Heterocyclic RIP1 inhibitory compounds
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 compounds may have a structure according to Formula I 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 I
or a pharmaceutically acceptable salt thereof, wherein:
ring B is heteroaryl;
each R 1 is an optionally substituted 8- to 12-membered spiroheterocyclyl or an optionally substituted bridged non-aromatic heterocyclyl;
R 2 is R a ;
R 3 is R a or R 3 together with the —N—C(O) moiety to which it is attached and two ring atoms from ring B, may form a 5- or 6-membered heterocyclyl that is fused to ring B;
if present, each R 4 independently is R e ;
L is a heteroatom or R a , provided that R a is not H or D;
Y is CH 2 ;
Z is C 1-10 aliphatic or aromatic;
m is 1, 2, 3, or 4; and
n is 0, 1 or 2;
R a is independently for each occurrence C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic, C 3-6 heterocyclic, or C 3-10 spiroheterocyclic, or H or D except for embodiments where L is R a ; and
R e is independently for each occurrence halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl, or —OR a .
2. The compound of claim 1 , wherein ring B is pyridinyl, pyrazolyl, triazolyl, or oxadiazolyl.
3. The compound of claim 1 , wherein L is heteroatom or C 1-10 aliphatic.
4. The compound of claim 3 , wherein L is O or —CH 2 —.
5. The compound of claim 1 , wherein m is 1.
6. The compound of claim 5 , wherein R 1 is
7. The compound of claim 1 , wherein R 2 is H or C 1-6 alkyl.
8. The compound of claim 1 , wherein R 3 is H, or R 3 , together with the —N—C(O)— moiety to which it is attached and two ring atoms from ring B, forms a 5- or 6-membered non-aromatic heterocyclyl that is fused to ring B.
9. The compound of claim 1 , wherein n is 0.
10. The compound of claim 1 , wherein n is 1 and R 4 is halogen.
11. The compound of claim 1 , wherein:
Z is
each R 5 independently is R e ; and
p is 0, 1, 2, 3, 4, or 5.
12. The compound of claim 11 , wherein p is 0.
13. The compound of claim 11 , wherein p is 1 and R 5 is halogen.
14. The compound of claim 1 , wherein the -L-Z moiety is phenoxy, benzyl, 4-fluorobenzyl, or 1-phenylcyclopropyl.
15. The compound of claim 1 , wherein the compound is:
I-11: 5-benzyl-N-(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;
I-12: N-(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;
I-13: 5-benzyl-N-(1-methyl-2-meth-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-11H-1,2,4-triazole-3-carboxamide;
1-14: 5-benzyl-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;
I-15: 5-benzyl-N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;
I-16: (S)-5-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;
I-17: 4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;
I-18: N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide;
I-19: N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide;
I-20: N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide;
I-21: N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide;
I-22: (S)-1-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-3-carboxamide;
I-25: 4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;
I-26: (S)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;
I-27: (R)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide.
16. A pharmaceutical composition, comprising a compound according claim 1 .
17. The composition according to claim 16 comprising an excipient, a therapeutic agent, or combinations thereof.
18. A method, comprising contacting a receptor-interacting protein-1 (RIP1) kinase with a compound according to claim 1 or a composition thereof.