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Last Updated: October 28, 2021

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Claims for Patent: 10,005,783

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Summary for Patent: 10,005,783
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 (Boulder, CO)
Assignee: Array BioPharma Inc. (Boulder, CO)
Application Number:15/399,389
Patent Claims:1. A method of attenuating or ameliorating one or more symptoms of neuroblastoma in a subject, the method comprising: a) determining that the neuroblastoma exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and b) administering to the subject a therapeutically effective amount of a dosage form comprising 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 Y is phenyl optionally substituted with one or more halogen atoms.

3. The method of claim 2, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

4. The method of claim 1, wherein n is zero or one.

5. The method of claim 4, wherein R.sup.3 is hydrogen.

6. The method of claim 5, wherein R.sup.1 is hydrogen.

7. The method of claim 1, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

8. The method of claim 7, wherein the compound of Formula (I) is a sulfate salt.

9. The method of claim 1, wherein the compound of Formula (I) is ##STR00157## (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.

10. The method of claim 9, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

11. The method of claim 1, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00158## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide sulfate.

12. The method of claim 1, wherein the dosage form is an oral preparation for oral administration.

13. The method of claim 12, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

14. The method of claim 13, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

15. The method of claim 1, wherein the Trk kinase is selected from the group consisting of TrkA, TrkB, and TrkC.

16. A method of attenuating or ameliorating one or more symptoms of neuroblastoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dosage form comprising 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.

17. The method of claim 16, wherein Y is phenyl optionally substituted with one or more halogen atoms.

18. The method of claim 17, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

19. The method of claim 16, wherein n is zero or one.

20. The method of claim 19, wherein R.sup.3 is hydrogen.

21. The method of claim 20, wherein R.sup.1 is hydrogen.

22. The method of claim 16, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

23. The compound of claim 22, wherein the compound of Formula (I) is a sulfate salt.

24. The method of claim 16, wherein the compound of Formula (I) is ##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.

25. The method of claim 24, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

26. The method of claim 16, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##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.

27. The method of claim 16, wherein the dosage form is an oral preparation for oral administration.

28. The method of claim 27, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

29. The method of claim 28, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

30. A method of attenuating or ameliorating one or more symptoms of glioma in a subject, the method comprising: a) determining that the glioma exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and b) administering to the subject a therapeutically effective amount of a dosage form comprising a compound of Formula (I) ##STR00162## 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.

31. The method of claim 30, wherein Y is phenyl optionally substituted with one or more halogen atoms.

32. The method of claim 31, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

33. The method of claim 30, wherein n is zero or one.

34. The method of claim 33, wherein R.sup.3 is hydrogen.

35. The method of claim 34, wherein R.sup.1 is hydrogen.

36. The method of claim 30, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

37. The compound of claim 36, wherein the compound of Formula (I) is a sulfate salt.

38. The method of claim 30, wherein the compound of Formula (I) is ##STR00163## (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.

39. The method of claim 38, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

40. The method of claim 30, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00164## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide sulfate.

41. The method of claim 30, wherein the dosage form is an oral preparation for oral administration.

42. The method of claim 41, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

43. The method of claim 42, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

44. The method of claim 30, wherein the Trk kinase is selected from the group consisting of TrkA, TrkB, and TrkC.

45. A method of attenuating or ameliorating one or more symptoms of glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dosage form comprising a compound of Formula (I) ##STR00165## 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.

46. The method of claim 45, wherein Y is phenyl optionally substituted with one or more halogen atoms.

47. The method of claim 46, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

48. The method of claim 45, wherein n is zero or one.

49. The method of claim 48, wherein R.sup.3 is hydrogen.

50. The method of claim 49, wherein R.sup.1 is hydrogen.

51. The method of claim 45, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

52. The compound of claim 51, wherein the compound of Formula (I) is a sulfate salt.

53. The method of claim 45, wherein the compound of Formula (I) is ##STR00166## (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.

54. The method of claim 53, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

55. The method of claim 45, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00167## (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate.

56. The method of claim 45, wherein the dosage form is an oral preparation for oral administration.

57. The method of claim 56, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

58. The method of claim 57, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

59. A method of attenuating or ameliorating one or more symptoms of thyroid cancer in a subject, the method comprising: a) determining that the thyroid cancer exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and b) administering to the subject a therapeutically effective amount of a dosage form comprising a compound of Formula (I) ##STR00168## 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.

60. The method of claim 44, wherein Y is phenyl optionally substituted with one or more halogen atoms.

61. The method of claim 59, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

62. The method of claim 59, wherein n is zero or one.

63. The method of claim 62, wherein R.sup.3 is hydrogen.

64. The method of claim 63, wherein R.sup.1 is hydrogen.

65. The method of claim 44, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

66. The compound of claim 65, wherein the compound of Formula (I) is a sulfate salt.

67. The method of claim 59, wherein the compound of Formula (I) is ##STR00169## (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.

