Oxazolidinones and pharmaceutical compositions thereof for treating bacterial infections, including infection of Mycobacterium tuberculosis

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.

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.

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.

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.

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.

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.

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.