Heteroaromatic compounds having activity against RSV

1. A compound of formula (I):

or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof,

wherein:

is formula (a), formula (b), formula (c), formula (d), formula (e), or formula (f):

wherein each CH is optionally substituted with halo, C 1-4 alkyl, or OC 1-4 alkyl;

A is formula (a-1), formula (a-2), formula (a-3), or formula (a-4):

wherein:

R 1 is CH 3 or CH 2 CH 3 ;

R 2 is H, halo, or C 1-4 alkyl;

R 12 is C 1-2 alkyl;

R 13 is C 1-6 alkyl; and

R 14 is C 1-6 alkyl;

R 4 is C 1-6 alkyl, C 1-4 alkylene-Heteroaryl 1 , N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, pyrrolidinyl, phenyl, or Heteroaryl 1 ;

wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 polyhaloalkyl, OH, and OC 1-4 alkyl, and

wherein the Heteroaryl 1 is thienyl, pyridinyl, or pyrimidinyl, wherein the thienyl, pyridinyl, or pyrimidinyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-4 alkyl, C(O)NH 2 , and NH 2 ;

R 5 is formula (b-1), formula (b-2), or formula (b-3):

wherein:

Y 1 is CH, CF, or N;

Y 2 is CH, CF, or N;

R 3 is halo; and

R 6 is (i), (ii), (iii), or (iv):

(i) C 2-6 alkenyl, wherein the C 2-6 alkenyl is substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, C(O)NR 8 R 9 , and C(O)OR 7 ;

(ii) NR 9 C(O)-Heterocyclyl;

wherein the Heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl; and

wherein the azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl is substituted with one or two substituents independently selected from the group consisting of halo, OH, and OC 1-4 alkyl; or

(iii) C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is substituted with one or two substituents independently selected from the group consisting of:

(a) C 1-6 alkyl;

wherein the C 1-6 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C(O)NH 2 , C(O)OH, OH, and C 3-6 cycloalkyl;

wherein the C 3-6 cycloalkyl substituent is optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkylene-C(O)OH, and C(O)OH;

(b) C 3-6 alkenyl, wherein the C 3-6 alkenyl is optionally substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, C(O)NR 8 R 9 , C(O)OR 7 , and OH; and

(c) CN, C(O)NR 10 R 11 , C(O)NR 9 C(O)S(O) 2 R 8 , C(O)NR 9 S(O) 2 R 8 , C(O)OR 7 , NR 8 R 9 , NR 9 C(O)C 1-4 alkyl, NR 9 C(O)NR 8 R 9 , NR 9 C(O)OR 8 , NR 9 C(O)C 3-6 cycloalkyl, NR 9 S(O) 2 R 8 , OH, OC(O)NR 10 R 11 , S(O) 2 R 8 , S(O) 2 NR 10 R 11 , S(O) 2 NR 9 C(O)R 8 , or Heteroaryl 2 ;

wherein each Heteroaryl 2 is independently pyrrolyl, pyrazolyl, or thiazolyl;

wherein each pyrrolyl, pyrazolyl, or thiazolyl is optionally and independently substituted with one or two substituents independently selected from the group consisting of halo, C 1-4 alkyl, C(O)NR 8 R 9 , and C(O)OR 7 ; or

(iv) Heterocyclyl;

wherein the Heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl; and

wherein the azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl is substituted with one or two substituents independently selected from the group consisting of:

(a) C 1-6 alkyl;

wherein the C 1-6 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C(O)NH 2 , C(O)OH, OH, and C 3-6 cycloalkyl; and

wherein the C 3-6 cycloalkyl substituent is optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkylene-C(O)OH, and C(O)OH;

(b) C 3-6 alkenyl, wherein the C 3-6 alkenyl is optionally substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, C(O)NR 8 R 9 , C(O)OR 7 , and OH; and

