Formulations containing heterocyclic protein kinase inhibitors

Abstract

Polyglycolized glycerides and the following structure (I): [C92] and a pharmaceutically acceptable salt thereof. Also provided are crystalline forms of the compound of structure (I), or a pharmaceutically acceptable salt thereof. Methods for making them and for using them in the treatment of cancer, autoimmune, inflammatory, and other Pim kinase-related diseases, disorders, or conditions are also disclosed. The present disclosure provides a crystalline form of the hydrochloride salt of the compound of structure (I).

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 962,833, filed January 17, 2020, U.S. Provisional Patent Application No. 62 / 925,153, filed October 23, 2019, and U.S. Provisional Patent Application No. 62 / 804,556, filed February 12, 2019, the entire teachings of which are incorporated herein by reference.

[0002] Field The present disclosure relates to compositions comprising compounds and their uses for the treatment of Pim kinase-mediated diseases or disorders. [Background technology]

[0003] background Proviral insertion in mouse (Pim) kinases (e.g., Pim-1 kinase, Pim-2 kinase, Pim-3 kinase) are a family of oncogenic serine / threonine kinases. Expression is found in prostate and oral epithelial cells. Pim-1 kinase is believed to be involved in the initiation or progression of malignant transformation leading to malignancies including Burkitt's lymphoma, prostate cancer, oral cancer and diffuse large cell lymphoma, among others. Pim kinases also play a role in immune regulation. For example, enhanced Pim kinase expression has been observed in various inflammatory conditions. Pim-2 kinase is also involved in cytokine-induced T cell proliferation and survival. Summary of the Invention [Means for solving the problem]

[0004] overview Various non-limiting aspects and embodiments of the present invention are described below.

[0005] There remains a need for new treatments and therapies for proviral insertions in mouse (Pim) kinase-associated disorders or diseases. The present disclosure provides crystalline forms and pharmaceutical compositions that meet this need. The present disclosure further provides a method of treating a disorder or disease, comprising administering to a subject in need of treating the disorder or disease a therapeutically effective amount of the crystalline forms and / or compositions of the present disclosure. Thus, certain embodiments of the present disclosure provide a method of treating a disorder or disease comprising administering to a subject in need of treating the disorder or disease a therapeutically effective amount of the crystalline forms and / or compositions of the present disclosure. Accordingly, certain embodiments of the present disclosure provide a method of treating a disorder or disease, comprising administering to a subject in need of treating the disorder or disease a therapeutically effective amount of the crystalline forms and / or compositions of the present disclosure. [ka] or a pharma- ceutically acceptable salt thereof. Certain embodiments provide a composition comprising crystalline Form I of the hydrochloride salt of the compound of structure (I) and a pharma- ceutically acceptable salt thereof. R and a carrier.

[0006] Certain embodiments provide a unit dosage form comprising a composition, the composition comprising polyglycolized glyceride in an amount of about 560 mg to about 600 mg and a compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 115 mg to about 125 mg, as determined using the molecular weight of the compound of structure (I) as a free base.

[0007] A particular embodiment provides a capsule comprising a composition, the composition comprising GELUCIRE® 44 / 14 in an amount of about 589 mg and the hydrochloride salt of a compound having the following structure (I) in an amount of about 130 mg, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt.

[0008] Certain embodiments provide a crystalline form of the hydrochloride salt of the compound of structure (I).

[0009] Certain embodiments provide crystalline forms and / or compositions that have utility across a broad range of therapeutic applications and can be used to treat diseases that are at least partially mediated by protein kinase activity, such as cancer, autoimmune diseases, and various inflammatory diseases or disorders.Accordingly, a further embodiment of the present disclosure provides a method for treating or preventing cancer (e.g., prostate cancer, colorectal cancer, or myelofibrosis), a protein kinase-mediated disease, a myeloproliferative neoplasm, or a fibrotic disease or disorder, comprising administering a therapeutically effective amount of the composition or unit dose disclosed herein to a subject in need thereof.

[0010] Some embodiments provide a method for treating moderate 2 or high risk primary or secondary myelofibrosis in a subject in need thereof, the method comprising administering a therapeutically effective amount of a crystalline form and / or composition described herein to the subject, wherein the subject has previously received ruxolitinib or a pharmaceutically acceptable salt thereof, or fedratinib or a pharmaceutically acceptable salt thereof; or is not suitable to receive ruxolitinib or a pharmaceutically acceptable salt thereof, or fedratinib or a pharmaceutically acceptable salt thereof.

[0011] Also provided are crystalline forms and / or compositions (e.g., pharmaceutical compositions) for use in treating a disorder or disease described herein, where the crystalline forms and / or compositions are as described herein. Also provided is the use of the crystalline forms and / or compositions described herein for the manufacture of a medicament for the treatment of a disorder or disease described herein.

[0012] One embodiment is a method for preparing a compound of structure (I) or a pharma- ceutically acceptable salt thereof, the method comprising: (i) a structure: [ka] or a salt thereof, [ka] with a compound having the following structure: [ka] and obtaining a compound having the formula: (ii) a structure: [ka] or a salt thereof, [ka] and reacting the compound having the formula:

[0013] One embodiment is a method for preparing a compound of structure (I) or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] with a compound having the formula:

[0014] One embodiment is a method for preparing a compound of structure (I) or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] with a compound having the formula:

[0015] One embodiment provides a method for purifying a compound of structure (I) or a pharma- ceutically acceptable salt thereof, the method comprising contacting a composition comprising the compound with a metal capture reagent.

[0016] One embodiment is a method for preparing a compound of structure (I) or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] With a compound having the formula:

[0017] One embodiment provides a process for preparing a crystalline form described herein comprising precipitating the crystalline form from a solution or suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. In an embodiment of the present invention, for example, the following items are provided: (Item 1) The following structure (I): [ka] A crystalline form of the hydrochloride salt of a compound having the formula: (Item 2) 2. The crystalline form according to item 1, including form I. (Item 3) 2. The crystalline form according to claim 1, consisting essentially of Form I. (Item 4) 4. The crystalline form according to any one of items 1 to 3, characterized by an X-ray powder diffraction pattern comprising peaks at 21.5±0.2°, 19.9±0.2° and 17.8±0.2° in terms of 2θ. (Item 5) 5. The crystalline form according to item 4, further characterized by an X-ray powder diffraction pattern comprising a peak at 19.3±0.2° 2θ. (Item 6) 6. The crystalline form according to item 4 or 5, further characterized by an X-ray powder diffraction pattern comprising a peak at 24.4±0.2° in terms of 2θ. (Item 7) 7. The crystalline form according to any one of items 4 to 6, further characterized by an X-ray powder diffraction pattern comprising a peak at 16.3±0.2° in terms of 2θ. (Item 8) 4. The crystalline form according to any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising at least three peaks at 2θ angles selected from the group consisting of 24.4±0.2°, 21.5±0.2°, 19.9±0.2°, 19.3±0.2°, 17.8±0.2° and 16.3±0.2°. (Item 9) 9. The crystalline form of any one of items 4 to 8, further characterized by an X-ray powder diffraction pattern substantially lacking a peak at 15.7±0.2° in terms of 2θ. (Item 10) 10. The crystalline form of any one of items 4 to 9, further characterized by an X-ray powder diffraction pattern substantially lacking a peak at 17.0±0.2° in terms of 2θ. (Item 11) 11. The crystalline form according to any one of items 4 to 10, further characterized by an X-ray powder diffraction pattern lacking a peak at 19.0±0.2° in terms of 2θ. (Item 12) 12. The crystalline form of any one of claims 1 to 11, having an X-ray powder diffraction pattern substantially in accordance with the X-ray powder diffraction pattern shown in Figure 1. (Item 13) 13. The crystalline form of any one of items 1 to 12, having a differential scanning calorimetry thermogram comprising an endothermic event at 226.9±3° C. (Item 14) 14. The crystalline form of any one of items 1 to 13, having a differential scanning calorimetry thermogram substantially in accordance with the differential scanning calorimetry thermogram shown in FIG. (Item 15) 15. The crystalline form of any one of claims 1 to 14, having a thermogravimetric diagram substantially in accordance with the thermogravimetric diagram shown in Figure 3. (Item 16) 16. The crystalline form according to any one of items 1 to 15, having a melting temperature of 226±3° C. (Item 17) 17. The crystalline form according to any one of items 1 to 16, wherein the crystalline form is substantially pure. (Item 18) The crystalline form according to any one of items 1 to 17 and a pharma- ceutically acceptable R A composition comprising: (Item 19) Polyglycolized glycerides; The following structure (I): [ka] or a pharma- ceutically acceptable salt thereof. (Item 20) 20. The composition according to item 19, wherein the polyglycolized glyceride has a melting point in the range of about 30° C. to about 50° C. (Item 21) 21. The composition according to item 20, wherein the polyglycolized glyceride has a melting point in the range of about 37° C. to about 48° C. (Item 22) 23. The composition according to claim 21, wherein the polyglycolized glyceride has a melting point of about 44° C. 23. The composition according to any one of items 19 to 22, wherein the polyglycolized glyceride has a hydrophilic / lipophilic balance (HLB) value ranging from about 8 to about 18. (Item 24) 24. The composition according to item 23, wherein the polyglycolized glyceride has a hydrophilic / lipophilic balance value in the range of about 10 to about 16. (Item 25) 25. The composition of claim 24, wherein the polyglycolized glyceride has a hydrophilic / lipophilic balance value of about 14. (Item 26) 26. The composition according to any one of items 19 to 25, wherein the composition further comprises a compounding agent, the compounding agent comprising polysorbate 20, polysorbate 60, polysorbate 80, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate, glyceryl dibehenate, propylene glycol dilaurate, propylene glycol monocaprylate, propylene glycol monolaurate, or a combination thereof. (Item 27) 27. The composition of claim 26, wherein the compounding agent is polysorbate 20. (Item 28) 27. The composition according to claim 26, wherein the compounding agent is glyceryl monocaprylate. (Item 29) 29. The composition according to any one of items 26 to 28, wherein the polyglycolized glyceride and the compounding agent are present in a weight ratio ranging from 2:1 to 1:1. (Item 30) 26. The composition according to any one of items 19 to 25, wherein the composition consists essentially of the compound and the polyglycolized glyceride. (Item 31) 31. The composition according to any one of items 19 to 30, wherein the composition is a suspension. (Item 32) 32. The composition according to any one of items 19 to 31, wherein the polyglycolized glyceride is GELUCIRE® 44 / 14. (Item 33) 33. The composition according to any one of items 19 to 32, comprising the hydrochloride salt of the compound of structure (I). (Item 34) 34. The composition according to any one of items 19 to 33, comprising Form I of the hydrochloride salt of the compound of structure (I). (Item 35) 35. The composition of any one of items 19-34, wherein the composition comprises about 100 mg to about 300 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. (Item 36) 36. The composition of claim 35, wherein the composition comprises about 100 mg to about 150 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as a free base. (Item 37) 37. The composition of claim 36, wherein the composition comprises about 115 mg to about 125 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as a free base. (Item 38) 38. The composition according to item 37, wherein the composition comprises about 120 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as a free base. (Item 39) 35. The composition of any one of items 19-34, wherein the composition comprises about 160 mg to about 200 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. (Item 40) 40. The composition of claim 39, wherein the composition comprises about 175 mg to about 185 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as a free base. (Item 41) 41. The composition according to item 40, wherein the composition comprises about 180 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as a free base. (Item 42) 35. The composition of any one of items 19-34, wherein the composition comprises about 220 mg to about 260 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. (Item 43) 43. The composition of claim 42, wherein the composition comprises about 230 mg to about 250 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as a free base. (Item 44) 44. The composition according to item 43, wherein the composition comprises about 240 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as a free base. (Item 45) 35. The composition of any one of items 19-34, wherein the composition comprises about 100 mg to about 160 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 46) 46. ​​The composition of claim 45, wherein the composition comprises about 120 mg to about 140 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 47) 47. The composition according to item 46, wherein the composition comprises about 130.44 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 48) 48. The composition of any one of items 19-47, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 10 weight percent (wt%) to about 40 wt%, as determined using the molecular weight of the compound of structure (I) as a hydrochloride salt. (Item 49) Item 49. The composition of item 48, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 14 wt% to about 22 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 50) 50. The composition of claim 49, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 18 wt% to about 19 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 51) 51. The composition of claim 50, wherein said composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 18.12 wt% as determined using the molecular weight of said compound of structure (I) as the hydrochloride salt. (Item 52) 51. The composition of claim 50, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 18.38 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 53) 49. The composition of any one of items 19-48, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 15 wt% to about 35 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 54) 54. The composition of claim 53, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 20 wt% to about 30 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 55) 55. The composition of claim 54, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 25 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 56) 48. The composition of any one of items 19-47, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 23.3 wt% to about 43.3 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 57) 57. The composition of claim 56, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 28.3 wt.% to about 38.3 wt.% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 58) 58. The composition of claim 57, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 33.3 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 59) 59. The composition according to any of items 19 to 58, wherein the composition comprises the polyglycolized glyceride in an amount ranging from about 500 mg to about 700 mg. (Item 60) 60. The composition according to item 59, wherein the composition comprises the polyglycolized glyceride in an amount ranging from about 550 mg to about 650 mg. (Item 61) 61. The composition according to item 60, wherein the composition comprises the polyglycolized glyceride in an amount ranging from about 560 mg to about 600 mg. (Item 62) Item 62. The composition according to item 61, wherein the composition comprises the polyglycolized glyceride in an amount ranging from about 585 mg to about 590 mg. (Item 63) 63. The composition of claim 62, wherein the composition comprises the polyglycolized glyceride in an amount of about 587.7 mg. (Item 64) 63. The composition of claim 62, wherein the composition comprises the polyglycolized glyceride in an amount of about 589.56 mg. (Item 65) 65. The composition according to any one of items 19 to 64, wherein the composition comprises the polyglycolized glyceride in a concentration ranging from about 50 wt% to about 90 wt%. (Item 66) Item 66. The composition according to item 65, wherein the composition comprises the polyglycolized glyceride in a concentration ranging from about 75 wt% to about 90 wt%. (Item 67) Item 67. The composition according to item 66, wherein the composition comprises the polyglycolized glyceride in a concentration ranging from about 78 wt% to about 84 wt%. (Item 68) Item 68. The composition according to item 67, wherein the composition comprises the polyglycolized glyceride in a concentration of about 81 wt% to about 82 wt%. (Item 69) 70. The composition of claim 68, wherein the composition comprises the polyglycolized glyceride at a concentration of about 81.62 wt%. (Item 70) 70. The composition of claim 68, wherein the composition comprises the polyglycolized glyceride at a concentration of about 81.88 wt%. (Item 71) 67. The composition according to any one of items 19 to 66, wherein the composition comprises the polyglycolized glyceride in a concentration ranging from about 65 wt% to about 85 wt%. (Item 72) 72. The composition according to claim 71, wherein the composition comprises the polyglycolized glyceride in a concentration ranging from about 70 wt% to about 80 wt%. (Item 73) 73. The composition of claim 72, wherein the composition comprises the polyglycolized glyceride at a concentration of about 75 wt%. (Item 74) 66. The composition according to any one of items 19 to 65, wherein the composition comprises the polyglycolized glyceride in a concentration ranging from about 56.7 wt% to about 76.7 wt%. (Item 75) 75. The composition of claim 74, wherein the composition comprises the polyglycolized glyceride in a concentration ranging from about 61.7 wt% to about 71.7 wt%. (Item 76) 76. The composition of claim 75, wherein the composition comprises the polyglycolized glyceride at a concentration of about 66.7 wt%. (Item 77) 77. The composition according to any one of items 19 to 76, wherein the composition is in the form of a capsule for oral administration. (Item 78) 78. The composition of any one of items 19-77, wherein said composition comprises said compound of structure (I) or a pharma- ceutically acceptable salt thereof and said polyglycolized glyceride in a weight ratio ranging from about 1:1 to about 1:10 as determined using the molecular weight of said compound of structure (I) as a free base. (Item 79) 79. The composition of claim 78, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio ranging from about 1:4 to about 1:6 as determined using the molecular weight of the compound of structure (I) as a free base. (Item 80) 80. The composition of claim 79, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio of about 1:5 as determined using the molecular weight of the compound of structure (I) as a free base. (Item 81) 80. The composition of claim 79, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio of about 1:4.9 as determined using the molecular weight of the compound of structure (I) as a free base. (Item 82) 78. The composition of any one of items 19-77, wherein said composition comprises said compound of structure (I) or a pharma- ceutically acceptable salt thereof and said polyglycolized glyceride in a weight ratio ranging from about 1:4 to about 1:6 as determined using the molecular weight of said compound of structure (I) as its hydrochloride salt. (Item 83) 83. The composition of claim 82, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio of about 1:4.5 as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. (Item 84) 79. The composition of any one of items 19-78, wherein said composition comprises said compound of structure (I) or a pharma- ceutically acceptable salt thereof and said polyglycolized glyceride in a weight ratio ranging from about 1:1.6 to about 1:3.6 as determined using the molecular weight of said compound of structure (I) as a free base. (Item 85) 85. The composition of claim 84, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio ranging from about 1:2.1 to about 1:3.1 as determined using the molecular weight of the compound of structure (I) as a free base. (Item 86) 86. The composition of claim 85, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio of about 1:2.6 as determined using the molecular weight of the compound of structure (I) as a free base. (Item 87) 79. The composition of any one of items 19-78, wherein said composition comprises said compound of structure (I) or a pharma- ceutically acceptable salt thereof and said polyglycolized glyceride in a weight ratio ranging from about 1:1 to about 1:2.5 as determined using the molecular weight of said compound of structure (I) as a free base. (Item 88) 88. The composition of claim 87, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio ranging from about 1:1.25 to about 1:2 as determined using the molecular weight of the compound of structure (I) as a free base. (Item 89) 89. The composition of claim 88, wherein the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof and the polyglycolized glyceride in a weight ratio of about 1:1.76 as determined using the molecular weight of the compound of structure (I) as a free base. (Item 90) 90. A unit dosage form comprising a therapeutically effective amount of the composition according to any one of items 19 to 89. (Item 91) A unit dose form comprising a composition, said composition comprising: a polyglycolized glyceride in an amount of about 560 mg to about 600 mg; 2. An amount of about 115 mg to about 125 mg of the compound of structure (I) as follows, as determined using the molecular weight of the compound of structure (I) as the free base: [ka] or a pharma- ceutically acceptable salt thereof. (Item 92) 92. The unit dosage form according to item 90 or 91, comprising the hydrochloride salt of the compound of structure (I). (Item 93) 93. The unit dosage form of any one of items 90 to 92, comprising Form I of the hydrochloride salt of the compound of structure (I). (Item 94) 94. The unit dosage form according to any one of items 90 to 93, wherein the polyglycolized glyceride is GELUCIRE® 44 / 14. (Item 95) 95. The unit dosage form of item 94, wherein the GELUCIRE® 44 / 14 is present in an amount of about 589 mg. (Item 96) 96. The unit dosage form of any one of items 90-95, wherein the compound of structure (I) or a pharma- ceutically acceptable salt thereof is present in an amount of about 120 mg as determined using the molecular weight of the compound of structure (I) as a free base. (Item 97) A capsule containing a composition, said composition comprising GELUCIRE® 44 / 14 in an amount of about 589 mg; 1. An amount of about 130 mg of the compound of structure (I) below, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt: [ka] and a hydrochloride salt of a compound having the formula: (Item 98) 98. The capsule according to item 97, comprising Form I of the hydrochloride salt of the compound having structure (I). (Item 99) The following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, said method comprising: (i) a structure: [ka] or a salt thereof, [ka] with a compound having the following structure: [ka] and obtaining a compound having the formula: (ii) a structure: [ka] or a salt thereof, [ka] and reacting the compound having the formula: (Item 100) (i) in the presence of a base and a catalyst, is reacted with a compound having the following structure: [ka] or a salt thereof, [ka] 99. The method of claim 99, comprising reacting with a compound having the formula: (Item 101) 101. The method of claim 100, wherein the base is an inorganic base and the catalyst is a palladium catalyst. (Item 102) The following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, said method comprising: In the presence of a palladium catalyst, an alkoxide and a solvent, a compound having the following structure: [ka] or a salt thereof, [ka] with a compound having the formula: (Item 103) Item 103. The method of item 102, wherein the palladium catalyst is tris(dibenzylideneacetone)dipalladium, the alkoxide is tert-butoxide, and the solvent is toluene. (Item 104) The following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, said method comprising: In the presence of potassium fluoride, the following structure: [ka] or a salt thereof, [ka] with a compound having the formula: (Item 105) The following structure: [ka] or a pharma- ceutically acceptable salt thereof, said method comprising: contacting a composition comprising said compound or a pharma- ceutically acceptable salt thereof with a metal capture reagent. (Item 106) Item 106. The method of item 105, wherein the metal capture reagent is a thiol. (Item 107) 107. The method of claim 106, wherein the metal capture reagent is a thiol-functionalized silica. (Item 108) A method for treating cancer, comprising administering a therapeutically effective amount of the crystalline form according to any one of items 1 to 17, or the composition according to any one of items 18 to 89, or the unit dose according to any one of items 90 to 96, or the capsule according to item 97 or 98 to a subject in need thereof. (Item 109) 109. The method of claim 108, wherein the cancer is a Pim kinase-expressing cancer. (Item 110) 110. The method of claim 108 or 109, wherein the cancer is prostate cancer. (Item 111) 110. The method of claim 108 or 109, wherein the cancer is colorectal cancer. (Item 112) 110. The method of claim 108 or 109, wherein the cancer is a fibroid cancer. (Item 113) 110. The method of claim 108 or 109, wherein the cancer is myelofibrosis. (Item 114) 114. The method of claim 113, wherein the myelofibrosis is intermediate 2 or high risk primary or secondary myelofibrosis. (Item 115) 110. The method of claim 108 or 109, wherein the cancer is bladder cancer. (Item 116) 110. The method of claim 108 or 109, wherein the cancer is a hematological malignancy. (Item 117) 117. The method of item 116, wherein the hematological malignancy is acute myeloid leukemia. (Item 118) 118. The method according to any one of items 108 to 117, wherein the method further comprises administering a therapeutically effective amount of a second anti-cancer agent. (Item 119) 118. The method of any one of items 108 to 117, wherein the method further comprises administering a therapeutically effective amount of ruxolitinib. (Item 120) A method for treating or preventing a fibrotic disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form according to any one of items 1-17, or the composition according to any one of items 18-89, or the unit dose according to any one of items 90-96, or the capsule according to item 97 or 98. (Item 121) 121. The method of claim 120, wherein the fibrotic disease or disorder is pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, vascular fibrosis, renal fibrosis, skin fibrosis, gastrointestinal fibrosis, athrofibrosis, Dupuytren's contracture, mediastinal fibrosis, Peyronie's disease, retroperitoneal fibrosis, systemic sclerosis, or a combination thereof. (Item 122) A method for treating or preventing fibrosis formation or deposition, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form according to any one of items 1-17, or the composition according to any one of items 18-89, or the unit dose according to any one of items 90-96, or the capsule according to item 97 or 98. (Item 123) A method for inhibiting viral infection or viral replication, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form according to any one of items 1 to 17, or the composition according to any one of items 18 to 89, or the unit dose according to any one of items 90 to 96, or the capsule according to item 97 or 98. (Item 124) A method for treating or preventing a myeloproliferative neoplasm, comprising administering a therapeutically effective amount of the crystalline form according to any one of items 1 to 17, or the composition according to any one of items 18 to 89, or the unit dose according to any one of items 90 to 96, or the capsule according to item 97 or 98 to a subject in need thereof. (Item 125) 125. The method of item 124, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia, or a combination thereof. (Item 126) A method for treating or preventing an inflammatory disease or disorder, comprising administering a therapeutically effective amount of the crystalline form according to any one of items 1-17, or the composition according to any one of items 18-89, or the unit dose according to any one of items 90-96, or the capsule according to item 97 or 98 to a subject in need thereof. (Item 127) Item 127. The method of item 126, wherein the inflammatory disease or disorder is non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, skin inflammation, psoriasis, or a combination thereof. (Item 128) A method for treating or preventing an autoimmune or inflammatory disease or disorder, comprising administering a therapeutically effective amount of the crystalline form according to any one of items 1 to 17, or the composition according to any one of items 18 to 89, or the unit dose according to any one of items 90 to 96, or the capsule according to item 97 or 98 to a subject in need thereof. (Item 129) 129. The method of item 128, wherein the autoimmune or inflammatory disease or disorder is osteoarthritis, rheumatoid arthritis, pain, inflammatory bowel disease, a respiratory disorder, a skin disorder, or a combination thereof. (Item 130) 130. The method according to any one of items 108 to 129, wherein the subject is a human. (Item 131) 131. The method of any one of items 108 to 130, wherein the crystalline form, composition, unit dose or capsule is administered daily to the subject in need thereof. (Item 132) 132. The method of claim 131, wherein the crystalline form, composition, unit dose or capsule is administered once daily to the subject in need thereof. (Item 133) 133. The method of any one of items 108 to 132, wherein the crystalline form, composition, unit dose or capsule is administered in a 28 day treatment cycle. (Item 134) 134. The method of any one of items 108-133, wherein the compound of structure (I) or a pharma- ceutically acceptable salt thereof is administered to the subject at a daily dose of about 350 mg to about 1.5 g, as determined using the molecular weight of the compound as a free base. (Item 135) 135. The method of any one of items 108-134, wherein the subject in need thereof is administered a dose of about 360 mg of the compound of structure (I), or about 480 mg of the compound of structure (I), or about 720 mg of the compound of structure (I), or about 1080 mg of the compound of structure (I), or about 1440 mg of the compound of structure (I), as determined using the molecular weight of the compound as a free base. (Item 136) 136. The method of item 135, wherein the dose is a daily dose. (Item 137) 137. The method of any one of items 108 to 136, wherein the subject has previously received ruxolitinib or a pharma- ceutically acceptable salt thereof or fedratinib or a pharma- ceutically acceptable salt thereof. (Item 138) The method of item 137, wherein the subject is intolerant, resistant, refractory, or has lost response to the ruxolitinib or a pharmaceutically acceptable salt thereof, or fedratinib or a pharmaceutically acceptable salt thereof. (Item 139) The method according to any one of items 108 to 138, wherein the subject is not suitable to receive ruxolitinib or a pharma- ceutically acceptable salt thereof or fedratinib or a pharma- ceutically acceptable salt thereof. (Item 140) A method for treating moderate 2 or high risk primary or secondary myelofibrosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form according to any one of items 1 to 17, or a composition according to any one of items 18 to 89, or a unit dose according to any one of items 90 to 96, or a capsule according to item 97 or 98, The subject has previously received ruxolitinib, or a pharma- ceutically acceptable salt thereof, or fedratinib, or a pharma- ceutically acceptable salt thereof; or The method is not suitable for receiving ruxolitinib or a pharma- ceutically acceptable salt thereof, or fedratinib or a pharma- ceutically acceptable salt thereof. (Item 141) Item 140. The method of item 140, wherein the compound of structure (I) or a pharma- ceutically acceptable salt thereof is administered to the subject at a daily dose of about 350 mg to about 1.5 g as determined using the molecular weight of the compound of structure (I) as a free base. (Item 142) 142. The method of item 140 or 141, further comprising administering to the subject in need thereof a therapeutically effective amount of ruxolitinib or a pharma- ceutically acceptable salt thereof. (Item 143) The following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, said method comprising: The following structure: [ka] or a salt thereof, [ka] with a compound having the formula: (Item 144) In the presence of a palladium catalyst and a first base, a compound having the following structure: [ka] or a salt thereof, having the following structure: [ka] The method of claim 143, comprising reacting with a compound having the formula: (Item 145) The palladium catalyst is Pd(PPh 3 ) 2 Cl 2 Item 145. The method according to Item 144, wherein (Item 146) The first base is NaHCO 3 146. The method according to item 144 or 145, wherein (Item 147) The method comprises providing a composition having the following structure: [ka] or a salt thereof, having the following structure: [ka] 147. The method of any one of items 143 to 146, further comprising reacting with a compound having the formula: (Item 148) In the presence of a second base and a catalyst, a compound having the following structure: [ka] or a salt thereof, having the following structure: [ka] 148. The method of claim 147, comprising reacting with a compound having the formula: (Item 149) Item 149. The method of item 148, wherein the second base is an amine base. (Item 150) Item 149. The method of item 149, wherein the second base is diisopropylethylamine. (Item 151) 151. The method according to any one of items 148 to 150, wherein the catalyst is cesium fluoride. (Item 152) 18. A process for preparing the crystalline form according to any one of claims 1 to 17, comprising precipitating said crystalline form from a solution or suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. (Item 153) Item 153. The process according to item 152, wherein the non-aqueous medium comprises methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), 1-butanol, acetonitrile (ACN), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), dichloromethane (DCM), 1,4-dioxane, toluene, heptane, tetrahydrofuran (THF) or acetone, or a combination thereof. (Item 154) Item 155. The process according to item 153, wherein the non-aqueous medium is a mixture of MeOH and EtOAc. 155. The process according to any one of claims 152 to 154, comprising precipitating said crystalline form from a solution comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. (Item 156) Item 156. The process of item 155, wherein the solution comprises the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol, methanol and ethyl acetate. (Item 157) 155. The process according to any one of claims 152 to 154, comprising precipitating said crystalline form from a suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. (Item 158) 158. The process of any one of items 152 to 157, further comprising cooling the solution or suspension to about 4°C. (Item 159) 159. The process of any one of items 152 to 158, further comprising contacting the solution or suspension with seed crystals of the crystalline form. (Item 160) 159. The process of any one of claims 152 to 159, further comprising contacting a solution or suspension comprising the free base of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium with hydrochloric acid to produce the solution or suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. (Item 161) 161. A crystalline form of the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol prepared by the process according to any one of items 152 to 160. (Item 162) A combination comprising a crystalline form according to any one of items 1 to 17 and 161 and a further therapeutic agent. (Item 163) Item 109. The method of item 108, wherein the cancer is a solid tumor. (Item 164) 164. The method of claim 163, wherein the solid tumor is lung cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, gastric cancer, small intestine cancer, colorectal cancer, pancreatic cancer, esophageal cancer, kidney cancer, ureter cancer, bladder cancer, urethral cancer, breast cancer, prostate cancer, penile cancer, hepatocellular carcinoma, endocrine system cancer or central nervous system neoplasm. (Item 165) 164. The method of item 163, wherein the solid cancer is non-small cell lung cancer, oat cell carcinoma, dermatofibrosarcoma protuberans, cutaneous melanoma, neoplastic skin disease, intraocular melanoma, uterine sarcoma, endometrial carcinoma, vaginal carcinoma, cervical carcinoma, vulvar carcinoma, fallopian tube carcinoma, colon carcinoma, anal region carcinoma, Barrett's esophagus, renal cell carcinoma, renal pelvis carcinoma, benign prostatic hyperplasia, parathyroid carcinoma, adrenal carcinoma, thyroid carcinoma, pituitary adenoma, primary central nervous system lymphoma, brain stem glioma, spinal axis tumor or medulloblastoma. (Item 166) 164. The method of claim 163, wherein the solid tumor is a soft tissue sarcoma or bone cancer. (Item 167) 109. The method according to item 108, wherein the cancer is lung cancer, non-small cell lung cancer, oat cell carcinoma, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, head or neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal region cancer, gastric cancer, colon cancer, breast cancer, gynecologic tumor Hodgkin's disease, hepatocellular carcinoma, esophageal cancer, small intestine cancer, endocrine system cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, childhood solid tumor, hypereosinophilia, lymphocytic lymphoma, bladder cancer, kidney cancer, ureter cancer, childhood malignant tumor or neoplasm of the central nervous system. (Item 168) 109. The method of item 108, wherein the cancer is uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, thyroid cancer, pancreatic cancer, parathyroid cancer, adrenal cancer, renal cell carcinoma, renal pelvis carcinoma, primary central nervous system lymphoma, spinal axis tumor, medulloblastoma, brain stem glioma, or pituitary adenoma. [Brief description of the drawings]

