Claims for Patent: 9,676,783

Summary for Patent: 9,676,783

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 (Stamford, CT)
Assignee:	Array BioPharma, Inc. (Boulder, CO)
Application Number:	14/846,166
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 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. 2. The method of claim 1, wherein the cancer exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase. 3. The method of claim 2, wherein the Trk kinase is TrkA. 4. The method of claim 2, wherein the Trk kinase is TrkB. 5. The method of claim 2, wherein the Trk kinase is TrkA and TrkB. 6. The method of claim 2, wherein the Trk kinase is selected from one or more of: TrkA, TrkB, and TrkC. 7. The method of claim 1, wherein the cancer exhibits overexpression of a Trk kinase. 8. The method of claim 1, wherein the cancer exhibits activation of a Trk kinase. 9. The method of claim 1, wherein the cancer exhibits amplification of a Trk kinase. 10. The method of claim 1, wherein the cancer exhibits mutation of a Trk kinase. 11. The method of claim 1, wherein the cancer is a hematological malignancy. 12. The method of claim 11, wherein the cancer is selected from the group consisting of myeloma and lymphoma. 13. The method of claim 1, wherein the cancer is a solid tumor. 14. The method of claim 13, 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. 15. 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. 16. The method of claim 15, wherein the cancer is a lung adenocarcinoma. 17. 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. 18. 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, a biological response modifier, 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. 19. The method of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. 20. The method of claim 1, wherein Y is phenyl optionally substituted with one or more halogen atoms. 21. The method of claim 20, wherein Y is phenyl optionally substituted with one or two fluorine atoms. 22. The method of claim 1, wherein n is zero or one. 23. The method of claim 22, wherein R.sup.3 is hydrogen. 24. The method of claim 23, wherein R.sup.1 is hydrogen. 25. The method of claim 1, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 26. The method of claim 25, wherein the compound of Formula (I) is a sulfate salt. 27. 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; (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-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--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. 28. The method of claim 27, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 29. The method of claim 28, wherein the compound of Formula (I) is a sulfate salt. 30. A method for attenuating or ameliorating one or more symptoms of a cancer in a mammal, the method comprising 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. 31. The method of claim 30, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 32. The method of claim 31, 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. 33. The method of claim 30, wherein the cancer is associated with one or more of overexpression, activation, amplification, and mutation of a Trk kinase. 34. The method of claim 33, wherein the Trk kinase is TrkA. 35. The method of claim 33, wherein the Trk kinase is TrkB. 36. The method of claim 33, wherein the Trk kinase is TrkA and TrkB. 37. The method of claim 33, wherein the Trk kinase is selected from one or more of: TrkA, TrkB, and TrkC. 38. The method of claim 30, wherein the cancer exhibits overexpression of a Trk kinase. 39. The method of claim 30, wherein the cancer exhibits activation of a Trk kinase. 40. The method of claim 30, wherein the cancer exhibits amplification of a Trk kinase. 41. The method of claim 30, wherein the cancer exhibits mutation of a Trk kinase. 42. The method of claim 30, wherein the cancer is a hematological malignancy. 43. The method of claim 42, wherein the cancer is selected from the group consisting of: myeloma and lymphoma. 44. The method of claim 30, wherein the cancer is a solid tumor. 45. The method of claim 44, 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. 46. The method of claim 30, 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. 47. The method of claim 46, wherein the cancer is a lung adenocarcinoma. 48. The method of claim 30, 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. 49. The method of claim 30, 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, a biological response modifier, 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. 50. The method of claim 30, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally. 51. A method for attenuating or ameliorating one or more symptoms of a lung cancer that exhibits one or more of an 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. 52. The method of claim 51, wherein the Trk kinase is TrkA. 53. The method of claim 51, wherein the Trk kinase is TrkB. 54. The method of claim 51, wherein the Trk kinase is TrkA and TrkB. 55. The method of claim 51, wherein the Trk kinase is selected from one or more of: TrkA, TrkB, and TrkC. 56. The method of claim 51, wherein the cancer exhibits overexpression of a Trk kinase. 57. The method of claim 51, wherein the cancer exhibits activation of a Trk kinase. 58. The method of claim 51, wherein the cancer exhibits amplification of a Trk kinase. 59. The method of claim 51, wherein the cancer exhibits mutation of a Trk kinase. 60. The method of claim 51, wherein the lung cancer is a lung adenocarcinoma. 61. The method of claim 51, 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. 62. The method of claim 51, 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, a biological response modifier, 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. 63. The method of claim 51, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. 64. The method of claim 51, wherein Y is phenyl optionally substituted with one or more halogen atoms. 65. The method of claim 64, wherein Y is phenyl optionally substituted with one or two fluorine atoms. 66. The method of claim 51, wherein n is zero or one. 67. The method of claim 66, wherein R.sup.3 is hydrogen. 68. The method of claim 67, wherein R.sup.1 is hydrogen. 69. The method of claim 51, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 70. The method of claim 69, wherein the compound of Formula (I) is a sulfate salt. 71. The method of claim 51, 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; (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[1,5,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5,5-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-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--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. 72. The method of claim 71, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 73. The method of claim 72, wherein the compound of Formula (I) is a sulfate salt. 74. A method for treating a lung cancer that exhibits one or more of an 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]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof. 75. The method of claim 74, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt. 76. The method of claim 75, 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. 77. The method of claim 74, wherein the Trk kinase is TrkA. 78. The method of claim 74, wherein the Trk kinase is TrkB. 79. The method of claim 74, wherein the Trk kinase is TrkA and TrkB. 80. The method of claim 74, wherein the lung cancer is a lung adenocarcinoma. 81. The method of claim 74, 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. 82. The method of claim 74, 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, a biological response modifier, 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. 83. The method of claim 74, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.