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

Patent metadata

Field	Value
Publication number	US-12202810-B2
Application number	US-202318206925-A
Country	US
Kind code	B2
Filing date	Jun 7, 2023
Priority date	Dec 7, 2018
Publication date	Jan 21, 2025
Grant date	Jan 21, 2025

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 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.

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 L 2 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. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is an oral pharmaceutical composition.

13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is an oral dosage form.

14. 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).

15. The method of claim 14 , wherein the disease is a respiratory disease.

16. The method of claim 14 , wherein administering comprises orally administering.

17. The method of claim 14 , wherein administering comprises administering an oral dosage form comprising the compound.

18. The method of claim 14 , 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