Peptide macrocycles against Acinetobacter baumannii

Patent metadata

Field	Value
Publication number	US-11098080-B2
Application number	US-201816006564-A
Country	US
Kind code	B2
Filing date	Jun 12, 2018
Priority date	Oct 27, 2015
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention provides compounds of formula (I)wherein X1 to X8 and R1 to R8 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by Acinetobacter baumannii.

First claim

The invention claimed is:

1. A method for the treatment or prevention of infections and resulting diseases caused by Acinetobacter baumannii , which method comprises administering to a human in need thereof a compound according to formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is C-L 1 -R 11 or N;
X 2 is C-L 2 -R 12 or N;
X 3 is C-L 3 -R 13 or N;
X 4 is C-L 4 -R 14 or N, with the proviso that not more than three of X 1 , X 2 , X 3 and X 4 are N;
X 5 is C-L 5 -R 15 or N;
X 6 is C-L 6 -R 16 or N;
X 7 is C-L 7 R 17 or N;
X 8 is C-L 8 -R 18 or N, with the proviso that not more than three of X 5 , X 6 , X 7 and X 8 are N;
R 1 is —(CH 2 ) m -heteroaryl or —(CH 2 ) m -heterocycloalkyl, wherein heteroaryl is optionally substituted with one or more halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl or C 1-7 -alkoxy;
R 2 , R 4 and R 6 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, and C 3-7 -cycloalkyl;
R 3 is —C 1-7 -alkyl, —(CH 2 ), —NR 20 R 21 , —(CH 2 ), —C(O)NR 20 R 21 or —(CH 2 ), —O—(CH 2 ) q —NR 20 R 21 ;
R 5 is hydrogen, C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, —(CH 2 ) o —NR 22 R 23 , —(CH 2 ) o —C(O)—NR 22 R 23 ,
—(CH 2 ) o —O—(CH 2 ) q —NR 20 R 21 , —(CH 2 ) o —NH—C(NH)—NR 22 R 23 , —(CH 2 ) o —NH—C(O)—NR 22 R 23 ,
—(CH 2 ) o —NH—C(O)—OR 26 , —(CH 2 ) o —C 3-7 -cycloalkyl, —(CH 2 ) o -heterocycloalkyl, —(CH 2 ) o -heteroaryl or —(CH 2 ) o -aryl, wherein cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted by halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -alkoxy or aryl;

R 5′ is hydrogen or C 1-7 -alkyl;
R 7 and R 8 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and C 1-7 -alkoxy;
R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each individually selected from hydrogen, halogen, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , hydroxy C 1-7 -alkoxy, haloC 1-7 -alkoxy, —B(OH) 2 , benzyloxy-propynyl (—C≡C—CH 2 —O-benzyl), C 3-7 -cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
wherein heteroaryl is optionally substituted with one C 1-7 -haloalkyl or C 1-7 -alkoxy;
R 17 is hydrogen, halogen, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , hydroxy, C 1-7 -alkoxy, haloC 1-7 -alkoxy, B(OH) 2 , benzyloxy-prop-1-ynyl, C 3-7 -cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
wherein heterocycloalkyl is optionally substituted with one —NR 24 R 25 , and
wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -hydroxyalkyl, hydroxy, C 1-7 -alkoxy, —NR 24 R 25 , SO 2 —C 1-7 -alkyl, —SO 2 —NR 24 R 25 , heterocycloalkyl and heterocycloalkyl substituted with C 1-7 -alkyl;

R 18 is hydrogen, halogen, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, hydroxy, C 1-7 -hydroxyalkyl, C 1-7 -alkoxy, C 1-7 -haloalkoxy, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , C 3-7 -cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, cyano, C 1-7 -alkyl C 1-7 -haloalkyl, hydroxy, C 1-7 -alkoxy,
—NR 24 -R 25 , C 1-7 -alkyl-NR 24 R 25 , —CO—NH—(CH 2 ), —NR 24 R 25 , —CO—NH—(CH 2 ), —OH, —CO—NH—(CH 2 ) r -heterocycloalkyl, —CO—OH, —O—C 1-7 -hydroxyalkyl, —O—(CH 2 ) r —CO—OH, —SO 2 —C 1-7 -alkyl, —SO 2 —NR 24 R 25 , heterocycloalkyl, —O-heterocycloalkyl and heterocycloalkyl substituted with C 1-7 -alkyl;