[0018] [Figure 1]FIG. 1 is a graphical representation of the X-ray force diffraction pattern of crystalline Form I.

[0019] [Diagram 2] FIG. 2 is a graphical representation of the DSC thermogram of crystalline Form I.

[0020] [Diagram 3] FIG. 3 is a graphical representation of the TGA thermogram of crystalline Form I.

[0021] [Figure 4] FIG. 4 is a graphical representation of a polarized microscope image of crystalline Form I.

[0022] [Diagram 5] FIG. 5 is a graphical representation of the X-ray powder diffraction pattern of crystalline Form II.

[0023] [Figure 6] FIG. 6 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0024] [Figure 7] FIG. 7 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0025] [Figure 8] FIG. 8 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0026] [Figure 9] FIG. 9 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0027] [Figure 10] FIG. 10 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0028] [Figure 11] FIG. 11 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0029] [Figure 12] FIG. 12 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0030] [Figure 13] FIG. 13 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0031] [Figure 14] FIG. 14 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0032] [Figure 15] FIG. 15 is a graphical representation of the X-ray powder diffraction patterns of the solids obtained in the slurry experiment described in Example 10.

[0033] [Figure 16] FIG. 16 is a graphical representation of the solids obtained in the solvent-thermal heating / cooling experiment described in Example 11.

[0034] [Figure 17] FIG. 17 is a graphical representation of the solids obtained in the slow evaporation experiment described in Example 12.

[0035] [Figure 18] FIG. 18 is a graphical representation of the solids obtained in the slow evaporation experiment described in Example 12.

[0036] [Figure 19A]FIG. 19A is a graphical representation of the X-ray force diffraction pattern of the crystalline form of the maleate salt of the compound of structure (I) obtained in Example 14.

[0037] [Figure 19B] FIG. 19B is a graphical representation of the DSC thermogram of the crystalline form of the maleate salt of the compound of structure (I) obtained in Example 14.

[0038] [Figure 19C] FIG. 19C is a graphical representation of the TGA thermogram of the crystalline form of the maleate salt of the compound of structure (I) obtained in Example 14.

[0039] [Figure 20A] FIG. 20A is a graphical representation of the X-ray force diffraction pattern of the crystalline form of the methanesulfonate salt of the compound of structure (I) obtained in Example 14.

[0040] [Figure 20B] FIG. 20B is a graphical representation of the DSC thermogram of the crystalline form of the methanesulfonate salt of the compound of structure (I) obtained in Example 14.

[0041] [Figure 20C] FIG. 20C is a graphical representation of the TGA thermogram of the crystalline form of the methanesulfonate salt of the compound of structure (I) obtained in Example 14. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Detailed Description Various (enumerated) embodiments of the present disclosure are described herein, it being recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0043] Embodiment 1 A method for producing a composition comprising: The following structure (I): [ka] or a pharma- ceutically acceptable salt thereof.

[0044] Embodiment 2. The composition of embodiment 1, wherein the polyglycolized glyceride has a melting point in the range of about 30°C to about 50°C.

[0045] Embodiment 3. The composition of any of the previous embodiments, wherein the polyglycolized glyceride has a melting point in the range of about 37° C. to about 48° C.

[0046] Embodiment 4. The composition of any of the previous embodiments, wherein the polyglycolized glyceride has a melting point of about 44° C.

[0047] Embodiment 5. The composition of any of the preceding embodiments, wherein the polyglycolized glyceride has a hydrophilic / lipophilic balance (HLB) value ranging from about 8 to about 18.

[0048] Embodiment 6. The composition of any of the previous embodiments, wherein the polyglycolized glyceride has a hydrophilic / lipophilic balance value ranging from about 10 to about 16.

[0049] Embodiment 7. The composition of any of the previous embodiments, wherein the polyglycolized glyceride has a hydrophilic / lipophilic balance value of about 14.

[0050] Embodiment 8. The composition of any of the preceding embodiments, wherein the composition further comprises a compounding agent, the compounding agent comprising polysorbate 20, polysorbate 60, polysorbate 80, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate, glyceryl dibehenate, propylene glycol dilaurate, propylene glycol monocaprylate, propylene glycol monolaurate, or combinations thereof.

[0051] Embodiment 9. The composition of embodiment 8, wherein the compounding agent is polysorbate 20.

[0052] Embodiment 10. The composition of embodiment 8, wherein the compounding agent is glyceryl monocaprylate.

[0053] Embodiment 11. The composition of any of embodiments 8-10, wherein the polyglycolized glyceride and the compounding agent are present in a weight ratio ranging from 2:1 to 1:1.

[0054] Embodiment 12. The composition of any of embodiments 1-7, wherein the composition consists essentially of the compound and the polyglycolized glyceride.

[0055] Embodiment 13. The composition of any of the preceding embodiments, wherein the composition is a suspension.

[0056] Embodiment 14. The composition of any of the preceding embodiments, wherein the polyglycolized glyceride is GELUCIRE® 44 / 14.

[0057] Embodiment 15. The composition of any of the previous embodiments, wherein the compound of structure (I) is the hydrochloride salt.

[0058] Embodiment 16. The composition of any one of the preceding embodiments, wherein the composition comprises from about 100 mg to about 300 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0059] Embodiment 17. The composition of any one of the preceding embodiments, wherein the composition comprises from about 100 mg to about 150 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0060] Embodiment 18. The composition of any one of the preceding embodiments, wherein the composition comprises from about 115 mg to about 125 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0061] Embodiment 19. The composition of any one of the preceding embodiments, wherein the composition comprises about 120 mg of the compound of structure (I), as determined using the molecular weight of the compound as a free base.

[0062] Embodiment 20. The composition of any one of embodiments 1-16, wherein the composition comprises from about 160 mg to about 200 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0063] Embodiment 21 The composition of embodiment 20, wherein the composition comprises from about 175 mg to about 185 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0064] Embodiment 22. The composition of embodiment 21, wherein the composition comprises about 180 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0065] Embodiment 23. The composition of any one of embodiments 1-16, wherein the composition comprises from about 220 mg to about 260 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0066] Embodiment 24 The composition of embodiment 23, wherein the composition comprises from about 230 mg to about 250 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0067] Embodiment 25. The composition of embodiment 24, wherein the composition comprises about 240 mg of the compound of structure (I), as determined using the molecular weight of the compound as the free base.

[0068] Embodiment 26 The composition of embodiment 15, wherein the composition comprises from about 100 mg to about 160 mg of the compound of structure (I), as determined using the molecular weight of the compound as the hydrochloride salt.

[0069] Embodiment 27 The composition of embodiment 15, wherein the composition comprises from about 120 mg to about 140 mg of the compound of structure (I), as determined using the molecular weight of the compound as the hydrochloride salt.

[0070] Embodiment 28. The composition of embodiment 15, wherein the composition comprises about 130.44 mg of the compound of structure (I), as determined using the molecular weight of the compound as the hydrochloride salt.

[0071] Embodiment 29. The composition of any one of the preceding embodiments, wherein the composition comprises a compound of structure (I) in a concentration ranging from about 10 wt.% to about 40 wt.%, as determined using the molecular weight of the compound as the hydrochloride salt.

[0072] Embodiment 30. The composition of any one of the preceding embodiments, wherein the composition comprises a compound of structure (I) in a concentration ranging from about 14 wt.% to about 22 wt.%, as determined using the molecular weight of the compound as the hydrochloride salt.

[0073] Embodiment 31 The composition of any one of the preceding embodiments, wherein the composition comprises a compound of structure (I) in a concentration ranging from about 18 wt % to about 19 wt %, as determined using the molecular weight of the compound as the hydrochloride salt.

[0074] Embodiment 32. The composition of any one of the preceding embodiments, wherein the composition comprises the compound at a concentration of about 18.12 wt %, as determined using the molecular weight of the compound as the hydrochloride salt.

[0075] Embodiment 33. The composition of any one of the preceding embodiments, wherein the composition comprises the compound at a concentration of about 18.38 wt %, as determined using the molecular weight of the compound as the hydrochloride salt.

[0076] Embodiment 34. The composition of any one of embodiments 1-25, wherein the composition comprises a compound of structure (I) in a concentration ranging from about 15 wt % to about 35 wt %, as determined using the molecular weight of the compound as the hydrochloride salt.

[0077] Embodiment 35. The composition of embodiment 34, wherein the composition comprises a compound of structure (I) in a concentration ranging from about 20 wt % to about 30 wt %, as determined using the molecular weight of the compound as the hydrochloride salt.

[0078] Embodiment 36. The composition of embodiment 35, wherein the composition comprises the compound at a concentration of about 25 wt % as determined using the molecular weight of the compound as the hydrochloride salt.

[0079] Embodiment 37. The composition of any one of embodiments 1-25, wherein the composition comprises a compound of structure (I) in a concentration ranging from about 23.3 wt % to about 43.3 wt %, as determined using the molecular weight of the compound as the hydrochloride salt.

[0080] Embodiment 38. The composition of embodiment 37, wherein the composition comprises the compound of structure (I) in a concentration ranging from about 28.3 wt % to about 38.3 wt %, as determined using the molecular weight of the compound as the hydrochloride salt.

[0081] Embodiment 39. The composition of embodiment 38, wherein the composition comprises the compound at a concentration of about 33.3 wt % as determined using the molecular weight of the compound as the hydrochloride salt.

[0082] Embodiment 40. The composition of any of the preceding embodiments, wherein the composition comprises polyglycolized glycerides in an amount ranging from about 500 mg to about 700 mg.

[0083] Embodiment 41 The composition of any of the preceding embodiments, wherein the composition comprises polyglycolized glycerides in an amount ranging from about 550 mg to about 650 mg.

[0084] Embodiment 42 The composition of any of the preceding embodiments, wherein the composition comprises polyglycolized glycerides in an amount ranging from about 560 mg to about 600 mg.

[0085] Embodiment 43. The composition of any of the preceding embodiments, wherein the composition comprises polyglycolized glycerides in an amount ranging from about 585 mg to about 590 mg.

[0086] Embodiment 44. The composition of any of the preceding embodiments, wherein the composition comprises polyglycolized glycerides in an amount of about 587.7 mg.

[0087] Embodiment 45. The composition of any of the preceding embodiments, wherein the composition comprises polyglycolized glycerides in an amount of about 589.56 mg.

[0088] Embodiment 46. The composition of any one of the preceding embodiments, wherein the composition comprises polyglycolized glycerides at a concentration ranging from about 50 wt% to about 90 wt%.

[0089] Embodiment 47. The composition of any one of the preceding embodiments, wherein the composition comprises polyglycolized glycerides at a concentration ranging from about 75 wt% to about 90 wt%.

[0090] Embodiment 48. The composition of embodiment 47, wherein the composition comprises polyglycolized glycerides in a concentration ranging from about 78 wt% to about 84 wt%.

[0091] Embodiment 49. The composition of embodiment 48, wherein the composition comprises polyglycolized glycerides at a concentration of about 81 wt% to about 82 wt%.

[0092] Embodiment 50. The composition of embodiment 49, wherein the composition comprises polyglycolized glycerides at a concentration of about 81.62 wt%.

[0093] Embodiment 51. The composition of embodiment 49, wherein the composition comprises polyglycolized glycerides at a concentration of about 81.88 wt%.

[0094] Embodiment 52. The composition of any of the preceding embodiments, wherein the composition comprises polyglycolized glycerides at a concentration ranging from about 65 wt% to about 85 wt%.

[0095] Embodiment 53. The composition of embodiment 52, wherein the composition comprises polyglycolized glycerides in a concentration ranging from about 70 wt% to about 80 wt%.

[0096] Embodiment 54. The composition of embodiment 53, wherein the composition comprises polyglycolized glycerides at a concentration of about 75 wt%.

[0097] Embodiment 55. The composition of any one of the preceding embodiments, wherein the composition comprises polyglycolized glycerides at a concentration ranging from about 56.7 wt% to about 76.7 wt%.

[0098] Embodiment 56. The composition of embodiment 55, wherein the composition comprises polyglycolized glycerides in a concentration ranging from about 61.7 wt% to about 71.7 wt%.

[0099] Embodiment 57. The composition of embodiment 56, wherein the composition comprises polyglycolized glycerides at a concentration of about 66.7 wt%.

[0100] Embodiment 58. The composition of any one of the preceding embodiments, wherein the composition is administered in the form of a capsule for oral administration.

[0101] Embodiment 59. The composition of any one of the preceding embodiments, wherein the composition comprises a compound of structure (I) and a polyglycolized glyceride in a weight ratio ranging from about 1:1 to about 1:10, as determined using the molecular weight of the compounds as free bases.

[0102] Embodiment 60. The composition of any one of the preceding embodiments, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio ranging from about 1:4 to about 1:6, as determined using the molecular weight of the compounds as the free base.

[0103] Embodiment 61. The composition of any one of the preceding embodiments, wherein the composition comprises a compound of structure (I) and a polyglycolized glyceride in a weight ratio of about 1:5 as determined using the molecular weights of the compounds as free bases.

[0104] Embodiment 62. The composition of any one of the preceding embodiments, wherein the composition comprises a compound of structure (I) and a polyglycolized glyceride in a weight ratio of about 1:4.9 as determined using the molecular weights of the compounds as free bases.

[0105] Embodiment 63. The composition of any one of the preceding embodiments, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio ranging from about 1:4 to about 1:6, as determined using the molecular weight of the compounds as their hydrochloride salts.

[0106] Embodiment 64. The composition of any one of the preceding embodiments, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio of about 1:4.5 as determined using the molecular weight of the compounds as their hydrochloride salts.

[0107] Embodiment 65. The composition of any one of embodiments 1-59, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio ranging from about 1:1.6 to about 1:3.6, as determined using the molecular weight of the compounds as free bases.

[0108] Embodiment 66. The composition of embodiment 65, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio ranging from about 1:2.1 to about 1:3.1, as determined using the molecular weight of the compounds as free bases.

[0109] Embodiment 67. The composition of embodiment 66, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio of about 1:2.6 as determined using the molecular weights of the compounds as free bases.

[0110] Embodiment 68. The composition of any one of embodiments 1-59, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio ranging from about 1:1 to about 1:2.5, as determined using the molecular weight of the compounds as free bases.

[0111] Embodiment 69. The composition of embodiment 68, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio ranging from about 1:1.25 to about 1:2, as determined using the molecular weight of the compounds as free bases.

[0112] Embodiment 70. The composition of embodiment 69, wherein the composition comprises the compound of structure (I) and the polyglycolized glyceride in a weight ratio of about 1:1.76 as determined using the molecular weights of the compounds as free bases.

[0113] Embodiment 71. A unit dosage form comprising a therapeutically effective amount of the composition of any one of embodiments 1 to 70.

[0114] Embodiment 72. A unit dose form comprising a composition, the composition comprising: a polyglycolized glyceride in an amount of about 560 mg to about 600 mg; 2. An amount of about 115 mg to about 125 mg of the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof.

[0115] Embodiment 73. The unit dosage form of embodiment 72, which is a capsule.

[0116] Embodiment 74. The unit dosage form of embodiment 72 or 73, wherein the compound of structure (I) is present as a hydrochloride salt.

[0117] Embodiment 75. The unit dosage form of embodiment 72, wherein the polyglycolized glyceride is GELUCIRE® 44 / 14 present in an amount of 589.56 mg.

[0118] Embodiment 76. The unit dosage form of embodiment 72, wherein the compound of structure (I) is present in an amount of about 120 mg, as determined using the molecular weight of the compound as a free base.

[0119] Embodiment 77. A capsule comprising the composition, wherein the composition GELUCIRE® 44 / 14 in an amount of about 589.56 mg; 130.44 mg of the following structure (I) as determined using the molecular weight of the compound as the hydrochloride salt: [ka] and a hydrochloride salt of a compound having the formula:

[0120] Embodiment 78 The following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] with a compound having the formula:

[0121] Embodiment 79. The method of embodiment 78, wherein the method further comprises adding a base and a catalyst.

[0122]

[0023] Embodiment 80: The method comprises: [ka] or a salt thereof, [ka] 80. The method of any one of embodiments 78 or 79, further comprising reacting with a compound having the formula:

[0123]

[0046] Embodiment 81: The method comprises: [ka] or a salt thereof with a base and a benzyl halide reagent to obtain the first compound having the following structure: [ka] 81. The method of any one of embodiments 78-80, further comprising converting to a second compound having the formula:

[0124] Embodiment 82: The base is K 2 CO 3 82. The method of embodiment 81, wherein

[0125] Embodiment 83: A composition comprising the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, with potassium fluoride and a compound having the following structure: [ka] with a compound having the formula:

[0126] Embodiment 84 A compound having the following structure: [ka] or a pharma- ceutically acceptable salt thereof, comprising: The method comprises contacting a composition comprising the compound with a metal capture reagent.

[0127] Embodiment 85. The method of embodiment 84, wherein the metal capture reagent is a thiol.

[0128] Embodiment 86. The method of embodiment 84, wherein the metal capture reagent is a thiol-functionalized silica.

[0129] Embodiment 87. A method for treating cancer, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 70, or a unit dose according to any one of embodiments 71 to 76, or a capsule according to embodiment 77 to a subject in need thereof.

[0130]

[0082] Embodiment 88. The method of embodiment 87, wherein the cancer is a Pim kinase-expressing cancer.

[0131] Embodiment 89. The method of any one of embodiments 87 or 88, wherein the cancer is prostate cancer.

[0132] Embodiment 90. The method of any one of embodiments 87 or 88, wherein the cancer is colorectal cancer.

[0133] Embodiment 91. The method of any one of embodiments 87 or 88, wherein the cancer is a fibroid cancer.

[0134] Embodiment 92. The method of any one of embodiments 87 or 88, wherein the cancer is myelofibrosis.

[0135] Embodiment 93. The method of any one of embodiments 87 or 88, wherein the cancer is bladder cancer.

