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

Patent metadata

Field	Value
Publication number	US-12286406-B2
Application number	US-202318355792-A
Country	US
Kind code	B2
Filing date	Jul 20, 2023
Priority date	Sep 27, 2019
Publication date	Apr 29, 2025
Grant date	Apr 29, 2025

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 method of inhibition of RIPK1 comprising contacting RIPK1 with a compound of structural Formula I:

or a salt thereof, wherein:
X is alkylene and is optionally substituted with one or more R 7 ,
or X is chosen from carbamoyl, carbonyl, and a bond;
R 1a and R 1b , together with the intervening nitrogen, combine to form a pyrazoline, which is optionally substituted with one R 3 , and which is optionally substituted with one or more R 4 ;
R 2 is chosen from hydrogen, hydroxy, cyano, and halo,
or R 2 is chosen from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which is optionally substituted with one or more R 5 ;
R 3 is chosen from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one or more R 6 ;
each R 4 is independently chosen from alkyl, halo, cyano, and hydroxy;
each R 5 is independently chosen from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH 3 ) 2 , SO 2 CH 3 , aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl;
two R 5 , together with the intervening atoms, optionally combine to form a cycloalkyl or heterocycloalkyl;
each R 6 is independently chosen from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and
each R 7 is independently chosen from alkyl, cyano, halo, and hydroxy.

2. A method of treatment of a RIPK1-mediated disease comprising the administration of a therapeutically effective amount of a compound 1 of structural Formula I:

or a salt thereof, wherein:
X is alkylene and is optionally substituted with one or more R 7 ,
or X is chosen from carbamoyl, carbonyl, and a bond;
R 1a and R 1b , together with the intervening nitrogen, combine to form a pyrazoline, which is optionally substituted with one R 3 , and which is optionally substituted with one or more R 4 ;
R 2 is chosen from hydrogen, hydroxy, cyano, and halo,
or R 2 is chosen from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which is optionally substituted with one or more R 5 ;
R 3 is chosen from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one or more R 6 ;
each R 4 is independently chosen from alkyl, halo, cyano, and hydroxy;
each R 5 is independently chosen from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH 3 ) 2 , SO 2 CH 3 , aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl;
two R 5 , together with the intervening atoms, optionally combine to form a cycloalkyl or heterocycloalkyl;
each R 6 is independently chosen from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and
each R 7 is independently chosen from alkyl, cyano, halo, and hydroxy,

to a patient in need thereof.

3. The method as recited in claim 2 , wherein said disease is a neurological disease.

4. The method as recited in claim 3 , wherein said neurological disease is chosen from Multiple Sclerosis, Neimann-Pick disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, frontotemporal dementia, glutamine expansion diseases, Huntington's disease, Kennedy's disease, and spinocerebellar ataxia.

5. The method as recited in claim 2 , wherein said disease is a neuropathy.

6. The method as recited in claim 5 , wherein said neuropathy is chosen from diabetic neuropathy and chemotherapy induced neuropathy.

7. The method as recited in claim 2 , wherein said disease is a retinal disease.

8. The method as recited in claim 7 , wherein said retinal disease is chosen from macular degeneration and retinitis.

9. The method as recited in claim 2 , wherein said disease is an autoimmune disorder.

10. The method as recited in claim 9 , wherein said autoimmune disorder is chosen from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease.

11. The method as recited in claim 2 , wherein said disease is an inflammatory disease.

12. The method as recited in claim 2 , wherein said disease is cancer.

13. A method of treatment of injury to the CNS comprising the administration of a therapeutically effective amount of a compound of structural Formula I:

or a salt thereof, wherein:
X is alkylene and is optionally substituted with one or more R 7 ,
or X is chosen from carbamoyl, carbonyl, and a bond;
R 1a and R 1b , together with the intervening nitrogen, combine to form a pyrazoline, which is optionally substituted with one R 3 , and which is optionally substituted with one or more R 4 ;
R 2 is chosen from hydrogen, hydroxy, cyano, and halo,
or R 2 is chosen from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which is optionally substituted with one or more R 5 ;
R 3 is chosen from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one or more R 6 ;
each R 4 is independently chosen from alkyl, halo, cyano, and hydroxy;
each R 5 is independently chosen from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH 3 ) 2 , SO 2 CH 3 , aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl;
two R 5 , together with the intervening atoms, optionally combine to form a cycloalkyl or heterocycloalkyl;
each R 6 is independently chosen from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and
each R 7 is independently chosen from alkyl, cyano, halo, and hydroxy,

to a patient in need thereof.

14. The method as recited in claim 2 , or a salt thereof, wherein X is alkylene and is optionally substituted with one or more R 7 .

15. The method as recited in claim 2 , wherein the compound is of structural Formula II:

or a salt thereof, wherein:
m is chosen from 0 and 1;
n is chosen from 0, 1, 2, and 3;
W is chosen from C(R 6a ) and N;
X is alkylene and is optionally substituted with one or more R 7 ,
or X is chosen from carbamoyl, carbonyl, and a bond;
Y is chosen from NH and N;
Y and the int

Assignees

• Univ Texas

Inventors

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

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D241/24 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title