Cycloalkyl substituted pyrazolopyrimidines having activity against RSV

1. A compound of formula (I):

or any stereochemically isomeric form thereof,

wherein

A is

n is 1;

X 1 and X 2 are selected from X 1 is CH and X 2 is CH,

or X 1 is N and X 2 is CH,

or X 1 is CH and X 2 is N;

R 1 is CH 3 ;

R 2 is hydrogen or fluoro;

R 3 is fluoro;

R 4 is cyclopropyl or phenyl;

R 5 is hydrogen;

R 6 is —CH 2 OH, —C(O)NHCH 2 CCH, —C(O)NHCH 2 CH 2 CN, —C(O)NH-oxetanyl, —C(O)NHCH 2 CH 2 OH, —C(O)NHSO 2 C 1-4 alkyl, —C(O)NHSO 2 -cyclopropyl, —NHC(O)NH— cyclopropyl, —NHCO 2 CH 3 , —NHC(O)CH 3 , —NHC(O)-cyclopropyl, —NHSO 2 CH 3 , —NHP(O)(CH 3 ) 2 , —OH, —OC(O)NH 2 , —CH 2 —OC(O)NH 2 , —CH 2 C(O)NH 2 , —CH 2 C(O)NHCH 3 , 3-oxo-2,3-dihydro-1,2-oxazolyl, 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl, or tetrazolyl; and

R 7 is hydrogen or fluoro;

provided that when R 6 is —NH(CO)-cyclopropyl, then X 1 is CH and X 2 is CH;

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 , wherein X 1 is CH and X 2 is CH.

3. The compound of claim 1 , wherein X 1 is N and X 2 is CH, or X 1 is CH and X 2 is N.

4. The compound of claim 1 , wherein radical A is of formula (a-1).

5. The compound of claim 1 , wherein radical A is of formula (a-2).

6. The compound of claim 1 , wherein n is 1.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

8. The pharmaceutical composition of claim 7 , further comprising another antiviral agent.

9. The pharmaceutical composition of claim 8 , wherein the other antiviral agent is a respiratory syncytial virus (RSV) inhibiting compound.

10. A process for preparing a pharmaceutical composition of claim 7 comprising intimately mixing a compound of claim 1 with a pharmaceutically acceptable carrier.

11. A method of treating a respiratory syncytial virus (RSV) infection comprising administering to a subject in need thereof an anti-virally effective amount of a compound of claim 1 .

12. The compound of claim 1 , wherein

R 2 is hydrogen.

13. A compound selected from:

[(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]methanol;

5-[(1R,2R)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]-2,3-dihydro-1,2-oxazol-3-one;

(1R)-2-(7-Cyclopropyl-2-{2-fluoro-4-[(1S,2S)-2-(1H-1,2,3,4-tetrazol-5-yl)cyclopropyl]phenyl}pyrazolo[1,5-a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]-4,5-dihydro-1,2,4-oxadiazol-5-one;

(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N-(prop-2-yn-1-yl)cyclopropane-1-carboxamide;

(1S,2S)—N-(2-Cyanoethyl)-2-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxamide;

(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N-(oxetan-3-yl)cyclopropane-1-carboxamide;

(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N-(2-hydroxyethyl)-cyclopropane-1-carboxamide;

(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N-methanesulfonyl-cyclopropane-1-carboxamide;

(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N-(ethanesulfonyl)-cyclopropane-1-carboxamide;

(1S,2S)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N-(2-methylpropanesulfonyl)-cyclopropane-1-carboxamide;

(1S,2S)—N-(Cyclopropanesulfonyl)-2-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-cyclopropane-1-carboxamide;

(1S,2S)-2-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N-methanesulfonyl-cyclopropane-1-carboxamide;

1-Cyclopropyl-3-[(1S,2R)-2-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]urea;

(1*S,2*S)-2-(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-phenylpyrazolo[1,5-a]pyrimidin-2-yl}phenyl)-N-methanesulfonyl-cyclopropane-1-carboxamide;

(1*R, 2*R)-2-(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-phenylpyrazolo[1,5-a]pyrimidin-2-yl}phenyl)-N-methanesulfonyl-cyclopropane-1-carboxamide;

Methyl N-[(1S,2R)-2-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]carbamate;

N-[(1S,2R)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]acetamide;

N-[(1S,2R)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]cyclopropane-carboxamide;

N-[(1S,2R)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl]methanesulfonamide;

(1R)-2-(7-Cyclopropyl-2-{4-[(1R,2S)-2-[(dimethylphosphoryl)amino]cyclopropyl]-2-fluorophenyl}pyrazolo[1,5-a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline;

(1S,2R)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropan-1-ol;

(1S,2R)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl carbamate;

(1S,2R)-2-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropyl N-methylcarbamate;

Trans-2-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-4-fluoropyridin-2-yl)-N-methanesulfonylcyclopropane-1-carboxamide; and

Trans-2-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-6-fluoropyridin-2-yl)-N-methanesulfonylcyclopropane-1-carboxamide;

and pharmaceutically acceptable salts thereof.

14. A method of preparing a compound of claim 1 comprising reacting an intermediate of formula (II):

with an intermediate of formula (III):

in a reaction-inert solvent to form the compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 .

15. The method of claim 14 , wherein reacting comprises reacting in the presence of PdCl 2 (dtbpf) and K 3 PO 4 .

16. The method of claim 14 , wherein the reaction-inert solvent is dioxane:H 2 O.