Inhibitors of metallo-beta-lactamases

Patent metadata

Field	Value
Publication number	US-11439622-B2
Application number	US-201615779775-A
Country	US
Kind code	B2
Filing date	Nov 30, 2016
Priority date	Nov 30, 2015
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

Abstract

The present invention relates to certain compounds, in particular, indole derivatives that function as inhibitors of bacterial metallo-beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of a bacterial infection.

First claim

The invention claimed is:

1. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as shown below:

wherein
A 1 , A 2 , A 3 and A 4 are C;
R 1 is hydrogen;
R 2 is —C(O)OH;
R 3 is selected from aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl, wherein said aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl is substituted by one or more R B ;
wherein R B is halo, cyano, nitro, hydroxy or a group:
—Y 3 —X 3 —Z 3

wherein
Y 3 is absent or a linker group of the formula —[CR B1 R B2 ] n — in which n is an integer selected from 1 or 2 and R B1 and R B2 are each independently selected from hydrogen or methyl;
X 3 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R B3 )—, —N(R B4 )—C(O)—, —N(R B4 )—C(O)O—, —C(O)—N(R B3 )—, —SO 2 —, —S(O) 2 N(R B3 )—, or —N(R B4 )SO 2 — wherein R B3 and R B4 are each independently selected from hydrogen or methyl; and
Z 3 is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;
and wherein Z 3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, hydroxy, carboxy, NR B5 R B6 , (1-4C)alkoxy or (1-4C)alkyl;

R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is selected from cyano, hydroxy or a group
—Y 7 —X 7 —Z 7

wherein:
Y 7 is absent or a linker group of the formula —[CR 7A R 7B ] q — in which q is an integer selected from 1, 2 or 3, and R 7A and R 7B are each independently selected from hydrogen or (1-2C)alkyl;
X 7 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R 7C )—, —N(R 7D )—C(O)—, —N(R 7D )—C(O)O—, —C(O)—N(R 7C )—, —S—, —SO—, —SO 2 —, —S(O) 2 N(R 7C )—, or —N(R 7D )SO 2 — wherein R 7C and R 7D are each independently selected from hydrogen or methyl; and
Z 7 is (2-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
and wherein Z 7 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR 7E R 7F , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, C(O)NR 7E R 7F , NR 7E C(O)R 7F , NR 7E S(O) 2 R 7F and S(O) 2 NR 7E R 7F ; wherein R 7E and R 7F are each independently selected from hydrogen or (1-4C)alkyl; or R 7E and R 7F can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring;
and wherein any alkyl, aryl, heterocyclyl or heteroaryl group present in a substituent group on Z 7 is optionally further substituted by halo, cyano, nitro, hydroxy, carboxy, NR 7G R 7H , (1-2C)alkoxy, or (1-2C)alkyl; wherein R 7G and R 7H are selected from hydrogen or (1-2C)alkyl;

or R 7C and Z 7 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring, which is optionally substituted by oxo, halo, cyano, nitro, hydroxy, carboxy, NR 7E R 7F , (1-4C)alkoxy or (1-4C)alkyl.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl, wherein said aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl is substituted by one or more R B ; and
wherein R B is halo, cyano, nitro, hydroxy or a group:
—Y 3 —X 3 —Z 3

wherein
Y 3 is absent or a linker group of the formula —[CR B1 R B2 ] n — in which n is 1 and R B1 and R B2 are each hydrogen;
X 3 is absent or —O—, —C(O)O—, —N(R B3 )—, —N(R B4 )—C(O), —C(O)—N(R B3 )—, —SO 2 —, —S(O) 2 N(R B3 )—, or —N(R B4 )SO 2 — wherein R B3 and R B4 are each independently selected from hydrogen or methyl; and
Z 3 is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;
and wherein Z 3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo or (1-4C)alkyl.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl or heterocyclyl is substituted by one or more R B ; and
R B is halo, cyano, nitro, or a group:
—Y 3 —X 3 —Z 3

wherein
Y 3 is absent or a linker group of the formula —[CR B1 R B2 ] n — in which n is 1 and R B1 and R B2 are hydrogen;
X 3 is absent or —O—, —C(O)O—, —N(R B3 )—, —N(R B4 )—C(O), —C(O)—N(R B3 )—, —SO 2 — or —S(O) 2 N(R B3 )—, or —N(R B4 )SO 2 —; wherein R B3 and R B4 are each independently selected from hydrogen or methyl; and
Z 3 is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;
and wherein Z 3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo or (1-4C)alkyl.

4. A compound according to claim 1 , wherein R 7 is selected from cyano, hydroxy or a group
—Y 7 —X 7 —Z 7

wherein:
Y 7 is absent or a linker group of the formula —[CR 7A R 7B ] q — in which q is an integer selected from 1, 2 or 3, and R 7A and R 7B are each independently selected from hydrogen or (1-2C)alkyl;
X 7 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R 7C )—, —N(R 7D )—C(O)—, —C(O)—N(R 7C )—, —SO 2 —, —S(O) 2 N(R 7C )—, or —N(R 7D )SO 2 —; wherein R 7C and R 7D are each independently selected from hydrogen or methyl; and
Z 7 is (2-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
and wherein Z 7 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR 7E R 7F , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, C(O)NR 7E R 7F or NR 7E C(O)R 7F ; wherein R 7E and R 7F are each independently selected from hydrogen or (1-4C)alkyl; or R 7E and R 7F can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring;
and wherein any alkyl, aryl, heterocyclyl or heteroaryl group present in a substituent group on Z 7 is optionally further substituted by halo, cyano, nitro, hydroxy, carboxy, NR 7G R 7H , (1-2C)alkoxy, or (1-2C)alkyl; wherein R 7G and R 7H are selected from hydrogen or (1-2C)alkyl.

5. A compound selected from any one of the following, or a pharmaceutically acceptable salt thereof:
3-(3-chlorophenyl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxylic acid
3-(3,5-dichlorophenyl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(pyridin-4-yl)-1H-indole-2-carboxylic acid
3-(4-carbamoylphenyl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(4-sulfamoylphenyl)-1H-indole-2-carboxylic acid
3-(4-cyanophenyl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(4-nitrophenyl)-1H-indole-2-carboxylic acid
3-(4-methoxyphenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-bromophenyl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid
7-methyl-3-(4-(methylsulfonyl)phenyl)-1H-indole-2-carboxylic acid
7-methyl-3-(4-morpholinophenyl)-1H-indole-2-carboxylic acid
7-methyl-3-(3-sulfamoylphenyl)-1H-indole-2-carboxylic acid
7-methyl-3-(3-nitrophenyl)-1H-indole-2-carboxylic acid
7-methyl-3-(3-(methylsulfonyl)phenyl)-1H-indole-2-carboxylic acid
3-(3-(dimethylamino)phenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(3-bromophenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(1H-indazol-5-yl)-7-methyl-1H-indole-2-carboxylic acid
3-(2-methoxyphenyl)-7-methyl-1H-indole-2-carboxylic acid
3-([1,2,4]triazolo[1,5-a]py

Assignees

• Univ Oxford Innovation Ltd

Inventors

• Brem Jürgen
• Rydzik Anna M
• Mcdonough Michael A
• Schofield Christopher J
• Morrison Angus
• Hewitt Joanne
• Pannifer Andrew
• Jones Philip

Classifications

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D209/42 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title