Claims for Patent: 8,389,524

Summary for Patent: 8,389,524

Title:	Tricyclic nitrogen containing compounds as antibacterial agents
Abstract:	Tricyclic nitrogen containing compounds and their use as antibacterials. Z1 and Z2 are independently selected from CH and N.
Inventor(s):	David Evan Davies, David Thomas Davies, Ilaria Giordano, Alan Joseph Hennessy, Neil David Pearson
Assignee:	Glaxo Group Ltd
Application Number:	US12/596,685
Patent Claims:	1. A compound of formula (I) or a pharmaceutically acceptable salt and/or N-oxide thereof: wherein: Z1 is CH; Z2 is N; R1a is H and R1b is selected from hydrogen; halogen; cyano; (C1-6)alkyl; (C1-6)alkylthio; trifluoromethyl; trifluoromethoxy; carboxy; hydroxy optionally substituted with (C1-6)alkyl or (C1-6)alkoxy-substituted(C1-6)alkyl; (C1-6)alkoxy-substituted(C1-6)alkyl; hydroxy (C1-6)alkyl; an amino group optionally N-substituted by one or two (C1-6)alkyl, formyl, (C1-6)alkylcarbonyl or (C1-6)alkylsulphonyl groups; and aminocarbonyl wherein the amino group is optionally substituted by (C1-4)alkyl; R2 is hydrogen, or (C1-4)alkyl, or together with R6 forms Y as defined below; A is a group (i): in which: R3 is as defined for R1a and R1b or is oxo and n is 1 or 2: or A is a group (ii) wherein: W1, W2 and W3 are CR4R8 or W2 and W3 are CR4R8 and W1 represents a bond between W3 and N; X is O, CR4R8, or NR6; one R4 is as defined for R1a and R1b and the remainder and R8 are hydrogen or one R4 and R8 are together oxo and the remainder are hydrogen; R6 is hydrogen or (C1-6)alkyl; or together with R2 forms Y; R7 is hydrogen; halogen; hydroxy optionally substituted with (C1-6)alkyl; or (C1-6)alkyl; Y is CR4R8CH2; CH2CR4R8; (C═O); CR4R8; CR4R8(C═O); or (C═O)CR4R8; or when X is CR4R8, R8 and R7 together represent a bond; U is selected from CO, and CH2 and R5 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; X1 is C or N when part of an aromatic ring, or CR14 when part of a non-aromatic ring; X2 is N, NR13, O, S(O)X, CO or CR14 when part of an aromatic or non-aromatic ring or may in addition be CR14R15 when part of a non aromatic ring; X3 and X5 are independently N or C; Y1 is a 0 to 4 atom linker group each atom of which is independently selected from N, NR13, O, S(O)x, CO and CR14 when part of an aromatic or non-aromatic ring or may additionally be CR14R15 when part of a non aromatic ring; Y2 is a 2 to 6 atom linker group, each atom of Y2 being independently selected from N, NR13, O, S(O)x, CO, CR14 when part of an aromatic or non-aromatic ring or may additionally be CR14R15 when part of a non aromatic ring; each of R14 and R15 is independently selected from: H; (C1-4)alkylthio; halo; carboxy(C1-4)alkyl; (C1-4)alkyl; (C1-4)alkoxycarbonyl; (C1-4)alkylcarbonyl; (C1-4)alkoxy (C1-4)alkyl; hydroxy; hydroxy(C1-4)alkyl; (C1-4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally mono- or di-substituted by (C1-4)alkyl; or R14 and R15 may together represent oxo; each R13 is independently H; trifluoromethyl; (C1-4)alkyl optionally substituted by hydroxy, (C1-6)alkoxy, (C1-6)alkylthio, halo or trifluoromethyl; (C2-4)alkenyl; (C1-4)alkoxycarbonyl; (C1-4)alkylcarbonyl; (C1-6)alkylsulphonyl; aminocarbonyl wherein the amino group is optionally mono or disubstituted by (C1-4)alkyl; and each x is independently 0, 1 or 2. 2. A compound according to claim 1 wherein R1a is hydrogen and R1b is hydrogen. 3. A compound according to claim 1 wherein A is (ia), n is 1 and R3 is H or hydroxy in the 3-position, A is (ii), X is CR4R8 and R8 is H and R4 is H or OH, or A is (ii), X is O, R7 is H and W1, W2 and W3 are each CH2. 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 CH2. 6. A compound according to claim 1 wherein R5 is an aromatic heterocyclic ring (B) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or NR13 in which Y2 contains 2-3 heteroatoms, one of which is 5 and 1-2 are N, with one N bonded to X3, or the heterocyclic ring (B) has ring (a) aromatic selected from optionally substituted benzo, pyrido, pyridazino and pyrimidino and ring (b) non aromatic and Y2 has 3-5 atoms, including at least one heteroatom, with O, S, CH2 or NR13 bonded to X5 where R13 is other than hydrogen, and either NHCO bonded via N to X3, or O, S, CH2 or NH bonded to X3. 7. A compound according to claim 1 wherein R5 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.