryl, or heteroaryl, wherein the C 1-10 aliphatic, aryl, or heteroaryl is optionally substituted with one or more R 5 ;

R 1 is independently for each occurrence —NR d R d wherein the two R d groups together with the nitrogen bound thereto provide a C 3-10 heterocyclic group; —C≡CH, or a -linker-R 6 group, wherein the linker is a divalent C 1-10 aliphatic or C 1-10 cycloaliphatic, and R 6 is R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ; C 5-10 aromatic, or C 3-6 heterocyclic, wherein each linker is optionally substituted with one or more halo, R a , or both;

R 2 and R 3 independently are R a ;

R 4 and R 5 independently are, for each occurrence, R e ;

R a is independently for each occurrence hydrogen, C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic, or C 3-6 heterocyclic;

R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR e R e , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , or —C(O)NR e R e

R c is independently for each occurrence C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, or C 5-10 aromatic, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, or C 5-10 aromatic is optionally substituted with 1, 2, or 3 R e ;

R d is C 1-9 aliphatic optionally substituted with 1, 2, or 3 groups selected from the group consisting of R a , R b and R e ;

R e is independently for each occurrence oxo (═O), —OR a , N(R a ) 2 , halo, 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 a nitrogen to which the two R e groups are bound;

m is 1 to 4; and

n is 0, 1 or 2.

2. The method of claim 1 , wherein the disease involving a receptor-interacting protein-1 (RIP1) kinase is amyotrophic lateral sclerosis (ALS) or multiple sclerosis.

3. The method of claim 1 , wherein the disease involving a receptor-interacting protein-1 (RIP1) kinase is rheumatoid arthritis, type I diabetes, Crohn's disease, ulcerative colitis, asthma, or leukemia.

4. A method for treating a disease in a subject, comprising administering to the subject

(i) a therapeutically effective amount of a compound; or

(ii) a therapeutically effective amount of a pharmaceutical composition comprising a compound and one or more pharmaceutically acceptable excipient;

wherein the subject has, or is suspected of having or developing, the disease, wherein the disease is a disease involving a receptor-interacting protein-1 (RIP1) kinase, wherein the disease involving a receptor-interacting protein-1 (RIP1) kinase is amyotrophic lateral sclerosis (ALS), type I diabetes, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, asthma, or leukemia;

wherein the compound is

5. A method of inhibiting receptor-interacting protein-1 (RIP1) kinase in a subject, comprising administering to the subject

(i) a therapeutically effective amount of a compound of Formula I; or

(ii) a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable excipient;

wherein the compound of Formula I is

wherein

ring B is a 5-membered or 6-membered heteroaryl;

X is CH 2 or O;

L is a heteroatom or R a , provided that R a is not hydrogen;

Z is C 1-10 aliphatic, aryl, or heteroaryl, wherein the C 1-10 aliphatic, aryl, or heteroaryl is optionally substituted with one or more R 5 ;

R 1 is independently for each occurrence —NR d R d wherein the two R d groups together with the nitrogen bound thereto provide a C 3-10 heterocyclic group; —C≡CH, or a -linker-R 6 group, wherein the linker is a divalent C 1-10 aliphatic or C 1-10 cycloaliphatic, and R 6 is R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ; C 5-10 aromatic, or C 3-6 heterocyclic, wherein each linker is optionally substituted with one or more halo, R a , or both;

R 2 and R 3 independently are R a ;

R 4 and R 5 independently are, for each occurrence, R e ;

R a is independently for each occurrence hydrogen, C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic, or C 3-6 heterocyclic;

R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR e R e , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , or —C(O)NR e R e

R c is independently for each occurrence C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, or C 5-10 aromatic, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, or C 5-10 aromatic is optionally substituted with 1, 2, or 3 R e ;

R d is C 1-9 aliphatic optionally substituted with 1, 2, or 3 groups selected from the group consisting of R a , R b and R e ;

R e is independently for each occurrence oxo (═O), —OR a , N(R a ) 2 , halo, 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 a nitrogen to which the two R e groups are bound;

m is 1 to 4; and

n is 0, 1 or 2.