# US 11,078,171 B2 · Non-ATP/catalytic site p38 mitogen activated protein kinase inhibitors

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- Number: US 11,078,171 B2
- Document ID: US11078171B2
- Status: Granted
- Kind: B2
- Application number: 16/872,114
- Filed: 2020-05-11
- Published: 2020-10-22
- Granted: 2021-08-03
- Earliest claimed: 2018-12-07
- Assignees: University of Maryland, Baltimore
- Applicants: University of Maryland, Baltimore
- Inventors: Paul S. Shapiro; Alexander D. Mackerell, Jr.; Jeffrey D. Hasday; Steven Fletcher
- Web page: https://patentgrep.com/patent/US11078171B2

## CPC

- C07D 295/03: with the ring nitrogen atoms directly attached to acyclic carbon atoms
- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- A61P 35/00: Antineoplastic agents
- C07D 211/22: by oxygen atoms
- C07D 213/82: in position 3
- C07D 215/54: attached in position 3
- C07D 279/12: not condensed with other rings
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein in Formula 1,
L1 is —CH2—;
L2 is —NH—SO2—;
each of R3, R4, R5, and R6 is hydrogen;
Ar1 is
wherein each of R1a and R2a is independently selected from hydrogen, C1-10 alkyl, and C1-10 alkyl substituted by one or more of substituents which are independently hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —S(O)tRa— (wherein t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (wherein t is 1 or 2), —S(O)tRa (wherein t is 1 or 2), —S(O)tORa (wherein t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2 wherein each Ra is independently hydrogen or C1-3 alkyl; and wherein —NR1R2 is selected from:
wherein,
R7 is selected from hydrogen, OH, C1-10 alkyl, and substituted C1-10 alkyl; and
Ar2 is a 5- to 18-membered heteroaryl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each of R1a and R2a is independently selected from hydrogen and C1-3 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein each of R1a and R2a is independently C1-3 alkyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein —NR1R2 is selected from:

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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).

### Claim 9 (depends on 7)

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).

### Claim 10 (depends on 1)

The compound of claim 1, wherein Ar2 is a 5 membered ring heteroaryl.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 1)

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).

### Claim 13 (depends on 7)

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).