US 11,439,622 B2Granted

Inhibitors of metallo-beta-lactamases

AssigneeOxford University Innovation Limited

InventorsJürgen Brem, Anna M. Rydzik, Michael A. McDonough, Christopher J. Schofield, Angus Morrison, Joanne Hewitt, Andrew Pannifer, Philip Jones

Life of this patent

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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.

Claims9

Dependent claims

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

wherein
A1, A2, A3 and A4 are C;
R1 is hydrogen;
R2 is —C(O)OH;
R3 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 RB;
wherein RB is halo, cyano, nitro, hydroxy or a group:
—Y3—X3—Z3
wherein
Y3 is absent or a linker group of the formula —[CRB1RB2]n— in which n is an integer selected from 1 or 2 and RB1 and RB2 are each independently selected from hydrogen or methyl;
X3 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(RB3)—, —N(RB4)—C(O)—, —N(RB4)—C(O)O—, —C(O)—N(RB3)—, —SO2—, —S(O)2N(RB3)—, or —N(RB4)SO2— wherein RB3 and RB4 are each independently selected from hydrogen or methyl;
and
Z3 is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;
and wherein Z3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, hydroxy, carboxy, NRB5RB6, (1-4C)alkoxy or (1-4C)alkyl;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen;
R7 is selected from cyano, hydroxy or a group
—Y7—X7—Z7
wherein:
Y7 is absent or a linker group of the formula —[CR7AR7B]q— in which q is an integer selected from 1, 2 or 3, and R7A and R7B are each independently selected from hydrogen or (1-2C)alkyl;
X7 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R7C)—, —N(R7D)—C(O)—, —N(R7D)—C(O)O—, —C(O)—N(R7C)—, —S—, —SO—, —SO2—, —S(O)2N(R7C)—, or —N(R7D)SO2— wherein R7C and R7D are each independently selected from hydrogen or methyl;
and
Z7 is (2-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
and wherein Z7 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR7ER7F, (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)NR7ER7F, NR7EC(O)R7F, NR7ES(O)2R7F and S(O)2NR7ER7F;
wherein R7E and R7F are each independently selected from hydrogen or (1-4C)alkyl;
or R7E and R7F 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 Z7 is optionally further substituted by halo, cyano, nitro, hydroxy, carboxy, NR7GR7H, (1-2C)alkoxy, or (1-2C)alkyl;
wherein R7G and R7H are selected from hydrogen or (1-2C)alkyl;
or R7C and Z7 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, NR7ER7F, (1-4C)alkoxy or (1-4C)alkyl.

26 more elements

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]pyridin-7-yl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(pyrimidin-5-yl)-1H-indole-2-carboxylic acid
3-(4-aminophenyl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(pyridin-3-yl)-1H-indole-2-carboxylic acid
3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid
3-(2-cyanophenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-(N,N-dimethylsulfamoyl)phenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-acetamidophenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(1H-indazol-4-yl)-7-methyl-1H-indole-2-carboxylic acid
3-(1H-indazol-6-yl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-((1H-pyrazol-1-yl)methyl)phenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-chlorophenyl)-1,7-dimethyl-1H-indole-2-carboxylic acid
3-(3,5-dimethylphenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(2-chlorophenyl)-7-methyl-1H-indole-2-carboxylic acid
3-([1,1′-biphenyl]-4-yl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(o-tolyl)-1H-indole-2-carboxylic acid
3-(4-chlorophenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-chloro-3-(trifluoromethyl)phenyl)-7-methyl-1H-indole-2-carboxylic acid
7-methyl-3-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid
3-(4-cyclopropylphenyl)-7-methyl-1H-indole-2-carboxylic acid
3-iodo-7-methyl-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-methoxy-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-(trifluoromethyl)-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-propyl-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-isopropyl-1H-indole-2-carboxylic acid
7-chloro-3-(4-fluorophenyl)-1H-indole-2-carboxylic acid
7-(tert-butyl)-3-(4-fluorophenyl)-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-(2-methoxyethyl)-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-(2-phenoxyethyl)-1H-indole-2-carboxylic acid
7-methyl-3-(pyridin-2-yl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-sulfamoylphenyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-phenyl-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-(methylsulfonyl)phenyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(pyridin-4-yl)-1H-indole-2-carboxylic acid
3-(4-carbamoylphenyl)-7-isopropyl-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-morpholinophenyl)-1H-indole-2-carboxylic acid
3-(4-chlorophenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(2-chlorophenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(4-(N,N-dimethylsulfamoyl)phenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(4-(dimethylcarbamoyl)phenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(1H-indazol-5-yl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(3,5-dichlorophenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(2,3-dimethoxyphenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(3,5-difluorophenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(4-((1H-pyrazol-1-yl)methyl)phenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(4-(N,N-dimethylsulfamoyl)phenyl)-7-(2-phenoxyethyl)-1H-indole-2-carboxylic acid
3-(4-(dimethylcarbamoyl)phenyl)-7-(2-phenoxyethyl)-1H-indole-2-carboxylic acid
3-(4-chlorophenyl)-7-(2-phenoxyethyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-(methylcarbamoyl)phenyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-(N-methylsulfamoyl)phenyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(5-methylthiophen-2-yl)-1H-indole-2-carboxylic acid
3-(4-(acetamidomethyl)phenyl)-7-isopropyl-1H-indole-2-carboxylic acid
3-(4-carboxyphenyl)-7-isopropyl-1H-indole-2-carboxylic acid
7-(tert-butyl)-3-(4-(dimethylcarbamoyl)phenyl)-1H-indole-2-carboxylic acid
7-(tert-butyl)-3-(4-(N,N-dimethylsulfamoyl)phenyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-(morpholinomethyl)phenyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-(morpholinosulfonyl)phenyl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-(methylsulfonamidomethyl)phenyl)-1H-indole-2-carboxylic acid
3-(4-((dimethylamino)methyl)phenyl)-7-isopropyl-1H-indole-2-carboxylic acid
7-isopropyl-3-(6-morpholinopyridin-3-yl)-1H-indole-2-carboxylic acid
7-isopropyl-3-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-1H-indole-2-carboxylic acid
3-(2-chloro-4-(dimethylcarbamoyl)phenyl)-7-isopropyl-1H-indole-2-carboxylic acid
4-(7-isopropyl-2-(1H-tetrazol-5-yl)-1H-indol-3-yl)-N,N-dimethylbenzenesulfonamide
3-cyclohexyl-7-methyl-1H-indole-2-carboxylic acid
3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methyl-1H-indole-2-carboxylic acid
7-cyclopropyl-3-(4-fluorophenyl)-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-(2-hydroxyethyl)-1H-indole-2-carboxylic acid
3-(4-fluorophenyl)-7-methyl-N′-(4-(methylsulfonyl)phenyl)-1H-indole-2-carbohydrazide 1-methyl-3-phenyl-1H-indole-2-carboxylic acid
7-fluoro-3-(4-fluorophenyl)-1H-indole-2-carboxylic acid
3-(2,3-dimethoxyphenyl)-7-methyl-1H-indole-2-carboxylic acid
3-(3,5-dimethylisoxazol-4-yl)-7-methyl-1H-indole-2-carboxylic acid
3-(4-(N,N-dimethylsulfamoyl)phenyl)-7-isopropyl-N-methyl-1H-indole-2-carboxamide
3-(4-(N,N-dimethylsulfamoyl)phenyl)-7-isopropyl-N-phenyl-1H-indole-2-carboxamide, and
3-(4-(N,N-dimethylsulfamoyl)phenyl)-7-isopropyl-N-(oxazol-2-yl)-1H-indole-2-carboxamide.

