# US 10,870,646 B2 · Oxazolidinones and pharmaceutical compositions thereof for treating bacterial infections, including infection of Mycobacterium tuberculosis

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- Number: US 10,870,646 B2
- Document ID: US10870646B2
- Status: Granted
- Kind: B2
- Application number: 16/489,234
- Filed: 2018-02-26
- Published: 2020-01-02
- Granted: 2020-12-22
- Earliest claimed: 2017-02-27
- Assignees: University of St. Thomas; The John Hopkins University
- Applicants: University of St. Thomas; The Johns Hopkins University
- Inventors: J. Thomas Ippoliti; Gyanu Lamichhane
- Web page: https://patentgrep.com/patent/US10870646B2

## CPC

- C07D 413/10: linked by a carbon chain containing aromatic rings
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 498/06: Peri-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are oxazolidinone compounds of Formula I: (I) salts thereof, antibacterial pharmaceutical compositions containing them, and use of the compounds to inhibit bacterial growth in mammals, including humans.

## Claims

### Claim 1

An oxazolidinone compound of Formula I
wherein X is —N—; and
R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6- alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted- C1-C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2-CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR,—C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is selected from the group consisting of —N(H)— and —O—;
Z is selected from the group consisting of H, —OH, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, —C(═O)-amino acid, —C(═O)-polypeptide having from two (2) to fifty (50) residues, an azole, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo;
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, -aryl, -heteroaryl, -heterocyclyl, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, —C1-C6-alkyl-heterocyclyl, —C1-C6-alkyl-amino-SCF2R, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo, -linker-polypeptide having from two (2) to fifty (50) residues, and -linker-siderophore;
provided that not all of R1, R2, R3, and R4 are simultaneously hydrogen; and
salts thereof.

### Claim 2

An oxazolidinone compound of Formula I
wherein:
X is selected from the group consisting of —N— and —O—;
when X is —O—, R5 and the dotted bonds are absent;
when X is —N—, R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted- C1-C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2-CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is —O—;
Z is selected from the group consisting of H, —OH, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, —C(═O)-amino acid, —C(═O)-polypeptide having from two (2) to fifty (50) residues, an azole, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo;
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—OH, —C(═O)—O—C1—C6-alkyl, -aryl, -heteroaryl, -heterocyclyl, -C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, —C1-C6-alkyl-heterocyclyl, —C1-C6-alkyl-amino-SCF2R, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo, -linker-polypeptide having from two (2) to fifty (50) residues, and -linker-siderophore;
provided that not all of R1, R2, R3, and R4 are simultaneously hydrogen; and
salts thereof.

### Claim 3

An oxazolidinone compound of Formula I
wherein:
X is selected from the group consisting of —N— and —O—;
when X is —O—, R5 and the dotted bonds are absent;
when X is —N—, R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2—CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is selected from the group consisting of —N(H)— and —O—;
Z is 3-isoxazole, 4-isoxazole, or 5-isoxazole;
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O )—OH, —C(═O)—O—C1—C6-alkyl, -aryl, -heteroaryl, -heterocyclyl, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, —C1-C6-alkyl-heterocyclyl, —C1-C6-alkyl-amino-SCF2R, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo, -linker-polypeptide having from two (2) to fifty (50) residues, and -linker-siderophore;
provided that not all of R1, R2, R3, and R4 are simultaneously hydrogen; and
salts thereof.

### Claim 4

An oxazolidinone compound of Formula I
wherein:
X is selected from the group consisting of —N— and —O—;
when X is —O—, R5 and the dotted bonds are absent;
when X is —N—, R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1—C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2-CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is selected from the group consisting of —N(H)— and —O—;
Z is selected from the group consisting of H, —OH, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, —C(═O)-amino acid, —C(═O)-polypeptide having from two (2) to fifty (50) residues, an azole, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo;
R1, R3, and R4 are hydrogen;
R2 is hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—OH, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo; and
salts thereof.

