Aryl substituted aminomethyl spectinomycin analogs as antibacterial agents

Patent metadata

Field	Value
Publication number	US-10266544-B2
Application number	US-201415024549-A
Country	US
Kind code	B2
Filing date	Sep 29, 2014
Priority date	Sep 29, 2013
Publication date	Apr 23, 2019
Grant date	Apr 23, 2019

Abstract

The invention relates to aryl substituted aminomethyl spectinomycin analogs, derivatives thereof, and related compounds, which are useful as anti-bacterial agents; methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating anti-bacterial infections using the compounds and compositions.

First claim

What is claimed is:

1. A compound having a structure represented by a Formula I:

wherein n is an integer selected from 1, 2, and 3;
wherein R 1 is selected from hydrogen and C1-C4 alkyl;
wherein each occurrence of R 2a and R 2b , when present, is independently selected from hydrogen and C1-C3 alkyl; and
wherein Ar is aryl or heteroaryl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 ,
wherein each occurrence of R 9 , when present, is selected from hydrogen and C1-C3 alkyl;
wherein each occurrence of R 10a and R 10b , when present, is independently selected from hydrogen and C1-C3 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is selected from hydrogen and methyl.

3. The compound of claim 1 , wherein each occurrence of R 2a and R 2b is hydrogen.

4. The compound of claim 1 , wherein Ar is phenyl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .

5. The compound of claim 4 , wherein Ar is phenyl substituted with 0 to 3 groups independently selected from —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 .

6. The compound of claim 1 , wherein Ar is heteroaryl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═(C═)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .

7. The compound of claim 6 , wherein Ar is heteroaryl substituted with 0 to 3 groups independently selected from —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 .

8. The compound of claim 1 , wherein Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and 1H-benzo[d]imidazolyl; and wherein Ar is substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .

9. The compound of claim 8 , wherein Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and 1H-benzo[d]imidazolyl; and wherein Ar is substituted with 0 to 3 groups independently selected from —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 .

10. The compound of claim 1 , having a structure represented by a formula:

wherein each of R 3a , R 3b , R 3c , R 3d , and R 3e are independently selected from hydrogen, halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 , provided that at least two of R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen.

11. The compound of claim 10 , wherein each of R 3a , R 3b , R 3c , R 3d , and R 3e are independently selected from hydrogen, —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 , provided that at least two of R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen.

12. The compound of claim 1 , having a structure represented by a formula:

wherein R 3c is selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .

13. The compound of claim 1 , selected from the group consisting of:

or a subgroup thereof.

14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is a solid dosage form selected from a capsule, a tablet, a pill, a powder, a granule, an effervescing granule, a gel, a paste, a troche, and a

Assignees

• St Jude Childrens Res Hospital Inc

Inventors

• Lee Richard E
• Waidyarachchi Samanthi L
• Bruhn David F
• Liu Jiuyu
• Zheng Zhong
• Rosch Jason W

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title