[0136] Embodiment 94 The method of any one of embodiments 87 or 88, wherein the cancer is a hematological malignancy.

[0137] Embodiment 95. The method of embodiment 94, wherein the hematological malignancy is acute myeloid leukemia.

[0138] Embodiment 96. The method of any one of embodiments 87-95, wherein the method further comprises administering a therapeutically effective amount of a second anti-cancer agent.

[0139] Embodiment 97. The method of any one of embodiments 87-96, wherein the method further comprises administering a therapeutically effective amount of ruxolitinib.

[0140] Embodiment 98. A method for treating or preventing a fibrotic disease or disorder, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 70, or a unit dose according to any one of embodiments 71 to 76, or a capsule according to embodiment 77 to a subject in need thereof.

[0141] Embodiment 99. The method of embodiment 98, wherein the fibrotic disease or disorder is pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, vascular fibrosis, renal fibrosis, skin fibrosis, gastrointestinal fibrosis, arthrofibrosis, Dupuytren's contracture, mediastinal fibrosis, Peyronie's disease, retroperitoneal fibrosis, systemic sclerosis, or a combination thereof.

[0142] Embodiment 100. A method for treating or preventing the formation or deposition of fibrosis, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 70, or a unit dose according to any one of embodiments 71 to 76, or a capsule according to embodiment 77 to a subject in need thereof.

[0143] Embodiment 101. A method for inhibiting viral infection or viral replication, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 70, or a unit dose according to any one of embodiments 71 to 76, or a capsule according to embodiment 77 to a subject in need thereof.

[0144] Embodiment 102. A method for treating or preventing a myeloproliferative neoplasm, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 70, or a unit dose according to any one of embodiments, or a capsule according to embodiment 77, to a subject in need thereof.

[0145] Embodiment 103. The method of embodiment 102, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia, or a combination thereof.

[0146] Embodiment 104. A method for treating or preventing an inflammatory disease or disorder, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 70, or a unit dose according to any one of embodiments, or a capsule according to embodiment 77, to a subject in need thereof.

[0147] Embodiment 105. The method of embodiment 104, wherein the inflammatory disease or disorder is non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, skin inflammation, psoriasis, or a combination thereof.

[0148] Embodiment 106. A method for treating or preventing an autoimmune or inflammatory disease or disorder, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 70, or a unit dose according to any one of embodiments, or a capsule according to embodiment 77, to a subject in need thereof.

[0149] Embodiment 107. The method of embodiment 106, wherein the autoimmune or inflammatory disease or disorder is osteoarthritis, rheumatoid arthritis, pain, inflammatory bowel disease, a respiratory disorder, a skin disorder, or a combination thereof.

[0150] Embodiment 108. The method of any one of embodiments 87 to 107, wherein the subject is a human.

[0151] Embodiment 109. The method of any one of embodiments 87-108, wherein a subject in need thereof is administered a dose of about 360 mg of the compound of structure (I), or about 480 mg of the compound of structure (I), or about 720 mg of the compound of structure (I), or about 1080 mg of the compound of structure (I), or about 1440 mg of the compound of structure (I), as determined using the molecular weight of the compound as a free base.

[0152] Embodiment 110. The method of embodiment 109, wherein the dose is a daily dose.

[0153] Embodiment 111 A composition comprising the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] with a compound having the formula:

[0154] Embodiment 112. The method of embodiment 111, wherein the method further comprises adding a first base and a catalyst.

[0155] Embodiment 113. The method of any one of embodiments 111 or 112, wherein the first base is an amine base.

[0156] Embodiment 114. The method of any one of embodiments 111 to 113, wherein the first base is diisopropylethylamine.

[0157] Embodiment 115. The method of any one of embodiments 111 to 114, wherein the catalyst is cesium fluoride.

[0158]

[0022] Embodiment 116: The method comprises: [ka] or a salt thereof, [ka] 116. The method of any one of embodiments 111-115, further comprising reacting with a compound having the formula:

[0159] Embodiment 117. The method of embodiment 116, wherein the method further comprises adding a palladium catalyst and a second base.

[0160] Embodiment 118: The palladium catalyst is Pd(PPh 3 ) 2 Cl 2 118. The method of embodiment 117, wherein

[0161] 119. The method of claim 119, wherein the second base is NaHCO 3 119. The method of any one of embodiments 117 or 118, wherein

[0162] Embodiment 120. A crystalline form of the hydrochloride salt of the compound 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol.

[0163] Embodiment 121. The crystalline form of embodiment 120, including form I.

[0164] Embodiment 122. The crystalline form of embodiment 120 or embodiment 121, consisting essentially of Form I.

[0165] Embodiment 123. The crystalline form of embodiment 121, wherein Form I is a substantially pure form.

[0166] Embodiment 124. A crystalline form according to any one of embodiments 120 to 123, characterized by an X-ray powder diffraction pattern comprising peaks at 21.5±0.2°, 19.9±0.2° and 17.8±0.2° in terms of 2θ.

[0167] Embodiment 125. The crystalline form of embodiment 124, further characterized by an X-ray powder diffraction pattern comprising peaks at 16.3±0.2°, 19.3±0.2°, and 24.4±0.2° in terms of 2θ.

[0168] Embodiment 126. The crystalline form of embodiment 124 or embodiment 125, further characterized by an X-ray powder diffraction pattern comprising peaks at 10.1±0.2°, 11.7±0.2°, 14.4±0.2° and 16.7±0.2° in terms of 2θ.

[0169] Embodiment 127. The crystalline form of any one of embodiments 120-126 having an X-ray powder diffraction pattern substantially as shown in FIG.

[0170] Embodiment 128. The crystalline form of any one of embodiments 120 to 127, having a differential scanning calorimetry thermogram comprising an endothermic event at 226.9±3° C.

[0171] Embodiment 129. The crystalline form of any one of embodiments 120-128 having a differential scanning calorimetry thermogram substantially as shown in FIG.

[0172] Embodiment 130. The crystalline form of any one of embodiments 120-129 having a thermogravimetric diagram substantially as shown in FIG.

[0173] Embodiment 131. The crystalline form of embodiment 120, including Form II.

[0174] Embodiment 132. The crystalline form of embodiment 120 or embodiment 131, characterized by an X-ray powder diffraction pattern comprising peaks at 15.7±0.2° and 17.0±0.2° in terms of 2θ.

[0175] Embodiment 133. The crystalline form of any one of embodiment 131 or embodiment 132, having an X-ray powder diffraction pattern substantially as shown in FIG.

[0176] Embodiment 134 The crystalline form of any one of embodiments 120 to 133 and a pharma- ceutically acceptable R and a carrier.

[0177] Embodiment 135. A pharmaceutical composition comprising a crystalline form selected from Form I or Form II.

[0178] Embodiment 136. The pharmaceutical composition of embodiment 134, wherein the crystalline form is Form I.

[0179] Embodiment 137. The pharmaceutical composition of embodiment 136, wherein Form I is substantially pure.

[0180] Embodiment 138 A pharma- ceutically acceptable R The pharmaceutical composition of any one of embodiments 134-137, wherein the carrier comprises an excipient, and the excipient comprises polysorbate 20, polysorbate 60, polysorbate 80, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate, glyceryl dibehenate, propylene glycol dilaurate, propylene glycol monocaprylate, propylene glycol monolaurate, or a combination thereof.

[0181] Embodiment 139. A method for treating cancer, comprising administering a therapeutically effective amount of a crystalline form according to any one of embodiments 120 to 133 to a subject in need thereof.

[0182] Embodiment 140. The method of embodiment 139, wherein the cancer is a Pim kinase-expressing cancer.

[0183] Embodiment 141 The method of any one of embodiments 139 or 140, wherein the cancer is prostate cancer.

[0184] Embodiment 142 The method of any one of embodiments 139 or 140, wherein the cancer is colorectal cancer.

[0185] Embodiment 143. The method of any one of embodiments 139 or 140, wherein the cancer is a fibroid cancer.

[0186] Embodiment 144 The method of any one of embodiments 139 or 140, wherein the cancer is myelofibrosis.

[0187] Embodiment 145 The method of any one of embodiments 139 or 140, wherein the cancer is bladder cancer.

[0188] Embodiment 146. The method of any one of embodiments 139 or 140, wherein the cancer is a hematological malignancy.

[0189] Embodiment 147. The method of embodiment 146, wherein the hematological malignancy is acute myeloid leukemia.

[0190] Embodiment 148. The method of any one of embodiments 139-147, wherein the method further comprises administering a therapeutically effective amount of a second anti-cancer agent.

[0191] Embodiment 149. The method of any one of embodiments 139-148, wherein the method further comprises administering a therapeutically effective amount of ruxolitinib.

[0192] Embodiment 150. A method for treating or preventing a fibrotic disease or disorder, comprising administering a therapeutically effective amount of a crystalline form according to any one of embodiments 120 or 133 to a subject in need thereof.

[0193] Embodiment 151 The method of embodiment 150, wherein the fibrotic disease or disorder is pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, vascular fibrosis, renal fibrosis, skin fibrosis, gastrointestinal fibrosis, arthrofibrosis, Dupuytren's contracture, mediastinal fibrosis, Peyronie's disease, retroperitoneal fibrosis, systemic sclerosis, or a combination thereof.

[0194] Embodiment 152. A method for treating or preventing the formation or deposition of fibrosis, comprising administering a therapeutically effective amount of a crystalline form according to any one of embodiments 120 or 133 to a subject in need thereof.

[0195] Embodiment 153. A method for inhibiting viral infection or viral replication, comprising administering a therapeutically effective amount of a crystalline form of any one of embodiments 120 or 133 to a subject in need thereof.

[0196] Embodiment 154. A method for treating or preventing a myeloproliferative neoplasm, comprising administering a therapeutically effective amount of a crystalline form according to any one of embodiments 120 or 133 to a subject in need thereof.

[0197] Embodiment 155. The method of embodiment 154, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia, or a combination thereof.

[0198] Embodiment 156. A method for treating or preventing an inflammatory disease or disorder, comprising administering a therapeutically effective amount of a crystalline form of any one of embodiments 120 or 133 to a subject in need thereof.

[0199] Embodiment 157. The method of embodiment 156, wherein the inflammatory disease or disorder is nonalcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, skin inflammation, psoriasis, or a combination thereof.

[0200] Embodiment 158. A method for treating or preventing an autoimmune or inflammatory disease or disorder, comprising administering a therapeutically effective amount of a crystalline form of any one of embodiments 120 or 133 to a subject in need thereof.

[0201] Embodiment 159. The method of embodiment 158, wherein the autoimmune or inflammatory disease or disorder is osteoarthritis, rheumatoid arthritis, pain, inflammatory bowel disease, a respiratory disorder, a skin disorder, or a combination thereof.

[0202] Embodiment 160. The method of any one of embodiments 139 to 159, wherein the subject is a human subject.

[0203] Embodiment 161. A process for preparing a crystalline form according to any one of embodiments 120 to 130, comprising precipitating the crystalline form from a solution comprising the hydrochloride salt of compound 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol, methanol and ethyl acetate.

[0204] Embodiment 162. The process of embodiment 161, wherein the precipitating comprises shaking the solution for 24 hours to form a slurry.

[0205] Embodiment 163. The process of embodiment 161 or embodiment 162, further comprising contacting the solution with seed crystals of the crystalline form.

[0206] Embodiment 164. A crystalline form of the hydrochloride salt of compound 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol prepared by the process according to any one of embodiments 161 to 163.

[0207] Embodiment 165. A process for preparing a crystalline form according to any one of embodiments 131 to 133, comprising precipitating the crystalline form from a solution comprising the hydrochloride salt of compound 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and water.

[0208] Embodiment 166. The process of embodiment 165, further comprising shaking the solution for 24 hours to form a slurry.

[0209] Embodiment 167. A crystalline form of the hydrochloride salt of the compound 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol prepared by the process of embodiment 165 or embodiment 166.

[0210] Detailed Description Although detailed embodiments of the present invention are disclosed herein, it should be understood that the disclosed embodiments are merely exemplary of the present invention, which may be embodied in various forms. Furthermore, each of the examples given in connection with the various embodiments of the present invention is intended to be illustrative and not limiting. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but merely as a representative basis for teaching those skilled in the art how to use the present invention in various ways. definition

[0211] For purposes of interpreting this specification, the following definitions will apply and, whenever appropriate, terms used in the singular will also include the plural. Terms used in this specification have the following meanings, unless the context clearly indicates otherwise.

[0212] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise stated.

[0213] As used in the context of this disclosure (particularly in the context of the claims), the terms "a," "an," "the," and similar terms are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0214] "Polyglycolized glycerides" refers to mixtures of mono-, di- and triesters of glycerol and mono- and diesters of polyethylene glycol having an average relative molecular mass between about 200 and 6000. Polyglycolized glycerides can be obtained by partial transesterification of triglycerides with polyethylene glycol or by esterification of glycerol and polyethylene glycol with fatty acids. In some embodiments, the fatty acid components contain between 8 and 22 carbon atoms, for example between 10 and 18 carbon atoms. Examples of natural vegetable oils from which polyglycolized glycerides can be derived include palm kernel oil and palm oil. Suitable polyol compounds generally have a molecular weight in the range of about 200 to about 6000 g / mol and preferably contain polyethylene glycol, although other polyols such as polyglycerol or sorbitol may be used. Polyglycolized glycerides are commercially available under the trade name GELUCIRE®. Examples of polyglycolized glycerides useful in various embodiments include WL2514CS, LABRASOL, LABRAFIL, GELUCIRE44 / 14 (lauroyl polyoxy-32 glyceride), GELUCIRE33 / 01, GELUCIRE35 / 10, GELUCIRE37 / 02, GELUCIRE50 / 13, GELUCIRE44 / 11, and mixtures thereof.

[0215] "GELUCIRE® 44 / 14" or "GELUCIRE 44 / 14" is a lipid-based excipient manufactured by Gattefosse Corporation, Westwood, NJ, that contains a mixture of pegylated fatty acid esters and glycerides. The number 44 represents the melting point of this compound, and 14 indicates the hydrophilic / lipophilic balance (HLB) value. Other GELUCIRE excipients similarly exhibit values ​​for melting point and HLB value. For example, GELUCIRE 33 / 01, GELUCIRE 35 / 10, GELUCIRE 37 / 02, GELUCIRE 50 / 13, and GELUCIRE 44 / 11.

[0216] The hydrophilic / lipophilic balance (HLB) value can be determined by the Griffin method. The HLB value is calculated by the following formula: HLB = 20 × (M h / M) (In the formula, M h (HLB is the molecular mass of the hydrophilic portion of the molecule, and M is the molecular mass of the entire molecule.) Thus, HLB values ​​range from 0 to 20, with a value of 0 corresponding to a lipophilic (i.e., hydrophobic) molecule and a value of 20 corresponding to a hydrophilic (i.e., lipophobic) molecule.

[0217] The term "pharmacologically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or with the mammal being treated therewith.

[0218] Depending on the process conditions, the final product of the present disclosure can be obtained in either free (base) or salt form. Both the free form and salt of these final products are within the scope of the present disclosure. If desired, one form of the compound can be converted into another form. Free base can be converted into salt, and salt can be converted into free form or into another salt.

[0219] Pharmaceutically acceptable salts are preferred, however other salts may be useful, for example, in isolation or purification steps that may be employed during preparation and, thus, are contemplated as being within the scope of the present disclosure.

[0220] As used herein, "pharmaceutical acceptable salt" refers to a pharmaceutical acceptable acid or base addition salt. For example, pharmaceutical acceptable salts include, but are not limited to, acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, hydrogen sulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate. , lauryl sulfate, malate, maleate, malonate / hydroxymalonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phenylacetate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfamate, sulfosalicylate, tartrate, tosylate, trifluoroacetate, or xinafoate forms.

[0221] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.Inorganic acid forms from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0222] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.Inorganic bases (from which salts can be derived) include, for example, ammonium salts and metals from group I to group XII of the periodic table.In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.Organic bases (from which salts can be derived) include, for example, primary amines, secondary amines, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0223] The pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds that contain basic or acidic moieties by conventional chemical methods.Generally, such salts can be prepared by reacting the free acid or base form of these compounds with stoichiometric amounts of suitable base or acid in water or organic solvent or in the mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.A list of suitable salts can be found in Allen, LV, Jr., ed., Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK (2012), the relevant disclosure of which is incorporated herein by reference in its entirety.

[0224] Any formula given herein is intended to represent the compound in unlabeled form as well as in isotopically labeled form.Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom with selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, for example, each 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 The present disclosure includes various isotopically labeled compounds as defined herein, e.g. 3 H and 14 Radioisotopes such as C or 2 H and 13 These include those that contain non-radioactive isotopes such as C. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radioactive treatment of a subject. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies.

[0225] Additionally, heavier isotopes, particularly deuterium (i.e. 2Substitution with H or D) may result in certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index, resulting from greater metabolic stability. It is understood that deuterium in this context is considered a substituent of the compounds of the present disclosure. The concentration of such heavier isotopes, particularly deuterium, may be defined by the isotopic enrichment factor.

[0226] The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.When the substituent in the compounds of the present disclosure is deuterium as indicated, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation).

[0227] Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art, or by the processes disclosed in the schemes or examples and preparations described below (or by processes similar to those described herein), by substituting suitable or readily available isotopically labeled reagents for non-isotopically labeled reagents used in other contexts. Such compounds have a variety of potential uses, for example, as standards and reagents in determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors, or for imaging compounds of the present disclosure bound to biological receptors in vivo or in vitro.

[0228] The term "malignant tumor," also called "cancer," refers to a disease in which abnormal cells divide without control and can invade nearby tissues. Malignant cells can also spread to other parts of the body via the blood and lymphatic system. There are several main types of malignant tumors. Carcinomas are malignant tumors that begin in the skin or in tissues lining or covering internal organs. Sarcomas are malignant tumors that begin in bone, cartilage, fat, muscle, blood vessels, or other connective or supporting tissues. Leukemias are malignant tumors that begin in blood-forming tissues, such as the bone marrow, and produce large numbers of abnormal blood cells that enter the blood. Lymphomas and multiple myelomas are malignant tumors that begin in cells of the immune system. Central nervous system cancers are malignant tumors that begin in tissues of the brain and spinal cord.

[0229] The term "solid tumor" refers to a malignant tumor / cancer formed from a mass of abnormal tissue that does not usually contain cysts or liquid areas. Solid tumors are named / classified according to the tissue / cell of origin. Examples include, but are not limited to, sarcomas and carcinomas.

[0230] The term "leukemia" refers to a hematological or blood cell malignancy / cancer that begins in blood-forming tissues such as bone marrow. Examples include, but are not limited to, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL).

[0231] The term "lymphoma" refers to lymphoid cell malignancies / cancers that begin in cells of the immune system. Examples include, but are not limited to, non-Hodgkin's lymphoma and multiple myeloma.

[0232] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject also refers to, for example, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. Exemplary subjects include humans of any age who have risk factors for cancer.

[0233] As used herein, a subject (preferably a human) is "in need" of a treatment if the subject would benefit from such treatment biologically, medically, or in their quality of life.

[0234] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or to a significant decrease in the baseline activity of a biological activity or process.

[0235] As used herein, the terms "treat," "treating," or "treatment" of any disease / disorder refer to the treatment of the disease / disorder in a subject (e.g., a mammal), particularly in a human, and include (a) inhibiting the disease / disorder (e.g., delaying or arresting or reducing the onset of the disease / disorder, or at least one of its clinical symptoms); (b) alleviating the disease / disorder physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both (e.g., causing regression of the disease / disorder or at least one of its clinical symptoms); (c) alleviating or improving at least one physical parameter, including those that may not be discernible by the subject; and / or (d) preventing or delaying the onset or development or progression of the disease or disorder from occurring in a subject (e.g., a mammal), particularly where such a subject (e.g., a mammal) is susceptible to the disease or disorder but has not yet been diagnosed as having the disease or disorder.

[0236] The term "therapeutically effective amount" (e.g., of a composition of the present disclosure) refers to an amount (e.g., of a composition of the present disclosure) sufficient to effect treatment when administered to a subject, such as a human. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount (e.g., of a composition of the present disclosure) that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and / or ameliorate a symptom or disorder or disease mediated by Pim kinase, or (2) reduce or inhibit activity of a Pim kinase. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount (e.g., of a composition of the present disclosure) that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit activity of a Pim kinase or to at least partially reduce or inhibit expression of a Pim kinase.

[0237] The therapeutically effective amount can vary depending on factors such as the size and weight of the subject, the type of illness, or the particular composition of the disclosure. One of ordinary skill in the art would be able to study the factors contained herein and make a determination regarding the therapeutically effective amount (e.g., of a composition of the disclosure) without undue experimentation.

[0238] The regimen of administration may affect what constitutes a therapeutically effective amount. The crystal form or composition of the present disclosure may be administered to a subject either before or after the onset of a Pim kinase-mediated disease, disorder, or condition. Furthermore, several divided doses as well as varying doses may be administered daily or sequentially, or the dose may be continuously infused or bolus injected. Furthermore, the dosage of the crystal form(s) and / or composition(s) of the present disclosure may be proportionally increased or decreased as indicated by the exigencies of the treatment or prophylactic situation.

[0239] "Radiotherapy" means exposing a subject to radiation emitters such as alpha particle-emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation, including, but not limited to, x-rays, gamma rays, and neutrons, using routine methods and compositions known to a physician.

[0240] "Prodrug" is intended to refer to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound (e.g., a compound of structure (I) or a pharma- ceutically acceptable salt thereof) used in the compositions described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharma- ceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject, but is converted in vivo, e.g., by hydrolysis, to an active compound used in an embodiment (e.g., of a composition) described herein. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs can be found in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound in vivo when such a prodrug is administered to a mammalian subject. As described herein, prodrugs of an active compound (e.g., of a composition) are typically prepared by modifying functional groups present in the active compound (e.g., of a composition) such that the modifications are cleaved to the parent active compound, either in routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group is bonded to any group that is cleaved to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of hydroxy functional groups, or acetamide, formamide and benzamide derivatives of amine functional groups in the active compound.

[0241] The term "in vivo" refers to events that take place inside a subject's body.

[0242] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the statement includes instances in which the event or circumstance occurs and instances in which the event does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the statement includes both substituted aryl groups and aryl groups with no substitution.

[0243] "Crystalline" as used herein refers to a homogeneous solid formed by a repeating three-dimensional pattern of atoms, ions, or molecules with fixed distances between the constituent parts. The unit cell is the simplest repeating unit in this pattern. An ideal crystal is homogeneous in nature, but perfect crystals rarely, if ever, exist. As used herein, "crystalline" encompasses crystal forms that contain crystal defects, such as those typically formed by manipulating (e.g., preparing, purifying) the crystal forms described herein. One of skill in the art can determine whether a sample of a compound is crystalline despite the presence of such defects.

[0244] The term "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms and / or ions that form the crystal. Polymorphs can be characterized by analytical methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), for example, as described herein.

[0245] As used herein, "solvate" refers to a crystalline form of a molecule, atom, and / or ion that further comprises one or more molecules of a solvent incorporated into the crystal lattice structure. The solvent molecules in a solvate may exist in an ordered arrangement and / or a non-ordered arrangement. A solvate may comprise either a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from a solvate. A solvate may exist as a dimer or oligomer that comprises more than one molecule or compound within the crystal lattice structure. In some embodiments, the compound of structure (I) or a pharma- ceutically acceptable salt thereof may be a solvate (e.g., a hydrate).

[0246] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns.

[0247] As used herein, the term "substantially pure", when used in reference to a crystalline form of the compound of structure (I), means a crystalline form having a purity of greater than about 90% by weight, including greater than about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% and about 99% by weight, based on the weight of the compound, including a purity equal to about 100% by weight. The remaining material includes other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, a crystalline form of the compound of structure (I) or a pharma- ceutically acceptable salt thereof may be considered substantially pure in that the crystalline form of the compound of structure (I) or a pharma- ceutically acceptable salt thereof has a purity of greater than 90% by weight, as measured by means known and generally accepted in the art at this time, and the remaining less than 10% by weight of the material includes other forms of the compound of structure (I) or a pharma- ceutically acceptable salt thereof and / or reaction and / or processing impurities. Purity can be assessed using techniques known in the art, for example, using the HPLC assay described herein.

[0248] An XRPD pattern, DSC thermogram or TGA spectrum that is "substantially consistent" with one or more figures herein showing an XRPD pattern or diffractogram or DSC thermogram or TGA spectrum, respectively, is an XRPD pattern or DSC thermogram that would be considered by a person skilled in the art to correspond to a single crystalline form of a compound identical to the sample of the compound that gave the pattern or diffractogram or thermogram or spectrum of one or more figures described herein. Thus, a substantially consistent XRPD pattern or DSC thermogram or TGA spectrum may be identical to the XRPD pattern or DSC thermogram of one of the figures, or, more likely, may differ somewhat from one or more of the figures. For example, an XRPD pattern that differs somewhat from one or more of the figures may not necessarily show each of the lines of the diffraction patterns presented herein and / or may show slight changes in the appearance or intensity of the lines or shifts in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the samples used to obtain the data. One of ordinary skill in the art can determine whether a sample of a crystalline compound is in the same form as or in a different form from the forms disclosed herein by comparison of the XRPD pattern or DSC thermogram or TGA spectrum of the sample of the crystalline compound to the corresponding XRPD pattern or DSC thermogram or spectrum disclosed herein.

