Antibacterial basic biaromatic derivatives with aminoalkoxy substitution

Patent metadata

Field	Value
Publication number	US-9850256-B2
Application number	US-201515516290-A
Country	US
Kind code	B2
Filing date	Oct 14, 2015
Priority date	Oct 15, 2014
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

The invention relates to antibacterial compounds of formula I

wherein R 1a , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , U 1 , U 2 , U 3 , U 4 , V 1 , V 2 , V 3 , V 4 , X and Q and n are as defined in the specification. It further relates pharmaceutical compositions containing these compounds and the uses of these compounds in the manufacture of medicaments for the treatment of bacterial infections. These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram-positive and Gram-negative aerobic and anaerobic bacteria.

First claim

The invention claimed is:

1. A compound of formula I

wherein
n represents 0, 1, 2 or 3;
R 1a represents H or (C 1 -C 3 )alkyl;
R 2a and R 2b each independently represents H or (C 1 -C 3 )alkyl;
R 3a and R 3b each independently represents H or (C 1 -C 3 )alkyl;
R 4 represents H, (C 1 -C 3 )alkyl, or (C 2 -C 3 )alkyl-NR 4a R 4b , wherein R 4a and R 4b are independently from each other H or (C 1 -C 3 )alkyl;
R 5 represents H, (C 1 -C 3 )alkyl, or (C 2 -C 3 )alkyl-NR 5a R 5b , wherein R 5a and R 5b are independently from each other H or (C 1 -C 3 )alkyl; or
R 2a and R 2b together with the carbon atom which bears them, form a 3 to 6-membered cycloalkyl ring; or
R 4 and R 5 together with the nitrogen atom which bears them, form a 4 to 6-membered heterocycloalkyl ring; or
R 4 and R 5 together with the nitrogen atom which bears them, form a 6 to 8-membered bicyclic heterocycloalkyl ring, which bicyclic heterocycloalkyl ring may optionally be substituted by a group NR 6 R 7 , wherein R 6 and R 7 are independently from each other H or (C 1 -C 3 )alkyl; or
R 4 and R 5 together with the nitrogen atom which bears them and the adjacent CR 2a R 2b or CR 3a R 3b together form an amidine group; or
R 1a and R 3a , together with the carbon atoms which bear them and the carbon atom which connects these latter two atoms, form a 4 to 6-membered cycloalkyl ring, whereby R 2a , R 2b and R 3b each represent H, and n represents 1; or
R 1a and R 4 , together with the carbon and nitrogen atoms which bear them and the carbon atom(s) which connect(s) the latter two atoms, form a 4 to 6-membered heterocycloalkyl ring, whereby R 2a , R 2b , optional R 3a and optional R 3b each represent H, n represents 0 or 1, and said 4 to 6-membered heterocycloalkyl ring optionally comprises a substituent selected from OCH 3 or CH 3 ; or
R 2a and R 4 together with the carbon and nitrogen atoms which bear them and the optional carbon atom(s) which connect the latter two atoms, form a 4 to 6-membered heterocycloalkyl ring, whereby R 1a , optional R 3a and optional R 3b each represent H, R 2b represents H, NH 2 or OH, and n represents 0, 1 or 2;
U 1 represents N or CH, U 2 represents N, CH, C—O(C 1 -C 3 )alkyl, or C—CN, U 3 represents N or CH and U 4 represents N or CH, it being understood that at most three of U 1 , U 2 , U 3 and U 4 can represent N at the same time;
V 1 represents N or CH, V 2 represents N or CH, V 3 represents N or CH and V 4 represents N or CH, it being understood that at most three of V 1 , V 2 , V 3 and V 4 can represent N at the same time;
X represents CH or N;
Q represents O or S;
or a salt of this compound.

2. The compound according to claim 1 , which is also a compound of formula I A

wherein
n represents 0, 1, 2 or 3;
R 1a represents H or (C 1 -C 3 )alkyl;
R 2a and R 2b each independently represents H or (C 1 -C 3 )alkyl;
R 3a and R 3b each independently represents H or (C 1 -C 3 )alkyl;
R 4 represents H, (C 1 -C 3 )alkyl, or (C 2 -C 3 )alkyl-NR 4a R 4b , wherein R 4a and R 4b are independently from each other H or (C 1 -C 3 )alkyl;
R 5 represents H, (C 1 -C 3 )alkyl, or (C 2 -C 3 )alkyl-NR 5a R 5b , wherein R 5a and R 5b are independently from each other H or (C 1 -C 3 )alkyl; or
R 2a and R 2b together with the carbon atom which bears them, form a 3 to 6-membered cycloalkyl ring; or
R 4 and R 5 together with the nitrogen atom which bears them, form a 4 to 6-membered heterocycloalkyl ring; or
R 4 and R 5 together with the nitrogen atom which bears them, form a 6 to 8-membered bicyclic heterocycloalkyl ring, which bicyclic heterocycloalkyl ring may optionally be substituted by a group NR 6 R 7 , wherein R 6 and R 7 are independently from each other H or (C 1 -C 3 )alkyl; or
R 4 and R 5 together with the nitrogen atom which bears them and the adjacent CR 2a R 2b or CR 3a R 3b together form an amidine group; or
R 1a and R 3a , together with the carbon atoms which bear them and the carbon atom which connects these latter two atoms, form a 4 to 6-membered cycloalkyl ring,
whereby R 2a , R 2b and R 3b each represent H, and n represents 1;
U 1 represents N or CH, U 2 represents N, CH, C—O(C 1 -C 3 )alkyl, or C—CN, U 3 represents N or CH and U 4 represents N or CH, it being understood that at most three of U 1 , U 2 , U 3 and U 4 can represent N at the same time;
V 1 represents N or CH, V 2 represents N or CH, V 3 represents N or CH and V 4 represents N or CH, it being understood that at most three of V 1 , V 2 , V 3 and V 4 can represent N at the same time;
X represents CH or N;
Q represents O or S;
or a salt of this compound.

3. The compound according to claim 1 , which is also a compound of formula I B

wherein
R 1a and R 4 , together with the carbon and nitrogen atoms which bear them and the carbon atom(s) which connect(s) the latter two atoms, form a 4 to 6-membered heterocycloalkyl ring, whereby R 2a , R 2b , optional R 3a and optional R 3b each represent H, n represents 0 or 1, and said 4 to 6-membered heterocycloalkyl ring optionally comprises a substituent selected from OCH 3 or CH 3 ; or
R 2a and R 4 together with the carbon and nitrogen atoms which bear them and the optional carbon atom(s) which connect(s) the latter two atoms, form a 4 to 6-membered heterocycloalkyl ring, whereby R 1a , optional R 3a and optional R 3b each represent H, R 2b represents H, NH 2 or OH, and n represents 0, 1 or 2;
R 5 represents H, (C 1 -C 3 )alkyl, or (C 2 -C 3 )alkyl-NR 5a R 5b , wherein R 5a and R 5b are independently from each other H or (C 1 -C 3 )alkyl;
U 1 represents N or CH, U 2 represents N, CH, C—O(C 1 -C 3 )alkyl, or C—CN, U 3 represents N or CH and U 4 represents N or CH, it being understood that at most three of U 1 , U 2 , U 3 and U 4 can represent N at the same time;
V 1 represents N or CH, V 2 represents N or CH, V 3 represents N or CH and V 4 represents N or CH, it being understood that at most three of V 1 , V 2 , V 3 and V 4 can represent N at the same time;
X represents CH or N;
Q represents O or S;
or a salt of this compound.

4. The compound according to claim 1 , wherein
R 1a represents H or CH 3 ;
R 2a and R 2b each independently represents H or CH 3 ;
R 3a and R 3b each independently represents H or CH 3 ;
R 4 represents H, CH 3 , or CH 2 CH 2 NH 2 ;
R 5 represents H, CH 3 , or CH 2 CH 2 NH 2 ; and
n represents 0, 1, 2 or 3;
or a salt of this compound.

5. The compound according to claim 1 , wherein
R 1a , R 2a , R 2b , R 3a and R 3b each represent H;
R 4 and R 5 together with the nitrogen atom which bears them, form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl ring; and
n represents 0, 1, 2 or 3;
or a salt of this compound.

6. The compound according to claim 1 , wherein
R 1a represents H or CH 3 ;
R 2a and R 2b , each independently from each other represents H or CH 3 ;
R 3a and R 3b each independently from each other represents H or CH 3 ;
R 4 and R 5 together with the nitrogen atom which bears them, form a 6-amino-3-az

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Cren Sylvaine
• Friedli Astrid
• Rueedi Georg
• Zumbrunn Cornelia

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• A61P31/00

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

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title

• C07D498/00

  Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms (4-oxa-1-azabicyclo [3.2.0] heptanes, e.g. oxapenicillins C07D503/00; 5-oxa-1-azabicyclo [4.2.0] octanes, e.g. oxacephalosporins C07D505/00; analogues thereof having ring oxygen atoms in other position C07D507/00) · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title