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1. WO2019075108 - CRYSTALLINE FORMS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

What is claimed is:

1. A crystalline form of a compound of Formula I having the formula


2. The crystalline form of claim 1, wherein the crystalline form is Form A, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 4.4±0.2, 14.6±0.2, and 18.3±0.2.

3. The crystalline form of claim 1, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 4.4±0.2, 13.5±0.2, 14.6±0.2, 18.3±0.2, and 18.8±0.2.

4. The crystalline form of claim 1, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 4.4±0.2, 13.5±0.2, 14.6±0.2, 17.4±0.2, 18.3±0.2, 18.8±0.2, 21.0±0.2, and 24.6±0.2.

5. The crystalline form of claim 1, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 4.4±0.2, 13.5±0.2, 14.6±0.2, 17.4±0.2, 18.3±0.2, 18.8±0.2, 21.0±0.2, 22.5±0.2, 24.6±0.2, and 27.7±0.2.

6. The crystalline form of claim 1, wherein the crystalline form is Form A, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 2A.

7. The crystalline form of any one of claims 2-6, wherein the crystalline form is Form A and has a differential scanning calorimetry (DSC) curve comprising an endotherm with an onset of about 187ºC.

8. The crystalline form of any one of claims 2-6, wherein the crystalline form is Form A and has a differential scanning calorimetry (DSC) curve comprising a melting transition with an onset of about 224ºC.

9. The crystalline form of any one of claims 2-6, wherein the crystalline form is Form A and has a DSC thermogram substantially as shown in Figure 2C.

10. A crystalline form of a compound of Formula II having the formula


.

11. The crystalline form of claim 10, wherein the crystalline form is Form 1, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 16.5±0.2, 18.9±0.2, and 26.0±0.2.

12. The crystalline form of claim 10, wherein the crystalline form is Form 1, characterized by having an XRPD pattern comprising peaks at º2θ values of 16.5±0.2, 18.9±0.2, 23.8±0.2, 25.3±0.2, and 26.0±0.2.

13. The crystalline form of claim 10, wherein the crystalline form is Form 1, characterized by having an XRPD pattern comprising peaks at º2θ values of 16.5±0.2, 17.8±0.2, 18.9±0.2, 23.8±0.2, 25.3±0.2, 25.6±0.2, 26.0±0.2, and 28.3±0.2.

14. The crystalline form of claim 10, wherein the crystalline form is Form 1, characterized by having an XRPD pattern comprising peaks at º2θ values of 9.8±0.2, 16.5±0.2, 17.8±0.2, 18.9±0.2, 23.8±0.2, 25.0±0.2, 25.3±0.2, 25.6±0.2, 26.0±0.2, and 28.3±0.2.

15. The crystalline form of claim 10, wherein the crystalline form is Form 1, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 19A.

16. The crystalline form of any one of claims 11-15, wherein the crystalline form is Form 1 and has a differential scanning calorimetry (DSC) curve comprising an endotherm with an onset of about 190ºC.

17. The crystalline form of any one of claims 11-15, wherein the crystalline form is Form 1 and has a DSC curve comprising a melting transition with an onset of about 203ºC.

18. The crystalline form of any one of claims 11-15, wherein the crystalline form is Form 1 and has a DSC thermogram substantially as shown in Figure 19B.

19. A crystalline form of a compound of Formula III having the formula


.

20. The crystalline form of claim 19, wherein the crystalline form is Form A, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 17.3±0.2, 19.2±0.2, and 23.9±0.2.

21. The crystalline form of claim 19, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 4.7±0.2, 17.3±0.2, 18.8±0.2, 19.2±0.2, and 23.9±0.2.

22. The crystalline form of claim 19, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 4.7±0.2, 6.8±0.2, 15.2±0.2, 17.3±0.2, 18.8±0.2, 19.2±0.2, 20.2±0.2, and 23.9±0.2.

23. The crystalline form of claim 19, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 4.7±0.2, 6.8±0.2, 13.4±0.2, 15.2±0.2, 15.9±0.2, 17.3±0.2, 18.8±0.2, 19.2±0.2, 20.2±0.2, and 23.9±0.2.

24. The crystalline form of claim 19, wherein the crystalline form is Form A, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 63A.

25. The crystalline form of any one of claims 20-24, wherein the crystalline form is Form A and has a DSC curve comprising a melting transition with an onset of about 83ºC.

26. The crystalline form of any one of claims 20-24, wherein the crystalline form is Form A and has a DSC thermogram substantially as shown in Figure 63B.

27. A crystalline form of a compound of Formula IV having the formula


.

28. The crystalline form of claim 27, wherein the crystalline form is Form A, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 8.3±0.2, 16.3±0.2, and 21.9±0.2.

29. The crystalline form of claim 27, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 8.3±0.2, 16.3±0.2, 16.6±0.2, 19.4±0.2, and 21.9±0.2.

30. The crystalline form of claim 27, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 8.3±0.2, 16.3±0.2, 16.6±0.2, 19.4±0.2, 20.0±0.2, 20.5±0.2, 21.6±0.2, and 21.9±0.2.

31. The crystalline form of claim 27, wherein the crystalline form is Form A, characterized by having an XRPD pattern comprising peaks at º2θ values of 8.3±0.2, 16.3±0.2, 16.6±0.2, 18.1±0.2, 18.8±0.2, 19.4±0.2, 20.0±0.2, 20.5±0.2, 21.6±0.2, and 21.9±0.2.

32. The crystalline form of claim 27, wherein the crystalline form is Form A, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 64A.

33. The crystalline form of any one of claims 28-32, wherein the crystalline form is Form A and has a DSC curve comprising a melting transition with an onset of about 149ºC.

34. The crystalline form of any one of claims 28-32, wherein the crystalline form is Form A and has a DSC thermogram substantially as shown in Figure 64B.

35. A solid oral pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

36. A solid oral pharmaceutical composition made by mixing a crystalline form according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

37. A process for making a solid oral pharmaceutical composition comprising mixing a crystalline form according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

38. A liquid pharmaceutical composition made by mixing a crystalline form according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

39. A process for making a liquid pharmaceutical composition comprising mixing a crystalline form according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

40. A method for treating cancer in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 35, 36, or 38.

41. A method for treating cancer in a subject in need thereof, the method comprising:

(a) determining if the cancer is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same; and

(b) if the cancer is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, administering to the subject a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38.

42. A method of treating a RET-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a RET-associated cancer a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, to the subject.

43. A method of treating a RET-associated cancer in a subject, the method comprising: determining if the cancer in the subject is a RET-associated cancer; and

administering to a subject determined to have a RET-associated cancer a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38.

44. A method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, to a subject having a clinical record that indicates that the subject has dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same.

45. A method of selecting a treatment for a subject, the method comprising selecting a treatment comprising administration of a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, for a subject identified or diagnosed as having a RET-associated cancer.

46. A method of selecting a treatment for a subject having a cancer, the method comprising:

determining if the cancer in the subject is a RET-associated cancer; and

selecting a treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, for a subject determined to have a RET-associated cancer.

47. A method of selecting a subject for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, the method comprising:

identifying a subject having a RET-associated cancer; and

selecting the subject for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38.

48. A method of selecting a subject having cancer for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, the method comprising:

determining if the cancer in the subject is a RET-associated cancer; and

selecting a subject determined to have a RET-associated cancer for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38.

49. The method of any one of claims 43, 46, and 48, wherein the step of determining if the cancer in the subject is a RET-associated cancer includes performing an assay to detect dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same in a sample from the subject.

50. The method of claim 49, further comprising obtaining a sample from the subject.

51. The method of claim 50, wherein the sample is a biopsy sample.

52. The method of any one of claims 49-51, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

53. The method of claim 52, wherein the FISH is break apart FISH analysis.

54. The method of claim 52, wherein the sequencing is pyrosequencing or next generation

sequencing.

55. The method of any one of claims 49-54, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutation in the RET gene.

56. The method of claim 55, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 1096.

57. The method of claim 56, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

58. The method of claim 57, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C,

G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

59. The method of claim 55, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

60. The method of any one of claims 49-54, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

61. The method of claim 60, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, RFG8/RET, ACBD5-RET, PTC1ex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1/RET, AFAP1-RET, RASGEF1A-RET, TEL-RET, RUFY1-

RET, UEVLD-RET, DLG5-RET, FOXP4-RET, TIF1G-RET, H4L-RET, OFLM4-RET, and RRBP1-RET.

62. The method of any one of claims 42, 43, and 47-61, wherein the RET-associated cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

63. The method of claim 62, wherein the cancer is RET fusion lung cancer or medullary thyroid cancer.

64. The method of claim 62, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchioles lung cell carcinoma, or lung adenocarcinoma.

65. The method of any one of claims 40-64, wherein the compound of Formula I-IV or a pharmaceutically acceptable salt thereof is orally administered.

66. The method of any one of claims 40-65, further comprising administering an additional therapy or therapeutic agent to the subject.

67. The method according to claim 66, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted-therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies and angiogenesis-targeted therapies.

68. The method according to claim 67, wherein the additional therapeutic agent is selected from one or more kinase targeted therapeutics.

69. The method according to any one of claims 66-68, wherein the compound of any one of claims 1-34 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, and the additional therapeutic agent are administered simultaneously as separate dosages.

70. The method according to any one of claims 66-68, wherein the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38, and the additional therapeutic agent are administered as separate dosages sequentially in any order.

71. Use of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a RET-associated cancer in a subject.

72. The use of claim 71, wherein the RET-associated cancer is a cancer having a dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same.

73. The use of claim 72, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.

74. The use of claim 73, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 1096.

75. The use of claim 74, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the

following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

76. The use of claim 75, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions:

S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q,

T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

77. The use of claim 73, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

78. The use of claim 72, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

79. The use of claim 78, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, RFG8/RET, ACBD5-RET, PTC1ex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1/RET, AFAP1-RET, RASGEF1A-RET, TEL-RET, RUFY1-RET, UEVLD-RET, DLG5-RET, FOXP4-RET, TIF1G-RET, H4L-RET, OFLM4-RET, and RRBP1-RET.

80. The use of any one of claims 71-79, wherein the RET-associated cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

81. The use of claim 80, wherein the cancer is RET fusion lung cancer or medullary thyroid cancer.

82. The use of claim 80, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchioles lung cell carcinoma, or lung adenocarcinoma.

83. The use of any one of claims 71-82, wherein the medicament is formulated for oral administration.

84. A compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof for use in treating a subject identified or diagnosed as having a RET-associated cancer.

85. The compound of claim 84, wherein the RET-associated cancer is a cancer having a dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same.

86. The compound of claim 85, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.

87. The compound of claim 86, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 1096.

88. The compound of claim 87, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

89. The compound of claim 88, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q,

T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

90. The compound of claim 86, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

91. The compound of claim 85, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

92. The compound of claim 91, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-

RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, RFG8/RET, ACBD5-RET, PTC1ex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1/RET, AFAP1-RET, RASGEF1A-RET, TEL-RET, RUFY1-RET, UEVLD-RET, DLG5-RET, FOXP4-RET, TIF1G-RET, H4L-RET, OFLM4-RET, and RRBP1-RET.

93. The compound of any one of claims 84-92, wherein the RET-associated cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

94. The compound of claim 93, wherein the cancer is RET fusion lung cancer or medullary thyroid cancer.

95. The compound of claim 93, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronciolus lung cell carcinoma, or lung adenocarcinoma.

96. A method for inhibiting RET kinase activity in a mammalian cell, the method comprising contacting the mammalian cell with a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

97. The method of claim 96, wherein the contacting occurs in vivo.

98. The method of claim 96, wherein the contacting occurs in vitro.

99. The method of any one of claims 96-98, wherein the mammalian cell is a mammalian cancer

cell.

100. The method of claim 99, wherein the mammalian cancer cell is a mammalian RET-associated cancer cell.

101. The method of any one of claims 96-100, wherein the cell has dysregulation of a RET gene, a RET kinase protein, or expression or activity or level of any of the same.

102. The method of claim 101, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.

103. The method of claim 102, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 1096.

104. The method of claim 103, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

105. The method of claim 104, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q,

T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

106. The method of claim 102, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

107. The method of claim 101, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

108. The method of claim 107, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-

RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, RFG8/RET, ACBD5-RET, PTC1ex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1/RET, AFAP1-RET, RASGEF1A-RET, TEL-RET, RUFY1-RET, UEVLD-RET, DLG5-RET, FOXP4-RET, TIF1G-RET, H4L-RET, OFLM4-RET, and RRBP1-RET.

109. A method of treating irritable bowel syndrome in a subject, the method comprising administering to a subject identified or diagnosed as having irritable bowel syndrome a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38 to the subject.

110. A method for reducing pain associated with irritable bowel syndrome in a subject in need thereof, the method comprising administering to a subject identified or diagnosed as having irritable bowel syndrome a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 35, 36, or 38 to the subject.

111. A method for inhibiting metastasis of a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 35, 36, or 38.

112. The method of claim 111, wherein the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof is used in combination with another chemotherapeutic agent.

113. A method of treating a subject having a cancer, wherein the method comprises:

(a) administering one or more doses of a first RET inhibitor to the subject for a period of time;

(b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); and

(c) administering a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); or

(d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a).

114. The method of claim 113, wherein the anticancer agent in step (c) is a second RET inhibitor, an immunotherapy, or a combination thereof.

115. The method of claim 114, wherein the anticancer agent in step (c) is the first RET inhibitor administered in step (a).

116. The method of claim 113, wherein the subject is administered additional doses of the first RET inhibitor of step (a), and the method further comprises (e) administering another anticancer agent to the subject.

117. The method of claim 116, wherein the anticancer agent of step (e) is a second RET inhibitor, an immunotherapy, or a combination thereof.

118. The method of claim 116, wherein the anticancer agent of step (e) is a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

119. A method of treating a subject having a cancer, wherein the method comprises:

(a) administering one or more doses of a first RET inhibitor, to the subject for a period of time;

(b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a);

(c) administering a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); or

(d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); wherein the mutation is a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.

120. The method of claim 119, wherein the anticancer agent of step (c) is the first RET inhibitor administered in step (a).

121. The method of claim 119, wherein the subject is administered additional doses of the first RET inhibitor of step (a), and the method further comprises (e) administering another anticancer agent.

122. The method of claim 121, wherein the anticancer agent of step (e) is a second RET inhibitor, an immunotherapy, or a combination thereof.

123. The method of claim 121, wherein the anticancer agent of step (e) is a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

124. A method of treating a subject having a cancer, wherein the method comprises:

(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more

RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; and

(b) administering a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; or

(c) administering additional doses of the first RET inhibitor to the subject if the subject has cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor previously administered to the subject.

125. The method of claim 124, wherein the anticancer agent of step (b) is a second RET inhibitor, an immunotherapy, or a combination thereof.

126. The method of claim 125, wherein the anticancer agent of step (b) is the first RET inhibitor previously administered to the subject.

127. The method of claim 126, wherein the subject is administered additional doses of the first RET inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.

128. The method of claim 127, wherein the anticancer agent of step (d) is a second RET inhibitor, an immunotherapy, or a combination thereof.

129. The method of claim 127, wherein the anticancer agent of step (d) is a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

130. A method of treating a subject having a cancer, wherein the method comprises:

(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more

RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor previously administered to the subject; and

(b) administering a second RET inhibitor to the subject as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; or

(c) administering additional doses of the first RET inhibitor that was previously administered to the subject if the subject has cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject.

131. The method of claim 130, wherein the anticancer agent of step (b) is the first RET inhibitor previously administered to the subject.

132. The method of claim 130, wherein the subject is administered additional doses of the first RET inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.

133. The method of claim 132, wherein the anticancer agent of step (d) is a second RET inhibitor, an immunotherapy, or a combination thereof.

134. The method of claim 132, wherein the anticancer agent of step (d) is a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

135. A method of treating a subject having a cancer, wherein the method comprises:

(a) administering one or more doses of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof for a period of time;

(b) after (a), determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof of step (a); and

(c) administering a second RET inhibitor or a second compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof as a monotherapy or in conjunction with another anticancer agent to a subject having a cancer cell that has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof of step (a); or

(d) administering additional doses of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof of step (a) to a subject having a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof of step (a).

136. The method of claim 135, wherein the second RET inhibitor is administered in step (c).

137. The method of claim 135, wherein the second compound of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof is administered in step (c).

138. The method of claim 135, wherein the anticancer agent of step (c) is a first RET inhibitor, an immunotherapy, or a combination thereof.

139. The method of claim 136, wherein the anticancer agent of step (c) is a second compound of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof that is different from that administered in step (a).

140. The method of claim 135, wherein the anticancer agent of step (c) is the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof administered in step (a).

141. The method of claim 135, wherein the subject is administered additional doses of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof of step (a), and the method further comprises (e) administering another anticancer agent to the subject.

142. The method of claim 141, wherein the anticancer agent of step (e) is a second RET inhibitor, an immunotherapy, or a combination thereof.

143. The method of claim 141, wherein the anticancer agent of step (e) is a second compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof that is different from the compound of step (a).

144. A method of treating a subject having a cancer, wherein the method comprises:

(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof that was previously administered to the subject;

(b) administering a second RET inhibitor or a second compound of any one of claims 1-34 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject having a cancer cell that has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof that was previously administered to the subject; or

(c) administering additional doses of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof previously administered to a subject having a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof that was previously administered to the subject.

145. The method of claim 144, wherein the second RET inhibitor is administered in step (b).

146. The method of claim 144, wherein the second compound of any one of claims 1-34 or a pharmaceutically acceptable salt or solvate thereof is administered in step (b).

147. The method of claim 144, wherein the anticancer agent of step (b) is a second RET inhibitor, an immunotherapy, or a combination thereof.

148. The method of claim 144, wherein the anticancer agent of step (b) is a second compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

149. The method of claim 144, wherein the anticancer agent of step (b) is the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof that was previously administered to the subject.

150. The method of claim 144, wherein the subject is administered additional doses of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof that was previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.

151. The method of claim 150, wherein the anticancer agent of step (d) is a second RET inhibitor, an immunotherapy, or a combination thereof.

152. The method of claim 150, wherein the anticancer agent of step (d) is a second compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

153. The crystalline form of claim 35, wherein the crystalline form is Form 2, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 15.1±0.2, 17.8±0.2, and 24.2±0.2.

154. The crystalline form of claim 10, wherein the crystalline form is Form 2, characterized by having an XRPD pattern comprising peaks at º2θ values of 15.1±0.2, 17.8±0.2, 20.4±0.2, 21.1±0.2, and 24.2±0.2.

155. The crystalline form of claim 10, wherein the crystalline form is Form 2, characterized by having an XRPD pattern comprising peaks at º2θ values of 15.1±0.2, 17.8±0.2, 18.1±0.2, 20.4±0.2, 21.1±0.2, 23.4±0.2, 24.2±0.2, and 24.6±0.2.

156. The crystalline form of claim 10, wherein the crystalline form is Form 2, characterized by having an XRPD pattern comprising peaks at º2θ values of 6.2±0.2, 15.1±0.2, 17.8±0.2, 18.1±0.2, 20.4±0.2, 21.1±0.2, 23.4±0.2, 24.2±0.2, 24.6±0.2, and 31.2±0.2.

157. The crystalline form of claim 10, wherein the crystalline form is Form 2, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 20A.

158. The crystalline form of any one of claims 153-157, wherein the crystalline form is Form 2 and has a differential scanning calorimetry (DSC) curve comprising an endotherm observed at around 197.5ºC.

159. The crystalline form of any one of claims 153-157, wherein the crystalline form is Form 2 and has a DSC curve comprising a melting transition observed at around 207.5ºC.

160. The crystalline form of any one of claims 153-157, wherein the crystalline form is Form 2 and has a DSC thermogram substantially as shown in Figure 20B.

161. The crystalline form of claim 10, wherein the crystalline form is Form 7, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 16.6±0.2, 18.0±0.2, and 19.9±0.2.

162. The crystalline form of claim 10, wherein the crystalline form is Form 7, characterized by having an XRPD pattern comprising peaks at º2θ values of 16.6±0.2, 18.0±0.2, 19.3±0.2, 19.9±0.2, and 23.3±0.2.

163. The crystalline form of claim 10, wherein the crystalline form is Form 7, characterized by having an XRPD pattern comprising peaks at º2θ values of 16.6±0.2, 17.3±0.2, 18.0±0.2, 19.0±0.2, 19.3±0.2, 19.9±0.2, 23.3±0.2, and 25.1±0.2.

164. The crystalline form of claim 10, wherein the crystalline form is Form 7, characterized by having an XRPD pattern comprising peaks at º2θ values of 15.8±0.2, 16.6±0.2, 17.3±0.2, 18.0±0.2, 19.0±0.2, 19.3±0.2, 19.91±0.2, 21.4±0.2, 23.3±0.2, and 25.1±0.2.

165. The crystalline form of claim 10, wherein the crystalline form is Form 7, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 21A.

166. The crystalline form of any one of claims 161-165, wherein the crystalline form is Form 7 and has a differential scanning calorimetry (DSC) curve comprising an endotherm observed at around 150ºC and an endotherm observed at around 201ºC.

167. The crystalline form of any one of claims 161-165, wherein the crystalline form is Form 7 and has a DSC curve comprising a melting transition observed at around 207ºC.

168. The crystalline form of any one of claims 161-165, wherein the crystalline form is Form 7 and has a DSC thermogram substantially as shown in Figure 21B.

169. The crystalline form of claim 10, wherein the crystalline form is an isopropyl alcohol solvate Form 8, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 15.1±0.2, 17.8±0.2, and 24.2±0.2.

170. The crystalline form of claim 10, wherein the crystalline form is an isopropyl alcohol solvate Form 8, characterized by having an XRPD pattern comprising peaks at º2θ values of 15.1±0.2, 17.8±0.2, 20.4±0.2, 21.1±0.2, and 24.2±0.2.

171. The crystalline form of claim 10, wherein the crystalline form is an isopropyl alcohol solvate Form 8, characterized by having an XRPD pattern comprising peaks at º2θ values of 15.1±0.2, 17.8±0.2, 18.1±0.2, 20.4±0.2, 21.1±0.2, 23.4±0.2, 24.2±0.2, and 24.6±0.2.

172. The crystalline form of claim 10, wherein the crystalline form is an isopropyl alcohol solvate Form 8, characterized by having an XRPD pattern comprising peaks at º2θ values of 6.2±0.2, 15.1±0.2, 17.8±0.2, 18.1±0.2, 20.4±0.2, 21.1±0.2, 23.4±0.2, 24.2±0.2, 24.6±0.2, and 31.2±0.2.

173. The crystalline form of claim 10, wherein the crystalline form is an isopropyl alcohol solvate Form 8, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 22A.

174. The crystalline form of any one of claims 169-173, wherein the crystalline form is an isopropyl alcohol solvate Form 8 and has a differential scanning calorimetry (DSC) curve comprising an endotherm observed at around 172ºC and an endotherm observed at around 196ºC.

175. The crystalline form of any one of claims 169-173, wherein the crystalline form is an isopropyl alcohol solvate Form 8 and has a DSC curve comprising a melting transition observed at around 206ºC.

176. The crystalline form of any one of claims 169-173, wherein the crystalline form is an isopropyl alcohol solvate Form 8 and has a DSC thermogram substantially as shown in Figure 22

177. The crystalline form of claim 27, wherein the crystalline form is Form B, characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at º2θ values of 7.5±0.2, 13.7±0.2, and 16.9±0.2.

178. The crystalline form of claim 27, wherein the crystalline form is Form B, characterized by having an XRPD pattern comprising peaks at º2θ values of 7.5±0.2, 9.7±0.2, 13.7±0.2, 16.9±0.2, and 19.9±0.2.

179. The crystalline form of claim 27, wherein the crystalline form is Form B, characterized by having an XRPD pattern comprising peaks at º2θ values of 7.5±0.2, 9.7±0.2, 13.7±0.2, 14.5±0.2, 16.9±0.2, 19.4±0.2, 19.9±0.2, and 21.3±0.2.

180. The crystalline form of claim 27, wherein the crystalline form is Form B, characterized by having an XRPD pattern comprising peaks at º2θ values of 7.5±0.2, 9.7±0.2, 9.9±0.2, 13.7±0.2, 14.5±0.2, 16.9±0.2, 19.4±0.2, 19.9±0.2, 21.3±0.2, and 27.4±0.2.

181. The crystalline form of claim 27, wherein the crystalline form is Form B, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 65A.

182. The crystalline form of any one of claims 177-181, wherein the crystalline form is Form B and has a differential scanning calorimetry (DSC) curve comprising an endotherm observed at around 172ºC and an endotherm observed at around 196ºC.

183. The crystalline form of any one of claims 177-181, wherein the crystalline form is Form B and has a DSC curve comprising a melting transition observed at around 206ºC.

184. The crystalline form of any one of claims 177-181, wherein the crystalline form is Form B and has a DSC thermogram substantially as shown in Figure 65B.

185. A method of treating a RET-associated cancer in a subject, the method comprising:

(a) administering one or more doses of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, as a monotherapy to a subject identified or diagnosed as having a RET-associated cancer;

(b) after step (a), determining a level of circulating tumor DNA in a biological sample obtained from the subject;

(c) administering a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, and an additional therapeutic agent or treatment to a subject identified as having about the same or an elevated level of circulating tumor DNA as compared to a reference level of circulating tumor DNA.

186. The method of claim 185, wherein the additional therapeutic agent is a second RET kinase inhibitor.

187. The method of claim 186, wherein the additional therapeutic agent or treatment comprises one or more of: radiation therapy, a chemotherapeutic agent, a checkpoint inhibitor, surgery, and one or more second kinase inhibitors.

188. The method of claim 186, wherein the reference level of circulating tumor DNA is a level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a).

189. A method of treating a RET-associated cancer in a subject, the method comprising:

administering a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, and an additional therapeutic agent or treatment to a subject (i) identified or diagnosed as having a RET-associated cancer, (ii) previously administered one or more doses of the compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, as a monotherapy, and (ii) after administration of the one or more doses of the compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, as a monotherapy, identified as having about the same or an elevated level of circulating tumor DNA as compared to a reference level of circulating tumor DNA.

190. The method of claim 189, wherein the reference level of circulating tumor DNA is a level of circulating tumor DNA in a biological sample obtained from the subject prior to administration of the one or more doses of the compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, as a monotherapy.

191. The method of claim 190, wherein the additional therapeutic agent is a second RET kinase inhibitor.

192. The method of claim 190, wherein the additional therapeutic agent or treatment comprises one or more of radiation therapy, a chemotherapeutic agent, a checkpoint inhibitor, surgery, and one or more second kinase inhibitors.

193. A method of selecting a treatment for a subject, the method comprising:

selecting a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, for a subject (i) identified or diagnosed as having a RET-associated cancer, (ii) previously administered one or more doses of a second RET kinase inhibitor, and (ii) after administration of the one or more doses of the second RET kinase inhibitor, identified as having about the same or an elevated level of circulating tumor DNA as compared to a reference level of circulating tumor DNA.

194. The method of claim 193, wherein the reference level of circulating tumor DNA is a level of circulating tumor DNA in a biological sample obtained from the subject prior to administration of the one or more doses of the second RET kinase inhibitor.

195. A method of selecting a treatment for a subject, the method comprising:

selecting a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, and an additional therapeutic treatment for a subject (i) identified or diagnosed as having a RET-associated cancer, (ii) previously administered one or more doses of the compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, as a monotherapy, and (ii) after administration of the one or more doses of the compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, identified as having about the same or an elevated level of circulating tumor DNA as compared to a reference level of circulating tumor DNA.

196. The method of claim 195, wherein the reference level of circulating tumor DNA is a level of circulating tumor DNA in a biological sample obtained from the subject prior to administration of the one or more doses of the compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof, as a monotherapy.

197. The method of claim 195, wherein the additional therapeutic treatment is a second RET kinase inhibitor.

198. The method of claim 197, wherein the additional therapeutic treatment comprises one or more of radiation therapy, a chemotherapeutic agent, a checkpoint inhibitor, and one or more second kinase inhibitors.

199. A method of determining efficacy of a treatment in a subject, the method comprising:

(a) determining a first level of circulating tumor DNA in a biological sample obtained from a subject identified or diagnosed as having a RET-associated cancer at a first time point;

(b) administering a treatment comprising one or more doses of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof to the subject, after the first time point and before a second time point;

(c) determining a second level of circulating tumor DNA in a biological sample obtained from the subject at the second time point; and

(d) identifying that the treatment is effective in a subject determined to have a decreased second level of circulating tumor DNA as compared to the first level of circulating tumor DNA; or

identifying the treatment is not effective in a subject determined to have about the same or an elevated second level of circulating tumor DNA as compared to the first level of circulating tumor DNA.

200. The method of claim 199, wherein the first time point and the second time point are about 1 week to about 1 year apart.

201. A method of determining whether a subject has developed resistance to a treatment, the method comprising:

(a) determining a first level of circulating tumor DNA in a biological sample obtained from a subject identified or diagnosed as having a RET-associated cancer at a first time point;

(b) administering a treatment comprising one or more doses of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous, or polymorph form thereof to the subject, after the first time point and before a second time point;

(c) determining a second level of circulating tumor DNA in a biological sample obtained from the subject at the second time point; and

(d) determining that a subject having a decreased second level of circulating tumor DNA as compared to the first level of circulating tumor DNA has not developed resistance to the treatment; or

determining that a subject having about the same or an elevated second level of circulating tumor DNA as compared to the first level of circulating tumor DNA has developed resistance to the treatment.

202. The method of claim 201, wherein the first time point and the second time point are about 1 week to about 1 year apart.