Claims for Patent: 9,447,104

Summary for Patent: 9,447,104

Title:	Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
Abstract:	Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.
Inventor(s):	Haas; Julia (Boulder, CO), Andrews; Steven W. (Boulder, CO), Jiang; Yutong (Boulder, CO), Zhang; Gan (Niwot, CO)
Assignee:	Array BioPharma, Inc. (Boulder, CO)
Application Number:	14/490,460
Patent Claims:	1. A method for attenuating or ameliorating one or more symptoms of a cancer in a mammal in need thereof, the method comprising: (a) determining if the cancer exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and (b) if the cancer is determined to exhibit one or more of overexpression, activation, amplification, and mutation of a Trk kinase, administering to the mammal a therapeutically effective amount of a compound of Formula (I): ##STR00156## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is H or (1-6C alkyl); R.sup.2 is NR.sup.bR.sup.c; NR.sup.bR.sup.c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO.sub.2, wherein the heterocyclic ring formed by NR.sup.bR.sup.c is optionally substituted with one or two substituents independently selected from OH, F, NH.sub.2, CO.sub.2H, CO.sub.2Et, NHCO.sub.2C(CH.sub.3).sub.3, CF.sub.3, methyl, ethyl, isopropyl, CO.sub.2C(CH.sub.3).sub.3 and oxo; Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF.sub.3 and CHF.sub.2; X is --CH.sub.2--; R.sup.3 is H or (1-4C alkyl); each R.sup.4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2; wherein the cancer is selected from the group consisting of: a solid tumor, a hematological malignancy, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a bone metastasis, and a large cell neuroendocrine tumor. 2. The method of claim 1, wherein the Trk kinase is selected from one or more of: TrkA, TrkB, and TrkC. 3. The method of claim 1, wherein the cancer exhibits overexpression of a Trk kinase. 4. The method of claim 1, wherein the cancer exhibits activation of a Trk kinase. 5. The method of claim 1, wherein the cancer exhibits amplification of a Trk kinase. 6. The method of claim 1, wherein the cancer exhibits a mutation of a Trk kinase. 7. The method of claim 1, wherein the cancer is a hematological malignancy. 8. The method of claim 7, wherein the cancer is selected from the group consisting of: myeloma and lymphoma. 9. The method of claim 1, wherein the cancer is a solid tumor. 10. The method of claim 1, wherein the cancer is selected from the group consisting of: a breast cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a prostate cancer, a pancreatic cancer, and a colorectal cancer. 11. The method of claim 1, wherein the cancer is selected from the group consisting of: a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a thyroid carcinoma, a lung adenocarcinoma, a bone metastasis, and a large cell neuroendocrine tumor. 12. The method of claim 11, wherein the cancer is a lung adenocarcinoma. 13. The method of claim 1, wherein the method further comprises treating the mammal with a second therapy selected from the group consisting of: surgery, radiotherapy, chemotherapy, a signal transduction inhibitor, or a monoclonal antibody. 14. The method of claim 1, wherein the method further comprises administering a second agent selected from the group consisting of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, an antisense DNA, an antisense RNA, an intercalating antibiotic, a growth factor inhibitor, a signal transduction inhibitor, a cell cycle inhibitor, an enzyme inhibitor, a retinoid receptor modulator, a proteasome inhibitor, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, a cytostatic agent, an anti-androgen, a targeted antibody, a HMG-CoA reductase inhibitor, and a prenyl-protein transferase inhibitor. 15. The method of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. 16. The method of claim 1, wherein Y is phenyl optionally substituted with one or more halogen atoms. 17. The method of claim 16, wherein Y is phenyl optionally substituted with one or two fluorine atoms. 18. The method of claim 1, wherein n is zero or one. 19. The method of claim 18, wherein R.sup.3 is hydrogen. 20. The method of claim 19, wherein R.sup.1 is hydrogen. 21. The method of claim 1, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt. 22. The method of claim 21, wherein the compound of Formula (I) is a sulfate salt. 23. The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)morpholine-4-carboxamide; and (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)morpholine-4-carboxamide; (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (3R,4R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)morpholine-4-carboxamide; (S)-tert-butyl 4-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-methylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-isopropylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-ethylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-methylpiperazine-1-carboxamide; N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-3,5-dimethylpiperazine-1-carboxamide; (S)-tert-butyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate; (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-methylpiperazine-1-carboxamide hydrochloride; (S)--N-(5-((R)-2-(3-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[- 1,5-a]pyrimidin-3-yl)-4-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-4-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a- ]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5((R)-2-(5-fluoro-2-methoxypheny)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; or a pharmaceutically acceptable salt thereof. 24. The method of claim 23, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 25. The method of claim 24, wherein the compound of Formula (I) is a sulfate salt. 26. A method for attenuating or ameliorating one or more symptoms of a cancer in a mammal in need thereof, the method comprising: (a) determining if the cancer exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and (b) if the cancer is determined to exhibit one or more of overexpression, activation, amplification, and mutation of a Trk kinase, administering to the mammal a therapeutically effective amount of a compound: ##STR00157## (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof; wherein the cancer is selected from the group consisting of: a solid tumor, a hematological malignancy, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a bone metastasis, and a large cell neuroendocrine tumor. 