2-(4-oxo-4H-quinazolin-3-yl)acetamides and their use as vasopressin V3 antagonists

1. A 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound of formula I,

wherein

R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl or benzyl, said C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylC 1-2 alkyl being optionally substituted with one or more halogens;

R 2 is a group selected from C 6-10 aryl optionally substituted with one to three substituents selected from halogen, hydroxy, cyano, COOR 13 , NR 14 R 15 , pyrrole, C 1-6 alkyl, C 3 -6 cycloalkyl, C 1-6 alkyloxy and C 3-6 cycloalkyloxy, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyloxy and C 3-6 cycloalkyloxy being optionally substituted with one or more halogens, wherein R 13 and R 14 are independently H or C 1-6 alkyl and R 15 is H, C 1-6 alkyl or C 1-6 acyl, and C 4-7 cycloalkyl or R 2 is a 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O and S optionally substituted with a substituent selected from methyl, C 1-6 alkyloxy and halogen;

R 3 is one or two substituents selected from H, C 1-6 alkyl, C 1-6 alkyloxy and halogen, said C 1-6 alkyl and C 1-6 alkyloxy being optionally substituted with one or more halogens;

R 4 is a group located at the 6- or 7-position of the quinazoline ring and is selected from

each R 5 is independently H or C 1-6 alkyl or one of R 5 when joined together with one of R 6 or R 7 forms a 5-6 membered heterocyclic ring;

R 6 and R 7 are independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-2 alkyl, C 6-10 aryl or C 6-10 arylC 1-2 alkyl; or R 6 and R 7 together with the nitrogen to which they are bound form a 4 to 8 membered saturated or unsaturated heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S and NR 10 , said heterocyclic ring being optionally substituted with one or two substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano and COOR 11 and said heterocyclic ring being optionally fused at two adjacent carbon atoms to a phenyl ring; or one of R 6 and R 7 when joined together with one of R 5 forms a 5-6 membered heterocyclic ring;

R 8 is one or two substituents selected from H, C 1-6 alkyl, C 1-6 alkyloxy and halogen or one of R 8 when joined together with R 9 forms a 5-6 membered ring;

R 9 is H or C 1-6 alkyl or R 9 when joined together with one of R 8 forms a 5-6 membered ring;

R 10 is H, C 1-6 alkyl or C 1-6 acyl;

R 11 is H or C 1-6 alkyl;

m is 2-4;

n is 1-2;

X is CH 2 , O, S, SO 2 or NR 12 ;

R 12 is H, C 1-6 alkyl, C 1-6 acyl or a C 6-10 aryl C 1-2 alkyl group, said C 6-10 aryl C 1-2 alkyl group being optionally substituted with methyl or methoxy;

Y is CH 2 , (CH 2 ) 2 or (CH 2 ) 3 ;

Q, T, V and W are C or N with the proviso that one of Q, T, V and W is N and the others are C;

Q′, T′ and V′ are selected from C, O, N and S with the proviso that one of Q′, T′ and V′ is O, N, or S and the others are C;

or a pharmaceutically acceptable salt thereof.

2. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 1 is isopropyl, iso-butyl, tertiary-butyl or cyclopropylmethyl.

3. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 2 is a 3-substituted phenyl ring.

4. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 2 is a substituted phenyl ring selected from 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-trifluoromethoxyphenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3-methoxyphenyl and 3,5-dimethoxyphenyl.

5. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 3 is a substituent at the 7-position of the quinazoline ring.

6. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 3 is selected from H, chloro, methyl and methoxy.

7. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 4 is a substituent at the 6-position of the quinazoline ring.

8. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 4 is a group selected from

wherein R 6 and R 7 have the previously defined meanings.

9. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 4 is a group selected from

wherein R 6 and R 7 have the previously defined meanings.

10. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 6 and R 7 are independently H or C 1-4 alkyl.

11. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 , wherein R 6 and R 7 together with the nitrogen to which they are bound form a heterocyclic ring selected from pyrrolidine, piperidine, 3-hydroxypiperidine and morpholine.

12. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 selected from:

2-[2-(3-Chloro-4-fluorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide;

N-Isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H -quinazolin-3-yl]acetamide;

2-[2-(4-Fluoro-3-methoxyphenyl)-4-oxo-6-(3-pip eridin-1-ylpropoxy)-4H-quinazolin -3-yl]-N-isopropylacetamide;

2-{2-(3-Chlorophenyl)-6-[3-(4-hydroxypiperidin-1-yl)propoxy]-4-oxo-4H -quinazolin-3-yl}-N-isopropylacetamide;

2-[2-(3-Chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N -isopropylacetamide;

(S)-(+)-2-[2-(3-Chlorophenyl)-6-(2-methyl-3-pyrrolidin-1-ylpropoxy)-4-oxo-4H -quinazolin-3-yl]-N-isopropylacetamide;

2-[6-(5-Dimethylaminomethyl-2-fluorophenyl)-2-(3-methoxyphenyl)-4-oxo-4H -quinazolin-3-yl]-N-isopropylacetamide;

2-[6-(3-Dimethylaminomethylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide;

N-tert-Butyl-2-[2-(3-chlorophenyl)-4-oxo-6-(3-pyrrolidin-1-ylpropoxy)-4H -quinazolin-3-yl] acetamide; and

2-[6-(3-Dimethylaminomethylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide;

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxiliaries.

14. The 2-(4-oxo-4H-quinazolin-3-yl)acetamide compound selected from: 2-[2-(3-Chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to claim 14 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxiliaries.