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 compound which is (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.
2. A compound which is (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.
3. A compound which is (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.
4. A compound which is (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.
5. A compound which is (S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
6. A compound which is (S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
7. A compound which is (S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
8. A compound which is (S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.
9. A compound which is (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
10. A compound which is (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
11. A compound which is (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
12. A compound which is (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.
13. A compound which is (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
14. A compound which is (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
15. A compound which is (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
16. A compound which is (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.
17. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising the compound of claim 2 and at least one pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising the compound of claim 3 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising the compound of claim 4 and at least one pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising the compound of claim 5 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
22. A pharmaceutical composition comprising the compound of claim 6 and at least one pharmaceutically acceptable carrier.
23. A pharmaceutical composition comprising the compound of claim 7 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
24. A pharmaceutical composition comprising the compound of claim 8 and at least one pharmaceutically acceptable carrier.
25. A pharmaceutical composition comprising the compound of claim 9 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising the compound of claim 10 and at least one pharmaceutically acceptable carrier.
27. A pharmaceutical composition comprising the compound of claim 11 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising the compound of claim 12 and at least one pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising the compound of claim 13 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
30. A pharmaceutical composition comprising the compound of claim 14 and at least one pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising the compound of claim 15 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising the compound of claim 16 and at least one pharmaceutically acceptable carrier.
33. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
34. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 2 .
35. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 3 , or a pharmaceutically acceptable salt thereof.
36. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 4 .
37. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
38. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 6 .
39. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 7 , or a pharmaceutically acceptable salt thereof.
40. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 8 .
41. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 9 , or a pharmaceutically acceptable salt thereof.
42. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 10 .
43. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 11 , or a pharmaceutically acceptable salt thereof.
44. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 12 .
45. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 13 , or a pharmaceutically acceptable salt thereof.
46. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 14 .
47. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 15 , or a pharmaceutically acceptable salt thereof.
48. A method of treating a disease in a patient, wherein said disease is selected from osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation, comprising administering to said patient a therapeutically effective amount of a compound of claim 16 .