NK1 antagonists

1. A method of treating an NK1 receptor mediated disease comprising:

administering to a patient in need thereof an oral dosage form comprising an effective amount of at least one compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 and R 2 are selected from the group consisting of alkyl, haloalkyl, alkyl substituted with one or more hydroxyl groups, —CN, alkynyl, —N(R 6 ) 2 , —N(R 6 )—S(O 2 )-alkyl, —N(R 6 )—C(O)—N(R 9 ) 2 , -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, —C(O)-alkyl, —C(═N—OR 5 )-alkyl, —C(O)—O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)—O-alkyl, -alkylene-C(O)—N(R 9 ) 2 ,

with the proviso that at least one of R 1 and R 2 is —CN,

W is ═C(R 8 )— or ═N—;

X is —C(O)— or —S(O 2 )—;

Y is selected from the group consisting of —CH 2 —, —O—, and —N(R 6 )—C(O)—, with the proviso that:

(a) the nitrogen atom of —N(R 6 )—C(O)— is bonded to X, and

(b) if R 1 and/or R 2 is

and Y is —O—, X is not —S(O 2 )—;

Z is —C(R 7 ) 2 , —N(R 6 )—, or —O—;

R 3 is selected from the group consisting of H, and unsubstituted alkyl;

R 4 is H;

R 5 is H or alkyl;

R 6 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl;

R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl;

each R 7 is independently H or alkyl; or

each R 7 , together with the ring carbon to which they are shown attached, form a cycloalkylene ring;

R 8 is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, —N(R 6 ) 2 , —N(R 6 )—S(O 2 )-alkyl, —N(R 6 )—S(O 2 )-aryl, —N(R 6 )—C(O)-alkyl, —N(R 6 )—C(O)-aryl, alkylene-O-alkyl, and —CN;

R 9 is selected from the group consisting of H, alkyl, and aryl, or each R 9 , together with the nitrogen to which they are shown attached, form a heterocycloalkyl ring;

Ar 1 is unsubstituted phenyl;

Ar 2 is phenyl substituted with 0-3 substituents selected from the group consisting of haloalkyl;

n is 0, 1, or 2; and

m is 1, 2 or 3.

2. The method of claim 1 , wherein the physiological disorder, symptom or disease is emesis.

3. The method of claim 1 , wherein the physiological disorder, symptom or disease is vomiting.

4. The method of claim 1 , wherein the physiological disorder, symptom or disease is nausea and vomiting.

5. The method of claim 1 , wherein the physiological disorder, symptom or disease is cough.

6. The method of claim 1 , further comprising administering to the patient an effective amount of at least one anti-depressant agent and/or at least one anti-anxiety agent.

7. The method of claim 6 , wherein the at least one anti-depressant agent and/or at least one anti-anxiety agent is a selective serotonin reuptake inhibitor.

8. The method according to claim 1 , further comprising administering an effective amount of at least one active ingredient selected from the group consisting of serotonin 5-HT 3 receptor antagonists and glucocorticoids.

9. The method of claim 8 , wherein the serotonin 5-HT 3 receptor antagonist is ondansetron and the glucocorticoid is dexamethasone.

10. The method according to claim 1 wherein the compound of formula I has the structure:

11. The method according to claim 1 wherein:

R 3 is unsubstituted alkyl;

Ar 2 is substituted phenyl; and

n is 1,

or a pharmaceutically acceptable salt thereof.

12. The method according to claim 1 wherein:

R 3 is unsubstituted alkyl;

Ar 2 is substituted phenyl; and

n is 1,

or a pharmaceutically acceptable salt thereof.

13. The method according to claim 1 wherein:

Ar 2 is 3,5-bis(trifluoromethyl)phenyl,

pharmaceutically acceptable salt thereof.

14. The method according to claim 1 wherein:

R 3 is —CH 3 ,

or a pharmaceutically acceptable salt thereof.

15. The method according to claim 1 wherein:

one of R 1 or R 2 is

or a pharmaceutically acceptable salt thereof.

16. The method according to claim 1 wherein:

one of R 1 or R 2 is

wherein W is ═C(R 8 )— or

a pharmaceutically acceptable salt thereof.

17. The method according to claim 1 wherein:

one of R 1 and R 2 is

or a pharmaceutically acceptable salt thereof.

18. The method according to claim 1 wherein:

one of R 1 or R 2 is —CN,

or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1 wherein:

X is —S(O 2 )—;

Y is —CH 2 —; and

m is 2,

or a pharmaceutically acceptable salt thereof.

20. The method according to claim 1 wherein:

X is —C(O)—;

Y is —CH 2 —; and

m is 2,

or a pharmaceutically acceptable salt thereof.

21. The method according to claim 1 wherein:

X is —C(O)—;

Y is —CH 2 —; and

m is 3,

or a pharmaceutically acceptable salt thereof.

22. The method according to claim 1 wherein:

X is —C(O)—;

Y is —O—; and

m is 2,

or a pharmaceutically acceptable salt thereof.

23. The method according to claim 1 wherein:

X is —C(O)—;

Y is —CH 2 —; and

m is 1,

or a pharmaceutically acceptable salt thereof.

24. The method according to claim 1 wherein:

X is —C(O)—;

Y is —NH—C(O)—;

m is 1,

or a pharmaceutically acceptable salt thereof.

25. The method according to claim 1 wherein:

Z is —NH—; and

R 8 is H,

or a pharmaceutically acceptable salt thereof.

26. The method according to claim 1 wherein:

Z is —NH—; and

R 8 is —NH—S(O 2 )—CH 3 ,

or a pharmaceutically acceptable salt thereof.

27. The method according to claim 1 wherein:

Z is —NH—;

R 8 is —CH 2 —OH,

or a pharmaceutically acceptable salt thereof.

28. The method according to claim 1 wherein:

Z is —NH—;

R 8 is —CH 2 —O—CH 3 ,

or a pharmaceutically acceptable salt thereof.

29. The method according to claim 1 wherein:

Z is —NH—;

R 8 is —NH 2 ,

or a pharmaceutically acceptable salt thereof.

30. The method according to claim 1 wherein:

Z is

and

R 8 is H,

or a pharmaceutically acceptable salt thereof.

31. The method according to claim 1 wherein:

Z is —C(CH 3 ) 2 —; and

R 8 is H,

or a pharmaceutically acceptable salt thereof.

32. The method according to claim 1 , having the formula IB

wherein R 1 and R 2 are selected from the group consisting of:

Compound

R 1

R 2

 1

—CN

 2

—CN

 5

—CH 2 CN

 6

—CH 3

 7

—CN

 8

—C(O)—O—CH 3

 9

—CN

12

—CH 2 OH

13

—CH 2 OCH 3

14

—CH 2 OCH 3

32

—CN

33

—CN

34

—CN

35

—CN

36

—NH—S(O 2 )—CH 3

—CN

37

—CN

—NH—S(O 2 )—CH 3

38

—CH 2 CN

39

—CN

—NH 2

40

—NH 2

—CN

41

—NH—C(O)—NH 2

—CN

42

—CN

or a pharmaceutically acceptable salt thereof.

33. The method according to claim 1 wherein the compound of formula I is

or a pharmaceutically acceptable salt thereof.

34. The method according to claim 1 wherein the compound of formula I is

or a pharmaceutically acceptable salt thereof.

35. The method according to claim 1 wherein the compound of formula I is

or a pharmaceutically acceptable salt thereof.

36. The method according to claim 2 wherein the emesis is chemotherapy induced emesis.

37. The method according to claim 2 wherein the emesis is radiation induced emesis.

38. The method according to claim 4 wherein the nausea and vomiting is post operative nausea and vomiting.