(c) CN, C(O)NR 10 R 11 , C(O)NR 9 C(O)S(O) 2 R 8 , C(O)NR 9 S(O) 2 R 8 , C(O)OR 7 , NR 8 R 9 , NR 9 C(O)C 1-4 alkyl, NR 9 C(O)NR 8 R 9 , NR 9 C(O)OR 8 , NR 9 C(O)C 3-6 cycloalkyl, NR 9 S(O) 2 R 8 , OH, OC(O)NR 10 R 11 , S(O) 2 R 8 , S(O) 2 NR 10 R 11 , S(O) 2 NR 9 C(O)R 8 , or Heteroaryl 2 ;

wherein each Heteroaryl 2 is independently pyrrolyl, pyrazolyl, or thiazolyl;

wherein each pyrrolyl, pyrazolyl, or thiazolyl is optionally and independently substituted with one or two substituents independently selected from the group consisting of halo, C 1-4 alkyl, C(O)NR 8 R 9 , and C(O)OR 7 ;

each R 7 is independently H or C 1-4 alkyl;

each R 8 is independently C 1-4 alkyl, C 1-4 polyhaloalkyl, or C 3-6 cycloalkyl;

each R 9 is independently H or C 1-4 alkyl;

each R 10 is independently H, CN, C 1-4 alkyl, C 1-4 polyhaloalkyl, C 3-6 alkenyl, or C 3-6 cycloalkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with one substituent selected from the group consisting of CN and OH; and

wherein each C 3-6 cycloalkyl is optionally and independently substituted with one C 1-4 alkyl substituent; and

each R 11 is independently H, CN, C 1-4 alkyl, C 1-4 polyhaloalkyl, C 3-6 alkenyl, or C 3-6 cycloalkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with one substituent selected from the group consisting of CN and OH; and

wherein each C 3-6 cycloalkyl is optionally and independently substituted with one C 1-4 alkyl substituent.

2. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein

is formula (c):

3. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein

is formula (e):

4. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein A is formula (a-1):

5. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein A is formula (a-2):

6. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 1 is CH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 2 is H.

8. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 4 is C 1-4 alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 4 is CH 2 CH 3 .

10. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 4 is C 3-6 cycloalkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 4 is cyclopropyl.

12. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 4 is Heteroaryl 1 .

13. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 4 is pyridinyl.

14. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 5 is formula (b-1):

wherein:

Y 1 is CH; and

Y 2 is CH.

15. The compound of claim 14 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 3 is F.

16. The compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof, wherein R 6 is C 3-6 cycloalkyl or pyrrolidinyl, wherein the C 3-6 cycloalkyl or pyrrolidinyl is substituted with one or two substituents independently selected from the group consisting of C(O)NR 10 R 11 and C(O)OR 7 .

17. The compound of claim 1 , wherein the compound is selected from the group consisting of:

(1S,2S)-2-(4-{5-Ethyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]indolizin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

(1S,2S)-2-(4-{5-Ethyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7,8-dihydroindolizin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxamide;

(3S)-1-(4-{5-Ethyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]indolizin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid;

trans-2-(4-{7-ethyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

trans-2-(4-{7-Ethyl-4-methoxy-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

trans-2-(4-{7-Cyclopropyl-4-fluoro-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid;

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

(3S)-1-(4-{7-Ethyl-4-methyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid;

(3S)-1-(4-{7-Cyclopropyl-4-fluoro-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxamide;

trans-2-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

cis-2-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

trans-2-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxamide;

(3S)-1-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid;

(3S)-1-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxamide;

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-c]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid;

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

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

trans-2-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] imidazo[1,2-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

trans-2-(4-{5-cyclopropyl-3-fluoro-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] imidazo[1,2-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

cis-2-(4-{5-cyclopropyl-3-fluoro-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] imidazo[1,2-a]pyrimidin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid;

(3S)-1-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] imidazo[1,2-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid; and

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

or a pharmaceutically acceptable acid addition salt thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof.

19. A method for treating a respiratory syncytial virus infection in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof.

20. A process for preparing the pharmaceutical composition of claim 18 , wherein the process comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable acid addition salt or stereochemically isomeric form thereof.