RIP1K inhibitors

Patent metadata

Field	Value
Publication number	US-11667643-B2
Application number	US-202117358698-A
Country	US
Kind code	B2
Filing date	Jun 25, 2021
Priority date	Jul 1, 2020
Publication date	Jun 6, 2023
Grant date	Jun 6, 2023

Abstract

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.

First claim

We claim:

1. A compound according to the formula

wherein
X is selected from CH 2 , O, S, S(O), S(O) 2 and NR a ;
R a is for each occurrence selected from hydrogen, C 1-6 alkyl and C 1-6 acyl;
Y 1 , Y 2 and Y 3 are independently selected from the group consisting of N, N(R a ), O, C(R b ) 1-2 and C═O;
R b is selected from hydrogen, C 1-6 alkyl and halo;
Z is C(R c ) or NR c ;
R c is a C 1-4 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 ring substituted with m R 1 groups;
R 1 is a linker-R 6 group, wherein the linker is a bond, (C1-C4) alkanyl, (C2-C4) alkenyl or (C2-C4) alkynyl, 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 5-10-membered heteroaryl;
R 3 is, for each occurrence, independently selected from R b and OR a ;
L is O, NR a or alkylene;
W is 5-10 membered aryl or heteroaryl optionally 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 1-6 alkyl, aralkyl, C 5-10 aryl or heteroaryl, or two R d together with a nitrogen to which they are both attached form a C 3-10 heterocyclic group optionally substituted by one or more R e ;
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 3-6 cycloalkyl group or a C 3-10 heterocyclic group each optionally substituted with one or more R e ;
m is 1, 2, 3, or 4;
n is 0, 1 or 2; and
p is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 , having the formula

3. The compound of claim 1 , having the formula

4. The compound of claim 1 , having the formula

5. The compound of claim 1 , having the formula

wherein Z 1 is selected from C and N; and
Z 2 , Z 3 and Z 4 independently are selected from O, S, S(O) 2 , CH, N, N(R a ) and CR 1 .

6. The compound of claim 1 , having the formula

wherein Z 1 is C or N and Z 3 is O, S, N or N(R a ).

7. A compound according to the formula

wherein
X is selected from CH 2 , O, S, S(O), S(O) 2 and NR a ;
R a is for each occurrence selected from hydrogen, C 1-6 alkyl and C 1-6 acyl;
Y 1 , Y 2 and Y 3 are independently selected from the group consisting of N, N(R a ), O, C(R b ) 1-2 and C═O;
R b is selected from hydrogen, C 1-6 alkyl and halo;
Z is C(R c ) or NR c ;
R c is a C 1-4 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 ring is substituted with m R 1 groups;
R 1 is halo or a linker-R 6 group, wherein the linker is a bond, (C1-C4) alkanyl, (C2-C4) alkenyl or (C2-C4) alkynyl, 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 5-10-membered heteroaryl;
R 3 is, for each occurrence, independently selected from R b and OR a ;
L is O, NR a or alkylene;
W is 5-10 membered aryl or heteroaryl optionally 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 1-6 alkyl, aralkyl, C 5-10 aryl or heteroaryl, or two R d together with a nitrogen to which they are both attached form a C 3-10 heterocyclic group optionally substituted by one or more R e ;
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 3-6 cycloalkyl group or a C 3-10 heterocyclic group each optionally substituted with one or more R e ;
m is 1, 2, 3, or 4;
n is 0, 1 or 2; and
p is 0, 1, 2, 3, 4, or 5.

8. The compound according to claim 1 , wherein X is O.

9. The compound according to claim 1 , wherein Y 1 is N.

10. The compound according to claim 1 , wherein Y 1 , Y 2 and Y 3 are each N.

11. The compound according to claim 1 , wherein Y 2 is O.

12. The compound according to claim 1 , wherein Y 3 is C═O.

13. The compound according to claim 1 , wherein Y 1 , Y 2 and Y 3 are each C(R b ) 1-2 .

14. The compound of claim 13 , wherein at least one R b of Y 1 , Y 2 and Y 3 is halo.

15. The compound according to claim 1 , wherein at least one R 1 is a linker-R 6 group.

16. The compound according to claim 1 , wherein W is

17. The compound according to claim 1 , wherein W is pyridyl.

18. The compound according to claim 1 , wherein the B ring has the formula

19. The compound according to claim 1 , wherein the compound is present in a salt form.

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Bhamidipati Somasekhar
• Shaw Simon
• Darwish Ihab
• Yu Jiaxin
• Kolluri Rao
• Taylor Vanessa
• Masuda Esteban
• Irving Mark

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/14

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title