Heterocyclic compounds as RSV inhibitors

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

is optionally substituted aryl or optionally substituted heteroaryl;

is aryl or heteroaryl, which, when possible, is optionally substituted with one or more substituents which are not R 2 ;

X is O, S or NR 4 , and Y is N or CR 5 ; or X is N or CR 5 , and Y is O, S or NR 4 ;

One Z is CR 3 , the other Zs are each independently selected from N and CR 3 ;

Each R 1 selected from the group consisting of: halogen, hydroxyl, protected hydroxyl, amino, protected amino, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —C 1 -C 8 alkoxy;

Each R 2 is selected from the group consisting of:

1) halogen;

2) optionally substituted —C 1 -C 8 alkoxy;

3) optionally substituted —C 1 -C 8 alkyl;

4) optionally substituted —C 2 -C 8 alkenyl;

5) optionally substituted —C 2 -C 8 alkynyl;

6) optionally substituted —C 3 -C 12 cycloalkyl;

7) optionally substituted —C 3 -C 12 cycloalkenyl;

8) optionally substituted 3- to 12-membered heterocycloalkyl;

9) optionally substituted aryl;

10) optionally substituted heteroaryl;

11) optionally substituted arylalkyl;

12) optionally substituted aryloxy;

13) —C(O)R 12 ;

14) —C(O)NR 13 R 14 ;

15) —C(O)NR 11 S(O) 2 R 12 ;

16) —S(O) 2 NR 13 R 14 ;

17) —NR 13 R 14 ;

18) —NR 11 S(O) 2 R 12 ;

19) —NR 11 C(O)R 12 ;

20) —NR 11 C(O)NR 13 R 14 ; and

21) —NR 11 C(O)NHS(O) 2 R 12 ;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, or 3;

R 3 is selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxyl,

protected hydroxyl, amino, protected amino, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —C 1 -C 8 alkoxy;

R 4 is hydrogen or optionally substituted —C 1 -C 8 alkyl;

R 5 is hydrogen, halogen, optionally substituted —C 1 -C 8 alkyl, or optionally substituted —C 1 -C 8 alkoxy;

R 12 at each occurrence is independently selected from the group consisting of:

1) Hydrogen;

2) Halogen;

3) Hydroxyl;

4) optionally substituted —C 1 -C 8 alkoxy;

5) optionally substituted —C 1 -C 8 alkyl;

6) optionally substituted —C 2 -C 8 alkenyl;

7) optionally substituted —C 2 -C 8 alkynyl;

8) optionally substituted —C 3 -C 8 cycloalkyl;

9) optionally substituted —C 3 -C 8 cycloalkenyl;

10) optionally substituted 3- to 8-membered heterocycloalkyl;

11) optionally substituted aryl;

12) optionally substituted arylalkyl;

13) optionally substituted heteroaryl; and

14) optionally substituted heteroarylalkyl;

R 11 , R 13 and R 14 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl; optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; alternatively, R 13 and R 14 are taken together with the nitrogen atom they attached to form a heterocyclic ring.

2. The compound of claim 1 , wherein is one of the following by removal of a hydrogen atom:

wherein each of the above is optionally substituted when possible.

3. The compound of claim 1 , wherein is selected from one of the following groups by removal of one hydrogen atom, wherein each of the groups is optionally substituted:

4. The compound of claim 1 , wherein R 2 is selected from one of the following groups, wherein each of the groups is optionally substituted:

5. The compound of claim 1 , represented by one of Formulas (IIa)˜(IIe), or a pharmaceutically acceptable salt thereof:

wherein R 3 ′ is selected from the group consisting of: halogen, cyano, nitro, hydroxyl, protected hydroxyl, amino, protected amino, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —C 1 -C 8 alkoxy; v is 0, 1, 2 or 3; X, Y, R 1 , R 2 , m, and n are as defined in claim 1 .

6. The compound of claim 1 , represented by one of Formulas (IIIa)˜(IIId), or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , R 5 , n, m, and Z are as defined in claim 1 .

7. The compound of claim 1 , represented by one of Formulas (IVa)˜(IVh), or a pharmaceutically acceptable salt thereof:

wherein m1 is 0, 1, 2, 3 or 4; m2 is 0, 1 or 2; each R 21 is independently selected from halogen, —NH 2 , optionally substituted —C 1 -C 3 alkyl, and optionally substituted —C 1 -C 3 alkoxy; each R 22 is independently selected from hydrogen and —CH 3 ; each R 23 is independently selected from hydrogen, halogen, —NH 2 , optionally substituted —C 1 -C 3 alkyl, and optionally substituted —C 1 -C 3 alkoxy; X, Y, Z, R 1 , R 2 , m, and n are as defined in claim 1 .

8. The compound of claim 1 , represented by one of Formulas (Va-1)˜(Va-5), or Formulas (Vb-1)˜(Vb-5), or a pharmaceutically acceptable salt thereof:

wherein m′ is 0, 1, or 2; R 3 ′ is selected from the group consisting of: halogen, cyano, nitro, hydroxyl, protected hydroxyl, amino, protected amino, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —C 1 -C 8 alkoxy; v is 0, 1, 2 or 3; X, Y, R 1 , R 2 , and n are as defined in claim 1 .

9. The compound of claim 1 , represented by one of Formulas (VI-1)˜(VI-2), or a pharmaceutically acceptable salt thereof:

wherein m′ is 0, 1, or 2; R 3 ′ is selected from the group consisting of: halogen, cyano, nitro, hydroxyl, protected hydroxyl, amino, protected amino, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —C 1 -C 8 alkoxy; v is 0, 1, 2 or 3; and X, Y, R 1 , R 2 , and n are as defined in claim 1 .

10. The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

Compound

Structure

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

11. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient.

12. A method of treating or preventing an RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1 .

13. The method of claim 12 , further comprising the step of administering to the subject an additional anti-RSV agent.

14. The method of claim 12 , further comprising administering to the subject a steroid anti-inflammatory compound.

15. A method of treating RSV and influenza in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , and a therapeutically effective amount of an anti-influenza agent.

16. The method of claim 13 , wherein the compound and the additional anti-RSV agent are co-formulated.

17. The method of claim 13 , wherein the compound and the additional anti-RSV agent are co-administered.