### Claim 5

A pharmaceutical composition comprising a bacterial growth-inhibiting amount of a compound of Formula I
wherein X is —N—; and
R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2-CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is selected from the group consisting of —N(H)— and —O—;
Z is selected from the group consisting of H, —OH, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, —C(═O)-amino acid, —C(═O)-polypeptide having from two (2) to fifty (50) residues, an azole, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo;
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, -aryl, -heteroaryl, -heterocyclyl, -C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, —C1-C6-alkyl-heterocyclyl, —C1-C6-alkyl-amino-SCF2R, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo, -linker-polypeptide having from two (2) to fifty (50) residues, and -linker-siderophore;
provided that not all of R1, R2, R3, and R4 are simultaneously hydrogen; and
pharmaceutically suitable salts thereof;
in combination with a pharmaceutically suitable carrier.

### Claim 6

A pharmaceutical composition comprising a bacterial growth-inhibiting amount of a compound of Formula I
wherein:
X is selected from the group consisting of —N— and —O—;
when X is —O—, R5 and the dotted bonds are absent;
when X is —N—, R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted- C1-C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2-CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR, —C(═O)R, —C1—C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is —O—;
Z is selected from the group consisting of H, —OH, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, —C(═O)-amino acid, —C(═O)-polypeptide having from two (2) to fifty (50) residues, an azole, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo;
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, -aryl, -heteroaryl, -heterocyclyl, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, —C1-C6-alkyl-heterocyclyl, —C1-C6-alkyl-amino-SCF2R, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo, -linker-polypeptide having from two (2) to fifty (50) residues, and -linker-siderophore;
provided that not all of R1, R2, R3, and R4 are simultaneously hydrogen; and
pharmaceutically suitable salts thereof;
in combination with a pharmaceutically suitable carrier.

### Claim 7

A pharmaceutical composition comprising a bacterial growth-inhibiting amount of a compound of Formula I
wherein:
X is selected from the group consisting of —N— and —O—;
when X is —O—, R5 and the dotted bonds are absent;
when X is —N—, R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted- C1-C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2-CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is selected from the group consisting of —N(H)— and —O—;
Z is 3-isoxazole, 4-isoxazole, or 5-isoxazole;
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—OH, —C(═O)—O—C1—C6-alkyl, -aryl, -heteroaryl, -heterocyclyl, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, —C1-C6-alkyl-heterocyclyl, —C1-C6-alkyl-amino-SCF2R, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo, -linker-polypeptide having from two (2) to fifty (50) residues, and -linker-siderophore;
provided that not all of R1, R2, R3, and R4 are simultaneously hydrogen; and
pharmaceutically suitable salts thereof;
in combination with a pharmaceutically suitable carrier.

### Claim 8

A pharmaceutical composition comprising a bacterial growth-inhibiting amount of a compound of Formula I
wherein:
X is selected from the group consisting of —N— and —O—;
when X is —O—, R5 and the dotted bonds are absent;
when X is —N—, R5 is selected from the group consisting of hydrogen, halogen, amino, C1-C6-alkyl, hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted- C1-C6-alkyl, —C(═O)—C1-C6-alkyl-(O—CH2—CH2)1-16—O—C1-C6-alkyl, —C(═O)—OR, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo, and the dashed bonds attached to R5 are absent; or R5 is —(C═O)—, in which case X, R5, the dashed bonds, and the carbons to which they are attached define a 5-membered lactam ring;
Y is selected from the group consisting of —N(H)— and —O—;
Z is selected from the group consisting of H, —OH, —C(═O)—OH, —C(═O)—O—C1-C6-alkyl, —C(═O)-amino acid, —C(═O)-polypeptide having from two (2) to fifty (50) residues, an azole, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl, unsubstituted or substituted with one or more hydroxyl or halo;
R1, R3, and R4 are hydrogen;
R2 is hydroxyl-substituted-C1-C6-alkyl, halo-substituted-C1-C6-alkyl, amino-substituted-C1-C6-alkyl, —C(═O)—OH, —C(═O)R, —C1-C6-alkyl(═O)R, and —C(═O)—NRR, wherein each R is independently hydrogen or C1-C6-alkyl unsubstituted or substituted with one or more hydroxyl or halo; and
pharmaceutically suitable salts thereof;
in combination with a pharmaceutically suitable carrier.