Spirocyclic compounds as tryptophan hydroxylase inhibitors
The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.
1. A method of treating carcinoid syndrome in a patient, comprising administering to the patient a therapeutically effective amount of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein administration is by inhalation.
3. The method of claim 2 , wherein inhalation is with a powder.
4. The method of claim 2 , wherein inhalation is with a spray or an aerosol.
5. The method of claim 4 , wherein inhalation is via a sonic nebulizer.
6. The method of claim 1 , wherein administration is by injection.
7. The method of claim 6 , wherein injection is subcutaneous, intravenous, or intramuscular.
8. The method of claim 1 , wherein administration is by infusion.
9. The method of claim 1 , wherein administration is oral.
10. A method of lowering peripheral serotonin in a patient having carcinoid syndrome, comprising administering a therapeutically effective amount of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein administration is by inhalation.
12. The method of claim 11 , wherein inhalation is with a powder.
13. The method of claim 11 , wherein inhalation is with a spray or an aerosol.
14. The method of claim 13 , wherein inhalation is via a sonic nebulizer.
15. The method of claim 10 , wherein administration is by injection.
16. The method of claim 15 , wherein injection is subcutaneous, intravenous, or intramuscular.
17. The method of claim 10 , wherein injection is subcutaneous, intravenous, or intramuscular.
18. The method of claim 10 , wherein administration is oral.
19. A method of treating carcinoid syndrome in a patient, comprising administering to the patient a therapeutically effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein administration is by inhalation.
21. The method of claim 20 , wherein inhalation is with a powder.
22. The method of claim 20 , wherein inhalation is with a spray or an aerosol.
23. The method of claim 22 , wherein inhalation is via a sonic nebulizer.
24. The method of claim 19 , wherein administration is by injection.
25. The method of claim 24 , wherein injection is subcutaneous, intravenous, or intramuscular.
26. The method of claim 19 , wherein administration is by infusion.
27. The method of claim 19 , wherein administration is oral.
28. A method of lowering peripheral serotonin in a patient having carcinoid syndrome, comprising administering a therapeutically effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof.
29. The method of claim 28 , wherein administration is by inhalation.
30. The method of claim 29 , wherein inhalation is with a powder.
31. The method of claim 29 , wherein inhalation is with a spray or an aerosol.
32. The method of claim 31 , wherein inhalation is via a sonic nebulizer.
33. The method of claim 28 , wherein administration is by injection.
34. The method of claim 33 , wherein injection is subcutaneous, intravenous, or intramuscular.
35. The method of claim 28 , wherein administration is by infusion.
36. The method of claim 28 , wherein administration is oral.