27. The method of claim 26, wherein the compound is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt. 28. The method of claim 27, wherein the compound is: ##STR00158## (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate. 29. The method of claim 26, wherein the Trk kinase is selected from one or more of: TrkA, TrkB, and TrkC. 30. The method of claim 26, wherein the cancer exhibits overexpression of a Trk kinase. 31. The method of claim 26, wherein the cancer exhibits activation of a Trk kinase. 32. The method of claim 26, wherein the cancer exhibits amplification of a Trk kinase. 33. The method of claim 26, wherein the cancer exhibits mutation of a Trk kinase. 34. The method of claim 26, wherein the cancer is a hematological malignancy. 35. The method of claim 34, wherein the cancer is selected from the group consisting of: myeloma and lymphoma. 36. The method of claim 26, wherein the cancer is a solid tumor. 37. The method of claim 26, wherein the cancer is selected from the group consisting of: a breast cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a prostate cancer, a pancreatic cancer, and a colorectal cancer. 38. The method of claim 26, wherein the cancer is selected from the group consisting of: a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a thyroid carcinoma, a lung adenocarcinoma, a brain metastasis, and a large cell neuroendocrine tumor. 39. The method of claim 38, wherein the cancer is a lung adenocarcinoma. 40. The method of claim 26, wherein the method further comprises treating the mammal with a second therapy selected from the group consisting of: surgery, radiotherapy, chemotherapy, a signal transduction inhibitor, or a monoclonal antibody. 41. The method of claim 26, wherein the method further comprises administering a second agent selected from the group consisting of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, an antisense DNA, an antisense RNA, an intercalating antibiotic, a growth factor inhibitor, a signal transduction inhibitor, a cell cycle inhibitor, an enzyme inhibitor, a retinoid receptor modulator, a proteasome inhibitor, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, a cytostatic agent, an anti-androgen, a targeted antibody, a HMG-CoA reductase inhibitor, and a prenyl-protein transferase inhibitor. 42. The method of claim 26, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally. 43. A method for attenuating or ameliorating one or more symptoms of a cancer exhibiting one or more of overexpression, activation, amplification, and mutation of a Trk kinase in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I): ##STR00159## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is H or (1-6C alkyl); R.sup.2 is NR.sup.bR.sup.c; NR.sup.bR.sup.c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO.sub.2, wherein the heterocyclic ring formed by NR.sup.bR.sup.c is optionally substituted with one or two substituents independently selected from OH, F, NH.sub.2, CO.sub.2H, CO.sub.2Et, NHCO.sub.2C(CH.sub.3).sub.3, CF.sub.3, methyl, ethyl, isopropyl, CO.sub.2C(CH.sub.3).sub.3 and oxo; Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF.sub.3 and CHF.sub.2; X is --CH.sub.2--; R.sup.3 is H or (1-4C alkyl); each R.sup.4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2; wherein the cancer is selected from the group consisting of: a solid tumor, a hematological malignancy, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a bone metastasis, and a large cell neuroendocrine tumor. 44. The method of claim 43, wherein the cancer exhibits overexpression of a Trk kinase. 45. The method of claim 43, wherein the cancer exhibits activation of a Trk kinase. 46. The method of claim 43, wherein the cancer exhibits amplification of a Trk kinase. 47. The method of claim 43, wherein the cancer exhibits a mutation of a Trk kinase. 48. The method of claim 47, wherein the Trk kinase is selected from one or more of: TrkA, TrkB, and TrkC. 49. The method of claim 43, wherein the cancer is a hematological malignancy. 50. The method of claim 49, wherein the cancer is selected from the group consisting of: myeloma and lymphoma. 51. The method of claim 43, wherein the cancer is a solid tumor. 52. The method of claim 43, wherein the cancer is selected from the group consisting of: a breast cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a prostate cancer, a pancreatic cancer, and a colorectal cancer. 53. The method of claim 43, wherein the cancer is selected from the group consisting of: a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a thyroid carcinoma, a lung adenocarcinoma, a bone metastasis, and a large cell neuroendocrine tumor. 54. The method of claim 53, wherein the cancer is a lung adenocarcinoma. 55. The method of claim 43, wherein the method further comprises treating the mammal with a second therapy selected from the group consisting of: surgery, radiotherapy, chemotherapy, a signal transduction inhibitor, or a monoclonal antibody. 56. The method of claim 43, wherein the method further comprises administering a second agent selected from the group consisting of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, an antisense DNA, an antisense RNA, an intercalating antibiotic, a growth factor inhibitor, a signal transduction inhibitor, a cell cycle inhibitor, an enzyme inhibitor, a retinoid receptor modulator, a proteasome inhibitor, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, a cytostatic agent, an anti-androgen, a targeted antibody, a HMG-CoA reductase inhibitor, and a prenyl-protein transferase inhibitor. 57. The method of claim 43, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. 58. The method of claim 43, wherein Y is phenyl optionally substituted with one or more halogen atoms. 59. The method of claim 43, wherein Y is phenyl optionally substituted with one or two fluorine atoms. 60. The method of claim 43, wherein n is zero or one. 61. The method of claim 60, wherein R.sup.3 is hydrogen. 62. The method of claim 61, wherein R.sup.1 is hydrogen. 