Inhibitors of receptor interacting protein kinase I for the treatment of disease

Patent metadata

Field	Value
Publication number	US-11718612-B2
Application number	US-202017014184-A
Country	US
Kind code	B2
Filing date	Sep 8, 2020
Priority date	Sep 6, 2019
Publication date	Aug 8, 2023
Grant date	Aug 8, 2023

Abstract

Disclosed herein are compounds which inhibit RIPK1, pharmaceutical compositions, and methods of treatment of RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer.

First claim

What is claimed is:

1. A compound of structural Formula I

or a salt thereof, wherein:
Y 2 is CR 2 ;
Y 3 a bond;
Y 4 CR 4 ;
Y 5 is N;
Y 6 is N;
R 1a is phenyl, which is optionally substituted with one or more R 7 ;
R 1b and R 2 , together with the intervening atoms, combine to form
an unsubstituted 6-membered heterocycloalkyl;

R 3 is chosen from hydrogen and alkyl;
R 4 is chosen from hydrogen and halo;
R 5 hydrogen;
R 5b is chosen from phenyl and pyridyl, either of which is optionally substituted with one or more R 10 ;
each R 7 is independently chosen from halo, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aminoalkyl, acylaminoalkyl, (haloalkyl)aminoalkyl, alkylsulfonylaminoalkyl, arylalkyl, heteroarylalkyl, haloalkoxy, heteroaryl optionally substituted with alkyl, and heterocycloalkyl optionally substituted with alkyl, or
two or more R 7 , together with the intervening atoms, can form a heterocycloalkyl or heteroaryl;
and
each R 10 is independently chosen from alkyl, haloalkyl, amino, aminoalkyl, aminocarbonyl, alkoxy, haloalkoxy, cyano, halo, and hydroxy.

2. The compound as recited in claim 1 , or a salt thereof, wherein each R 7 is independently chosen from halo, cyano, and hydroxy.

3. The compound as recited in claim 2 , or a salt thereof, wherein each R 7 is independently chosen from F and Cl.

4. The compound as recited in claim 1 , or a salt thereof, wherein R 1a is

and each R 7 is the same or different.

5. The compound as recited in claim 1 , or a salt thereof, wherein R 5b is phenyl optionally substituted with one or more R 10 .

6. The compound as recited in claim 5 , or a salt thereof, wherein each R 10 is independently chosen from halo and cyano.

7. The compound as recited in claim 5 , or a salt thereof, wherein R 5b is chosen from

8. A compound of structural Formula VI:

or a salt thereof, wherein:
Y 2b is C;
Y 5 is N;
R 4 is chosen from hydrogen, and halo;
R 5a hydrogen;
each R 7 is independently chosen from halo, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aminoalkyl, acylaminoalkyl, (haloalkyl)aminoalkyl, alkylsulfonylaminoalkyl, arylalkyl, heteroarylalkyl, haloalkoxy, heteroaryl optionally substituted with alkyl, and heterocycloalkyl optionally substituted with alkyl, or
two or more R 7 , together with the intervening atoms, can form a heterocycloalkyl or heteroaryl;
each R 10 is independently chosen from alkyl, haloalkyl, amino, aminoalkyl, aminocarbonyl, alkoxy, haloalkoxy, cyano, halo, and hydroxy;
m is chosen from 0, 1, and 2; and
n is chosen from 0, 1, 2, and 3.

9. A compound chosen from:

10. A pharmaceutical composition comprising a compound as recited in claim 1 , or a salt thereof, together with a pharmaceutically acceptable carrier.

Assignees

• Univ Texas

Inventors

• Lewis Richard T
• Hamilton Matthew
• Ray William J
• Alvarez Fernando
• Reyna Naphtali
• Cross Jason
• Ramaswamy Suyambu Kesava Vijayan

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61K31/4035

  Isoindoles, e.g. phthalimide · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• A61K31/4172

  Imidazole-alkanecarboxylic acids, e.g. histidine · CPC title