RIP1 inhibitory compounds and methods for making and using the same

Patent metadata

Field	Value
Publication number	US-10815206-B2
Application number	US-201916402111-A
Country	US
Kind code	B2
Filing date	May 2, 2019
Priority date	May 3, 2018
Publication date	Oct 27, 2020
Grant date	Oct 27, 2020

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, having a formula

or a pharmaceutically acceptable salt thereof, wherein:
ring B is substituted or non-substituted 5-membered or 6-membered heteroaryl;
L is a heteroatom, CH 2 , or R a , provided that R a is not H or D;
Z is substituted or non-substituted C 1-10 aliphatic or

R 1 is —C≡CH, or a -linker-R 6 group, wherein the linker is CH 2 or R a , provided that R a is not H or D, and R 6 is R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R 2 and R 3 independently are R a ;
R 4 and R 5 independently are R e ;
R a is independently for each occurrence H, D, C 1 alkyl, substituted or non-substituted C 2-10 aliphatic, substituted or non-substituted C 1-10 haloaliphatic, substituted or non-substituted C 5-10 aromatic, or substituted or non-substituted C 3-6 heterocyclic;
R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , or —C(O)NR d R d ;
R c is independently for each occurrence substituted or non-substituted C 1-10 alkyl, substituted or non-substituted C 2-10 alkenyl, substituted or non-substituted C 2-10 alkynyl, or substituted or non-substituted C 3-6 cycloalkyl;
R d is independently for each occurrence H; substituted or non-substituted C 1-6 alkyl; substituted or non-substituted C 3-6 cycloalkyl; substituted or non-substituted C 3-6 heterocyclic; substituted or non-substituted C 5-10 aryl; substituted or non-substituted C 5-10 heteroaryl; or two R d groups together with the nitrogen bound thereto provide a substituted or non-substituted C 3-9 heterocyclic group, or a substituted or non-substituted C 5-10 heteroaryl;
R e is independently for each occurrence halogen, substituted or non-substituted C 1-6 alkyl, substituted or non-substituted C 2-10 alkenyl, substituted or non-substituted C 2-10 alkynyl, substituted or non-substituted C 1-6 haloalkyl, substituted or non-substituted C 3-6 cycloalkyl, substituted or non-substituted C 5-10 heteroaryl, or —OR a ;
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 substituted or non-substituted C 3-6 cycloalkyl group or a substituted or non-substituted C 3-10 heterocyclic group;

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 formula

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

wherein L is oxygen or CH 2 .

4. 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.

5. The compound of claim 1 , wherein ring B is a diazole, a triazole, an oxadiazole, an oxazole, or a pyridinyl.

6. The compound of claim 5 , wherein the triazole is

the diazole is

the oxadiazole is

the oxazole is

7. The compound of claim 1 , wherein R 5 is R e , wherein R e is halogen or methyl.

8. The compound of claim 1 , wherein the linker of the linker-R 6 group is CH 2 , or non-substituted C 2 , C 3 , or C 4 aliphatic group.

9. The compound of claim 8 , wherein the substituted or non-substituted C 2 aliphatic group comprises a substituted or non-substituted alkyne and wherein R 6 is —C(R f ) 3 , wherein one R f is R e and each other R f independently for each occurrence is substituted or non-substituted C 1-4 alkyl.

10. The compound of claim 9 , wherein R e is —OR a , wherein R a is H.

11. The compound of claim 9 , wherein the substituted or non-substituted C 1-4 alkyl is methyl.

12. The compound of claim 9 , wherein ring B is

13. The compound of claim 1 , wherein R 1 is

14. A compound selected from:

15. A compound selected from:

16. A method for making the compound of claim 1 , comprising:
coupling a starting material having a Formula A with an R 1 -containing reagent, by combining the starting material and the R 1 -containing reagent, wherein R 1 comprises a linker-R 6 group, with a transition metal catalyst, a base, and a solvent to form a functionalized product;
deprotecting an amine group of the functionalized product to provide an amine compound; and
forming an amide bond between the amine compound and an acid-containing coupling partner to provide an amide-containing compound;
wherein Formula A is

the 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 tr

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Masuda Esteban
• Shaw Simon
• Taylor Vanessa
• Bhamidipati Somasekhar

Classifications

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P17/06

  Antipsoriatics · CPC title