63. The method of claim 43, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt. 64. The method of claim 63, wherein the compound of Formula (I) is a sulfate salt. 65. The method of claim 43, wherein the compound of Formula (I) is selected from the group consisting of: (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)morpholine-4-carboxamide; and (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)morpholine-4-carboxamide; (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (3R,4R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)morpholine-4-carboxamide; (S)-tert-butyl 4-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-methylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-isopropylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-ethylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-methylpiperazine-1-carboxamide; N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-3,5-dimethylpiperazine-1-carboxamide; (S)-tert-butyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate; (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-methylpiperazine-1-carboxamide hydrochloride; (S)--N-(5-((R)-2-(3-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[- 1,5-a]pyrimidin-3-yl)-4-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-4-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a- ]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5((R)-2-(5-fluoro-2-methoxypheny)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; or a pharmaceutically acceptable salt thereof. 66. The method of claim 65, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 67. The method of claim 66, wherein the compound of Formula (I) is a sulfate salt. 68. A method for attenuating or ameliorating one or more symptoms of a cancer exhibiting one or more of overexpression, activation, amplification, and mutation of a Trk kinase in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound: ##STR00160## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof; wherein the cancer is selected from the group consisting of: a solid tumor, a hematological malignancy, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a bone metastasis, and a large cell neuroendocrine tumor. 69. The method of claim 68, wherein the compound is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt. 70. The method of claim 69, wherein the compound is: ##STR00161## (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate. 71. The method of claim 68, wherein the cancer exhibits overexpression of a Trk kinase. 72. The method of claim 68, wherein the cancer exhibits activation of a Trk kinase. 73. The method of claim 68, wherein the cancer exhibits amplification of a Trk kinase. 74. The method of claim 68, wherein the cancer exhibits a mutation of a Trk kinase. 75. The method of claim 74, wherein the Trk kinase is selected from one or more of: TrkA, TrkB, and TrkC. 76. The method of claim 68, wherein the cancer is a hematological malignancy. 77. The method of claim 76, wherein the cancer is selected from the group consisting of: myeloma and lymphoma. 78. The method of claim 68, wherein the cancer is a solid tumor. 79. The method of claim 68, wherein the cancer is selected from the group consisting of: a breast cancer, a lung cancer, a renal cancer, a thyroid cancer, an ovarian cancer, a prostate cancer, a pancreatic cancer, and a colorectal cancer. 80. The method of claim 68, wherein the cancer is selected from the group consisting of: a neuroblastoma, a multiple myeloma, an astrocytoma, a medulloblastoma, a glioma, a melanoma, a thyroid carcinoma, a lung adenocarcinoma, a brain metastasis, and a large cell neuroendocrine tumor. 81. The method of claim 80, wherein the cancer is a lung adenocarcinoma. 82. The method of claim 68, wherein the method further comprises treating the mammal with a second therapy selected from the group consisting of: surgery, radiotherapy, chemotherapy, a signal transduction inhibitor, or a monoclonal antibody. 83. The method of claim 68, wherein the method further comprises administering a second agent selected from the group consisting of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, an antisense DNA, an antisense RNA, an intercalating antibiotic, a growth factor inhibitor, a signal transduction inhibitor, a cell cycle inhibitor, an enzyme inhibitor, a retinoid receptor modulator, a proteasome inhibitor, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, a cytostatic agent, an anti-androgen, a targeted antibody, a HMG-CoA reductase inhibitor, and a prenyl-protein transferase inhibitor. 84. The method of claim 68, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally. 85. The method of claim 1, wherein the one or more symptoms are selected from the group consisting of: pain, tumor growth, tumor metastasis, bone metastases, pathologic fractures, hypercalcemia, spinal cord compression, nerve-compression, and bone weakness. 86. The method of claim 1, wherein the one or more symptoms are selected from the group consisting of tumor growth and tumor metastasis. 87. The method of claim 26, wherein the one or more symptoms are selected from the group consisting of: pain, tumor growth, tumor metastasis, bone metastases, pathologic fractures, hypercalcemia, spinal cord compression, nerve-compression, and bone weakness. 88. The method of claim 26, wherein the one or more symptoms are selected from the group consisting of tumor growth and tumor metastasis. 89. The method of claim 43, wherein the one or more symptoms are selected from the group consisting of: pain, tumor growth, tumor metastasis, bone metastases, pathologic fractures, hypercalcemia, spinal cord compression, nerve-compression, and bone weakness. 90. The method of claim 43, wherein the one or more symptoms are selected from the group consisting of tumor growth and tumor metastasis. 91. The method of claim 68, wherein the one or more symptoms are selected from the group consisting of: pain, tumor growth, tumor metastasis, bone metastases, pathologic fractures, hypercalcemia, spinal cord compression, nerve-compression, and bone weakness. 92. The method of claim 68, wherein the one or more symptoms are selected from the group consisting of tumor growth and tumor metastasis.