# US 11,440,918 B2 · p38α mitogen-activated protein kinase inhibitors

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- Number: US 11,440,918 B2
- Document ID: US11440918B2
- Status: Granted
- Kind: B2
- Application number: 17/667,898
- Filed: 2022-02-09
- Published: 2022-05-26
- Granted: 2022-09-13
- Earliest claimed: 2020-05-18
- Assignees: Gen1E Lifesciences Inc.
- Applicants: Gen1E Lifesciences Inc.
- Inventors: Adam Galan; Wendy Luo; Ritu Lal
- Web page: https://patentgrep.com/patent/US11440918B2

## CPC

- C07D 267/08: having the hetero atoms in positions 1 and 4
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 207/12: Oxygen or sulfur atoms
- C07D 211/42: attached in position 3 or 5
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- C07D 239/28: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D 239/30: Halogen atoms or nitro radicals
- C07D 241/08: with oxygen atoms directly attached to ring carbon atoms
- C07D 265/30: not condensed with other rings
- C07D 267/10: not condensed with other rings
- 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
- C07D 295/185: from aliphatic carboxylic acids
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/08: Bridged systems
- C07D 498/18: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and therapeutic methods of using the p38α mitogen-activated protein kinase inhibitors.

## Claims

### Claim 1

A compound having the structure of Formula (1):
or a pharmaceutically acceptable salt thereof, wherein,
R1 is selected from C1-4 alkanediyl and C1-4 heteroalkanediyl; and
R2 is a moiety having the structure of Formula (2d):
wherein,
each of A1 and A2 is independently selected from —CH2— and —C(═O)—;
each n is independently selected from 1, 2, and 3; and
X is —NR3— and R3 is —C(═O)—CH3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is C1-4 alkanediyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is selected from methanediyl and ethanediyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein one n is 1 and the other n is selected from 2 and 3.

### Claim 5 (depends on 1)

The compound of claim 1, wherein each n is 2 or each n is 3.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the etiology of the disease is associated with up-regulation of the p38α MAPK protein, with the down-regulation of the p38α MAPK protein, or with both the up-regulation and the down-regulation of the p38α MAPK protein.

### Claim 8 (depends on 6)

The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from cancer, an inflammatory disease, and autoimmune disease, and a viral disease.

### Claim 9 (depends on 6)

The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, and cystic fibrosis.

### Claim 10 (depends on 1)

A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

### Claim 11 (depends on 6)

A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the pharmaceutical composition of claim 6, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

### Claim 12

A compound having the structure of Formula (1):
or a pharmaceutically acceptable salt thereof, wherein,
R1 is C1-4 alkanediyl; and
R2 is a moiety having the structure of Formula(2d
wherein,
each n is independently selected from, 1, 2, and 3;
each of A1 and A2 is independently selected from —CH2 and —C(═O)—,
and at least one of A1 and A2 is —C(═O)—; and
X is —NR3—, wherein R3 is selected from hydrogen, C1-6 alkyl, and substituted C1-6 alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein each substituent is selected from —OH and ═o.

### Claim 14 (depends on 12)

The compound of claim 12, wherein R1 is selected from methanediyl and ethanediyl.

### Claim 15

A compound having the structure of Formula (1):
or a pharmaceutically acceptable salt thereof, wherein,
R1 is selected from C1-4 alkanediyl, C1-4 heteroalkanediyl, substituted C1-4 alkanediyl, and substituted C1-4 heteroalkanediyl; and
R2 is a moiety having the structure of Formula (2d):
wherein,
one n is 1 and the other n is selected from 2 and 3;
each of A1 and A2 is independently selected from —CH2— and —C(═O)—, and at least one of A1 and A2 is —C(═O)—; and
X is —NR3—, wherein R3 is selected from hydrogen, C1-6 alkyl, and substituted C1-6 alkyl.

### Claim 16 (depends on 12)

The compound of claim 12, wherein each n is 2 or each n is 3.

### Claim 17 (depends on 12)

The compound of claim 12, wherein the compound is selected from:
4-chloro-N-(4-((3-oxopiperazin-1-yl)methyl)phenyl)benzamide (15); and
4-chloro-N-(4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)benzamide (16);
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 18 (depends on 12)

A pharmaceutical composition comprising the compound of claim 12 or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the etiology of the disease is associated with up-regulation of the p38α MAPK protein, with the down-regulation of the p38α MAPK protein, or with both the up-regulation and the down-regulation of the p38α MAPK protein.

### Claim 20 (depends on 18)

The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from cancer, an inflammatory disease, and autoimmune disease, and a viral disease.

### Claim 21 (depends on 18)

The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, and cystic fibrosis.

### Claim 22 (depends on 12)

A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

### Claim 23 (depends on 18)

A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the pharmaceutical composition of claim 18, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

### Claim 24 (depends on 15)

A pharmaceutical composition comprising the compound of claim 15 or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The pharmaceutical composition of claim 24, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the etiology of the disease is associated with up-regulation of the p38α MAPK protein, with the down-regulation of the p38α MAPK protein, or with both the up-regulation and the down-regulation of the p38α MAPK protein.

### Claim 26 (depends on 24)

The pharmaceutical composition of claim 24, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from cancer, an inflammatory disease, and autoimmune disease, and a viral disease.

### Claim 27 (depends on 24)

The pharmaceutical composition of claim 24, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof for treating a disease in a patient, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis, and cystic fibrosis.

### Claim 28 (depends on 15)

A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.

### Claim 29 (depends on 15)

A method of treating a disease in a patient comprising administering to a patient in need thereof a therapeutically effective of amount of the pharmaceutical composition of claim 15, wherein the disease is selected from cancer, an inflammatory disease, an autoimmune disease, and a viral disease.