[0249] To this end, one skilled in the art can determine when an XRPD pattern described herein is "substantially devoid" of a peak at a particular 2θ angle. Thus, a pattern may show a peak at a particular 2θ angle, but the pattern may still be "substantially devoid" of a peak at that angle, for example, because such a peak may be the result of an impurity in the sample, or, for example, because its intensity may not be as significant as a peak that is below the detection limit and / or within the background signal. In some embodiments, an XRPD pattern is substantially devoid of a peak at an identified 2θ angle when the relative intensity of the peak at the identified 2θ angle is less than or equal to 20%, for example, less than or equal to 15%, less than or equal to 10%, less than or equal to 9%, less than or equal to 8%, less than or equal to 7%, less than or equal to 6%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%.

[0250] Unless otherwise indicated, any XRPD peak specified herein, except for those in Tables 1 or 2, Figures, or Examples, should be understood to mean the specified value ±0.2 or less. For example, unless otherwise indicated, if an embodiment or claim specifies a peak at 20.0 in 2θ, this should be understood to mean 20.0° ±0.2° or less, i.e., a 2θ angle of 19.8° to 20.2°. In preferred embodiments, the 2θ angle is the specified value ±0.1° or less, and in more preferred embodiments ±0.05° or less.

[0251] The crystalline forms provided herein can also be identified based on differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA). DSC is a thermal analysis technique in which the difference in the amount of heat required to increase the temperature of a sample is measured as a function of temperature. DSC can be used to detect physical transformations, such as phase transitions, of a sample. For example, DSC can be used to detect the temperature at which a sample undergoes crystallization, melting, or glass transition. Any temperature associated with DSC specified herein, except for DSC temperatures in the figures or examples, should be understood to mean the specified value ±5°C or less. For example, if an embodiment or claim specifies an endothermic peak at 264°C, this should be understood to mean a temperature of 264°C ±5°C or less, i.e., 259°C to 269°C. In preferred embodiments, the DSC is at the specified value ±3°C or less, and in more preferred embodiments ±2°C or less.

[0252] The chemical naming protocol and structural diagrams used herein are modified versions of the IUPAC nomenclature, using the ACD / Name Version 9.07 software program and / or the ChemDraw Ultra Version 11.0.1 software naming program (CambridgeSoft). For complex chemical names used herein, a substituent is typically named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. All bonds are identified in the chemical structural diagrams herein, except for all bonds on some carbon atoms that are assumed to be attached to sufficient hydrogen atoms to satisfy all valences. Preparation of Compounds of Structure (I)

[0253] The compounds and compositions of the present disclosure can be prepared in light of the novel methods, reaction schemes and examples provided herein. The compounds of the present disclosure can be synthesized using the methods described below together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereof as recognized by those skilled in the art. The reactions are carried out in a solvent or solvent mixture that is appropriate for the reagents and materials used and for the transformation being effected. Those skilled in the art of organic synthesis will understand that the functional groups present on the molecule should be consistent with the proposed transformation. This may require judgment to change the order of synthetic steps or to select one particular process scheme over another in order to obtain the desired compounds of the present disclosure.

[0254] The starting materials are generally available from commercial sources, such as Sigma Aldrich or other commercial suppliers, or are prepared as described in this disclosure, or are readily prepared using methods well known to those of skill in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), Larock, RC, Comprehensive Organic Transformations, 2 nd -ed., Wiley-VCH Weinheim, Germany (1999) or in Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including its addenda (also available via the Beilstein online database).

[0255] In the preparation of the compound of structure (I) or its pharma- ceutically acceptable salt, protection of remote functionality of intermediates may be necessary. The necessity of such protection varies depending on the nature of the remote functionality and the conditions of the preparation method. The necessity of such protection is easily determined by those skilled in the art. For a general description of protecting groups and their use, see Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Ed., Wiley (2007). Protecting groups such as benzyl protecting groups can be incorporated in the preparation of the compounds of the present disclosure.

[0256] As the Examples herein demonstrate, it has been discovered that compounds of structure (I), or pharma- ceutically acceptable salts thereof, can be prepared according to a new process.

[0257] One embodiment has the following structure: [ka] or a salt thereof, comprising: [ka] or a salt thereof, [ka] With a compound having the formula: One aspect of this embodiment further comprises adding a base and a catalyst. In some more specific embodiments, the catalyst is a palladium catalyst (e.g., Pd(OAc) 2 In some embodiments, the base is K 2 CO 3 In some embodiments, the method further comprises adding a phosphine reagent (e.g., tricyclohexylphosphine).

[0258] One embodiment has the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: (i) a structure: [ka] or a salt thereof, [ka] (e.g., by reacting with a compound having a base, e.g., K 2 CO 3 and catalysts such as Pd(OAc) 2 in the presence of a palladium catalyst such as [ka] and obtaining a compound having the formula: (ii) a structure: [ka] or a salt thereof, [ka] and reacting the compound having the formula:

[0259] In certain embodiments, the method comprises the step of: [ka] or a salt thereof, with a second base (e.g., K 2 CO 3 ) and a benzyl halide reagent (e.g., benzyl bromide) to provide the first compound having the following structure: [ka] to a second compound having the formula:

[0260] One embodiment has the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] With a compound having the formula: In a more specific embodiment, the method further comprises adding a base. In a particular embodiment, the base is an amine base (e.g., diisopropylethylamine).

[0261] Another embodiment has the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] With a compound having the formula: In some embodiments, the palladium catalyst is tris(dibenzylideneacetone)dipalladium. In some embodiments, the alkoxide is a tert-butoxide (e.g., sodium tert-butoxide). In some embodiments, the solvent is toluene. In some embodiments, the reaction is carried out in the additional presence of a phosphine ligand (e.g., 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), such as (R)-BINAP).

[0262] Another embodiment has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, the method comprising contacting a composition comprising the compound or a pharma- ceutically acceptable salt thereof with a metal capture reagent. In some more specific embodiments, the metal capture reagent is a palladium capture reagent (e.g., silica thiol). In some embodiments, the method further comprises adding a solvent (e.g., a polar aprotic solvent such as ether or tetrahydrofuran). In some embodiments, the method further comprises heating the composition. In some embodiments, the method further comprises isolating the compound. In some embodiments, the method further comprises repeating the contacting step (e.g., a total of 2 to 5 times).

[0263] Another embodiment has the following structure: [ka] or a salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] With a compound having the formula: In some embodiments, the method further comprises adding a first base and a catalyst. In certain embodiments, the first base is an amine base (e.g., triethylamine or diisopropylethylamine). In some more specific embodiments, the catalyst comprises a fluoride (e.g., cesium fluoride).

[0264] Another embodiment has the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: The following structure: [ka] or a salt thereof, [ka] Compounds having the formula (e.g., Pd(PPh 3 ) 2 Cl 2 or Pd(PPh 3 ) 4 Palladium catalysts such as NaHCO 3 or Na 2 CO 3 In some embodiments, the method includes reacting the aryl group with a palladium catalyst (e.g., Pd(PPh 3 ) 2 Cl 2 or Pd(PPh 3 ) 4 ) and a first base (e.g., NaHCO 3 or Na 2 CO 3In some embodiments, the method further comprises forming a hydrochloride salt of the compound of structure (I). In more specific embodiments, the method further comprises contacting the compound of structure (I) with hydrochloric acid. In some embodiments, the method further comprises contacting the compound of structure (I) with a seed crystal (e.g., a seed crystal of the HCl salt of the compound of structure (I)). In some embodiments, the method further comprises contacting the compound of structure (I) with a seed crystal of the HCl salt of the compound of structure (I). In some embodiments, the method further comprises contacting the compound of structure (I) with a seed crystal of the HCl salt of the compound of structure (I) with a seed crystal of the HCl salt of the compound of structure (I). [ka] or a salt thereof, [ka] (eg, in the presence of a second base, for example an amine base such as diisopropylethylamine, and a catalyst such as cesium fluoride) with a compound having the formula:

[0265] Any of the methods and / or processes for preparing a compound of structure (I) or a pharma- ceutically acceptable salt thereof disclosed herein can further include a process for preparing a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, such as a process described herein for preparing a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as described herein. Compositions, combinations and dosage forms

[0266] "Pharmaceutically acceptable carriers (diluents or excipients)" refers to vehicles generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, including generally regarded as safe (GRAS) solvents, dispersing media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption retarding agents, salts, preservatives, drug stabilizers, binders, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to one of skill in the art (see, e.g., Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012)).

[0267] The embodiments of the present disclosure are based in part on the fact that certain formulations comprising Pim kinase inhibitors are unexpectedly superior to other formulations. Specifically, embodiments of compositions comprising polyglycolized glycerides and Pim kinase inhibitors provide higher overall exposure compared to compositions in which other formulating agents are used in addition to or in place of polyglycolized glycerides.

[0268] Thus, embodiments generally relate to compositions (e.g., pharmaceutical compositions) comprising a polyglycolized glyceride and a Pim kinase inhibitor. Certain embodiments relate to a composition (e.g., pharmaceutical composition) comprising a polyglycolized glyceride and a Pim kinase inhibitor having the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of the compound of structure (I), a crystalline form of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, e.g., Form I of the hydrochloride salt of the compound of structure (I)).

[0269] For the desired application and delivery of the composition, the melting point of the polyglycolized glyceride may be selected to optimize the therapeutic effectiveness of the composition. Thus, in some embodiments, the polyglycolized glyceride has a melting point of about 30 to about 50°C. In related embodiments, the polyglycolized glyceride has a melting point in the range of about 31 to about 49°C, about 32 to about 48°C, about 33 to about 48°C, about 34 to about 48°C, about 35 to about 48°C, about 36 to about 48°C, about 37 to about 48°C, about 38 to about 47°C, about 39 to about 46°C, about 40 to about 45°C, about 41 to about 45°C, about 42 to about 45°C, or about 43 to about 45°C. In certain specific embodiments, the polyglycolized glyceride has a melting point of about 44°C.

[0270] Relatedly, the hydrophilic / lipophilic balance of the polyglycolized glyceride may also be selected to optimize the composition embodiment. Thus, in certain embodiments, the polyglycolized glyceride has a hydrophilic / lipophilic balance (HLB) value ranging from about 8 to about 18, from about 9 to about 17, from about 9 to about 16, from about 10 to about 16, from about 11 to about 15, from about 11 to about 15, from about 12 to about 15, or from about 13 to about 15. In certain specific embodiments, the polyglycolized glyceride has a hydrophilic / lipophilic balance value of about 14.

[0271] A crystalline form of the compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., Form I of the hydrochloride salt of the compound of structure (I)) and a pharma- ceutically acceptable salt thereof R Also provided herein are compositions (eg, pharmaceutical compositions) that include a carrier.

[0272] The pharmaceutical composition of the present disclosure can be formulated for a specific route of administration, such as oral administration. In addition, the pharmaceutical composition of the present disclosure can be configured in solid form, including capsules, tablets, pills, granules, powders, or suppositories. The pharmaceutical composition can be subjected to conventional pharmaceutical operations, such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers. In some embodiments, the pharmaceutical composition comprises: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; likewise for tablets c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colouring agents, flavouring agents and sweeteners The active ingredient is preferably a tablet or gelatin capsule containing one or more of the following:

[0273] Tablets may be film coated or enteric coated according to methods known in the art.

[0274] Compositions suitable for oral administration include the form of tablets, troches, suspensions (e.g., aqueous or oily suspensions), dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for producing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to obtain pharma-ceutically elegant and palatable preparations. Tablets may contain the active ingredient mixed with non-toxic pharma-ceutically acceptable excipients suitable for the manufacture of tablets (in addition to, for example, polyglycolized glycerides). These additional excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as, for example, corn starch or alginic acid; binding agents such as, for example, starch, gelatin, or acacia; and lubricants such as, for example, magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.The preparation for oral use can be presented as a hard gelatin capsule in which active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as a soft gelatin capsule in which active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0275] In some embodiments, the composition further comprises a compounding agent, such as polysorbate 20, polysorbate 60, polysorbate 80, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate, glyceryl dibehenate, propylene glycol dilaurate, propylene glycol monocaprylate, propylene glycol monolaurate, or combinations thereof. In a particular embodiment, the compounding agent is polysorbate 20. In another particular embodiment, the compounding agent is glyceryl monocaprylate.

[0276] The ratio (e.g., weight ratio) of polyglycolized glyceride to compounding agent can be optimized to ensure the effectiveness of the composition. Thus, in certain embodiments, the polyglycolized glyceride and compounding agent are present in a weight ratio ranging from 2:1 to 1:1.

[0277] In some embodiments, the composition consists of a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride (e.g., GELUCIRE® 44 / 14). In some embodiments, the composition consists essentially of a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride (e.g., GELUCIRE® 44 / 14). In some embodiments, the composition does not include other ingredient(s) other than the polyglycolized glyceride. For example, in some embodiments, the composition does not include other ingredient(s) other than the polyglycolized glyceride and includes other ingredients (e.g., sealants such as HPMC, water, ethanol, etc.).

[0278] In some embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:1 to about 1:10, as determined using the molecular weight of the compound of structure (I) as the free base (i.e., a molecular weight of 419.92). In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:1.25 to about 1:10, about 1:1.5 to about 1:10, about 1:1.75 to about 1:10, about 1:2 to about 1:10, about 1:2 to about 1:9, about 1:2.5 to about 1:8; about 1:3 to about 1:7, about 1:4 to about 1:6, as determined using the molecular weight of the compound of structure (I) as the free base. In some specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:5, as determined using the molecular weight of the compound of structure (I) as a free base. In some specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:4.9, as determined using the molecular weight of the compound of structure (I) as a free base. In some specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:2.6, as determined using the molecular weight of the compound of structure (I) as a free base. In some other embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:3, 1:4, 1:4.5, 1:4.9, 1:5.5, or 1:6, as determined using the molecular weight of the compound of structure (I) as a free base.

[0279] In some embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:1.6 to about 1:3.6, as determined using the molecular weight of the compound of structure (I) as a free base. In certain embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:2.1 to about 1:3.1, as determined using the molecular weight of the compound of structure (I) as a free base. In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:2.6, as determined using the molecular weight of the compound of structure (I) as a free base.

[0280] In some embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:1 to about 1:2.5, as determined using the molecular weight of the compound of structure (I) as a free base. In certain embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:1.25 to about 1:2, as determined using the molecular weight of the compound of structure (I) as a free base. In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:1.76, as determined using the molecular weight of the compound of structure (I) as a free base.

[0281] In some embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:1 to about 1:10, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt (i.e., a molecular weight of 454.92). In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio ranging from about 1:1.25 to about 1:10, about 1:1.5 to about 1:10, about 1:1.75 to about 1:10, about 1:2 to about 1:10, about 1:2 to about 1:9, about 1:2.5 to about 1:8; about 1:3 to about 1:7, about 1:4 to about 1:6, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:4.5, as determined using the molecular weight of the compound as the hydrochloride salt. In some other embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof and a polyglycolized glyceride in a weight ratio of about 1:3, 1:4, 1:4.5, 1:5.5, or 1:6, as determined using the molecular weight of the compound as the hydrochloride salt.

[0282] Additionally, the concentration of the pharma- ceutically acceptable carrier(s) (e.g., polyglycolized glycerides) can be varied to suit various applications. In some embodiments, the pharma- ceutically acceptable carrier(s) (e.g., polyglycolized glycerides) is present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88 The polyglycolized glycerides comprise 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% v / v, w / w, v / w or w / v. In certain specific embodiments, the polyglycolized glycerides comprise 20% v / v, w / w, v / w or w / v of the composition.

[0283] One particular embodiment provides a unit dose form comprising a composition according to any one of the embodiments disclosed herein (e.g., a therapeutically effective amount of a composition according to any one of the embodiments disclosed herein). In one particular embodiment, the unit dose form is a capsule.

[0284] One particular embodiment is a unit dose form comprising the composition, the composition comprising: A polyglycolized glyceride (e.g., GELUCIRE® 44 / 14) in an amount of about 560 mg to about 600 mg (e.g., about 589 mg); 2. An amount of about 115 mg to about 125 mg (e.g., about 120 mg) of the following structure (I): [ka] or a pharma- ceutically acceptable salt thereof.

[0285] In one embodiment, the unit dosage form is a capsule. In one embodiment, the unit dosage form contains the compound of structure (I) as a hydrochloride salt (e.g., Form I of the hydrochloride salt of the compound of structure (I)). In one embodiment of the unit dosage form, the polyglycolized glyceride is GELUCIRE® 44 / 14, which is present in an amount of about 589.56 mg. In one embodiment, the unit dosage form contains the compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg, as determined using the molecular weight of the compound of structure (I) as a free base.

[0286] One particular embodiment is GELUCIRE® 44 / 14 in an amount of about 589 mg; 1. An amount of about 130 mg of the following structure (I) as determined using the molecular weight of the compound as the hydrochloride salt: [ka] and a hydrochloride salt of a compound having structure (I) (e.g., hydrochloride Form I of the compound having structure (I)).

[0287] The polyglycolized glyceride can be selected based on the desired properties and applications of the composition.Thus, in some embodiments, the polyglycolized glyceride comprises WL 2514CS, LABRASOL, LABRAFIL, GELUCIRE® 44 / 14, GELUCIRE® 33 / 01, GELUCIRE® 35 / 10, GELUCIRE® 37 / 02, GELUCIRE® 50 / 13, GELUCIRE® 44 / 11 and mixtures thereof.In related embodiments, the polyglycolized glyceride comprises GELUCIRE® 33 / 01, GELUCIRE® 35 / 10, GELUCIRE® 37 / 02, GELUCIRE® 50 / 13, GELUCIRE® 44 / 11 or mixtures thereof.In certain specific embodiments, the polyglycolized glyceride is GELUCIRE® 44 / 14.

[0288] In some embodiments, the composition is formulated for oral administration.

[0289] In further embodiments, the compositions described herein further comprise an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described below.

[0290] In one particular embodiment, the disclosure describes the administration of a unit dosage form comprising a composition comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg, as determined using the molecular weight of the compound of structure (I) as a free base, to a subject in need of administration of said unit dosage form. In one embodiment, such a unit dosage form is a capsule comprising a composition comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg, as determined using the molecular weight of the compound of structure (I) as a free base.

[0291] In certain embodiments, the compositions include a mixture of chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients.

[0292] In one embodiment, the composition is formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from physiologically compatible buffers, such as, by way of example only, Hank's solution, Lingard's solution, or saline buffer. In other embodiments, the composition is formulated for transmucosal administration. In certain embodiments, compositions formulated for transmucosal administration include a penetrant appropriate for the barrier to be permeated. In yet other embodiments, when the compositions described herein are formulated for other parenteral injection methods, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such compositions include physiologically compatible buffers and / or excipients.

[0293] In another embodiment, the compositions described herein are formulated for oral administration. In various embodiments, the compositions described herein are formulated into oral dosage forms, including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0294] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In certain embodiments, concentrated sugar solutions are used to coat dosage forms. The sugar solutions optionally contain additional components such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures, just to name a few. For identification purposes, dyes and / or pigments are also optionally added to the coating. In addition, dyes and / or pigments are optionally utilized to characterize different combinations of doses of active composition.

[0295] In certain embodiments, therapeutically effective amounts of the compositions described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (such as glycerol or sorbitol). In specific embodiments, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, lactose, binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally, stabilizers. In other embodiments, the soft capsules contain one or more compositions dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are added as needed.

[0296] In one embodiment, the composition is formulated in the form of a capsule for oral administration. In a more specific embodiment, the compound of structure (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable salt thereof are R The carrier (e.g., polyglycolized glyceride) is formulated into capsules using hydroxypropylmethylcellulose (HPMC). In some specific embodiments, the compound and polyglycolized glyceride are formulated into capsules using hydroxypropylmethylcellulose (HPMC) in a weight ratio of 1:5 (calculated using the molecular weight of the compound of structure (I) as a free base).

[0297] The capsules can be sealed according to methods known in the art. For example, hydroxypropyl methylcellulose (HPMC) can be dissolved in ethanol and applied as a sealant. In some embodiments, the capsules include a sealant (e.g., HPMC). In some more specific embodiments, the capsules include about 5.0±0.5% by weight of sealant. In some embodiments, the capsules include about 5.0±0.5 mg of sealant.

[0298] Pharmaceutical compositions can also be formulated for administration routes other than oral.Other suitable administration routes include intravenous administration, rectal administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, transmucosal administration, transdermal administration, vaginal administration, ear administration, nasal administration and topical administration.Furthermore, by way of example only, parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, as well as intrathecal injection, direct intraventricular injection, intraperitoneal injection, intralymphatic injection and intranasal injection.

[0299] In certain embodiments, the compositions described herein are administered in a local rather than systemic manner (e.g., by direct injection of the composition into an organ, often in a depot preparation or sustained release formulation). In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. In yet other embodiments, the compositions are delivered in the form of targeted drug delivery systems (e.g., liposomes coated with organ-specific antibodies). In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In yet other embodiments, the compositions are provided in the form of rapid release formulations, extended release formulations, or intermediate release formulations. In yet other embodiments, the compositions are administered locally.

[0300] In other embodiments, the composition is formulated for transmucosal administration. In certain embodiments, transmucosal formulations contain penetrants appropriate for the barrier to be permeated. In yet other embodiments, when the composition is formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions contain physiologically compatible buffers and / or excipients.

[0301] In other embodiments, the compositions described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.

[0302] In yet other embodiments, the compositions described herein are formulated for parental injection, including bolus injection or continuous infusion. In a specific embodiment, the formulation for injection is in unit dose form (e.g., in ampoules) or in multi-dose containers. Preservatives are added to the injection formulation as needed. In still other embodiments, the composition is formulated in a form suitable for parenteral injection as a suspension, solution, or emulsion in a sterile oily or aqueous vehicle. The parenteral injection formulation may include a formulary agent, such as a suspending agent, a stabilizing agent, and / or a dispersing agent, as needed. In a further embodiment, the suspension is prepared as a suitable oily injection suspension. Lipophilic solvents or vehicles suitable for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils (such as sesame oil), synthetic fatty acid esters (such as ethyl oleate or triglycerides), or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the active agent to allow the preparation to be a highly concentrated solution. Alternatively, in other different embodiments, the active ingredient is in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0303] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents.Useful polymers include water-soluble polymers (such as cellulosic polymers (e.g., hydroxypropylmethylcellulose)) and water-insoluble polymers (such as cross-linked carboxyl-containing polymers).Certain compositions described herein contain mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0304] Useful compositions also optionally include a solubilizing agent to aid in the solubility of the compound of structure (I) or a pharma- ceutically acceptable salt thereof. The term "solubilizing agent" generally includes agents that form micellar or true solutions of the compound. Certain acceptable non-ionic surfactants (e.g., polysorbate 80) are useful as solubilizing agents, and ophthalmically acceptable glycols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers may also be useful.

[0305] Furthermore, in some embodiments, the composition also optionally contains one or more salts in an amount required to make the osmolality of the composition acceptable.Such salts include, for example, those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions, suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0306] Still other compositions contain one or more surfactants to improve physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil); and polyoxyethylene alkyl ethers and alkyl phenyl ethers (e.g., Octoxynol 10, Octoxynol 40).

[0307] In certain embodiments, the compositions described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations (such as magnesium and zinc); or (n) combinations thereof.

[0308] In some embodiments, the concentration of the compound of structure (I) or a pharma- ceutically acceptable salt thereof in the composition is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.18%, 0.19%, 0.20%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39 ... %, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (w / w, w / v or v / v).

[0309] In some embodiments, the concentration of the compound of structure (I) or a pharma- ceutically acceptable salt thereof in the composition is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%19%, 18.75%, 18.50%, 18.25%18%, 17.75%, 17.50%, 17.25%17%, 16.75%, 16.50%, 16.25%16%, 15.75%, 15.50%, 15.25%15%, 14.75%, 14.50%, 14.25%14%, 13.75%, 13.50%, 13.25%13%, 12.75%, 12.50%, 12.25%12%, 11.75%, 11.50%, 11.25%11%, 10.75%, 10.50%, 10.25%10%, 9.75%, 9.50%, 9.25%9%, 8.75%, 8.50%, 8.25%8%, 7.75%, 7.5 0%,7.25%7%,6.75%,6.50%,6.25%6%,5.75%,5.50%,5.25%5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%,0.0 Greater than 5%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (w / w, w / v, or v / v).

[0310] In some embodiments, the concentration of the compound of structure (I) or a pharma- ceutically acceptable salt thereof in the composition is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, and The range is approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% (w / w, w / v or v / v).