94 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/779,775Filed 30 Nov 2016
Priority: GB 1521059.430 Nov 2015
Published: US 2020/0375946 A13 Dec 2020
Granted: 13 Sep 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification26 codes

A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol
A61K 31/4025
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: not condensed and…
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles

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US 2020/0375946 A1Pre-grant publication · published 3 Dec 2020
US 11,439,622 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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

wherein
A1, A2, A3 and A4 are C;
R1 is hydrogen;
R2 is —C(O)OH;
R3 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 RB;
wherein RB is halo, cyano, nitro, hydroxy or a group:
—Y3—X3—Z3
wherein
Y3 is absent or a linker group of the formula —[CRB1RB2]n— in which n is an integer selected from 1 or 2 and RB1 and RB2 are each independently selected from hydrogen or methyl;
X3 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(RB3)—, —N(RB4)—C(O)—, —N(RB4)—C(O)O—, —C(O)—N(RB3)—, —SO2—, —S(O)2N(RB3)—, or —N(RB4)SO2— wherein RB3 and RB4 are each independently selected from hydrogen or methyl;
and
Z3 is (1-6C)alkyl, aryl, heteroaryl or heterocyclyl;
and wherein Z3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, hydroxy, carboxy, NRB5RB6, (1-4C)alkoxy or (1-4C)alkyl;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen;
R7 is selected from cyano, hydroxy or a group
—Y7—X7—Z7
wherein:
Y7 is absent or a linker group of the formula —[CR7AR7B]q— in which q is an integer selected from 1, 2 or 3, and R7A and R7B are each independently selected from hydrogen or (1-2C)alkyl;
X7 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R7C)—, —N(R7D)—C(O)—, —N(R7D)—C(O)O—, —C(O)—N(R7C)—, —S—, —SO—, —SO2—, —S(O)2N(R7C)—, or —N(R7D)SO2— wherein R7C and R7D are each independently selected from hydrogen or methyl;
and
Z7 is (2-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
and wherein Z7 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR7ER7F, (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)NR7ER7F, NR7EC(O)R7F, NR7ES(O)2R7F and S(O)2NR7ER7F;
wherein R7E and R7F are each independently selected from hydrogen or (1-4C)alkyl;
or R7E and R7F 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 Z7 is optionally further substituted by halo, cyano, nitro, hydroxy, carboxy, NR7GR7H, (1-2C)alkoxy, or (1-2C)alkyl;
wherein R7G and R7H are selected from hydrogen or (1-2C)alkyl;
or R7C and Z7 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, NR7ER7F, (1-4C)alkoxy or (1-4C)alkyl.

26 more elements

Facts

Application

15/779,775Filed 30 Nov 2016

Priority

GB 1521059.430 Nov 2015

Published

US 2020/0375946 A13 Dec 2020

Granted

13 Sep 2022

Term ends

Not estimatedThe source records don’t support an estimate.

Classification26 codes

A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol
A61K 31/4025
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: not condensed and…
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles