Tricyclic nitrogen containing compounds as antibacterial agents

1. A compound of formula (I) or a pharmaceutically acceptable salt and/or N-oxide thereof:

wherein:

Z 1 is CH;

Z 2 is N;

R 1a is H and R 1b is selected from hydrogen; halogen; cyano; (C 1-6 )alkyl; (C 1-6 )alkylthio; trifluoromethyl; trifluoromethoxy; carboxy; hydroxy optionally substituted with (C 1-6 )alkyl or (C 1-6 )alkoxy-substituted(C 1-6 )alkyl; (C 1-6 )alkoxy-substituted(C 1-6 )alkyl; hydroxy (C 1-6 )alkyl; an amino group optionally N-substituted by one or two (C 1-6 )alkyl, formyl, (C 1-6 )alkylcarbonyl or (C 1-6 )alkylsulphonyl groups; and aminocarbonyl wherein the amino group is optionally substituted by (C 1-4 )alkyl;

R 2 is hydrogen, or (C 1-4 )alkyl, or together with R 6 forms Y as defined below;

A is a group (i):

in which: R 3 is as defined for R 1a and R 1b or is oxo and n is 1 or 2:

or A is a group (ii)

wherein:

W 1 , W 2 and W 3 are CR 4 R 8

or W 2 and W 3 are CR 4 R 8 and W 1 represents a bond between W 3 and N;

X is O, CR 4 R 8 , or NR 6 ;

one R 4 is as defined for R 1a and R 1b and the remainder and R 8 are hydrogen or one R 4 and R 8 are together oxo and the remainder are hydrogen;

R 6 is hydrogen or (C 1-6 )alkyl; or together with R 2 forms Y;

R 7 is hydrogen; halogen; hydroxy optionally substituted with (C 1-6 )alkyl; or (C 1-6 )alkyl;

Y is CR 4 R 8 CH 2 ; CH 2 CR 4 R 8 ; (C═O); CR 4 R 8 ; CR 4 R 8 (C═O); or (C═O)CR 4 R 8 ;

or when X is CR 4 R 8 , R 8 and R 7 together represent a bond;

U is selected from CO, and CH 2 and

R 5 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (B):

containing up to four heteroatoms in each ring in which

at least one of rings (a) and (b) is aromatic;

X 1 is C or N when part of an aromatic ring, or CR 14 when part of a non-aromatic ring;

X 2 is N, NR 13 , O, S(O) X , CO or CR 14 when part of an aromatic or non-aromatic ring or may in addition be CR 14 R 15 when part of a non aromatic ring;

X 3 and X 5 are independently N or C;

Y 1 is a 0 to 4 atom linker group each atom of which is independently selected from N, NR 13 , O, S(O) x , CO and CR 14 when part of an aromatic or non-aromatic ring or may additionally be CR 14 R 15 when part of a non aromatic ring;

Y 2 is a 2 to 6 atom linker group, each atom of Y 2 being independently selected from N, NR 13 , O, S(O) x , CO, CR 14 when part of an aromatic or non-aromatic ring or may additionally be CR 14 R 15 when part of a non aromatic ring;

each of R 14 and R 15 is independently selected from: H; (C 1-4 )alkylthio; halo; carboxy(C 1-4 )alkyl; (C 1-4 )alkyl; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylcarbonyl; (C 1-4 )alkoxy (C 1-4 )alkyl; hydroxy; hydroxy(C 1-4 )alkyl; (C 1-4 )alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally mono- or di-substituted by (C 1-4 )alkyl; or

R 14 and R 15 may together represent oxo;

each R 13 is independently H; trifluoromethyl; (C 1-4 )alkyl optionally substituted by hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, halo or trifluoromethyl; (C 2-4 )alkenyl; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylcarbonyl; (C 1-6 )alkylsulphonyl; aminocarbonyl wherein the amino group is optionally mono or disubstituted by (C 1-4 )alkyl; and

each x is independently 0, 1 or 2.

2. A compound according to claim 1 wherein R 1a is hydrogen and R 1b is hydrogen.

3. A compound according to claim 1 wherein A is (ia), n is 1 and R 3 is H or hydroxy in the 3-position, A is (ii), X is CR 4 R 8 and R 8 is H and R 4 is H or OH, or A is (ii), X is O, R 7 is H and W 1 , W 2 and W 3 are each CH 2 .

4. A compound according to claim 3 wherein A is piperidin-4-yl or pyrrolidin-4-ylmethyl.

5. A compound according to claim 1 wherein U is CH 2 .

6. A compound according to claim 1 wherein R 5 is an aromatic heterocyclic ring (B) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or NR 13 in which Y 2 contains 2-3 heteroatoms, one of which is 5 and 1-2 are N, with one N bonded to X 3 , or the heterocyclic ring (B) has ring (a) aromatic selected from optionally substituted benzo, pyrido, pyridazino and pyrimidino and ring (b) non aromatic and Y 2 has 3-5 atoms, including at least one heteroatom, with O, S, CH 2 or NR 13 bonded to X 5 where R 13 is other than hydrogen, and either NHCO bonded via N to X 3 , or O, S, CH 2 or NH bonded to X 3 .

7. A compound according to claim 1 wherein R 5 is selected from the group consisting of:

3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl;

3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl;

2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl;

[1,3]oxathiolo[5,4-c]pyridin-6-yl;

6-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl;

2,3-dihydro[1,4]oxathiino[2,3-c]pyridin-7-yl;

3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl;

5-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl;

5-carbonitro-2,3-dihydro-1,4-benzodioxin-7-yl; and

2,3-dihydro-benzo[1,4]dioxin-6-yl.

8. A compound which is:

(2R)-2-({-4-[([1,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2S)-2-({-4-[([1,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

2-({-4-[([1,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-({4-[(2,3-Dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

2-({4-[(2,3-Dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2S)-2-({4-[(2,3-Dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

2-({4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-({4-[(2,1,3-Benzothiadiazol-5-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-[(4-{[(7-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-({4-[(3,4-Dihydro-2H-[1,4]oxathiepino[2,3-c]pyridin-8-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-({-4-[([1,3]Oxathiolo[4,5-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-[(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-({4-[(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-[(4-{[(8-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

7-{[(1-{[(2R)-3,8-Dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-2-yl]methyl}-4-piperidinyl)amino]methyl}-2,3-dihydro-1,4-benzodioxin-5-carbonitrile;

(2R)-2-({4-[(2,3-Dihydrofuro[2,3-c]pyridin-5-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione;

(2R)-2-[(4-{[(5-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione; or

(R)-2-((4-((6,7-dihydro-5H-thieno[3,2-b]pyran-2-yl)amino)piperidin-1-yl)methyl)-1,2-dihydro-2a,5,8a-triazaacenaphthylene-3,8-dione; or

a pharmaceutically acceptable salt thereof.

9. A method for treating a bacterial infection which comprises administering a therapeutically effective amount of a compound according to claim 1 to a human in need thereof;

wherein:

the bacterial infection is selected from upper respiratory tract infections, lower respiratory tract infections, skin infections, soft tissue infections, urinary tract infections or tuberculosis; and

the bacterial infection is caused by:

a Gram positive organism selected from Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis or Enterococcus faecium;

a Gram-negative organism selected from Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae and or Stenotrophomonas maltophilia ; or

Mycobacterium tuberculosis.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A compound which is (2R)-2-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione:

a pharmaceutically acceptable salt thereof.

12. A compound which is (2R)-2-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride:

13. A pharmaceutical composition comprising a compound according to claim 11 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier.

15. A method for treating a bacterial infection, which comprises administering a therapeutically effective amount of a compound according to claim 11 to a human in need thereof;

wherein:

the bacterial infection is selected from upper respiratory tract infections, lower respiratory tract infections, skin infections, soft tissue infections, urinary tract infections or tuberculosis; and

the bacterial infection is caused by:

a Gram positive organism selected from Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis or Enterococcus faecium;

a Gram-negative organism selected from Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumonia, Stenotrophomonas maltophilia ; or

Mycobacterium tuberculosis.

16. A method for treating a bacterial infection, which comprises administering a therapeutically effective amount of a compound according to claim 12 to a human in need thereof;

wherein:

the bacterial infection is selected from upper respiratory tract infections, lower respiratory tract infections, skin infections, soft tissue infections, urinary tract infections or tuberculosis; and

the bacterial infection is caused by:

a Gram positive organism selected from Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis or Enterococcus faecium;

a Gram-negative organism selected from Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumonia, Stenotrophomonas maltophilia ; or

Mycobacterium tuberculosis.

17. A method for treating a bacterial infection, which comprises administering a therapeutically effective amount of a compound according to claim 8 to a human in need thereof;

wherein:

the bacterial infection is selected from upper respiratory tract infections, lower respiratory tract infections, skin infections, soft tissue infections, urinary tract infections or tuberculosis; and

the bacterial infection is caused by:

a Gram positive organism selected from Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis or Enterococcus faecium;

a Gram-negative organism selected from Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumonia, Stenotrophomonas maltophilia ; or

Mycobacterium tuberculosis.

18. The compound according to claim 11 , which is (2R)-2-({4-[(3,4-Dihydro-2H- pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a- triazaacenaphthylene-3,8-dione:

19. The compound according to claim 11 , wherein the pharmaceutically acceptable salt is an acid addition salt or quaternary ammonium salt.

20. The compound according to claim 19 , wherein the acid addition salt is formed from:

mineral acids selected from hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid; or

organic acids selected from acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, p-toluenesulphonic acid, methanesulphonic acid, naphthalenesulphonic acid or tartaric acid.

21. The compound according to claim 19 , wherein the acid addition salt is a methane sulphonic acid salt.