Non-ATP/catalytic site p38 mitogen activated protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11078171-B2
Application number	US-202016872114-A
Country	US
Kind code	B2
Filing date	May 11, 2020
Priority date	Dec 7, 2018
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

Compounds that inhibit p38α MAPK protein, and methods of using the same, are provided for treating or preventing diseases such as cancer or inflammatory diseases.

First claim

The invention claimed is:

1. A compound of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein in Formula 1,
L 1 is —CH 2 —;
L 2 is —NH—SO 2 —;
each of R 3 , R 4 , R 5 , and R 6 is hydrogen;
Ar 1 is

wherein each of R 1a and R 2a is independently selected from hydrogen, C 1-10 alkyl, and C 1-10 alkyl substituted by one or more of substituents which are independently hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —S(O) t R a — (wherein t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —N(R a )C(O)R a , —N(R a )C(O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )S(O) t R a (wherein t is 1 or 2), —S(O) t R a (wherein t is 1 or 2), —S(O) t OR a (wherein t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO(OR a ) 2 wherein each R a is independently hydrogen or C 1-3 alkyl; and wherein —NR 1 R 2 is selected from:

wherein,
R 7 is selected from hydrogen, OH, C 1-10 alkyl, and substituted C 1-10 alkyl; and

Ar 2 is a 5- to 18-membered heteroaryl.

2. The compound of claim 1 , wherein each of R 1a and R 2a is independently selected from hydrogen and C 1-3 alkyl.

3. The compound of claim 1 , wherein each of R 1a and R 2a is independently C 1-3 alkyl.

4. The compound of claim 1 , wherein —NR 1 R 2 is selected from:

5. The compound of claim 1 , wherein the compound is selected from a compound having the structure of Formula (1087):

6. The compound of claim 1 , wherein the compound is selected from a compound having the structure of Formula (1085):

7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. A method of treating an inflammatory disease in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the inflammatory disease is selected from rheumatoid arthritis, a cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).

9. A method of treating an inflammatory disease in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 7 , wherein the inflammatory disease is selected from rheumatoid arthritis, a cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).

10. The compound of claim 1 , wherein Ar 2 is a 5 membered ring heteroaryl.

11. The compound of claim 10 , wherein the 5 membered ring heteroaryl is selected from furan, thiophene, pyrrole, and imidazole.

12. A method of treating an inflammatory disease in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the inflammatory disease is selected from chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).

13. A method of treating an inflammatory disease in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 7 , wherein the inflammatory disease is selected from chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).

Assignees

• Univ Maryland

Inventors

• Shapiro Paul S
• Mackerell Jr Alexander D
• Hasday Jeffrey D
• Fletcher Steven

Classifications

• C07D295/03 Primary

  with the ring nitrogen atoms directly attached to acyclic carbon atoms · CPC title

• C07D295/135 Primary

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07D307/52

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title