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

Patent metadata

Field	Value
Publication number	US-2020331874-A1
Application number	US-202016872114-A
Country	US
Kind code	A1
Filing date	May 11, 2020
Priority date	Dec 7, 2018
Publication date	Oct 22, 2020
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 .- 43 . (canceled)

44 . 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 substituted C 1-10 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 heterocycle.

45 . The compound of claim 44 , wherein each of R 1a and R 2a is independently selected from hydrogen and C 1-3 alkyl.

46 . The compound of claim 44 , wherein each of R 1a and R 2a is independently C 1-3 alkyl.

47 . The compound of claim 44 , wherein —NR 1 R 2 is selected from:

48 . The compound of claim 44 , wherein the compound is selected from a compound having the structure of Formula (1087):

49 . The compound of claim 44 , wherein the compound is selected from a compound having the structure of Formula (1085):

50 . The compound of claim 44 , wherein the compound is a p38α MAPK inhibitor.

51 . The compound of claim 44 , wherein the compound is capable of binding to a pocket near the ED substrate-docking site of p38α MAPK, wherein the ED substrate-docking site is defined at least by residues R49, H107, L108, and K165 in p38α MAPK.

52 . The compound of claim 44 , wherein the binding pocket is defined by residues R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 in p38α MAPK.

53 . The compound of claim 44 , wherein the compound is a p38α MAPK selective inhibitor.

54 . A pharmaceutical composition comprising the compound of claim 44 or a pharmaceutically acceptable salt thereof.

55 . The pharmaceutical composition of claim 54 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for treating a disease in a patient.

56 . The pharmaceutical composition of claim 55 , wherein the disease is treated by inhibiting p38α MAPK activity.

57 . The pharmaceutical composition of claim 55 , wherein the disease is cancer.

58 . The pharmaceutical composition of claim 55 , wherein the disease is an inflammatory disease.

59 . 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 44 , wherein the disease is treated by inhibiting p38α MAPK activity.

60 . 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 44 , wherein the disease is selected from cancer and an inflammatory disease.

61 . A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 54 , wherein the disease is treated by inhibiting p38α MAPK activity.

62 . A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 54 , wherein the disease is selected from cancer and an inflammatory disease.

Assignees

• Univ Maryland

Inventors

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

Classifications

• C07D307/52

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

• C07D295/03 Primary

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

• C07D213/82

  in position 3 · CPC title

• C07D405/12

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