[0311] In some specific embodiments, the concentration of the compound of structure (I) or a pharma- ceutically acceptable salt thereof in the composition ranges from about 10 wt% to about 40 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some specific embodiments, the concentration of the compound of structure (I) or a pharma- ceutically acceptable salt thereof in the composition ranges from about 10 wt% to about 25 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some other embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 14 wt% to about 22 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some other embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 18 wt% to about 19 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some other embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.38 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.38±0.2 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.38±0.4 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.38±0.8 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.12 wt % as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt.In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.12±0.2 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.12±0.4 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 18.12±0.8 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt.

[0312] In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 50 wt% to about 90 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 75 wt% to about 90 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 78 wt% to about 84 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 81 wt% to about 82 wt%. In some more specific embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 81.62 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 81.62±0.5 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 81.62±1 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 81.62±2 wt%. In some more specific embodiments, the composition comprises polyglycolized glycerides at a concentration of about 81.88 wt%. In some embodiments, the composition comprises polyglycolized glycerides at a concentration of about 81.88±0.5 wt%. In some embodiments, the composition comprises polyglycolized glycerides at a concentration of about 81.88±1 wt%. In some embodiments, the composition comprises polyglycolized glycerides at a concentration of about 81.88±2 wt%.

[0313] In some specific embodiments, the concentration of the compound of structure (I) or a pharma- ceutically acceptable salt thereof in the composition ranges from about 15 wt% to about 35 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some other embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 20 wt% to about 30 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some other embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 25 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 25±0.2 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 25±0.4 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises a concentration of about 25±0.8 wt% of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt.

[0314] In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 65 wt% to about 85 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 70 wt% to about 80 wt%. In some more specific embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 75 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 75±0.5 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 75±1 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 75±2 wt%.

[0315] In some specific embodiments, the concentration of the compound of structure (I) or a pharma- ceutically acceptable salt thereof in the composition ranges from about 23.3 wt% to about 43.3 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some other embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from about 28.3 wt% to about 38.3 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some other embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 33.3 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises the compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration of about 33.3±0.2 wt%, as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 33.3±0.4 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt. In some more specific embodiments, the composition comprises a compound of structure (I) or a pharma- ceutically acceptable salt thereof at a concentration of about 33.3±0.8 wt% as determined using the molecular weight of the compound of structure (I) as the hydrochloride salt.

[0316] In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 56.7 wt% to about 76.7 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration ranging from about 61.7 wt% to about 71.7 wt%. In some more specific embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 66.7 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 66.7±0.5 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 66.7±1 wt%. In some embodiments, the composition comprises a polyglycolized glyceride at a concentration of about 66.7±2 wt%.

[0317] In some embodiments, the composition comprises about 100 mg to about 300 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the hydrochloride salt of the compound of structure (I). In some embodiments, the composition comprises about 100 mg to about 160 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the hydrochloride salt of the compound of structure (I). In some embodiments, the composition comprises about 120 mg to about 140 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the hydrochloride salt of the compound of structure (I). In some specific embodiments, the composition comprises about 130.44 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the hydrochloride salt of the compound of structure (I). In some embodiments, the composition comprises about 130.44±0.5 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the hydrochloride salt of the compound of structure (I). In some embodiments, the composition comprises about 130.44±1 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the hydrochloride salt of the compound of structure (I). In some embodiments, the composition comprises about 130.44±3 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the hydrochloride salt of the compound of structure (I).

[0318] In some embodiments, the composition comprises about 100 mg to about 300 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 100 mg to about 150 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 115 mg to about 125 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some specific embodiments, the composition comprises about 120 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 120±0.5 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 120±1 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as the free base. In some embodiments, the composition comprises about 120±3 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as the free base.

[0319] In some embodiments, the composition comprises about 500 mg to about 700 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 550 mg to about 650 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 560 mg to about 600 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 585 mg to about 590 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 587.7 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 587.7 ± 1 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 587.7 ± 2 mg of polyglyceride. In some embodiments, the composition comprises about 587.7 ± 5 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 589.56 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 589.56 ± 1 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 589.56±2 mg of polyglycolized glycerides.In some embodiments, the composition comprises about 589.56±5 mg of polyglycolized glycerides.

[0320] In some embodiments, the composition comprises about 160 mg to about 200 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 175 mg to about 185 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some specific embodiments, the composition comprises about 180 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 180±0.5 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 180±1 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 180±3 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0321] In some embodiments, the composition comprises about 520 mg to about 560 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 535 mg to about 545 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 540 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 540±1 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 540±2 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 540±5 mg of polyglycolized glyceride.

[0322] In some embodiments, the composition comprises about 220 mg to about 260 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 235 mg to about 245 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some specific embodiments, the composition comprises about 240 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 240±0.5 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 240±1 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, the composition comprises about 240±3 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0323] In some embodiments, the composition comprises about 440 mg to about 500 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 475 mg to about 485 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 480 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 480±1 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 480±2 mg of polyglycolized glyceride. In some embodiments, the composition comprises about 480±5 mg of polyglycolized glyceride.

[0324] The compound of structure (I) used in the compositions described herein may be in free base form, or a pharma- ceutically acceptable salt form, or a crystalline form, or any combination thereof. In some embodiments, the compound of structure (I) exists as a free base. In some embodiments, the compound of structure (I) exists as a salt. In some embodiments, the compound of structure (I) exists as a hydrochloride salt. In some embodiments, the compound of structure (I) exists as a crystalline salt form. In some embodiments, the compound of structure (I) exists as Form I of the hydrochloride salt of the compound of structure (I). Crystal morphology

[0325] Different crystalline forms of the compound of structure (I) and its pharma- ceutically acceptable salts, including the hydrochloride salt of the compound of structure (I), have been discovered. Accordingly, provided herein are crystalline forms of the compound of structure (I) or its pharma- ceutically acceptable salts, such as the hydrochloride salt thereof.

[0326] Although crystallization is often performed on organic compounds, it is not possible to predict in advance which conditions will provide the appropriate conditions for resulting in the formation of a particular crystalline form, and furthermore, it is not possible to predict which particular crystalline form will provide the requisite mix of physical properties to result in a desired drug dosage form when formulated.

[0327] Crystallization of the hydrochloride salt of the compound of structure (I) in selected solvents and under selected conditions led to the discovery of crystalline forms I and II, which have distinct physical behavior. Experimental equipment and conditions:

[0328] X-ray powder diffraction was performed using a Rigaku D / MAS 2200 X-ray powder diffractometer. Standard measurement conditions were: X-ray generator: Cu, kα (λ=1.54056 Å); tube voltage: 40 kV, tube current: 20 mA; DivSlit: 1 degree; DivH.L.Slit: 10 mm; SctSlit: 1 degree; RecSlit: 0.15 mm; fixed monochromator; scan range: 4-40 degrees; scan step: 10 degrees / min. Thus, when a crystalline form described herein is characterized by its X-ray powder diffraction pattern, for example by listing selected peaks, the pattern and / or peaks are, in some embodiments, measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0329] Polarized light microscopy was performed on a Nikon LV 100 polarized light microscope equipped with a 5 megapixel CCD and a 10x eyepiece and a 20x objective.

[0330] Differential scanning calorimetry (DSC) was performed using a TA Q2000 DSC at a heating rate of 10° C. / min over the range of 30° C. to 300° C. Thus, when the crystalline forms described herein are characterized by DSC thermograms, e.g., by listing the temperatures associated with various events, the temperatures and / or thermograms are, in some embodiments, measured by DSC over the range of 30° C. to 300° C. using a heating rate of 10° C. / min.

[0331] Thermogravimetric analysis (TGA) was performed using a TA Q5000 IR TGA at a heating rate of 10° C. / min over the range of 30° C. to 300° C. Thus, when the crystalline forms described herein are characterized by a TGA spectrum, the spectrum is, in some embodiments, measured by TGA over the range of 30° C. to 300° C. using a heating rate of 10° C. / min. Amorphous Form:

[0332] The amorphous solid form of the hydrochloride salt of the compound of structure (I) was obtained using the slow evaporation method described in Example 12, for example, by slowly evaporating a solution of the hydrochloride salt of the compound of structure (I) in methanol. The product thus obtained had an X-ray powder diffraction pattern with no peaks (FIG. 18), thus revealing that the reaction product was in amorphous form. Thus, in some embodiments, the compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt) is in amorphous form. The compound of structure (I) is also referred to herein as 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol. Crystal form I:

[0333] In some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound of structure (I) comprises, consists of, or consists essentially of Form I. In some embodiments, the crystalline form of the hydrochloride salt of the compound of structure (I) is Form I. Form I can generally be prepared by suspending the hydrochloride salt of the compound of structure (I) in a solution of ethyl acetate and methanol and optionally stirring the resulting mixture.

[0334] Crystalline Form I comprises the X-ray powder diffraction pattern shown in Figure 1. Peak assignments and their relative intensities corresponding to the diffraction pattern of crystalline Form I are listed in Table 1. [Table 1]

[0335] In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern including peaks at 21.5±0.2°, 19.9±0.2°, and 17.8±0.2° in terms of 2θ. In some embodiments, crystalline form I is further characterized by an X-ray powder diffraction pattern including peaks at 16.3±0.2°, 19.3±0.2°, and 24.4±0.2° in terms of 2θ. In some embodiments, crystalline form I is further characterized by an X-ray powder diffraction pattern including peaks at 10.1±0.2°, 11.7±0.2°, 14.4±0.2°, and 16.7±0.2° in terms of 2θ. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern including a peak at 19.3±0.2° in terms of 2θ. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern including a peak at 24.4±0.2° in terms of 2θ. In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern comprising a peak at 16.3±0.2 degrees in terms of 2θ.

[0336] In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern comprising at least three peaks (e.g., three peaks, at least four peaks, four peaks, at least five peaks, five peaks, six peaks) at 2θ angles selected from the group consisting of 24.4±0.2°, 21.5±0.2°, 19.9±0.2°, 19.3±0.2°, 17.8±0.2°, and 16.3±0.2°.

[0337] In any of the embodiments of crystalline form I described herein, crystalline form I is further characterized by an X-ray diffraction pattern substantially lacking a peak at 15.7±0.2 degrees in terms of 2θ. In any of the embodiments of crystalline form I described herein, crystalline form I is further characterized by an X-ray diffraction pattern substantially lacking a peak at 17.0±0.2 degrees in terms of 2θ. In any of the embodiments of crystalline form I described herein, crystalline form I is further characterized by an X-ray diffraction pattern substantially lacking a peak at 19.0±0.2 degrees in terms of 2θ.

[0338] In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0339] A graph of differential scanning calorimetry of crystalline form I performed at a rate of 10°C / min while heating from 30°C to 300°C is shown in Figure 2. A peak is seen at about 226.9°C, which correlates with an endothermic event. A peak onset is seen at 226.2°C, which correlates with the melting temperature of crystalline form I. Thus, in some embodiments, crystalline form I is characterized by a differential scanning calorimetry thermogram that includes an endothermic event at 226.9±3°C. In some embodiments, crystalline form I has a melting temperature of 226±3°C (e.g., 226.2±3°C), as measured, for example, by differential scanning calorimetry. In some embodiments, crystalline form I has a DSC thermogram substantially in accordance with that shown in Figure 2.

[0340] The thermogravimetric analysis graph of Form I is shown in Figure 3. A mass loss of about 0.4% is observed between 30°C and 118°C. In some embodiments, crystalline Form I has a TGA diagram substantially in accordance with that shown in Figure 3.

[0341] A polarized light microscopy (PLM) image of crystalline form I is shown in FIG.

[0342] Form I exhibits good crystallinity by XRPD and birefringence by PLM.

[0343] Crystalline Form I can be prepared according to a process comprising precipitating said crystalline form from a solution or suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. In some embodiments, the non-aqueous medium comprises methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), 1-butanol, acetonitrile (ACN), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), dichloromethane (DCM), 1,4-dioxane, toluene, heptane, tetrahydrofuran (THF) or acetone, or a combination thereof. In some embodiments, the non-aqueous medium is a mixture of MeOH and EtOAc.

[0344] Some embodiments of the process for preparing crystalline form I include precipitating said crystalline form from a solution comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium (e.g., a solution comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol, methanol, and ethyl acetate). Some embodiments include precipitating said crystalline form from a suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. Some embodiments further include cooling the solution or suspension to about 4° C. Some embodiments further include heating the solution or suspension (e.g., before cooling the solution or suspension), for example, to about 50° C. to about 75° C. Some embodiments further include contacting the solution or suspension with a seed crystal of a crystalline form. Some embodiments further include contacting a solution or suspension comprising the free base of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium with hydrochloric acid to produce the solution or suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium. Crystal form II:

[0345] In some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound of structure (I) comprises, consists of, or consists essentially of Form II. In some embodiments, the crystalline form of the hydrochloride salt of the compound of structure (I) is Form II. Form II can generally be prepared by combining the hydrochloride salt of the compound of structure (I) with a solvent such as water and optionally stirring the resulting mixture.

[0346] Crystalline Form II comprises the X-ray powder diffraction pattern shown in Figure 5. Peak assignments and their relative intensities corresponding to the diffraction pattern of crystalline Form II are listed in Table 2. [Table 2]

[0347] In some embodiments, crystalline form II is characterized by an X-ray powder diffraction pattern comprising peaks at 21.5±0.2°, 19.9±0.2°, and 17.7±0.2° in terms of 2θ. In some embodiments, crystalline form II is further characterized by an X-ray powder diffraction pattern comprising a peak at 15.7±0.2° in terms of 2θ. In some embodiments, crystalline form II is further characterized by an X-ray powder diffraction pattern comprising a peak at 17.0±0.2° in terms of 2θ. In some embodiments, crystalline form II is further characterized by an X-ray powder diffraction pattern comprising a peak at 19.0±0.2° in terms of 2θ. In some embodiments, crystalline form II is further characterized by an X-ray powder diffraction pattern comprising a peak at 24.3±0.2° in terms of 2θ.

[0348] In some embodiments, crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least three peaks (e.g., three peaks, at least four peaks, four peaks, at least five peaks, five peaks, six peaks) at 2θ angles selected from the group consisting of 24.3±0.2°, 21.5±0.2°, 19.9±0.2°, 19.0±0.2°, 17.7±0.2°, 17.0±0.2°, and 15.7±0.2°.

[0349] In some embodiments, crystalline Form II is characterized by an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0350] Crystalline Form II can be prepared according to a process comprising precipitating said crystalline form from a suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and water. In some embodiments, the precipitating is performed at room temperature. Some embodiments further comprise contacting the suspension with a seed crystal of the crystalline form. Some embodiments further include contacting the solution or suspension containing the free base of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol with hydrochloric acid to produce the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol.

[0351] The above method can be used to prepare crystalline forms I and II and amorphous forms. Although the preparation of each of crystalline forms I and II and amorphous forms is illustrated using a specific solvent system and crystallization conditions, it is envisioned that each form can be obtained by using a different solvent or combination of solvents and / or different crystallization conditions. Furthermore, crystals of either crystalline form I or II can be added to the solution or slurry of the amorphous form to seed the crystallization of that particular form. Therefore, the above description is not meant to limit the present invention in any way.

[0352] Additionally, either of the crystalline forms I and II may be treated to regenerate the amorphous form. In some embodiments of the invention, it may be desirable to use forms I and II at higher levels of purity, but it may also be desirable to utilize the amorphous form in formulations therein to deliver a therapeutically effective amount of the hydrochloride salt of the compound of structure (I).

[0353] A partial list of useful solvents includes, for example, methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), 1-butanol, acetonitrile (ACN), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), dichloromethane (DCM), 1,4-dioxane, toluene, heptane, tetrahydrofuran (THF), acetone, and water, and combinations thereof.

[0354] In some embodiments, the crystalline forms described herein are substantially pure (eg, as determined by high pressure liquid chromatography).

[0355] In some embodiments of the present invention, the purity of the amorphous form of the hydrochloride salt of the compound of structure (I) (e.g., as measured by high pressure liquid chromatography) is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% (e.g., total area under the curve observed at about 220 nm). In some embodiments of the present invention, the amorphous form of the hydrochloride salt of the compound of structure (I) is about 100.0 pure (e.g., as measured by high pressure liquid chromatography as the area under the curve observed at about 220 nm).

[0356] In some embodiments of the present invention, the purity of crystalline Form I of the hydrochloride salt of the compound of structure (I) (e.g., as measured by high pressure liquid chromatography) is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% (e.g., total area under the curve observed at about 220 nm). In some embodiments of the present invention, crystalline Form I of the hydrochloride salt of the compound of structure (I) is about 100.0 pure (e.g., as measured by high pressure liquid chromatography as the area under the curve observed at about 220 nm).

[0357] In some embodiments of the present invention, the purity of crystalline Form II of the hydrochloride salt of the compound of structure (I) (e.g., as measured by high pressure liquid chromatography) is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% of the total area under the curve observed at about 220 nm. In some embodiments of the present invention, crystalline Form II of the hydrochloride salt of the compound of structure (I) is about 100.0 pure (e.g., as measured by high pressure liquid chromatography as the area under the curve observed at about 220 nm).

[0358] In some embodiments of the process of manufacture of the present invention, the optical purity of the amorphous form of the hydrochloride salt of the compound of structure (I) (e.g., as measured by chiral chromatography, e.g., at 220 nm and / or 260 nm) is about 75.0%, about 75.5%, about 76.0%, about 76.5%, about 77.0%, about 77.5%, about 78.0%, about 78.5%, about 79.0%, about 79.5%, about 80.0%, about 80.5%, about 81.0%, about 81.5%, about 82.0%, about 82.5%, about 83.0%, about 83.5%, about 84.0%, about 84. The optical purity is greater than 5%, about 85.0%, about 85.5%, about 86.0%, about 86.5%, about 87.0%, about 87.5%, about 88.0%, about 88.5%, about 89.0%, about 89.5%, about 90.0%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9%. In some embodiments, the optical purity of the amorphous form of the hydrochloride salt of the compound of structure (I) (eg, as measured at 220 nm and / or 260 nm) is about 100%.

[0359] In some embodiments of the process of manufacture of the present invention, the optical purity of Form I of the hydrochloride salt of compound of structure (I) (e.g., as measured by chiral chromatography at 220 nm and / or 260 nm) is about 75.0%, about 75.5%, about 76.0%, about 76.5%, about 77.0%, about 77.5%, about 78.0%, about 78.5%, about 79.0%, about 79.5%, about 80.0%, about 80.5%, about 81.0%, about 81.5%, about 82.0%, about 82.5%, about 83.0%, about 83.5%, about 84.0%, about 84.5%, about 85.0%, about 86.0%, about 87.0%, about 88.0%, about 89.0%, about 90.0%, about 91.0%, about 92.0%, about 93.0%, about 94.0%, about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 9 ... The optical purity is greater than about 85.0%, about 85.5%, about 86.0%, about 86.5%, about 87.0%, about 87.5%, about 88.0%, about 88.5%, about 89.0%, about 89.5%, about 90.0%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9%. In some embodiments, the optical purity (eg, as measured at 220 nm and / or 260 nm) of Form I of the hydrochloride salt of the compound of structure (I) is about 100%.

[0360] In some embodiments of the process of manufacture of the present invention, the optical purity of Form II of the hydrochloride salt of compound of structure (I) (e.g., as measured by chiral chromatography at 220 nm and / or 260 nm) is about 75.0%, about 75.5%, about 76.0%, about 76.5%, about 77.0%, about 77.5%, about 78.0%, about 78.5%, about 79.0%, about 79.5%, about 80.0%, about 80.5%, about 81.0%, about 81.5%, about 82.0%, about 82.5%, about 83.0%, about 83.5%, about 84.0%, about 84.5%, about 85.0%, about 86.0%, about 87.0%, about 88.0%, about 89.0%, about 90.0%, about 91.0%, about 92.0%, about 93.0%, about 94.0%, about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 9 ... The optical purity is greater than about 85.0%, about 85.5%, about 86.0%, about 86.5%, about 87.0%, about 87.5%, about 88.0%, about 88.5%, about 89.0%, about 89.5%, about 90.0%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9%. In some embodiments, the optical purity of Form II of the hydrochloride salt of the compound of structure (I) (eg, as measured at 220 nm and / or 260 nm) is about 100%.

[0361] In some embodiments of the process of manufacture of the present invention, the amorphous form of the hydrochloride salt of the compound of structure (I) is free of about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, or about 1.0% of any one impurity derived, obtained, or produced as a result of chemical synthesis. %, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, or less than about 0.009% (e.g., as measured by chromatography at about 220 nm). In some embodiments, the impurity is a synthetic by-product.

[0362] In some embodiments of the process of manufacture of the present invention, Form I of the hydrochloride salt of the compound of structure (I) has less than about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, or about 0.009% of any one impurity derived, obtained or produced as a result of chemical synthesis (e.g., as measured by chromatography at about 220 nm). In some embodiments, the impurity is a synthetic by-product.

[0363] In some embodiments of the process of manufacture of the present invention, Form II of the hydrochloride salt of the compound of structure (I) has less than about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, or about 0.009% of any one impurity derived, obtained or produced as a result of chemical synthesis (e.g., as measured by chromatography at about 220 nm). In some embodiments, the impurity is a synthetic by-product.

[0364] In some embodiments of the process of manufacture of the present invention, the amorphous form of the hydrochloride salt of the compound of structure (I) has less than about 3.0%, about 2.9%, about 2.8%, about 2.7%, about 2.6%, about 2.5%, about 2.4%, about 2.3%, about 2.2%, about 2.1%, about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09% of total impurities derived, obtained or produced as a result of chemical synthesis (e.g., as measured by chromatography at about 220 nm). In some embodiments, the impurity is a synthetic by-product.

[0365] In some embodiments of the process of manufacture of the present invention, Form I of the hydrochloride salt of the compound of structure (I) has less than about 3.0%, about 2.9%, about 2.8%, about 2.7%, about 2.6%, about 2.5%, about 2.4%, about 2.3%, about 2.2%, about 2.1%, about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09% of total impurities derived, obtained or produced as a result of chemical synthesis (e.g., as measured by chromatography at about 220 nm). In some embodiments, the impurity is a synthetic by-product.

[0366] In some embodiments of the process of manufacture of the present invention, Form II of the hydrochloride salt of the compound of structure (I) has less than about 3.0%, about 2.9%, about 2.8%, about 2.7%, about 2.6%, about 2.5%, about 2.4%, about 2.3%, about 2.2%, about 2.1%, about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09% of total impurities derived, obtained or produced as a result of chemical synthesis (e.g., as measured by chromatography at about 220 nm). In some embodiments, the impurity is a synthetic by-product. Pharmacology and Usefulness

[0367] In certain embodiments, a method for treating cancer is provided.The method comprises administering a therapeutically effective amount of a compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, or a composition or unit dose form comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof, e.g., a crystalline form or a composition or unit dose disclosed herein) to a subject in need thereof.

[0368] In certain embodiments, methods are provided for treating a disease or disorder described herein, comprising administering a therapeutically effective amount of a crystalline form or composition or unit dose disclosed herein to a subject in need thereof.

[0369] In some embodiments, the cancer is bladder cancer, prostate cancer, colorectal cancer, a hematological malignancy, or acute myeloid leukemia. In some embodiments, the cancer is a Pim kinase-mediated cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is a fibrotic cancer (e.g., myelofibrosis).

[0370] As used herein, "fibrotic cancer" refers to cancer associated with fibrosis.Examples of fibrotic cancer include, but are not limited to, myelofibrosis, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), kidney cancer, liver cancer, lung cancer (e.g., large cell lung cancer, such as squamous cell carcinoma), breast cancer (e.g., inflammatory breast cancer), ovarian cancer (e.g., high-grade severe ovarian cancer), endometrial cancer, uterine cancer, uterine sarcoma (e.g., uterine leiomyosarcoma), renal cell carcinoma, sarcoma (e.g., soft tissue sarcoma), malignant fibrous histiocytoma, fibrosarcoma (e.g., dermatofibrosarcoma protuberans) and hepatocellular carcinoma.

[0371] In some embodiments, the cancer to be treated is a blood cancer. Cancers that can be treated by the methods described herein include leukemia and lymphoma (e.g., B-cell lymphoma, T-cell lymphoma). In some embodiments, the blood cancer is selected from acute myeloid leukemia (AML), follicular lymphoma, acute lymphoblastic leukemia (ALL), mantle cell lymphoma, diffuse large B-cell lymphoma, lymphocytic lymphoma, mycosis fungoides, chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and non-Hodgkin's lymphoma (e.g., AML, follicular lymphoma, ALL, CLL and non-Hodgkin's lymphoma). In more specific embodiments, the blood cancer is AML. In other more specific embodiments, the blood cancer is CLL. In more specific embodiments, the blood cancer is MM. In yet other specific embodiments, the blood cancer is myelodysplastic syndrome (MDS).

