RIP1K inhibitors
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 method of treating a RIP1K associated condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula
wherein
X is CH 2 , O, S, S(O), S(O) 2 , or NR a ;
R a is for each occurrence hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 acyl;
Y 1 , Y 2 and Y 3 are independently N, N(R a ), O, C(R b ) 1-2 , or C═O;
R b is hydrogen, C 1-6 alkyl, or halo;
Z is C(R c ) or NR c ;
R c is a C 1 -C 4 alkyl unsaturated carbon chain optionally substituted with one or more R 1 groups, optionally interrupted by 1 or 2 heteroatoms selected from O, N and S;
R z is N, CH or C(R 1 ) and together with ZR c and the carbon to which they are bound form a 5- or 6-membered heteroaryl or 6-membered aryl, wherein the 5- or 6-membered heteroaryl or 6-membered aryl is substituted with m R 1 groups;
R 1 is a linker-R 6 group, wherein the linker is a bond, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl is optionally substituted by one or more R b , and R 6 is R e , —C(R f ) 3 , or —C(R f )=C(R f ) 2 ;
R 2 is R a ;
ring B is 5- to 10-membered heteroaryl;
R 3 is, for each occurrence, independently is R b or OR a ;
L is O, NR a , or alkylene;
W is 5- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered aryl or 5- to 10-membered heteroaryl is substituted by p R 4 ;
R 4 is for each occurrence selected from R b and OR a ;
R d is for each occurrence independently selected from hydrogen, C 1 -C 6 alkyl, aralkyl, C 5-10 aryl or heteroaryl, or two Rd together with a nitrogen to which they are both attached form a C 3-10 heterocyclic group optionally substituted by one or more Re;
R e is independently for each occurrence halo, —OR d , —SR d , —S(O) 2 R d , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR a , or —C(O)NR d R d ,
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 C 3 -C 6 cycloalkyl or a C 3 -C 10 heterocyclic, wherein the C 3 -C 6 cycloalkyl or C 3 -C 10 heterocyclic is optionally substituted with one or more Re;
m is 1, 2, 3, or 4;
n is 0, 1 or 2; and
p is 0, 1, 2, 3, 4, or 5;
wherein the RIP1K associated condition is Parkinson's disease, Alzheimer's disease, or multiple sclerosis.
2. The method of claim 1 , wherein the RIP1K associated condition is Parkinson's disease.
3. The method of claim 1 , wherein the RIP1K associated condition is Alzheimer's disease.
4. The method of claim 1 , wherein the RIP1K associated condition is multiple sclerosis.