R 20 and R 22 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and —C(═NH)—NH 2 ;
R 21 and R 23 are each individually selected from hydrogen and C 1-7 -alkyl;
R 24 and R 25 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -hydroxyalkyl, and C 3-7 -cycloalkyl;
R 26 is hydrogen, C 1-7 -alkyl or benzyl;
L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are each individually selected from a single bond, —C(O)—, —SO 2 —,
—(CH 2 ) p —, —CH═CH— and —C≡C—;

m is 1, 2, 3, or 4;
n is 1, 2, 3, or 4;
o is 0, 1, 2, 3, or 4;
p is 1, 2, 3, or 4;
q is 1, 2, 3, or 4; and
r is 1, 2, 3, or 4.

2. The method of claim 1 , wherein the compound has a structure of formula (I′):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is C-L 2 -R 11 or N;
X 2 is C-L 2 -R 12 or N;
X 3 is C-L 3 -R 13 or N;
X 4 is C-L 4 -R 14 or N, with the proviso that not more than three of X 1 , X 2 , X 3 and X 4 are N;
X 5 is C-L 5 -R 15 or N;
X 6 is C-L 6 -R 16 or N;
X 7 is C-L 7 R′ 7 or N;
X 8 is C-L 8 -R 18 or N, with the proviso that not more than three of X 5 , X 6 , X 7 and X 8 are N;
R 1 is —(CH 2 ) m -heteroaryl, wherein heteroaryl is optionally substituted with one or more halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl or C 1-7 -alkoxy;
R 2 , R 4 and R 6 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, and C 3-7 -cycloalkyl;
R 3 is —(CH 2 ) n —NR 20 R 21 ;
R 5 is C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, —(CH 2 ) o —NR 22 R 23 , —(CH 2 ) o —C(O)—NR 22 R 23 , —(CH 2 ) o —NH—C(O)—NR 22 R 23 , —(CH 2 ) o —C 3-7 -cycloalkyl, —(CH 2 ) o -heterocycloalkyl, —(CH 2 ) o -heteroaryl or —(CH 2 ) o -aryl, wherein cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted by halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl or C 1-7 -alkoxy;
R 7 and R 8 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and C 1-7 -alkoxy;
R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each individually selected from hydrogen, halogen, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, —NR 24 R 25 , hydroxy, C 1-7 -alkoxy, haloC 1-7 -alkoxy, C 3-7 -cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R 20 and R 22 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and —C(═NH)—NH 2 ;
R 21 and R 23 are each individually selected from hydrogen and C 1-7 -alkyl;
R 24 and R 25 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, and C 3-7 -cycloalkyl;
L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are each individually selected from a single bond, —C(O)—, —SO 2 —, —(CH 2 ) p —, —CH═CH— and —C≡C—; and
m, n, o and p are each individually selected from 1, 2, 3 and 4.

3. The method of claim 1 , wherein the compound has a structure of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:
R 9 is hydrogen, halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -alkoxy, C 1-7 -haloalkoxy or C 3-7 -cycloalkyl;
R 10 is hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-7 -cycloalkyl;
R 19 is hydrogen, halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -alkoxy, C 1-7 -haloalkoxy or C 3-7 -cycloalkyl.

4. The method of claim 1 , wherein the compound has a structure of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen, halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 alkoxy, C 1-7 -haloalkoxy or C 3-7 -cycloalkyl and Y is —CH 2 — or —CO—.

5. The method of claim 1 , wherein the compound has a structure of formula (Ic):

Assignees

• Hoffmann La Roche

Inventors

• Alanine Alexander
• Beignet Julien
• Bleicher Konrad
• Fasching Bernhard
• Hilpert Hans
• Hu taishan
• Macdonald Dwight
• Jackson Stephen
• Kolczewski Sabine
• Kroll Carsten
• Schaeublin Adrian
• Shen Hong
• Stoll Theodor
• Thomas Helmut
• Wahhab Amal
• Zampaloni Claudia

Classifications

• A61K31/04 Primary

  Nitro compounds · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07K5/081

  the side chain containing O or S as heteroatoms, e.g. Cys, Ser · CPC title

• C07K5/02 Primary

  containing at least one abnormal peptide link · CPC title