Inhibitors of metallo-beta-lactamases

Patent metadata

Field	Value
Publication number	US-11413272-B2
Application number	US-201816616515-A
Country	US
Kind code	B2
Filing date	May 25, 2018
Priority date	May 26, 2017
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

Abstract

The present invention relates to compounds of Formula (I) 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. (Formula (I))

First claim

The invention claimed is:

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

wherein
R 1 is selected from hydrogen or; (1-4C)alkyl, wherein each (1-4C)alkyl is optionally substituted by one or more substituent groups selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR 1A R 1B or (1-4C)alkoxy, wherein R 1A and R 1B are each independently selected from hydrogen or (1-2C)alkyl;
R 2 is selected from:
i) —C(O)OH;
ii) —C(O)OR 2A , wherein R 2A is selected from (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl or heterocyclyl-(1-2C)alkyl, each of which is optionally substituted by one or more substituent groups R A ;
iii) —C(O)NR 2B R 2C ; wherein R 2B and R 2C are each independently selected from hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl or heterocyclyl-(1-2C)alkyl, each of which is optionally substituted by one or more substituent groups R A ;
iv) —C(O)NR 2D NR 2B R 2E ; wherein R 2D is selected from hydrogen or (1-6C)alkyl and R 2B and R 2C are as defined above;
v) tetrazolyl;
vi) triazolyl;
vii) —B(OR 2F )(OR 2G ), wherein R 2F and R 2G are each independently selected from hydrogen, (1-6C)alkyl or R 2F and R 2G are linked such that, together with the B and O atoms, they form a 5 or 6-membered heterocyclic ring, which is optionally substituted by (1-2C)alkyl;
viii) trifluoromethylketone; or
ix) cyano;
x) —[C(O)] v S(NR 2X )(O)NR 2B R 2C (where v is 0 or 1), wherein R 2X is selected from hydrogen, (1-6C)alkyl, C(O)R X , C(O)OR X , aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl or heterocyclyl-(1-2C)alkyl, wherein R X is selected from (1-6C)alkyl, aryl or heteroaryl, each of which is optionally substituted with one or more R A , and wherein R 2B and R 2C are as defined above;
xi) —[C(O)] w N(R 2B )S(NR 2X )(O)R X (where w is 0 or 1), wherein R 2B , R 2X and R X are each as defined above; or
xii) —S(O) y NR 2B R 2C (wherein y is 1 or 2), and wherein R 2B and R 2C are as defined above,
and wherein R A is selected from oxo, halo, cyano, nitro or a group of the formula:
—Y 2 —X 2 —Z 2

wherein
Y 2 is absent or a linker group of the formula —[CR A1 R A2 ] m — in which m is an integer selected from 1, 2, 3 or 4, and R A1 and R A2 are each independently selected from hydrogen or (1-2C)alkyl;
X 2 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR A3 )—, —N(R A3 )—, —N(R A3 )—C(O)—, —N(R A3 )—C(O)O—, —C(O)—N(R A3 )—, —N(R A3 )C(O)N(R A3 )—, —S—, —SO—, —SO 2 —, —S(O) 2 N(R A3 )—, or —N(R A3 )SO 2 — wherein R A3 is selected from hydrogen or methyl; and
Z 2 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
and wherein Z 2 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR A4 R A5 , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NR A4 R A5 , NR A4 C(O)R A5 , NR A4 S(O) 2 R A5 and S(O) 2 NR A4 R A5 ; wherein R A4 and R A5 are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R A4 and R A5 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 2 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NR A6 R A7 , (1-2C)alkoxy, or (1-2C)alkyl; wherein R A6 and R A7 are selected from hydrogen or (1-2C)alkyl;

R 3 is selected from halo, cyano, hydroxyl, aryl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl, wherein said aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl is optionally substituted by one or more R B ;
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, 2, 3 or 4, and R B1 and R B2 are each independently selected from hydrogen or (1-2C)alkyl;
X 3 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR B3 )—, —N(R B3 )—, —N(R B4 )—C(O)—, —N(R B4 )—C(O)O—, —C(O)—N(R B3 )—, —N(R B4 )C(O)N(R B3 )—, —S—, —SO—, —SO 2 —, or —N(R B4 )SO 2 — wherein R B3 and R B4 are each independently selected from hydrogen or methyl; and
Z 3 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl or heterocyclyl;
and wherein Z 3 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR B5 R B6 , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, aryl, aryloxy, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NR B5 R B6 , NR B5 C(O)R B6 , NR B5 S(O) 2 R B6 and S(O) 2 NR B5 R B6 ; wherein R B5 and R B6 are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R B5 and R B6 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 3 is optionally further substituted by halo, cyano, nitro, hydroxy, caboxy, NR B7 R B8 , (1-2C)alkoxy, or (1-2C)alkyl; wherein R B7 and R B8 are selected from hydrogen or (1-2C)alkyl;

or R B3 and Z 3 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 B5 R B6 , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, C(O)NR B5 R B6 , NR B5 C(O)R B6 , NR B5 S(O) 2 R B6 and S(O) 2 NR B5 R B6 ;
X 1 is selected from N or C—R 4 ;
R 4 is selected from halo, cyano, nitro, hydroxy or a group
—Y 4 —X 4 —Z 4

wherein:
Y 4 is absent or a linker group of the formula —[CR 4A R 4B ] n — in which q is an integer selected from 1 or 2 and R 4A and R 4B are each independently selected from hydrogen or methyl;
X 4 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR 4C )—, —N(R 4C )—, —N(R 4D )—C(O)—, —N(R 4D )—C(O)O—, —C(O)—N(R 4C )—, —S—, —SO—, —SO 2 —, —S(O) 2 N(R 4C )—, or —N(R 4D )SO 2 — wherein R 4C and R 4D are each independently selected from hydrogen or (1-4C)alkyl; and
Z 4 is hydrogen or (1-4C)alkyl which is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR 4E R 4F or (1-2C)alkoxy; wherein R 4E and R 4F are each independently selected from hydrogen or (1-2C)alkyl;

R 5 is selected from hydrogen, halo, cyano, nitro, hydroxy or a group of the formula:
—Y 5 —X 5 -Q 5 -Z 5

wherein Y 5 is absent or a linker group of the formula —[CR 5A R 5B ] p — in which p is an integer selected from 1 or 2, and R 5A and R 5B are each independently selected from hydrogen or (1-2C)alkyl;
X 5 is absent or —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR 5C )—, —N(R 5C )—, N(R 5D )—C(O)—, —N(R 5D )—C(O)O—, —C(O)—N(R 5C )—, —N(R 5D )C(O)N(R

Assignees

• Univ Oxford Innovation Ltd

Inventors

• Panduwawala Tharindi
• Brandt Peter
• Wang David
• Andaloussi Mounir
• Brem Jürgen
• Schofield Christopher J

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07D403/04

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

• C07D233/90

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

• A61K31/401

  Proline; Derivatives thereof, e.g. captopril · CPC title

• C07D209/70

  containing carbocyclic rings other than six-membered · CPC title