NON-ATP/CATALYTIC SITE p38 MITOGEN ACTIVATED PROTEIN KINASE INHIBITORS

Patent metadata

Field	Value
Publication number	US-2025100985-A1
Application number	US-202418970196-A
Country	US
Kind code	A1
Filing date	Dec 5, 2024
Priority date	Dec 7, 2018
Publication date	Mar 27, 2025
Grant date	—

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

1 . A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein,
L 1 is selected from —CH 2 —, —C(CH 3 ) 2 —, and —C(CH 2 CH 2 )—;
L 2 is selected from —NH—SO 2 —, —NHCH 2 —, —CH 2 NH—, —NHCO—, —CONH, and —SO 2 NH—; and
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 , —SR 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 (wherein t is 1 or 2), or —PO(OR a ) 2 wherein each R a is independently hydrogen and C 1-3 alkyl; and

—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 heteroaryl.

2 . The compound of claim 1 , wherein L 1 is —CH 2 —.

3 . The compound of claim 1 , wherein L 2 is —NH—SO 2 —.

4 . The compound of claim 1 , wherein L 2 is —NHCH 2 —.

5 . The compound of claim 1 , wherein L 2 is —CH 2 NH—.

6 . The compound of claim 1 , wherein L 2 is —NHCO—.

7 . The compound of claim 1 , wherein L 2 is —CONH—.

8 . The compound of claim 1 , wherein L2 is —SO 2 —NH—.

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

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

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

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

13 . The compound of claim 1 , wherein the 5 membered ring heteroaryl is selected from furan, thiophene, pyrrole, and imidazole.

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

15 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is an oral pharmaceutical composition.

16 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is an oral dosage form.

17 . A method of treating a 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 disease is treated by inhibiting p38α MAPK activity.

18 . 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).

19 . The method of claim 18 , wherein administering comprises orally administering.

20 . The method of claim 18 , wherein administering comprises administering from 0.1 mg/kg to 200 mg/kg of the compound.

Assignees

• Univ Maryland

Inventors

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

Classifications

• C07D405/12

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

• C07D401/12

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

• C07D307/52

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

• C07D295/03 Primary

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

• C07D279/12

  not condensed with other rings · CPC title