# US 12,006,337 B2 · Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof

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- Number: US 12,006,337 B2
- Document ID: US12006337B2
- Status: Granted
- Kind: B2
- Application number: 17/863,657
- Filed: 2022-07-13
- Published: 2023-06-22
- Granted: 2024-06-11
- Earliest claimed: 2018-05-30
- Assignees: Washington University
- Applicants: Washington University
- Inventors: Michael J. Holtzman; Arthur G. Romero; Benjamin J. Gerovac; Zhenfu Han; Shamus P. Keeler; Kangyun Wu; Yong Zhang
- Web page: https://patentgrep.com/patent/US12006337B2

## CPC

- A61P 11/00: Drugs for disorders of the respiratory system
- C07F 7/0812: {comprising a heterocyclic ring}
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- 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 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/14: containing three or more hetero rings
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds that inhibit mitogen-activated protein kinases (MAPKs) are disclosed. Some inhibitor compounds specifically target a single MAPK such as MAPK13, while others target multiple MAPKs such as MAPK13 and MAPK12. The compounds can be used therapeutically for a variety of diseases, including cancer and respiratory diseases. Methods of synthesis of the compounds are also disclosed.

## Claims

### Claim 1

A method for treating a respiratory disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I having the structure
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is hydrogen or —NH(CO)R2;
R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, OR3, and NR4R4;
R3 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl;
each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, and cycloalkylalkyl;
J1 is —CH2— and is substituted at position 4 on the pyridine;
G1 is thiazole wherein L1 is CH, L2 is N, and L3 is S;
Z1 and Z2 are each NH;
G2 is pyrazole, isoxazole, or phenyl;
E1 is CH or CR1 when G2 is phenyl, E1 is NR1 when G2 is pyrazole, or E1 is N or O when G2 is isoxazole;
wherein R1 is selected from the group consisting of H, C1-8 alkyl, cycloalkyl, cycloalkylalkyl, and halogen;
E2 is N when G2 is pyrazole, E2 is N or O when G2 is isoxazole, or E2 is CH—CH when G2 is phenyl;
E3 is C when G2 is pyrazole, isoxazole, or phenyl;
E4 is CH when G2 is pyrazole, isoxazole, or phenyl; and
M1 is selected from the group consisting of C and Si;
wherein if M1 is Si, each of M2 and M3 is methyl, R6 is methyl, and X is absent;
wherein if M1 is C, each of M2 and M3 is selected from the group consisting of CH3 and CH2, R6 is selected from the group consisting of H and C1-8 alkyl, and X is selected from the group consisting of CH2, O, and S, or is absent;
wherein if M1 is C and X is CH2, O, or S, then M1, M2, M3, and X together form a 4-member ring;
wherein the respiratory disease is selected from the group consisting of asthma, rhinitis, sinusitis, COPD, pulmonary fibrosis, and a combination thereof.

### Claim 2

A method for treating a respiratory disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the structure of

### Claim 3

A method of reducing inflammation or reducing mucus production in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I having the structure
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is hydrogen or —NH(CO)R2;
R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, OR3, and NR4R4;
R3 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl;
each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, and cycloalkylalkyl;
J1 is —CH2— and is substituted at position 4 on the pyridine;
G1 is thiazole wherein L1 is CH, L2 is N, and L3 is S;
Z1 and Z2 are each NH;
G2 is pyrazole, isoxazole, or phenyl;
E1 is CH or CR1 when G2 is phenyl, E1 is NR1 when G2 is pyrazole, or E1 is N or O when G2 is isoxazole;
wherein R1 is selected from the group consisting of H, C1-8 alkyl, cycloalkyl, cycloalkylalkyl, and halogen;
E2 is N when G2 is pyrazole, E2 is N or O when G2 is isoxazole, or E2 is CH—CH when G2 is phenyl;
E3 is C when G2 is pyrazole, isoxazole, or phenyl;
E4 is CH when G2 is pyrazole, isoxazole, or phenyl; and
M1 is selected from the group consisting of C and Si;
wherein if M1 is Si, each of M2 and M3 is methyl, R6 is methyl, and X is absent;
wherein if M1 is C, each of M2 and M3 is selected from the group consisting of CH3 and CH2, R6 is selected from the group consisting of H and C1-8 alkyl, and X is selected from the group consisting of CH2, O, and S, or is absent;
wherein if M1 is C and X is CH2, O, or S, then M1, M2, M3, and X together form a 4-member ring.

### Claim 4 (depends on 3)

The method of claim 3, wherein the compound is

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is