68. The method of claim 67, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

69. The method of claim 59, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00170## (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate.

70. The method of claim 59, wherein the dosage form is an oral preparation for oral administration.

71. The method of claim 70, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

72. The method of claim 71, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

73. The method of claim 59, wherein the Trk kinase is selected from the group consisting of TrkA, TrkB, and TrkC.

74. A method of attenuating or ameliorating one or more symptoms of thyroid cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dosage form comprising a compound of Formula (I) ##STR00171## 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.

75. The method of claim 74, wherein Y is phenyl optionally substituted with one or more halogen atoms.

76. The method of claim 75, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

77. The method of claim 74, wherein n is zero or one.

78. The method of claim 75, wherein R.sup.3 is hydrogen.

79. The method of claim 76, wherein R.sup.1 is hydrogen.

80. The method of claim 74, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

81. The compound of claim 80, wherein the compound of Formula (I) is a sulfate salt.

82. The method of claim 74, wherein the compound of Formula (I) is ##STR00172## (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.

83. The method of claim 82, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

84. The method of claim 74, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00173## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide sulfate.

85. The method of claim 74, wherein the dosage form is an oral preparation for oral administration.

86. The method of claim 85, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

87. The method of claim 86, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

88. A method of attenuating or ameliorating one or more symptoms of breast cancer in a subject, the method comprising: a) determining that the breast cancer exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and b) administering to the subject a therapeutically effective amount of a dosage form comprising a compound of Formula (I) ##STR00174## 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.

89. The method of claim 88, wherein Y is phenyl optionally substituted with one or more halogen atoms.

90. The method of claim 89, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

91. The method of claim 88, wherein n is zero or one.

92. The method of claim 91, wherein R.sup.3 is hydrogen.

93. The method of claim 92, wherein R.sup.1 is hydrogen.

94. The method of claim 88, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

95. The compound of claim 94, wherein the compound of Formula (I) is a sulfate salt.

96. The method of claim 88, wherein the compound of Formula (I) is ##STR00175## (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.

97. The method of claim 96, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

98. The method of claim 88, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00176## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide sulfate.

99. The method of claim 88, wherein the dosage form is an oral preparation for oral administration.

100. The method of claim 99, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

101. The method of claim 100, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

102. The method of claim 88, wherein the Trk kinase is selected from the group consisting of TrkA, TrkB, and TrkC.

103. The method of claim 88, wherein administration of the therapeutically effective amount of a dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof is in combination with the administration of one or more additional therapeutic agents or therapies selected from the group consisting of surgery, radiotherapy, signal transduction inhibitors, monoclonal antibodies, anti-inflammatory compounds, steroids, mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, prenyl-protein transferase inhibitors, chemotherapeutic agents, hormone therapy drugs, targeted therapy drugs, and aromatase inhibitors.

104. The method of claim 103, wherein the aromatase inhibitor is selected from the group consisting of aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, and 1,4,6-androstatriene-3,17-dione (ATD).

105. The method of claim 103, wherein the one or more additional therapeutic agents is selected from the group consisting of palbociclib, abemaciclib, fulvestrant, topotecan, gemcitabine, imatinib mesylate, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, decitabine, cyclophosphamide, vinca alkaloids, imatinib, lapatinib, anthracyclines, rituximab, tamoxifen, irinotecan (CPT 11), pertuzumab, trastuzumab, and ado-trastuzumab emtansine.

106. The method of claim 103, wherein the breast cancer is selected from the group consisting of secretory breast carcinoma, ductal carcinoma, ductal carcinoma in situ, invasive ductal carcinoma, invasive ductal carcinoma with secretory features, lobular carcinoma, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma, tubular carcinoma, mucinous (colloid) carcinoma, Paget's disease of the breast, inflammatory carcinoma, angiosarcoma, invasive comedocarcinoma, scirrhous carcinoma, metaplastic carcinoma, papillary carcinoma, papillary carcinoma in situ, micropapillary carcinoma, cribriform carcinoma, undifferentiated or anaplastic carcinoma, male breast cancer, phyllodes tumors, adenoid cystic carcinoma, onset breast cancer, relapse breast cancer, and refractory breast cancer.

107. The method of claim 103, wherein the breast cancer is selected from the group consisting of metastatic, hormone resistant, hormone receptor positive, estrogen receptor positive, estrogen receptor negative, progesterone receptor negative, progesterone receptor positive, HER2 positive, HER2 negative, double positive, triple-negative, triple-positive, and combinations thereof.

