Derivatives and analogs of N-ethylquinolones and N-ethylazaquinolones

1. This invention provides a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:

wherein:

two of Z 1 , Z 2 , Z 3 and Z 4 are independently CR 1c or N and the remainder are independently CR 1c ; or

Z 3 and Z 4 together represent S and one of Z 1 and Z 2 is CR 1c or N and the other is independently CR 1c ;

R 1a , R 1b and R 1c are independently 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(C1-6)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; or aminocarbonyl wherein the amino group is optionally substituted by (C 1-4 )alkyl; or two of R 1a , R 1b and R 1c on adjacent carbon atoms may together form an ethylenedioxy group;

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 , R 1b and R 1c or is oxo or aminomethyl and n is 1 or 2:

or A is a group (ii)

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 , R 1b and R 1c 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

in which:

Y 3 is CH 2 or O; and

R 10 is independently selected from hydrogen, halogen, (C 1-6 )alkyl and (C 1-6 )alkoxy.

2. A compound according to claim 1 wherein each of R 1a , R 1b and R 1c is independently hydrogen, methoxy, methyl, ethyl, cyano, or halogen.

3. A compound according to claim 2 wherein R 1a is methoxy, cyano, fluoro, chloro or bromo and R1b and R1c are hydrogen.

4. A compound according to claim 1 wherein R 2 is hydrogen.

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

6. A compound according to claim 1 wherein R 6 is selected from:

2-substituted 1H-pyrimido[5,4-b][1,4]oxazin-7(6H)-one;

2-substituted 4-chloro-1H-pyrimido[5,4-b][1,4]oxazin-7(6H)-one;

2-substituted 5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

2-substituted 4-chloro-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

2-substituted 4-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

2-substituted 4-methyloxy-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

7. A compound according to claim 1 wherein:

each of Z 1 , Z 2 , Z 3 and Z 4 is independently CR 1c ;

Z 1 is N and each of Z 2 , Z 3 and Z 4 is independently CR 1c ;

Z 2 is N and each of Z 1 , Z 3 and Z 4 is independently CR 1c ;

Z 3 is N and each of Z 1 , Z 2 and Z 4 is independently CR 1c ,

Z 1 and Z 3 are N and Z 2 and Z 4 are independently CR 1c ;

Z 2 and Z 3 are N and Z 1 and Z 4 are independently CR 1c ;

Z 3 and Z 4 are N and Z 1 and Z 2 are independently CR 1c ;

Z 3 and Z 4 together are S and Z 1 and Z 2 are independently CR 1c ;

Z 3 and Z 4 together are S and Z 1 is CR 1c and Z 2 is N; or

Z 1 and Z 2 are N and Z 3 and Z 4 are independently CR 1c .

8. A compound according to claim 1 wherein A is a group (ia) in which n is 1 and R 3 is hydrogen or hydroxy or A is 3-hydroxypyrrolidin-4-ylmethyl or 4-hydroxypiperidin-3-ylmethyl.

9. A compound according to claim 1 wherein A is a 4-hydroxypiperidin-3-ylmethyl.

10. A compound selected from:

2-[({1-[2-(7-Fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-1H-pyrimido[5,4-b][1,4]oxazin-7(6H)-one;

4-Chloro-2-[({1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-1H-pyrimido[5,4-b][1,4]oxazin-7(6H)-one;

2-{[(1-{2-[6-(Methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-4-piperidinyl)amino]methyl}-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

4-Chloro-2-{[(1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-4-piperidinyl)amino]methyl}-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

4-Methyl-2-{[(1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-4-piperidinyl)amino]methyl}-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

4-(Methyloxy)-2-{[(1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-4-piperidinyl)amino]methyl}-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

2-({[((3S)-1-{2-[6-(Methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-3-piperidinyl)methyl]amino}methyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one;

the free base of a compound of the following table;

TABLE

Example

number

Stucture

142

143

144

145

146

147

148

149

150

151

152

153

267

278

312

313

314

315

or a pharmaceutically acceptable salt thereof.

11. A method of treatment of bacterial infections in mammals, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound according to claim 1 .

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

13. A compound according to claim 6 wherein:

each of Z 1 , Z 2 , Z 3 and Z 4 is independently CR 1c ;

Z 1 is N and each of Z 2 , Z 3 and Z 4 is independently CR 1c ;

Z 2 is N and each of Z 1 , Z 3 and Z 4 is independently CR 1c ;

Z 3 is N and each of Z 1 , Z 2 and Z 4 is independently CR 1c ;

Z 1 and Z 3 are N and Z 2 and Z 4 are independently CR 1c ;

Z 2 and Z 3 are N and Z 1 and Z 4 are independently CR 1c ;

Z 3 and Z 4 are N and Z 1 and Z 2 are independently CR 1c ;

Z 3 and Z 4 together are S and Z 1 and Z 2 are independently CR 1c ;

Z 3 and Z 4 together are S and Z 1 is CR 1c and Z 2 is N; or

Z 1 and Z 2 are N and Z 3 and Z 4 are independently CR 1c .

14. A compound according to claim 6 wherein A is a group (ia) in which n is 1 and R 3 is hydrogen or hydroxy or A is 3-hydroxypyrrolidin-4-ylmethyl or 4-hydroxypiperidin-3-ylmethyl.

15. A compound according to claim 7 wherein A is a group (ia) in which n is 1 and R 3 is hydrogen or hydroxy or A is 3-hydroxypyrrolidin-4-ylmethyl or 4-hydroxypiperidin-3-ylmethyl.

16. A compound according to claim 13 wherein A is a group (ia) in which n is 1 and R 3 is hydrogen or hydroxy or A is 3-hydroxypyrrolidin-4-ylmethyl or 4-hydroxypiperidin-3-ylmethyl.