# US 2023/0053465 A1 · Pyridinone mk2 inhibitors and uses thereof

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- Number: US 2023/0053465 A1
- Document ID: US20230053465A1
- Status: Published application
- Kind: A1
- Application number: 17/859,496
- Filed: 2022-07-07
- Published: 2023-02-23
- Earliest claimed: 2021-07-09
- Assignees: XinThera, Inc.
- Applicants: Xinthera, Inc.
- Inventors: Robert L. HOFFMAN; Lynnie TRZOSS; Qing DONG; Stephen W. KALDOR
- Web page: https://patentgrep.com/patent/US20230053465A1

## CPC

- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 213/69: Two or more oxygen atoms
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Described herein are MK2 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

## Claims

### Claim 1

A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof:
wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R10 is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R10a;
or two R10 on the same atom are taken together to form an oxo;
each R10a is independently deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R10a on the same atom are taken together to form an oxo;
n is 1-4;
R1 and R2 are independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;
or R1 and R2 are taken together to form an oxo;
or R1 and R2 are taken together to form a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
X is —C(R3)2—, —NR4—, —O—, or —S—;
each R3 are independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;
or two R3 are taken together to form an oxo;
R4 is hydrogen, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;
R5 is hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;
R6 is hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;
R7 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R11a;
or two R11 on the same atom are taken together to form an oxo;
each R11a is independently deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R11a on the same atom are taken together to form an oxo;
m is 1-4;
Ring C is N-linked pyridinone, N-linked pyrimidinone, N-linked pyrazinone, or N-linked pyridazinone;
each R12 is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —S(═O)(═NRb)Ra, —SiRcRdORb, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R12a;
each R12a is independently deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═O)C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R12a on the same atom are taken together to form an oxo;
p is 1-4;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and
each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocyclo alkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or Rb and Rc are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or Ra and Rb are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or two Rb are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the compound of Formula (I) is a compound of Formula (Ia):

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the compound of Formula (I) is a compound of Formula (Ib):

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the compound of Formula (I) is a compound of Formula (Ic):

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the compound of Formula (I) is a compound of Formula (Id):

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the compound of Formula (I) is a compound of Formula (Ie):

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring A is pyridyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein each R10 is independently hydrogen or halogen.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein n is 1 or 2.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein R1 and R2 are hydrogen or deuterium.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein X is —O—.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein R5 is hydrogen, deuterium, halogen, —CN, or C1-C6alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein R6 is hydrogen, deuterium, halogen, —CN, or C1-C6alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein R7 is hydrogen, deuterium, or halogen.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring B is a phenyl or a 6-membered heteroaryl.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein each R11 is independently hydrogen or C1-C6alkyl.

### Claim 17 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein m is 1 or 2.

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein each R12 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R12a.

### Claim 19 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein each R12 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R12a.

### Claim 20 (depends on 1)

The compound claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein p is 1 or 2.

### Claim 21 (depends on 1)

The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 22 (depends on 1)

The compound of claim 1 that is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 23 (depends on 1)

The compound of claim 1 that is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 24 (depends on 1)

The compound of claim 1 that is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 25 (depends on 1)

The compound of claim 1 that is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 26 (depends on 1)

The compound of claim 1 that is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 27 (depends on 1)

The compound of claim 1 that is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 28 (depends on 1)

The compound of claim 1 that is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

### Claim 29 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, and a pharmaceutically acceptable excipient.

### Claim 30 (depends on 1)

A method for treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the condition is selected from the group consisting of an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an auto-inflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplastic disorder, and a cardiovascular or a cerebrovascular disorder.