108. The method of claim 103, wherein the compound of Formula (I) is ##STR00177## (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.

109. The method of claim 108, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

110. The method of claim 103, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00178## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide sulfate.

111. The method of claim 103, wherein the dosage form is an oral preparation for oral administration.

112. The method of claim 111, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

113. The method of claim 112, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

114. The method of claim 103, wherein the Trk kinase is selected from the group consisting of TrkA, TrkB, and TrkC.

115. A method of attenuating or ameliorating one or more symptoms of breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dosage form comprising a compound of Formula (I) ##STR00179## 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.

116. The method of claim 115, wherein Y is phenyl optionally substituted with one or more halogen atoms.

117. The method of claim 116, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

118. The method of claim 115, wherein n is zero or one.

119. The method of claim 118, wherein R.sup.3 is hydrogen.

120. The method of claim 119, wherein R.sup.1 is hydrogen.

121. The method of claim 115, wherein the compound of Formula (I) is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

122. The compound of claim 121, wherein the compound of Formula (I) is a sulfate salt.

123. The method of claim 115, wherein the compound of Formula (I) is ##STR00180## (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.

124. The method of claim 123, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

125. The method of claim 115, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00181## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide sulfate.

126. The method of claim 115, wherein the dosage form is an oral preparation for oral administration.

127. The method of claim 126, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

128. The method of claim 127, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

129. The method of claim 115, wherein administration of the therapeutically effective amount of a dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof is in combination with the administration of one or more additional therapeutic agents or therapies selected from the group consisting of surgery, radiotherapy, signal transduction inhibitors, monoclonal antibodies, anti-inflammatory compounds, steroids, mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, prenyl-protein transferase inhibitors, chemotherapeutic agents, hormone therapy drugs, targeted therapy drugs, and aromatase inhibitors.

130. The method of claim 129, wherein the aromatase inhibitor is selected from the group consisting of aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, and 1,4,6-androstatriene-3,17-dione (ATD).

131. The method of claim 129, wherein the one or more additional therapeutic agents is selected from the group consisting of palbociclib, abemaciclib, fulvestrant, topotecan, gemcitabine, imatinib mesylate, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, decitabine, cyclophosphamide, vinca alkaloids, imatinib, lapatinib, anthracyclines, rituximab, tamoxifen, irinotecan (CPT 11), pertuzumab, trastuzumab, and ado-trastuzumab emtansine.

132. The method of claim 129, wherein the breast cancer is selected from the group consisting of secretory breast carcinoma, ductal carcinoma, ductal carcinoma in situ, invasive ductal carcinoma, invasive ductal carcinoma with secretory features, lobular carcinoma, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma, tubular carcinoma, mucinous (colloid) carcinoma, Paget's disease of the breast, inflammatory carcinoma, angiosarcoma, invasive comedocarcinoma, scirrhous carcinoma, metaplastic carcinoma, papillary carcinoma, papillary carcinoma in situ, micropapillary carcinoma, cribriform carcinoma, undifferentiated or anaplastic carcinoma, male breast cancer, phyllodes tumors, adenoid cystic carcinoma, onset breast cancer, relapse breast cancer, and refractory breast cancer.

133. The method of claim 129, wherein the breast cancer is selected from the group consisting of metastatic, hormone resistant, hormone receptor positive, estrogen receptor positive, estrogen receptor negative, progesterone receptor negative, progesterone receptor positive, HER2 positive, HER2 negative, double positive, triple-negative, triple-positive, and combinations thereof.

134. The method of claim 129, wherein the compound of Formula (I) is ##STR00182## (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.

135. The method of claim 134, wherein the compound is a trifluoroacetate salt, a sulfate salt, or a hydrochloride salt.

136. The method of claim 129, wherein the dosage form comprises the hydrogen sulfate salt of the compound of Formula (I) having the formula ##STR00183## (S)--N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy- pyrrolidine-1-carboxamide sulfate.

137. The method of claim 129, wherein the dosage form is an oral preparation for oral administration.

138. The method of claim 137, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

139. The method of claim 138, wherein the oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

140. The method of claim 129, wherein the Trk kinase is selected from the group consisting of TrkA, TrkB, and TrkC.

Details for Patent 10,005,783

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Genentech, Inc. RITUXAN rituximab Injection 103705 1997-11-26 ⤷  Free Forever Trial 2028-10-22
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 1998-09-25 ⤷  Free Forever Trial 2028-10-22
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 2017-02-10 ⤷  Free Forever Trial 2028-10-22
Genentech, Inc. PERJETA pertuzumab Injection 125409 2012-06-08 ⤷  Free Forever Trial 2028-10-22
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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