Piperidine substituted tricyclic pyrazolo[1,5-a]pyrimidine derivatives with inhibitory activity on the replication of the respiratory syncytial virus (RSV)

1. A compound of formula (I-a) or formula (I-b), wherein

n is an integer 0, 1 or 2;

X is selected from the group consisting of: CH 2 , O, CH 2 O and NR 4 , wherein R 4 is hydrogen, C 1-4 alkyl or benzyl;

Z is selected from the group consisting of: CH 2 , O and NR 4 , wherein R 4 is hydrogen, C 1-4 alkyl or benzyl;

and at least one of X or Z is CH 2 ;

R 1 is selected from the group consisting of: hydrogen, hydroxy, C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino, and Heterocyclyl 1 ;

Heterocyclyl 1 is selected from the group consisting of: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; wherein each azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is optionally substituted with one or two substituents each independently selected from the group consisting of: C 1-4 alkyl, hydroxy, halo, trifluoromethyl, C 1-4 alkyloxycarbonyl, amino, C 1-4 alkylaminocarbonyl, and C 1-4 alkylsulfonyl;

R 2 is phenyl-(CO)—, wherein the phenyl is substituted with one or two substituents each independently selected from the group consisting of: hydrogen, halo, trifluoromethyl, C 1-4 alkyl, C 1-4 alkyloxy, and C 1-4 alkylsulfonylamino;

or R 2 is a bicyclic heterocycle selected from cinnolinyl, quinazolinyl, or quinoxalinyl, wherein said cinnolinyl, quinazolinyl, or quinoxalinyl is substituted with one or two substituents each independently selected from the group consisting of: hydrogen, halo, trifluoromethyl, C 1-4 alkyl, C 1-4 alkyloxy, and C 1-4 alkylsulfonylamino; and

R 3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, hydroxy, and halo;

and a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1 wherein

n is an integer 0, 1 or 2;

X is CH 2 , O, CH 2 O or NR 4 , wherein R 4 is C 1-4 alkyl;

Z is CH 2 , O or NR 4 , wherein R 4 is C 1-4 alkyl;

and at least one of X or Z is CH 2 ;

R 1 is hydrogen, hydroxy, C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino, or Heterocyclyl 1 ;

Heterocyclyl 1 is pyrrolidinyl, or morpholinyl;

R 2 is phenyl-(CO)— wherein the phenyl is substituted with one or two substituents each independently selected from hydrogen, C 1-4 alkyl, or C 1-4 alkylsulfonylamino;

or R 2 is a bicyclic heterocycle selected from cinnolinyl, quinazolinyl, or quinoxalinyl, wherein said bicyclic heterocycle is substituted with one or two substituents each independently selected from hydrogen, halo, trifluoromethyl, C 1-4 alkyloxy, and C 1-4 alkylsulfonylamino; and

R 3 is hydrogen;

or a pharmaceutically acceptable salt thereof.

3. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 0; X is CH 2 ; and Z is CH 2 .

4. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 1; X is CH 2 ; and Z is CH 2 .

5. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 2; X is CH 2 ; and Z is CH 2 .

6. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 0; X is CH 2 ; and Z is O.

7. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 1; X is CH 2 ; and Z is O.

8. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 2; X is CH 2 ; and Z is O.

9. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is di(C 1-4 alkyl)amino; n is 1; X is NR 4 ; R 4 is C 1-4 alkyl; and Z is CH 2 .

10. The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is C 1-4 alkyl; n is 1; X is CH 2 ; and Z is CH 2 .

11. The compound as claimed in claim 1 wherein the compound is of formula (I-b) wherein R 1 is C 1-4 alkyl; n is 1; X is CH 2 ; and Z is CH 2 .

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

13. A process for preparing a pharmaceutical composition as claimed in claim 12 wherein a therapeutically active amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, is mixed with a pharmaceutically acceptable carrier.

14. A method of treating a respiratory syncytial virus infection in a patient comprising administering the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof to said patient.

15. A compound selected from the group consisting of:

N-(4-methyl-2-(2-(9-morpholino-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-2-yl)piperidine-1-carbonyl)phenyl)methanesulfonamide;

(R)—N-(4-methyl-2-(2-(9-morpholino-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-2-yl)-piperidine-1-carbonyl)phenyl)methanesulfonamide;

(S)—N-(4-methyl-2-(2-(9 morpholino-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-2-yl)piperidine-1-carbonyl)phenyl)methanesulfonamide;

4-(2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo [5,1-b]quinazolin-9-yl)morpholine;

4-(2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-9-yl)morpholine;

4-(2-(1-(2-chloro-5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-9-yl)morpholine;

N-(5-methyl-4-(2-(9-morpholino-5,6,7,8-tetrahydropyrazolo[5, 1 b]¬quinazolin-2-yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamide;

4-(2-(1-(2-chloro-6-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-9-yl)morpholine;

N-(6-methyl-4-(2-(9-morpholino-5,6,7,8-tetrahydropyrazolo[5, 1 b]¬quinazolin-2-yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamide;