[0372] In other embodiments, the cancer comprises a solid tumor. Thus, in some embodiments, the cancer is a solid tumor cancer. In various embodiments, the solid tumor cancer is breast cancer, bladder cancer, liver cancer, pancreatic cancer, lung cancer, colorectal cancer, ovarian cancer, prostate cancer, or melanoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In other embodiments, the cancer is liver cancer. In some embodiments, the cancer is a sarcoma, bladder cancer, or renal cancer. In some embodiments, the cancer is prostate cancer (e.g., castration-resistant prostate cancer, castration-sensitive prostate cancer). In other embodiments, the cancer is bladder cancer, pancreatic cancer, colorectal cancer, renal cancer, non-small cell lung cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer, testicular cancer, or vulvar cancer. In some embodiments, the cancer is endometrial cancer, pancreatic cancer, testicular cancer, renal cancer, melanoma, colorectal cancer, thyroid cancer, bladder cancer, pancreatic cancer, vulvar cancer, sarcoma, prostate cancer, lung cancer, or anal cancer. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is renal cell carcinoma.

[0373] Further examples of cancers treatable according to the methods described herein include lung cancer, non-small cell lung cancer (NSCLC), oat cell cancer, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (e.g., uterine sarcoma, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, hepatocellular carcinoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., thyroid cancer, , pancreatic, parathyroid or adrenal gland cancer), sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer (e.g., castration-resistant prostate cancer), chronic or acute leukemia, solid tumors of childhood, hypereosinophilia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, renal pelvis carcinoma), childhood malignancies, neoplasms of the central nervous system (e.g., primary central nervous system lymphoma, spinal axis tumor, medulloblastoma, brain stem glioma or pituitary adenoma), Barrett's esophagus (e.g., a precancerous syndrome) and mycosis fungoides.

[0374] Still further examples of cancers treatable according to the methods described herein include acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related cancers (e.g., Kaposi's sarcoma, AIDS-related lymphoma, primary central nervous system lymphoma); anal cancer; appendix cancer; astrocytoma, pediatric; atypical teratoma / rhabdoid tumor, pediatric, central nervous system; basal cell carcinoma of the skin; bile duct cancer; bladder cancer; bladder cancer, pediatric; bone cancer (including Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma); brain tumor / cancer; breast cancer; Burkitt's lymphoma. lymphoma;carcinoid tumors (gastrointestinal);carcinoid tumors, children;cardiac (heart) tumors, children;embryonal tumors, children;germ cell tumors, children;primary central nervous system lymphoma;cervical cancer;pediatric cervical cancer;cholangiocarcinoma;chordoma, children;chronic lymphocytic leukemia (CLL);chronic myeloid leukemia (CML);chronic myeloproliferative neoplasms;colorectal cancer;pediatric colorectal cancer;craniopharyngioma, children;cutaneous T-cell lymphoma (e.g., mycosis fungoides and Sézary syndrome);ductal carcinoma in situ (DCIS);embryonal tumors, central nervous system, children;endometrial cancer (uterine cancer);ependymoma, children;esophageal cancer;childhood Esophageal cancer;Esthesioneuroblastoma;Ewing's sarcoma;Extracranial germ cell tumors, children;Extragonadal germ cell tumors;Eye cancer;Childhood intraocular melanoma;Intraocular melanoma;Retinoblastoma;Fallen tube cancer;Fibrous histiocytoma, malignant, and osteosarcoma of bone;Gallbladder cancer;Stomach (gastric) cancer;Childhood gastric (gastric) cancer;Gastrointestinal carcinoid tumors;Gastrointestinal stromal tumors (GIST);Childhood gastrointestinal stromal tumors;Germ cell tumors;Childhood central nervous system germ cell tumors (e.g., pediatric extracranial germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer);Gestational trophoblastic disease;Hairy cell leukemia;Head and neck cancer;Cardiac tumors, children;Hepatocellular ( liver) cancer;histiocytosis, Langerhans cell;Hodgkin's lymphoma;hypopharyngeal cancer;intraocular melanoma;pediatric intraocular melanoma;pancreatic islet tumors, pancreatic neuroendocrine tumors;Kaposi's sarcoma;kidney (renal cell) cancer;Langerhans cell histiocytosis;laryngeal cancer;leukemia;cancer of the lip and oral cavity;hepatic cancer;lung cancer (non-small cell and small cell);pediatric lung cancer;lymphoma;male breast cancer;malignant fibrous histiocytoma and osteosarcoma of bone;melanoma;pediatric melanoma;melanoma, intraocular (eye);pediatric intraocular melanoma;Merkel cell carcinoma;mesothelioma, malignant;pediatric mesothelioma;metastatic carcinoma;metastatic squamous cell neck carcinoma of unknown primary;Midline duct carcinoma with NUT gene alterations;Oral cavity cancer;Multiple endocrine neoplasia syndrome;Multiple myeloma / plasma cell neoplasm;Mycosis fungoides;Myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm;Myeloid leukemia, chronic (CML);Myeloid leukemia, acute (AML);Myeloproliferative neoplasm, chronic;Nasal cavity and paranasal sinus cancer;Nasopharyngeal carcinoma;Neuroblastoma:Non-Hodgkin's lymphoma;Non-small cell lung cancer;Oral cavity, lip and oral cavity, and oropharyngeal cancer; Osteosarcoma and malignant fibrous histiocytoma of bone;ovarian cancer;pediatric ovarian cancer;pancreatic cancer;pediatric pancreatic cancer;pancreatic neuroendocrine tumors;papilloma (pediatric larynx);paraganglioma;pediatric paraganglioma;sinoasal and nasal cancer;parathyroid cancer;penile cancer;pharyngeal cancer;pheochromocytoma;pediatric pheochromocytoma;pituitary tumors;plasma cell neoplasms / multiple myeloma;pleuropulmonary blastoma;pregnancy and breast cancer;primary central nervous system (CNS) lymphoma;primary peritoneal cancer;prostate cancer;rectal Cancer;Recurrent cancer;Renal cell (kidney) cancer;Retinoblastoma;Rhabdomyosarcoma, childhood;Salivary gland cancer;Sarcoma (e.g. childhood rhabdomyosarcoma, childhood vascular tumor, Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma);Sezary syndrome;Skin cancer;Childhood skin cancer;Small cell lung cancer;Small intestine cancer;Soft tissue sarcoma;Squamous cell carcinoma of the skin;Squamous cell neck carcinoma of unknown primary;Gastric (stomach) cancer;Childhood gastric (stomach) cancer;T-cell lymphoma, skin (e.g. cancer; cancer of the throat (e.g., nasopharyngeal, oropharyngeal, hypopharyngeal); thymoma and thymic carcinoma; thyroid cancer; transitional cell carcinoma of the renal pelvis and ureter; transitional cell carcinoma of the ureter and renal pelvis; urethral cancer; uterine cancer, endometrium; uterine sarcoma; vaginal cancer; pediatric vaginal cancer; vascular tumors; vulvar cancer; and Wilms' tumor and other pediatric kidney tumors.

[0375] Metastases of the aforementioned cancers can also be treated according to the methods described herein.

[0376] Myeloproliferative neoplasms are also amenable to the treatment methods disclosed herein. Myeloproliferative neoplasms (NPMs) refer to a group of disorders in which bone marrow stem cells grow and reproduce abnormally. The abnormal stem cells of MPNs produce an excessive number of one or more types of blood cells (e.g., red blood cells, white blood cells, and / or platelets). As disclosed herein, myeloproliferative neoplasms include, but are not limited to, polycythemia vera (PV), primary or essential thrombocythemia (ET), primary or idiopathic myelofibrosis (MF), secondary myelofibrosis (e.g., myelofibrosis secondary to polycythemia vera or essential thrombocythemia), chronic myelogenous (myelocytic) leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), juvenile myelomonocytic leukemia (JML), systemic mastocytosis, and chronic eosinophilic leukemia (CEL) / hypereosinophilic syndrome (HES).

[0377] In some specific embodiments, the myeloproliferative neoplasm of the mammal treated for myeloproliferative neoplasm according to the embodiments described herein comprises a JAK2 mutation, a thrombopoietin receptor (MPL) mutation, or a calreticulin (CALR) mutation. In some embodiments, the JAK2 mutation comprises a JAK2 V617 mutation. JAK2 V617F refers to a mutant JAK2 with a V→F amino acid substitution at position 617 relative to human wild-type JAK2 (UniProt.060674). In some embodiments, the MPL mutation comprises an MPL W515L mutation. MPL W515L refers to a mutant thrombopoietin receptor (MPL) with a W→L substitution at position 515 relative to human wild-type MPL (UniProt.P40238). In some embodiments, the mutation in CALR comprises a CALR exon 9 indel.

[0378] The International Prognostic Scoring System (IPSS) is the main method for stratifying myelofibrosis patients. Risk factors using IPSS include age, general symptoms (e.g., weight loss, fever or excessive sweating), white blood cell count, hemoglobin, peripheral blasts, complex or abnormal karyotype, transfusion dependency, and platelet count. Patients with low-risk myelofibrosis have an IPSS score of 0. An IPSS score of 0 is usually associated with a median survival of about 180 months. In some embodiments, the myelofibrosis is low-risk myelofibrosis.

[0379] Patients with medium risk myelofibrosis have an IPSS score of 1, 2, or 3. An IPSS score of 1, also referred to as medium risk 1, is usually associated with a median survival of about 80 months. An IPSS score of 2 or 3, also referred to as medium risk 2, is usually associated with a median survival of about 35 months. In some embodiments, the myelofibrosis is medium risk myelofibrosis (e.g., medium risk 1 myelofibrosis, medium risk 2 myelofibrosis).

[0380] Patients with high-risk myelofibrosis have an IPSS score of 4 or higher. An IPSS score of 4 or higher is usually associated with a median survival of about 16 months. In some embodiments, the myelofibrosis is high-risk myelofibrosis.

[0381] In some embodiments, the disease or disorder (e.g., cancer, MPN) treated according to the treatment methods disclosed herein is myelofibrosis. In some embodiments, the myelofibrosis is intermediate 2 or high risk primary or secondary MF.

[0382] In some embodiments, the MPN is a JAK inhibitor-resistant MPN (e.g., ruxolitinib-resistant and / or fedratinib-resistant MPN, e.g., ruxolitinib-resistant myelofibrosis, fedratinib-resistant myelofibrosis). In some embodiments, the MPN (e.g., myelofibrosis) has been previously treated with a JAK inhibitor (e.g., ruxolitinib and / or fedratinib), e.g., in the absence of a compound of structure (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously treated with a JAK inhibitor (e.g., ruxolitinib and / or fedratinib) and is intolerant, resistant, refractory, or has lost response to the JAK inhibitor.

[0383] In some embodiments, the subject is not suitable to receive a JAK inhibitor (eg, ruxolitinib and / or fedratinib).

[0384] In some embodiments, the subject has previously been treated with a JAK inhibitor (e.g., ruxolitinib and / or fedratinib) or is not suitable to receive a JAK inhibitor (e.g., ruxolitinib and / or fedratinib). In some embodiments, the subject who has previously been treated with a JAK inhibitor is intolerant, resistant, refractory, or has lost response to the JAK inhibitor.

[0385] Some embodiments are methods of treating intermediate-2 or high-risk primary or secondary myelofibrosis in a subject in need of treatment for intermediate-2 or high-risk primary or secondary myelofibrosis, comprising administering to the subject a therapeutically effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof (e.g., a crystalline form of the compound of structure (I) or a pharmaceutically acceptable salt thereof, or a composition or unit dosage form comprising the compound of structure (I) or a pharmaceutically acceptable salt thereof, e.g., a crystalline form or composition or unit dosage disclosed herein), wherein the subject has previously received ruxolitinib or a pharmaceutically acceptable salt thereof, or fedratinib or a pharmaceutically acceptable salt thereof, or is not suitable to receive ruxolitinib or a pharmaceutically acceptable salt thereof, or fedratinib or a pharmaceutically acceptable salt thereof. In some aspects, the method further comprises administering ruxolitinib or a pharmaceutically acceptable salt thereof or fedratinib or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0386] In some embodiments, treatment of the MPN or cancer described herein results in complete remission in the subject. As used to refer to a subject having an MPN, such as myelofibrosis, "complete remission" means that the subject has met the following diagnostic criteria for ≥ 12 weeks: (i) according to European classification, the bone marrow shows age-adjusted normal normocellularity, < 5% blast cells, and myelofibrosis ≤ grade 1, and (ii) hemoglobin in peripheral blood is ≥ 100 g / L and < UNL, neutrophil count is ≥ 1 × 10 9 / L and < UNL, and (iii) platelet count is ≥ 100 × 10 9 / L and < UNL, and immature myeloid cells are < 2% (except that < 5% immature myeloid cells are acceptable in splenectomized patients), and (iv) disappearance of disease symptoms, non-palpable spleen and liver, and no evidence of EMH This means that

[0387] In some embodiments, the treatment of MPN or cancer described herein results in the mammal being measurable residual disease (MRD) negative.

[0388] In the context of myeloproliferative neoplasms such as MF, measurable residual disease, minimal residual disease and MRD refer to the presence of cells with acquired mutations in the JAK2, CALR and MPL genes in subjects with myeloproliferative neoplasms such as MF. Common mutations in JAK2 include V617F mutations and exon 12 mutations (e.g., substitutions, deletions, insertions, duplications). Common mutations in CALR include exon 9 mutations. Common mutations in MPL include exon 10 mutations (e.g., W515L and W515K). MRD is used diagnostically in the context of myeloproliferative neoplasms, but can also be used quantitatively to indicate the depth of response to therapeutic intervention. MRD testing for myeloproliferative neoplasms such as MF is usually performed using allele-specific quantitative PCR (qPCR), digital PCR or next-generation sequencing. The above-mentioned methods are reviewed in Haslam, K. and Langabeer, SE, "Monitoring Residual Disease in the Myeloproliferative Neoplasms: Current Applications and Emerging Approaches," Biomed. Res. Intl. 2016:7241591, the relevant teachings of which are incorporated herein by reference in their entirety.

[0389] In some embodiments, a subject with MPN, such as MF, is measurable residual disease negative, e.g., after administration of a compound of structure (I) or a pharma- ceutically acceptable salt thereof. A subject with a myeloproliferative neoplasm, such as MF, is "measurable residual disease negative," "minimal residual disease negative," "MRD negative," or "MRD negative." -When a subject is described herein as having a myeloproliferative neoplasm, the subject is free of or measurably free of cells with acquired mutations in at least one of JAK2, CALR, or MPL (e.g., JAK2 V617F mutation, JAK2 exon 12 mutation, CALR exon 9 mutation, MPL W515K / L mutation) associated with myeloproliferative neoplasm. For example, in some embodiments, the MRD-negative subject is free of or measurably free of cells with JAK2 V617F mutation. In some embodiments, the MRD-negative subject is free of or measurably free of cells with CALR exon 9 mutation. In some embodiments, the MRD-negative subject is free of or measurably free of cells with MPL exon 10 mutation. Acquired mutations associated with myeloproliferative neoplasms are known in the art and are described in Haslam, K. and Langabeer, SE, "Monitoring Residual Disease in the Myeloproliferative Neoplasms: Current Applications and Emerging Approaches," Biomed. Res. Intl. 2016:7241591, the relevant teachings of which are incorporated herein by reference in their entirety.

[0390] In some embodiments, the cancer is myelofibrosis. In some more specific embodiments, the method further comprises administering a second therapeutic agent (e.g., ruxolitinib). In some embodiments, the cancer is myelofibrosis and the method further comprises administering ruxolitinib.

[0391] The usual starting dose of ruxolitinib is 200 × 10 9 For patients with platelet counts above 100 × 10 / L, 20 mg is administered orally twice daily. 9 / L and 200 x 10 9For patients with platelet counts between 0.01 and 0.1 / L, 15 mg is administered twice daily. The dose of ruxolitinib can be increased based on the patient's response up to a maximum of 25 mg twice daily. If patients who have received ruxolitinib under these conditions for 6 months do not have a shrinkage of the spleen or improvement of symptoms, ruxolitinib treatment is usually discontinued.

[0392] In embodiments involving ruxolitinib or a pharma- ceutically acceptable salt thereof, the dosage of ruxolitinib or a pharma- ceutically acceptable salt thereof is in the range of about 1 mg to about 100 mg per day, about 2.5 mg to about 60 mg per day, about 5 mg to about 60 mg per day, or about 10 mg to about 50 mg per day. In some embodiments, ruxolitinib or a pharma- ceutically acceptable salt thereof is administered at a dosage of about 5 mg to about 100 mg per day or about 10 mg to about 50 mg per day. For example, ruxolitinib is typically given as an oral formulation twice daily at individual doses of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg.

[0393] In some embodiments, the methods of the invention are particularly useful for treating patients with myelofibrosis who have been previously treated with a JAK inhibitor (e.g., ruxolitinib or fedratinib) and have become intolerant, resistant, refractory or unsuitable, and / or for treating myelofibrosis with thrombocytopenia (i.e., platelet counts below 50K and ruxolitinib cannot be used). Suitable patients may also exhibit one or more of the following characteristics: a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate 2 or high risk; myelofibrosis grade of 2 or higher; 1×10 9 Absolute neutrophil count (ANC) ≥ 50 × 10 / L (without granulocyte growth factor) 9platelet count > 8 g / dL (without growth factor or platelet transfusion); hemoglobin > 8 g / dL; peripheral blood blast count < 10%; at least two measurable (score ≥ 1) symptoms using the MFSAF (v 4.0); and / or spleen length > 5 cm by palpitation or 450 cm by MRI or CT scan 3 Splenomegaly as evidenced by splenic volume greater than or equal to 100 mm.

[0394] Individualized treatment for patients with myelofibrosis may include assessment of prognosis and estimation of disease burden by current clinical scoring systems. Useful biomarker assessments for myelofibrosis treatment are summarized below. [Table 33]

[0395] In some embodiments, the disease or disorder is fibrotic disease or disorder.In some more specific embodiments, the disease or disorder is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), acute exacerbation of IPF and familial pulmonary fibrosis), liver fibrosis (e.g., liver cirrhosis and biliary cirrhosis), cardiac fibrosis, vascular fibrosis, renal fibrosis, skin fibrosis, gastrointestinal fibrosis, arthrofibrosis, Dupuytren's contracture, mediastinal fibrosis, Peyronie's disease, retroperitoneal fibrosis, systemic sclerosis or combinations thereof.

[0396] One embodiment provides a method for treating or preventing the formation or deposition of fibrosis in or around a tissue (i.e., tissue fibrosis), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, or a composition or unit dose form comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof, e.g., a crystalline form or a composition or unit dose disclosed herein).

[0397] Another embodiment provides a method for inhibiting viral infection or viral replication, the method comprising administering a therapeutically effective amount of a compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, or a composition or unit dose form comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof, e.g., a crystalline form or a composition or unit dose disclosed herein) to a subject in need thereof.

[0398] Yet another embodiment provides a method for treating a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocythemia, or a combination thereof), the method comprising administering a therapeutically effective amount of a compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, or a composition or unit dose form comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof, e.g., a crystalline form or a composition or unit dose disclosed herein) to a subject in need thereof. In some embodiments, the myeloproliferative neoplasm is polycythemia vera. In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia.

[0399] Some embodiments provide a method for treating or preventing an inflammatory disease or disorder, the method comprising administering a therapeutically effective amount of a compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, or a composition or unit dose form comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof, e.g., a crystalline form or a composition or unit dose disclosed herein) to a subject in need thereof. In some embodiments, the inflammatory disease or disorder is nonalcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, skin inflammation, psoriasis, or a combination thereof.

[0400] Certain embodiments provide a method for treating or preventing an autoimmune and / or inflammatory disease or disorder, the method comprising administering a therapeutically effective amount of a compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., a crystalline form of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, or a composition or unit dose form comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof, e.g., a crystalline form or composition or unit dose disclosed herein) to a subject in need thereof. In some more specific embodiments, the autoimmune and / or inflammatory disease or disorder is mediated at least in part by protein kinase activity (e.g., Pim kinase activity). In certain embodiments, the autoimmune and / or inflammatory disease or disorder includes osteoarthritis, rheumatoid arthritis, pain, inflammatory bowel disease, respiratory disorders, skin disorders, or combinations thereof.

[0401] "Therapeutically effective amount" means an amount of a composition sufficient to effect treatment (e.g., an amount effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated). Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0402] For example, for any composition described herein, therapeutically effective amount or dose can be estimated first from cell culture assay.The dosage can then be formulated for use in animal models to achieve a circulating concentration range that includes the IC50 determined in cell culture (i.e., the concentration of the test composition that achieves half-maximal inhibition of protein kinase activity).Then, such information can be used to more accurately determine the dose that is useful in humans.

[0403] The toxicity and therapeutic efficacy of the compositions described herein can be evaluated, for example, by IC 50 and L.D. 50The amount of the active ingredient can be determined by standard pharmaceutical procedures in cell cultures or experimental animals by determining the amount of the active ingredient. The data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage can vary depending on the dosage form and the route of administration used. The exact formulation, route of administration and dosage can be selected by the individual physician depending on the disease or disorder of interest (see, for example, GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 3, 9th ed., Ed. by Hardman, J., and Limbard, L., McGraw-Hill, New York City, 1996, p.46.).

[0404] Dosage and intervals can be individually adjusted to provide plasma levels of the active species sufficient to maintain the kinase modulating effect. These plasma levels are called minimal effective concentrations (MEC). MECs vary from composition to composition but can be estimated from in vitro data, e.g., the concentration required to achieve 50-90% inhibition of the kinase. The dosage required to achieve the MEC depends on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.

[0405] Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for about 10-90% of the time, preferably about 30-90% of the time, and most preferably about 50-90% of the time.

[0406] The amount of a composition administered will, of course, be dependent on, for example, the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0407] In some embodiments, the crystalline form and / or composition and / or unit dose is administered in multiple doses. In some embodiments, the administration is about once, twice, three times, four times, five times, six times or more than six times per day. In other embodiments, the administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the composition further comprising another agent is administered about once per day to about six times per day. In another embodiment, the administration of the composition further comprising another agent continues for less than about seven days. In yet another embodiment, the administration continues for more than about six, ten, fourteen, twenty-eight days, two months, six months, or one year. In some cases, continuous administration is achieved and maintained for as long as necessary.

[0408] Administration of the crystalline form and / or composition and / or unit dose (e.g., composition) may continue for as long as necessary. In some embodiments, the crystalline form and / or composition and / or unit dose (e.g., composition) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the crystalline form and / or composition (e.g., composition) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the crystalline form and / or composition and / or unit dose (e.g., composition) is administered chronically on an ongoing basis, for example, to treat a chronic effect.

[0409] In some embodiments, the compound of structure (I) or a pharma- ceutically acceptable salt thereof, or a composition comprising the compound of structure (I) or a pharma- ceutically acceptable salt thereof, is administered in a dosage amount (e.g., daily dose) of about 250 mg to about 2.5 g, about 300 mg to about 1.5 g, about 350 mg to about 2.5 g, or about 450 mg to about 1.5 g, as determined using the molecular weight of the compound of structure (I) as a free base. In some embodiments, a subject in need thereof is administered a dose (e.g., daily dose) of about 360 mg, or about 480 mg, or about 720 mg, or about 1,080 mg, or about 1,440 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0410] In one embodiment, a subject in need thereof is administered a dose (e.g., daily dose) of about 360 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0411] In one embodiment, a subject in need thereof is administered a dose (e.g., daily dose) of about 480 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0412] In one embodiment, a subject in need thereof is administered a dose (e.g., daily dose) of about 720 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0413] In one embodiment, a subject in need thereof is administered a dose (e.g., daily dose) of about 1,080 mg of the compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0414] In one embodiment, a subject in need thereof is administered a dose (e.g., daily dose) of about 1,440 mg of a compound of structure (I) or a pharma- ceutically acceptable salt thereof, as determined using the molecular weight of the compound of structure (I) as a free base.

[0415] In one embodiment, a subject in need thereof is administered a dose of 2 capsules, or 3 capsules, or 4 capsules, or 5 capsules, or 6 capsules, or 7 capsules, or 8 capsules, or 9 capsules, or 10 capsules, or 11 capsules, or 12 capsules, or 13 capsules, or 14 capsules, each capsule containing a composition comprising a compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg as determined using the molecular weight of the compound of structure (I) as a free base.

[0416] In one embodiment, a subject in need thereof is administered a dose of three capsules, each capsule containing a composition comprising the compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg as determined using the molecular weight of the compound of structure (I) as a free base.

[0417] In one embodiment, a subject in need thereof is administered a dose of four capsules, each capsule containing a composition comprising the compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg as determined using the molecular weight of the compound of structure (I) as a free base.

[0418] In one embodiment, a subject in need thereof is administered a dose of 6 capsules, each capsule containing a composition comprising the compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg as determined using the molecular weight of the compound of structure (I) as a free base.

[0419] In one embodiment, a subject in need thereof is administered a dose of 9 capsules, each capsule containing a composition comprising the compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg as determined using the molecular weight of the compound of structure (I) as a free base.

[0420] In one embodiment, a subject in need thereof is administered a dose of 12 capsules, each capsule containing a composition comprising the compound of structure (I) or a pharma- ceutically acceptable salt thereof in an amount of about 120 mg as determined using the molecular weight of the compound of structure (I) as a free base.

[0421] In one embodiment, the administration of the crystalline form and / or composition and / or unit dose (e.g., unit dose) is a daily administration (e.g., a single administration per day). In one embodiment, the administration of the capsule is a daily administration (e.g., a single administration per day). In this regard, it is understood that a subject administered a compound of structure (I) or a pharma- ceutically acceptable salt thereof by capsule will likely be administered, for example, two or more capsules at a time, each of which may be very large (e.g., size 00). Thus, the administration can span a period of time (e.g., a period of one hour). For example, a dose administered once a day that requires one hour to complete will be understood to be a single daily administration, regardless of the number of capsules or the long-term administration.

[0422] It is known in the art that individualization of dosing regimens is necessary for optimal treatment due to subject-to-subject variability in pharmacokinetics. Dosing of the compositions can be found by routine experimentation in light of the present disclosure.

[0423] The compositions may, if desired, be provided in a pack or dispenser device, such as a kit approved by the FDA, which may contain one or more unit dosage forms containing the active ingredient (e.g., a compound of structure (I) or a pharma- ceutically acceptable salt thereof). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by labeling associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which reflects the form of the composition or its approval by the agency for human or veterinary administration. Such labeling may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. The compositions of certain embodiments, optionally formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated disease, disorder, or condition. Suitable diseases, disorders or conditions indicated on the label can include those described herein (e.g., cancer, myeloproliferative neoplasms, fibrotic diseases or disorders, autoimmune diseases or disorders, inflammatory diseases or disorders, etc.).

[0424] In certain instances, it may be advantageous to administer the crystalline forms and / or compositions (e.g., compositions) of the present disclosure in combination with one or more therapeutically active agents independently selected from anti-cancer agents (e.g., chemotherapeutic agents), anti-allergy agents, antiemetics, pain relief agents, immunomodulatory agents, and cytoprotective agents. Thus, in some embodiments, the method of treatment further comprises administering to the subject a therapeutically effective amount of one or more additional therapeutic agents (e.g., anti-cancer agents such as chemotherapeutic agents, anti-allergy agents, antiemetics, pain relief agents, immunomodulatory agents, and / or cytoprotective agents).

[0425] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic disease, disorder, or condition described in the present disclosure. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, such as a single capsule with a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiples or in separate containers for each active ingredient (e.g., capsules, powders, and liquids). The crystalline forms or compositions of the present disclosure and the additional therapeutic agents can be administered via the same route of administration or via different routes of administration. The powders and / or liquids may be reconstituted or diluted to the desired dose before administration. Additionally, such administration also includes the use of each type of therapeutic agent in separate compositions in a sequential manner, at about the same time or at different times.

[0426] Common chemotherapy agents that may be used in combination therapy include capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), doxorubicin (DTX-1000®), and rifampicin (Renvoy®). These include rubicin hydrochloride (Adriamycin®, Rubex®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), gemcitabine (difluorodeoxycytidine), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), pentostatin, 6-thioguanine, thiotepa, and injectable topotecan hydrochloride (Hycamptin®).

[0427] Anti-cancer drugs of particular interest for combination with the compositions of the present disclosure include:

[0428] Purine antimetabolites and / or inhibitors of de novo purine synthesis: pemetrexed (Alimta®), gemcitabine (Gemzar®), 5-fluorouracil (Adrucil®, Carac®, and Efudex®), methotrexate (Trexall®), capecitabine (Xeloda®), floxuridine (FUDR®), decitabine (Dacogen®), azacitidine (Vidaza®), (Trademark) and Azadine (Azadine®), 6-mercaptopurine (Purinethol®), cladribine (Leustatin®, Litak®, and Movectro®), fludarabine (Fludara®), pentostatin (Nipent®), nelarabine (Arranon®), clofarabine (Clolar® and Evoltra®), and cytarabine (Cytosar®).

[0429] MTAP inhibitor: (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-((methylthio)methyl)pyrrolidin-3-ol (MT-DADMe-immucillin-A, CAS 653592-04-2).

[0430] Methylthioadenosine: ((2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5-((methylthio)methyl)tetrahydrofuran-3,4-diol, CAS 2457-80-9).

[0431] Epidermal growth factor receptor (EGFR) inhibitors: erlotinib hydrochloride (Tarceva®) and gefitonib (Iressa®).

[0432] EGFR antibody: cetuximab (Erbitux®).

[0433] MET inhibitors: capmatinib (INC280, CAS 1029712-80-8).

[0434] Platelet-derived growth factor (PDGF) receptor inhibitors: imatinib (Gleevec®); linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); sunitinib malate (Sutent®); quizartinib (AC220, CAS 950769-58-1); pazopanib (Votrient®); axitinib (Inlyta®); sorafenib (Nexavar®); vargatef (BIBF1120, CAS 928326-83-4); telatinib (BAY57-9352, CAS 332012-40-5); vatalanib dihydrochloride (PTK787, CAS 212141-51-0); and motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, which is described in PCT Publication No. WO02 / 066470).

[0435] Phosphoinositide 3-kinase (PI3K) inhibitors: 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO09 / 036082 and WO09 / 055730); 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (also known as BKM120 or NVP-BKM120 and described in PCT Publication No. WO2007 / 084786); alpelisib (BYL719): (5Z )-5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS 958852-01-2); 5-[8-methyl-9-(1-methylethyl)-2-(4-morpholinyl)-9H-purin-6-yl]-2-pyrimidinamine (VS-5584, CAS 1246560-33-7), and everolimus (AFINITOR®).

[0436] Cyclin-dependent kinase (CDK) inhibitors: ribociclib (LEE011, CAS 1211441-98-3); aloisine A; alvocidib (also known as flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone and described in U.S. Pat. No. 5,621,002); crizotinib (PF-02341066, CAS 877399-52-5); 2-(2-chlorophenyl)-5 ,7-Dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P276-00, CAS920113-03-7);1-Methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine (RAF265, CAS927880-90-8);Indisulam (E7070);Roscovitine (CY C202;6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (PD0332991);dinaciclib (SCH727965);N-[5-[[(5-tert-butyroxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (BMS387032, CAS345627-80-7);4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pi Limido[5,4-d][2]benzoazepin-2-yl]amino]-benzoic acid (MLN8054, CAS869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS837364-57-5); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS844442-38-2);4-[2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438, CAS602306-29-6); palbociclib (PD-0332991); and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol (BAY10000394).

[0437] p53-MDM2 inhibitors: (S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one, (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyro r[3,4-d]imidazol-4-one, [(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone (RG7112), 4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid acid (RG7388), SAR299155, 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (AMG232), {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S,3S)-2-hydroxy-3-pentanyl]-3-methyl-2-oxo-3-piperidinyl}acetic acid (AM-8553), (±)-4-[4,5-bis (4-Chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one (Nutlin-3), 2-methyl-7-[phenyl(phenylamino)methyl]-8-quinolinol (NSC66811), 1-N-[2-(1H-indol-3-yl)ethyl]-4-N-pyridin-4-ylbenzene-1,4-diamine (JNJ-26854165), 4-[4,5-bis(3,4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carboxyl]-piperazin-2-one (Keirin-1), 4-[4,5-bis(4-trifluoromethyl-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carboxyl]-piperazin-2-one (Keirin-2), 5-[[3-dimethylamino)propyl]amino]-3,10-dimethylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione dihydrochloride (HLI373), and trans-4-iodo-4'-boranyl-chalcone (SC204072).

[0438] Mitogen-activated protein kinase (MEK) inhibitors: XL-518 (also known as GDC-0973, Cas No. 1029872-29-4, available from ACC Corp.); selumetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, also known as AZD6244 or ARRY142886, described in PCT Publication No. WO2003077914); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropyl)-1H-benzoimidazole-6-carboxamide, also known as AZD6244 or ARRY142886, described in PCT Publication No. WO2003077914); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901 and described in PCT Publication No. WO2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]butanedinitrile (also known as U0126 and described in U.S. Pat. No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in the PCT publication (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione (also known as E6201 and described in PCT Publication No. WO2003076424): 2'-amino-3'-methoxyflavone (Biaffin GmbH & Co.also known as PD98059 available from Sigma-Aldrich Co., KG, Germany; (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9); trametinib dimethylsulfoxide (GSK-1120212, CAS 1204531-25-80); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxypropyl) 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH4987655 or Ro4987655);(); and 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide (MEK162).

[0439] B-RAF inhibitors: regorafenib (BAY73-4506, CAS755037-03-7); tubizanib (AV951, CAS475108-18-0); vemurafenib (Zelboraf®, PLX-4032, CAS918504-65-1); encorafenib (also known as LGX818); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H- imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl-1H-benzimidazol-2-amine (RAF265, CAS927880-90-8); 5-[1-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydroinden-1-one oxime (GDC-0879, CAS905281- 76-7;5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime (GSK2118436 or SB590885);(+ / -)-Methyl(5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoin N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (also known as PLX4720).

[0440] ALK inhibitor: crizotinib (Xalkori®).

[0441] BRD formula:JQ-1(Nature 2010 Dec 23;468(7327):1067-73), BI2536(ACS Chem.Biol.2014 May 16;9(5):1160-71; Boehringer Ingelheim), TG101209(ACS). Chem.Biol.2014 May 16;9(5):1160-71) OTX015(Mol.Cancer Ther.Nov 201312;C244;Oncoethix)、IBET762(J Med Chem.2013 Oct 10;56(19):7498-500;GlaxoSmithKline), IBET151(Bioorg.Med.Chem.Lett.2012 Apr 15;22(8):2968-72; 26;55(22):9831-7;Cancer Res.2013 Jun 1;73(11):3336-46;In other embodiments, the BRD inhibitor is selected from the group consisting of IBET 762 (GSK525762), TEN-010 (Tensha Therapeutics), CPI-203 (Leukemia. 28(10):2049-59, 2014), RVX-208 (Proceedings of the National Academy of Sciences of the United States of America. 110(49):19754-9, 2013), LY294002 (ACS Chemical Biology. 9(2):495-502, 2014), AZD5153 (Journal of Medicinal Chemistry. 59(17):7801-17, 2016), MT-1 (Nature Chemical Biology. 12(12):1089-1096 2016) or MS645 (Proceedings of the National Academy of Sciences of the United States of America). America.115(31):7949-7954,2018).

[0442] Histone methyltransferase inhibitors: include DOT1-like histone methyltransferase (DOT1L) inhibitors. DOT1L is a histone methyltransferase enzyme that targets lysine 79 in the globular domain of histone H3 for mono-, di- or trimethylation. In some of these embodiments, the additional therapeutic agent is EPZ004777, EPZ-5676 (Blood.2013 Aug 8;122(6):1017-25) or SGC 0946 (Nat.Commun.2012;3:1288), e.g., EPZ-5676.

[0443] Histone deacetylase (HDAC) inhibitors. HDAC proteins can be divided into classes based on their homology to yeast HDAC proteins: class I is composed of HDAC1, HDAC2, HDAC3 and HDAC8, class IIa is composed of HDAC4, HDAC5, HDAC7 and HDAC9, class IIb is composed of HDAC6 and HDAC10, and class IV is composed of HDAC11. In some of these embodiments, the additional therapeutic agent is selected from the group consisting of trichostatin A, vorinostat (Proc. Natl. Acad. Sci. USA 1998 Mar 17;95(6):3003-7), gibinostat, abexinostat (Mol. Cancer Ther. 2006 May;5(5):1309-17), belinostat (Mol. Cancer Ther. 2003 Aug;2(8):721-8), panobinostat (Clin. Cancer Res. 2006 Aug 1;12(15):4628-35), resminostat (Clin. Cancer Res. 2013 Oct 1;19(19):5494-504), xinostat (Clin. Cancer Res. 2013 Aug 1;19(15):4262-72), depsipeptide (Blood.2001 Nov 1;98(9):2865-8), entinostat (Proc.Natl.Acad.Sci.USA1999 Apr 13;96(8):4592-7), mocetinostat (Bioorg.Med.Chem.Lett.2008 Feb 1;18(3):1067-71) or valproic acid (EMBO J.2001 Dec 17;20(24):6969-78). For example, in some embodiments, the additional therapeutic agent is panobinostat. In other embodiments, the additional therapeutic agent is panobinostat or SAHA.

[0444] Histone demethylase inhibitors. In certain embodiments, the histone demethylase inhibitor is a lysine-specific demethylase 1A (Lsd1) inhibitor. In some of these embodiments, the additional therapeutic agent is HCI-2509 (BMC Cancer. 2014 Oct 9;14:752), tranylcypromine or ORY-1001 (J. Clin. Oncol 31, 2013(suppl;abstr e13543). In other embodiments, the additional therapeutic agent is HCI-2509.

[0445] MLL-menin inhibitors: MI-453, M-525 and MI-503.

[0446] Immunomodulators: afutuzumab (available from ROCHE®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®); Actimid (CC 4047); and IRX-2 (a mixture of human cytokines including interleukin-1, interleukin-2 and interferon-gamma, CAS 951209-71-5, available from IRX Therapeutics).

[0447] Chimeric antigen receptor T cell (CAR-T) therapies: tisagenlecleucel (Novartis), axicabtagene ciloleucel (Kite) and tocilizumab and atlizumab (Roche).

[0448] Immune checkpoint inhibitors. In certain aspects of all embodiments, the additional therapeutic agent is an immune checkpoint inhibitor (e.g., a PD-1 inhibitor, such as pembrolizumab or nivolumab; a PD-L1 inhibitor, such as atezolizumab, avelumab or durvalumab; a CTLA-4 inhibitor; a LAG-3 inhibitor; or a Tim-3 inhibitor). Other immune checkpoint inhibitors of interest for use in combination with the compounds of the present disclosure include: PD-1 inhibitors, such as pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), spartalizumab (PDR001), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab (REGN2810), dostarimab (TSR-042), PF-06801591 (Pfizer), tislelizumab (BGB-A317), camrelizumab (INCSHR 1210, SHR-1210, and AMP-224 (Amplimmune); PD-L1 inhibitors such as atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), FAZ053 (Novartis) and BMS-936559 (Bristol-Myers Squibb); and drugs that target CTLA-4 such as ipilimumab (Yervoy®).

[0449] In various embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In certain embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, or a combination thereof. In certain embodiments, the PD-1 inhibitor is pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or Keytruda®). Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369(2):134-44, U.S. Patent No. 8,354,509, and WO 2009 / 114335, which are incorporated by reference in their entireties. In certain embodiments, the PD-1 inhibitor is nivolumab (also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or Opdivo®). Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in U.S. Patent No. 8,008,449 and WO 2006 / 121168, which are incorporated by reference in their entireties.In some other embodiments, the PD-1 inhibitor is selected from the group consisting of AMP-224 (Amplimmune), CBT-501 (CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), JS001 (Junshi Biosciences), IBI308 (Innovent Biologics), INCSHR1210 (Incyte), SHR-1210 (Hengrui Medicine), BGBA317 (Beigene), BGB-108 (Beigene), BAT-I306 (Bio-Thera Solutions), GLS-010 (Gloria Pharmaceuticals; WuXi Biologics), AK103, AK104, AK105 (Akesio Biopharma; Hangzhou Hansi Biologics; Hanzhong Biologics), LZM009 (Livzon), HLX-10 (Henlius It is also known as PD-1 agonist, ... Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J et al., (2011) J Immunotherapy 34(5):409-18, U.S. Patent No. 7,695,715, U.S. Patent No. 7,332,582, and U.S. Patent No. 8,686,119, which are incorporated by reference in their entireties.

[0450] In one embodiment, the anti-PD-1 antibody molecule is cemiplimab. In one embodiment, the anti-PD-1 antibody molecule is sintilimab. In one embodiment, the anti-PD-1 antibody molecule is toripalimab. In one embodiment, the anti-PD-1 antibody molecule is camrelizumab.

[0451] Additional known anti-PD-1 antibody molecules include those described in, for example, WO 2015 / 112800, WO 2016 / 092419, WO 2015 / 085847, WO 2014 / 179664, WO 2014 / 194302, WO 2014 / 209804, WO 2015 / 200119, U.S. Patent No. 8,735,553, U.S. Patent No. 7,488,802, U.S. Patent No. 8,927,697, U.S. Patent No. 8,993,731, and U.S. Patent No. 9,102,727, each of which is incorporated by reference in its entirety.

[0452] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US Patent Application Publication No. 2015 / 0210769. In one embodiment, the anti-PD-1 antibody molecule comprises the CDRs, variable regions, heavy chain and / or light chain of BAP049-Clone-E or BAP049-Clone-B as disclosed in US Patent Application Publication No. 2015 / 0210769. The antibody molecules described herein can be made by the vectors, host cells and methods described in US Patent Application Publication No. 2015 / 0210769, which is incorporated by reference in its entirety.

[0453] In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, e.g., as described in U.S. Patent No. 8,907,053, which is incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin that includes an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In one embodiment, the PD-1 inhibitor is AMP-224 (e.g., B7-DCIg (Amplimmune) disclosed in WO 2010 / 027827 and WO 2011 / 066342, which are incorporated by reference in their entireties).

[0454] In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some such embodiments, the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, or a combination thereof. In certain embodiments, the PD-L1 inhibitor is MPDL3280A, RG7446, RO5541267, YW 243.55.S70, or Tecentriq. TMAtezolizumab, also known as MSB0010718 C. Atezolizumab and other anti-PD-L1 antibodies are disclosed in U.S. Patent No. 8,217,149, which is incorporated by reference in its entirety. In certain embodiments, the PD-L1 inhibitor is avelumab, also known as MSB0010718 C. Avelumab and other anti-PD-L1 antibodies are disclosed in International Publication No. WO 2013 / 079174, which is incorporated by reference in its entirety. In certain embodiments, the PD-L1 inhibitor is durvalumab, also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in U.S. Patent No. 8,779,108, which is incorporated by reference in its entirety. In certain embodiments, the PD-L1 inhibitor is KN035 (alfamab; 3DMed), BMS 936559 (Bristol-Myers Squibb), CS1001 (CStone Pharmaceuticals), FAZ053 (Novartis), SHR-1316 (Hengrui Medicine), TQB2450 (Chiatai Tianqing), STI-A1014 (Zhaoke Pharm; Lee's Pharm), BGB-A333 (Beigene), MSB2311 (Mabspace Biosciences) or HLX-20 (Henlius Biotech). In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in U.S. Patent No. 7,943,743 and WO 2015 / 081158, which are incorporated by reference in their entireties. In some embodiments, the PD-L1 inhibitor is a monoclonal antibody (such as that made by Hisun Pharm and applied in clinical trials).

[0455] In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule disclosed in US Patent Application Publication No. 2016 / 0108123, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises the CDRs, variable regions, heavy chain and / or light chain of BAP058-Clone O or BAP058-Clone N disclosed in US Patent Application Publication No. 2016 / 0108123.

[0456] Further known anti-PD-L1 antibodies include those described in, for example, WO 2015 / 181342, WO 2014 / 100079, WO 2016 / 000619, WO 2014 / 022758, WO 2014 / 055897, WO 2015 / 061668, WO 2013 / 079174, WO 2012 / 1 Nos. 4,5493, 2015 / 112805, 2015 / 109124, 2015 / 195163, U.S. Pat. No. 8,168,179, 8,552,154, 8,460,927 and 9,175,082, which are incorporated by reference in their entireties.

[0457] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is ipilimumab. In other embodiments, the CTLA4 inhibitor is tremelimumab.

[0458] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb) or TSR-033 (Tesaro). In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule disclosed in US Patent Application Publication No. 2015 / 0259420, the entirety of which is incorporated by reference. In one embodiment, the anti-LAG-3 antibody molecule comprises the CDRs, variable regions, heavy chains and / or light chains of BAP050-Clone I or BAP050-Clone J disclosed in US Patent Application Publication No. 2015 / 0259420.

[0459] In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015 / 116539 and U.S. Pat. No. 9,505,839, which are incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008 / 132601 and U.S. Pat. No. 9,244,059, which are incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed).

[0460] Additional known anti-LAG-3 antibodies include those described in, for example, WO 2008 / 132601, WO 2010 / 019570, WO 2014 / 140180, WO 2015 / 116539, WO 2015 / 200119, WO 2016 / 028672, U.S. Patent No. 9,244,059, and U.S. Patent No. 9,505,839, which are incorporated by reference in their entireties.

[0461] In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, such as IMP321 (Prima BioMed), as disclosed, for example, in WO 2009 / 044273, which is incorporated by reference in its entirety.

[0462] In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is MGB453 (Novartis) or TSR-022 (Tesaro).

[0463] In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule disclosed in U.S. Patent Application Publication No. 2015 / 0218274, which is incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule comprises the CDRs, variable regions, heavy chain and / or light chain of ABTIM3-hum11 or ABTIM3-hum03 disclosed in U.S. Patent Application Publication No. 2015 / 0218274.

[0464] In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio / Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or the entire CDR sequences), the heavy or light chain variable region sequence, or the heavy or light chain sequence of APE5137 or APE5121. APE5137, APE5121 and other anti-TIM-3 antibodies are disclosed in WO 2016 / 161270, which is incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule is the antibody clone F38-2E2.

[0465] Additional known anti-TIM-3 antibodies include those described, for example, in WO 2016 / 111947, WO 2016 / 071448, WO 2016 / 144803, U.S. Pat. No. 8,552,156, U.S. Pat. No. 8,841,418, and U.S. Pat. No. 9,163,087, which are incorporated by reference in their entireties.

[0466] Some subjects may experience allergic reactions to the compositions of the present disclosure and / or other anti-cancer agent(s) during or after administration; therefore, anti-allergy agents are often administered to minimize the risk of allergic reactions. Suitable anti-allergy agents include corticosteroids (Knutson, S., et al., PLoS One, DOI:10.1371 / journal.pone.0111840 (2014)), such as dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (sold under the trademarks Corticone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), prednisolone (sold under the trademarks Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (Deltasone®, Liquid Red®, Meticorten®, and Orasone®), methylprednisolone (6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the trademarks Duralone®, Medralone®, Medrol®, M-Prednisol®, and Solu-Medrol®); antihistamines, such as diphenhydramine (e.g., Benadryl®), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists, albuterol (e.g., Proventil®), and terbutaline (Brethine®).

[0467] Some subjects may experience nausea during and after administration of the compositions of the present disclosure and / or other anti-cancer drug(s); therefore, anti-emetic agents are used to prevent nausea (upper stomach) and vomiting. Suitable anti-emetic agents include aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®), dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof.

[0468] Medication that reduces the pain experienced during the treatment period is often prescribed to make the subject more comfortable. Common over-the-counter painkillers such as Tylenol® are often used. However, opioid analgesics such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), and fentanyl (e.g., Duragesic®) are also useful for moderate or severe pain.

[0469] Immunomodulatory agents of particular interest for combination with the compositions of the present disclosure include: afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and IRX-2 (a mixture of human cytokines including interleukin-1, interleukin-2, and interferon-gamma, CAS951209-71-5, available from IRX Therapeutics).

[0470] In an effort to protect normal cells from the toxicity of the treatment and limit organ toxicity, cytoprotectants (neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, and the like) may be used as adjunctive therapy in combination with the compositions of the present disclosure.Suitable cytoprotectants include amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), Mentha (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0471] Some patients may experience allergic reactions to the compounds of the present disclosure and / or other therapeutic agents (e.g., anti-cancer agents) during or after administration. Therefore, to minimize the risk of allergic reactions, anti-allergic agents can be administered in combination with the compounds of the present disclosure and / or other therapeutic agents (e.g., anti-cancer agents). Suitable anti-allergy agents include dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate and sold under the trade names ALA-CORT®, hydrocortisone phosphate, SOLU-CORTEF®, HYDROCORT ACETATE® and LANACORT®), prednisolone (sold under the trade names DELTA-CORTEL®, ORAPRED®, PEDIAPRED® and PRERON®), prednisone (DELTA-SONE®, LIQUID RED®, IL-10 ... It is sold under the trade names RED®, Methycortene® and Orasone®; methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate and sold under the trade names DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL® and Solu-Medrol®.), (Knutson, S. et al., PLoS One, DOI: 10.1371 / journal.pone.0111840 (2014)); antihistamines, such as diphenhydramine (e.g., Benadryl®), hydroxyzine and cyproheptadine; and bronchodilators, such as the β-adrenergic receptor agonists, albuterol (e.g., Proventil®) and terbutaline (BRETHINE®).

[0472] Some patients may experience nausea during and after administration of the compounds described herein and / or other therapeutic agents (e.g., anticancer agents). Therefore, antiemetic drugs can be used in combination with the compounds disclosed herein and / or other therapeutic agents (e.g., anticancer agents) to prevent nausea (upper stomach) and vomiting. Suitable antiemetic drugs include aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®, dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Resonic® and Zunlisa®) and combinations thereof.