4-(2-(1-(5-fluoroquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo¬[5,1-n]-quinazolin-9-yl)morpholine;

4-(2-(1-(5-(trifluoromethyl)quinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-9-yl)morpholine;

4-(2-(1-(5-methoxyquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydro¬pyrazolo[5,1-b]quinazolin-9-yl)morpholine;

4-(2-(1-(6-ethyl-5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydro¬pyrazolo[5,1-b]quinazolin-9-yl)morpholine;

N-(2-(2-(9-hydroxy-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-2 yl)¬piperidine-1-carbonyl)-4-methylphenyl)methanesulfonamide;

N-(2-(2-(9-(dimethylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-2 yl)piperidine-1-carbonyl)-4-methylphenyl)methanesulfonamide;

N,N-dimethyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetra-hydropyrazolo[5,1-b]quinazolin-9-amine;

N-(4-methyl-2-(2-(5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-2-yl)¬piperidine-1-carbonyl)phenyl)methanesulfonamide;

2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo¬[5,1-b]quinazoline;

N-(2-(2-(9-amino-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolin-2-yl)¬piperidine-1-carbonyl)-4-methylphenyl)methanesulfonamide;

N-(4-methyl-2-(2-(8-morpholino-6,7-dihydro-5H-cyclopenta[d]pyrazolo¬[1,5 a]pyrimidin-2-yl)piperidine-1-carbonyl)phenyl)methanesulfonamide;

4-(2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-6,7-dihydro-5H-cyclo-penta[d]pyrazolo[1,5-a]pyrimidin-8-yl)morpholine;

2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-8-(pyrrolidin-1-yl)-6,7 dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine;

N-(4-methyl-2-(2-(10-morpholino-6,7,8,9-tetrahydro-5H cyclohepta¬[d]¬pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)phenyl)-methanesulfonamide;

4-(2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-6,7,8,9-tetrahydro-5H cyclohepta[d]pyrazolo[1,5-a]pyrimidin-10-yl)morpholine;

N-(4-methyl-2-(2-(8-morpholino-5,7-dihydrofuro[3,4-d]pyrazolo[1,5 a]¬pyrimidin-2-yl)piperidine-1-carbonyl)phenyl)methanesulfonamide;

N-(2-(2-(9-(dimethylamino)-5-methyl-5,6,7,8-tetrahydropyrazolo¬[1,5 a]pyrido[2,3-d]pyrimidin-2-yl)piperidine-1-carbonyl)-4-methylphenyl)-methane¬sulfonamide;

N-(2-(2-(5-(dimethylamino)-9-methyl-6,7,8,9-tetrahydro¬pyrazolo¬[1,5-a]pyrido[3,2-e]pyrimidin-2-yl)piperidine-1-carbonyl)-4 methylphenyl)methane¬sulfonamide;

N-(4-methyl-2-(2-(9-morpholino-7,8-dihydro-5H-pyrano[3,4-d]pyrazolo¬[1,5 a]pyrimidin-2-yl)piperidine-1-carbonyl)phenyl)methane-sulfonamide;

2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-9-morpholino-7,8-dihydro-5H-pyrano[3,4-d]pyrazolo[1,5-a]pyrimidine;

2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-9-morpholino-6,8-dihydro-5H-pyrano[4,3-d]pyrazolo[1,5-a]pyrimidine;

2-(1-(2-chloro-5-methylquinazolin-4-yl)piperidin-2-yl)-9-morpholino-6,8-dihydro-5H-pyrano[4,3-d]pyrazolo[1,5-a]pyrimidine;

N-(5-methyl-4-(2-(9-morpholino-6,8-dihydro-5H-pyrano[4,3-d]pyrazolo¬[1,5 a]pyrimidin-2-yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamide;

2-(1-(2-ethoxy-5-methylquinazolin-4-yl)piperidin-2-yl)-9-morpholino-6,8-dihydro-5H-pyrano[4,3-d]pyrazolo[1,5-a]pyrimidine;

N-(4-methyl-2-(2-(9-morpholino-6,8-dihydro-5H-pyrano[4,3-d]pyrazolo¬[1,5 a]pyrimidin-2-yl)piperidine-1-carbonyl)phenyl)methanesulfonamide;

9-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydro¬pyrazolo[5,1-b]quinazoline;

5-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2 yl)-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline;

(S)-9-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazoline;

(R)-9-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazoline;

(S)-5-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline;

(R)-5-methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline;

N-(5-methyl-4-(2-(8-morpholino-6,7-dihydro-5H-cyclopenta[d]pyrazolo¬[1,5a]pyrimidin-2-yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamide; and

N,N,5-trimethyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-8-amine;

and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition comprising (a) a therapeutically active amount of at least one compound of claim 15 or a pharmaceutically acceptable salt thereof; and (b) at least one pharmaceutically acceptable carrier.

17. A method of treatment of a subject suffering from a respiratory syncytial virus infection, comprising administering to the subject a therapeutically active amount of a compound as claimed in claim 15 or a pharmaceutically acceptable salt thereof.