[0473] To make the patient more comfortable, medications are often prescribed to alleviate the pain experienced during the procedure. Common over-the-counter painkillers such as Tylenol® can also be used in combination with the compounds of the present disclosure and / or other therapeutic agents (e.g., anti-cancer drugs). Opioid painkillers such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g., ASTRAMORPH® or Avinza®), oxycodone (e.g., Oxycontin® or Percocet®), oxymorphone hydrochloride (Opana®) and fentanyl (e.g., Duragesic®) can be useful for moderate or severe pain and can be used in combination with the compounds of the present disclosure and / or other therapeutic agents (e.g., anti-cancer drugs).

[0474] The structures of the active compositions identified by code numbers, generic names or trade names can be taken from the actual edition of the standard overview "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0475] In one embodiment, the present disclosure provides a pharmaceutical composition, alone or together with other anti-cancer agents.

[0476] In one embodiment, the additional therapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, cell cycle inhibitors, enzymes, topoisomerase inhibitors such as CAMPTOSAR (irinotecan), biological response modifiers, antihormones, antiangiogenic agents such as MMP-2, MMP-9 and COX-2 inhibitors, antiandrogens, platinum coordination complexes (such as cisplatin), substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine; adrenocortical suppressants such as mitotane, aminoglutethimide, hormones and hormone antagonists such as corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate), estrogens (e.g., diethylstilbesterol), antiestrogens such as tamoxifen, androgens such as testosterone propionate, and aromatase inhibitors such as anastrozole, and AROMASIN (exemestane).

[0477] Furthermore, the compositions and methods of administration described herein can be used in combination with one or more JAK inhibitors.In some other embodiments, the JAK inhibitor is ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, gandotinib, lestaurtinib, momelotinib, pacritinib, PF-04965842, updacitinib, perficitinib, fedratinib, cucurbitacin I, CHZ868, decernotinib, CEP-33779, R348, fibotinib, ABT-494, and these compounds are known in the art.In some embodiments, the JAK inhibitor is BMS-911543, ASN002, itacitinib, NS-018, AZD1480, gandotinib, and combinations thereof.

[0478] In some embodiments, the JAK inhibitor is a JAK1, a JAK2 inhibitor, or both. For example, in some embodiments, the JAK inhibitor is selected from the group consisting of ruxolitinib, gandotinib, lestaurtinib, momelotinib, pacritinib, and fedratinib. In more specific embodiments, the JAK inhibitor is ruxolitinib. In some of these embodiments, the JAK inhibitor can be administered in combination with a Pim kinase inhibitor and an additional therapeutic agent, if desired. That is, in some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent includes hydroxyurea, interferon alpha, cladribine, thalidomide (including its derivatives, e.g., pomalidomide, lenolidamide), corticosteroids (e.g., prednisone), everolimus, androgens (e.g., testosterone), and combinations thereof. In some embodiments, the additional therapeutic agent is a Pim kinase inhibitor. In some embodiments, the additional Pim kinase inhibitor is PIM447 or INCB053914.

[0479] In some embodiments, the method further comprises administering an immune checkpoint inhibitor. In some embodiments, the immune checkpoint molecule is CTLA-4, PD-1 or PD-L1. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is ipilimumab. In other embodiments, the CTLA-4 inhibitor is tremelimumab.

[0480] In some embodiments, the method further comprises administering a PD-1 inhibitor. Exemplary PD-1 inhibitors include, but are not limited to, pembrolizumab, nivolumab, CBT-501 (CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), JS001 (Junshi Biosciences), IBI308 (Innovent Biologics), SHR-1210 (Hengrui Medicine), BGB-A317 (Beigene), BAT-I306 (Bio-Thera Solutions), GLS-010 (Gloria Pharmaceuticals; WuXi Biologics), AK103, AK104, AK105 (Akesio Biopharma; Hangzhou Hansi Biologics; Hanzhong Biologics), LZM009 (Livzon), HLX-10 (Henlius Biotech), CS1003 (CStone Pharmaceuticals), or combinations thereof.

[0481] In some embodiments, the PD-1 inhibitor is a monoclonal antibody (e.g., made by Genor Biopharma, in Phase I clinical trials at the time of this filing; made by Shenzhou Gongcheng, in clinical trials at the time of this filing; made by Lunan Hope Pharmaceuticals, in clinical trials at the time of this filing).

[0482] In some embodiments, the method further comprises administering a PD-L1 inhibitor. Exemplary PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, or a combination thereof. In certain embodiments, the PD-L1 inhibitor is KN035 (Alphamab; 3DMed), CS1001 (CStone Pharmaceuticals), SHR-1316 (Hengrui Medicine), TQB2450 (Chiatai Tianqing), STI-A1014 (Zhaoke Pharm; Lee's Pharm), BGB-A333 (Beigene), MSB2311 (Mabspace Biosciences), HLX-20 (Henlius Biotech), or a combination thereof. In some embodiments, the PD-L1 inhibitor is a monoclonal antibody (e.g., produced by Hisun Pharm and pending clinical trial application at the time of this application).

[0483] In some embodiments, the method includes the use of an FLT3 inhibitor, a caspase 3 activator, a BET inhibitor, an LSD1 inhibitor, a PI3K inhibitor, a PLK inhibitor, a cyclic AMP phosphodiesterase, a histone deacetylase inhibitor, an mTOR inhibitor, an iron chelator, a SYK inhibitor, an SMO antagonist or inhibitor, a hedgehog signaling pathway inhibitor, a BCR-ABL / Kit inhibitor, a BCR-ABL inhibitor, a DNA methylation inhibitor, a SMAC mimetic, an ACVR2a fusion protein, a thromopoietin (thromopoietin) inhibitor, a cytotoxic TNF-α ... eitin receptor agonist, PI3K delta inhibitor, tyrosine kinase inhibitor, recombinant amyloid P / pentraxin 2 protein, CDK4 / 6 inhibitor, telomerase inhibitor, TGF-β superfamily inhibitor, LOXL2 inhibitor (e.g., antibody), BCL-2 inhibitor, WNT signal inhibitor, PD-L1 antibody, PD-1 antibody, VEGF1 / 2 inhibitor, tubulin polymerization inhibitor, Aurora kinase inhibitor, PNP inhibitor, AKT inhibitor, or combinations thereof. In some embodiments, the method further comprises administering a hypoxia-activated prodrug of bromo-isophosphoramide mustard (Br-IPM).In more specific embodiments, the method includes administering to the patient an effective amount of any of the following: alvocidib, plitidepsin, INCB054329, INCB057643, INCB053914, INCB059872, rigosertib, anagrelide, gibinostat, ridaforolimus, deferasirox, ASN002, LDE225 / sonidegib, Gleevec, dasatinib, RAD001, azacitidine, pracinostat, CPI-0610, LCL-161, sotatercept, eltrombopag, INCB050465, vismodegib, lestaurtinib (and other staurosporins). The method further comprises administering one or more of the following: ribociclib, imetelstat, luspatercept, salidegib, simtuzumab, obatoclax, navitoclax, buparlisib, idelalisib, panobinostat, IMG-7289, Luitpold azacitidine, CWP232291, durvalumab, vatalanib, MKC-1, TAK-901, evofosfamide, TXA127, glasdegib, AC220, holodesine (and related purine analogs), triciribine, or combinations thereof.

[0484] Furthermore, the method can be performed in combination with radiation therapy, and the amount of the composition in combination with the radiation therapy is effective to treat the disease. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.

[0485] In some embodiments, the compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., Form I of the hydrochloride salt of the compound of structure (I)) is administered in a treatment cycle, e.g., a 28-day treatment cycle. In some embodiments, one or more treatment cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc. cycles) of the compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., Form I of the hydrochloride salt of the compound of structure (I)) are administered. In some embodiments, the compound of structure (I) or a pharma- ceutically acceptable salt thereof (e.g., Form I of the hydrochloride salt of the compound of structure (I)) is administered once or twice per day (e.g., once per day) for 28 days in a 28-day cycle.

[0486] The present invention will be described in more detail by specific examples. The following examples are presented for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results. EXAMPLES

[0487] In certain instances, for example in the polymorph synthesis and screening experiments described below, the following solvents were used: Acetonitrile, HPLC grade, Merck, lot number 1L1IF61732; Ethanol, HPLC grade, Sigma, lot no. 11085CH; Methanol, HPLC grade, Merck, lot no. SF1SF61609; Isopropanol, AR, SCRC, Lot No. T20110623; 1-Butanol, AR, Jiangsu Enox Reagent Company, Lot No. 20110318; Isopropyl acetate, AR, SCRC, Lot No. T20110217; Acetone, AR, Jiangsu Enox Reagent Company, Lot No. 20110315; MIBK, AR, Jiangsu Enox Reagent Company, Lot No. 20110216; MEK, AR, SCRC, Lot No. T20090724; Dichloromethane, AR, Shanghai Lingfeng Reagent Company, Lot No. 20111020; Tetrahydrofuran, AR, Shanghai Lingfeng Reagent Company, Lot No. 20110901; 2-MeTHF, AR, Shanghai Jiachen Chemical Reagent Co. Ltd., Lot No. 100411; N-Methylpyrrolidone, AR, Shanghai Runjie Reagent Company, Lot No. 20120116; MTBE, HPLC grade, Scharlau, Lot No. 12670903; 1,4-Dioxane, AR, Jiangsu Enox Reagent Company, Lot No. 20110701; DMSO, HPLC grade, Merck, lot number SBOS600084; DMF, AR, Jiangsu Enox Reagent Company, Lot No. 20110801; Toluene, AR, SCRC, Lot No. T20100303; Heptane, HPLC grade, Sigma-Aldrich, Lot No. 05442LH; and Ethyl acetate, AR, Jiangsu Qiangsheng Reagent Company, Lot No. 20120201. [Example 1] Pharmacokinetic study 1

[0488] Fasted male Sprague-Dawley rats were tested using four different formulation vehicles (PO1, PO2, PO3 and PO4), the contents of each formulation are summarized in Table 3a below. [Table 3a]

[0489] Each formulation contained a nominal dose of 21.7 mg / kg of the compound of structure (I). A summary of the pharmacokinetic profile of each of the different formulations is summarized below in Table 3b. [Table 3b]

[0490] The data indicates that the bioavailability of compositions containing GELUCIRE® 44 / 14 alone is approximately 1.5-3.7 times higher than compositions not containing GELUCIRE® 44 / 14 or GELUCIRE® 44 / 14 in combination with other formulating agents. [Example 2] Pharmacokinetic study 2

[0491] Fasted male Sprague-Dawley rats were tested using four different formulation vehicles (PO5, PO6, PO7 and PO8), the contents of each formulation are summarized in Table 4 below. [Table 4]

[0492] For each formulation type (i.e., GELUCIRE® suspension or Capmul / GELUCIRE® combination), a dose of 200 or 400 mg / kg of the compound of structure (I) was tested. A summary of the pharmacokinetic profile of each formulation is shown in Table 5 below: [Table 5]

[0493] As the data shows, the formulations containing GELUCIRE® alone (i.e., PO5 and PO6) show much better bioavailability than the formulations of GELUCIRE® containing Capmul MCM C8 at a 1:1 ratio (i.e., PO7 and PO8). At a dose of 200 mg / kg, PO5 shows 1.5-fold better bioavailability than PO7. Furthermore, PO6 shows a greater than 25% increase in bioavailability over PO8 at a dose of 400 mg / kg. [Example 3] Pharmacokinetic Study 3

[0494] Fasted male Sprague-Dawley rats were tested using four different formulation vehicles (PO9, PO10, PO11 and PO12), the contents of each formulation are summarized in Table 6 below. [Table 6]

[0495] Each composition was formulated with a compound of structure (I) at a dose of 21.7 mg / kg. A summary of the pharmacokinetic profiles of the different formulations is shown in Table 7 below: [Table 7]

[0496] As the data from Table 7 shows, formulations containing GELUCIRE® 44 / 14 alone have the best bioavailability of all compositions tested. Specifically, formulations containing GELUCIRE® 44 / 14 alone exhibit bioavailability that is 2.2-4.4 times higher than compositions that do not contain GELUCIRE® in combination with GELUCIRE® or other formulating agents (e.g., Tween® 20 or Capmul). [Example 4] Bioavailability Studies

[0497] Formulation studies have shown that the compound of structure (I), in Table 8 below, has poor bioavailability when administered alone (designated "Dry Powder (Capsule)"). [Table 8]

[0498] Therefore, formulations were investigated to improve the bioavailability of the compound of structure (I). First, solubility studies were performed to determine which potential excipients would improve bioavailability. In these studies, the compound of structure (I) (HCl salt) was added to various lipid components, solvents, and co-solvents and vigorously stirred for 24 hours. Additional drug was added to all solutions until there was residual undissolved drug in all preparations. Multi-component and single-component excipient screens demonstrated improved saturated solubility with GELUCIRE® 44 / 14, as shown in Table 9 below. [Table 9]

[0499] Rat pharmacokinetic (PK) formulation of compound of structure (I) (HCl salt) at 20 mg / kg in GELUCIRE® 44 / 14 showed significant improvement in bioavailability (%F), as shown in Table 10. [Table 10]

[0500] Based on this data, GELUCIRE® 44 / 14 performs best when used as the primary and sole excipient. [Example 5] Pharmacokinetic Study 4

[0501] Various formulations of the compound of structure (I) in different formulation vehicles (PO13-PO20) were tested for their pharmacokinetic profile in rats. The contents of each formulation are summarized in the table below. [Table 11]

[0502] Each composition was formulated with a compound of structure (I) at a dose of 21.7 mg / kg. A summary of the pharmacokinetic profiles of the different formulations is shown in Table 12 below:

[0503] [Table 12]

[0504] As the data from Table 12 shows, the formulation containing GELUCIRE® 44 / 14 alone (PO20) is superior to all compositions tested. Specifically, the formulation containing GELUCIRE® alone (PO20) shows superior AUC, normalized AUC, highest Cmax and bioavailability (%F) compared to all other formulations tested. [Example 6] Synthesis of compounds of structure (I) [ka]

[0505] 2-((1R,4R)-4-aminocyclohexyl)propan-2-ol was synthesized according to the reaction steps under the reaction conditions shown above. 2-((1R,4R)-4-aminocyclohexyl)propan-2-ol can also be synthesized according to the procedure described in WO 2013 / 013188, the entire contents of which are incorporated herein by reference.

[0506] In parallel, 6-chloroimidazo[1,2-b]pyridazine, potassium carbonate (K 2 CO 3 ), 1-bromo-3-(trifluoromethyl)benzene and toluene were placed in a reactor and degassed with nitrogen. Palladium acetate (Pd(OAc) 2) and tricyclohexylphosphine were also charged into the reactor. The mixture was degassed with nitrogen and heated. After completion of the reaction, the mixture was cooled and silica thiol was charged into the reactor. The mixture was stirred, filtered and the filter cake was washed with toluene.

[0507] The filtrate was returned to the reactor, and the organic phase was washed with water and concentrated. n-heptane was added dropwise to the mixture with stirring, which was then cooled and filtered. The filter cake was rinsed with n-heptane and dried under reduced pressure. The typical yield for this step was 65.6%, with an HPLC purity of 91.4% (assay 76.8%).

[0508] 6-Chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine and 2-((1R,4R)-4-aminocyclohexyl)propan-2-ol were placed in a reactor containing potassium fluoride (KF), N,N-diisopropylethylamine (DIPEA) and dimethylsulfoxide (DMSO) and degassed with nitrogen. The mixture was heated while additional 2-((1R,4R)-4-aminocyclohexyl)propan-2-ol, KF and DIPEA were added to drive the reaction to completion. The mixture was cooled and filtered through a pad of diatomaceous earth. The filter cake was washed with DMSO.

[0509] The filtrate containing the desired product was then transferred to a new reactor and water was added dropwise. The mixture was stirred and then filtered, and the filter cake was washed with water. To this wet cake, silica thiol and tetrahydrofuran (THF) were added, the mixture was heated and stirred, cooled, filtered, and the filter cake was washed with THF. This silica thiol treatment was repeated twice for a total of three treatments.

[0510] The filtrate was concentrated, then n-heptane was added dropwise and stirred The resulting slurry was filtered and the cake was washed with n-heptane.

[0511] The filtrate and filter cake were added to a new reactor and charged with methanol. This was then heated and stirred. The mixture was then cooled and filtered. The filter cake was washed with methanol and dried under reduced pressure. The typical yield for this step was 60.8% with an HPLC purity of 99.3% (assay 96.4%).

[0512] 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol, silica thiol and THF were placed in a reactor and heated with stirring. The mixture was then cooled, filtered and the filter cake was washed with THF. This was repeated twice for a total of three cycles.

[0513] A solvent exchange from THF to MeOH was performed by repeated concentration, and ethyl acetate was added. A solution of hydrochloric acid in ethyl acetate was added dropwise to the mixture. Seed crystals of the HCl salt of the compound of structure (I) were added, and the resulting slurry was stirred and then filtered. The filter cake was washed with ethyl acetate and then dried under vacuum to obtain Form I of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol hydrochloride (i.e., Form I of the HCl salt of the compound of structure (I)). The typical yield for this step was 82.6% with an HPLC purity of 99.9%.

[0514] The process involving treatment with KF, DIPEA and DMSO was carried out with t-BuONa, (R)-BINAP, Pd 2 (dba) 3 Compounds of structure (I) were also synthesized following the reaction steps and conditions set forth in Example 6 above, except that the step involving treatment with 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine and 2-((1R,4R)-4-aminocyclohexyl)propan-2-ol were replaced with t-BuONa, (R)-BINAP, Pd 2 (dba) 3and toluene were added to the reactor. Then, the reaction was carried out, and after completion of the reaction, the resulting slurry was filtered. The filtered solid was placed in a reactor and DMSO was added. Water was then added to obtain a slurry, which was filtered, washed, and dried under vacuum. The typical yield of this process was 71.5% and the HPLC purity was 97.9%. [Example 7] Alternative synthesis of compounds of structure (I) [ka]

[0515] 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol was synthesized according to the reaction scheme and conditions described above.

[0516] 6-Chlorimidazo[1,2-b]pyridazine and 2-((1R,4R)-4-aminocyclohexyl)propan-2-ol were placed in a reactor with the addition of cesium fluoride (CsF), N,N-diisopropylethylamine (DIPEA) and dimethyl sulfoxide (DMSO). The mixture was heated at 140 °C. After completion of the reaction, the mixture was filtered and then water was added to precipitate the desired product. The slurry was filtered and dried to obtain 2-((1R,4R)-4-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol. The typical yield of the process was 66.3-69.8% and the HPLC purity was 96.2-96.8%.

[0517] 2-((1R,4R)-4-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol, 3-trifluoromethylboronic acid, sodium bicarbonate, Pd(PPh 3 ) 2 Cl 2 and a solvent mixture (toluene-methanol-water) was added and the mixture was refluxed. After completion of the reaction, Water was added and cooled to form a precipitate, and the solid formed was filtered and dried under vacuum to give 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol. The above isolated product was dissolved in tetrahydrofuran (THF) and treated with silica thiol to remove residual palladium. The typical yield of the process was 89.7% with an HPLC purity of 97.9%.

[0518] The free base was converted to the HCl salt using concentrated hydrochloric acid in 2-propanol. 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol was suspended in 2-propanol with heating and concentrated hydrochloric acid was added. The formed slurry was then filtered and dried under reduced pressure to give 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol hydrochloride. The typical yield of the process was 92% with an HPLC purity of 98.9%. [Example 8] Preparation of the hydrochloride salt of the compound of structure (I) (Form I and Form II)

[0519] In this example, a crystalline form of the hydrochloride salt of compound of structure (I) (Form I) was synthesized according to the following reaction scheme: [ka] It was prepared according to Form I was characterized by X-ray powder diffraction (XRPD) (Figure 1), differential scanning calorimetry (Figure 2), thermogravimetric analysis (Figure 3), and polarized light microscopy (Figure 4). Form I showed good crystallinity by XRPD and birefringence by polarized light microscopy. The melting point of the hydrochloride salt was 226.2 °C, and a weight loss of 0.43% was detected from 30 °C to 118 °C by TGA.

[0520] A series of reactions was performed to screen various crystallization solvents based on the solubility of the free base and hydrochloride salt of the compound of structure (I). As detailed below, the methanol (MeOH) / ethyl acetate (EA) solvent system was identified as a particularly favorable solvent system for forming Form I.

[0521] One reaction was carried out on a 2.0 g scale to evaluate the process as detailed in Table 13. 1.8 g of the hydrochloride salt of compound of structure (I) was obtained with an HPLC purity of 98.75%. [Table 13]

[0522] The hydrochloride salt of compound of structure (I) was prepared by carrying out two reactions with the addition of 4N HCl / EA at 60-65° C. to reduce the volume of the crystallization system (Table 14). XRPD data showed that the crystallization conditions were acceptable. [Table 14]

[0523] One reaction was carried out on a 30.0 g scale to prepare a standard sample of the hydrochloride salt. 31 g of the hydrochloride salt was obtained as a pale yellow product with an HPLC purity of 98.74% (Table 15). However, TGA data showed that the residual THF (1.05%) could not be completely removed even at 120°C. [Table 15]

[0524] Five reactions were performed and reaction solvents were screened, as shown in Table 16. Analytical data showed that Me-THF and EA could not be removed very well by drying. However, residual MeOH was tolerable, and the solubility of the hydrochloride salt of compound structure (I) in MeOH was 50-100 mg / mL. [Table 16]

[0525] Two reactions were run on a 4.0 g scale each to screen temperatures using EtOH as the solvent. Conditions of HCl / EA solution at 20-30° C. (Table 17) were particularly advantageous, as shown below. [Table 17]

[0526] Although EtOH was found to be a favorable solvent for the synthesis, pilot studies showed that residual EtOH could not be easily removed. For example, two work-up procedures, each at a 1.0 g scale, were performed to attempt to remove residual EtOH by slurry in water, as shown in Table 18. Residual EtOH could not be removed very well under these conditions, and the process produced a mixture of Form I and Form II. [Table 18]

[0527] Five reactions were performed to screen for crystallization solvents, as shown in Table 19. As shown below, MeOH was found to be acceptable as a crystallization solvent. [Table 19]

[0528] Two reactions were run at 5.0 g scale to optimize the crystallization conditions, as shown in Table 20. The data show that the addition of 3V of EA for workup increases the yield from about 70% to about 90%. [Table 20]

[0529] Two reactions were carried out, each at a 1.0 g scale, to remove residual Pd, as shown in Table 21. Analytical data showed that the residual Pd could be reduced from 200 ppm to 17 ppm. [Table 21]

[0530] One reaction was carried out on a 60.0 g scale to prepare crystalline seeds of Form I, as shown in Table 22. 59.35 g of Form I was obtained in 90.99% yield with 99.95% HPLC purity. [Table 22]

[0531] In summary, crystalline Form I of the hydrochloride salt of the compound of structure (I) can be prepared, for example, by treating a THF solution of the free base with silica thiol, filtering the solution, and concentrating the resulting solution 2-3 times. The solution can be transferred to MeOH and concentrated 3-4 times. HCl / EA can be added dropwise at 20-30°C. Crystal seeds can be added and the mixture can be stirred at 20-30°C for 4-6 hours. The mixture can then be cooled to 0-5°C and stirred at 0-5°C for 10-15 hours. EA can be added dropwise at 0-5°C and the resulting mixture can be stirred for 4-6 hours. The mixture can then be filtered and dried at 55-65°C for 15-20 hours to obtain Form I. [Example 9] Hydrochloride salt of compound of structure (I): Solubility

[0532] In this example, the solubility of the hydrochloride salt of compound structure (I) was tested in different solvents at room temperature by manual dilution combined with visual observation. The solvents included methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), 1-butanol, acetonitrile (ACN), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), dichloromethane (DCM), 1,4-dioxane, toluene, heptane, tetrahydrofuran (THF), acetone and water. The results are listed in Table 23 below. [Table 23] [Example 10] Hydrochloride salt of compound of structure (I): Polymorph screening (slurry method)

[0533] In this experiment, suspensions of the hydrochloride salt (Form I) of compound of structure (I) in different solvents or solvent mixtures (Table 24) were prepared and kept shaking at room temperature for 24 hours. The residue was characterized by XRPD. The results are shown in Figures 6-15 and in Table 24 below. Form II was isolated in water by the slurry method described in this example. [Table 24-1] [Table 24-2] [Example 11] Hydrochloride salts of compounds of structure (I): Solvent-thermal heat / cool screening

[0534] In this experiment, saturated solutions of the hydrochloride salt of compound of structure (I) in different solvents or solvent mixtures (Table 25) were prepared at 70° C., then cooled and precipitated at −20° C. The precipitates were characterized by XRPD. The results are shown in Table 25 and FIG. 16. [Table 25] [Example 12] Hydrochloride salts of compounds of structure (I): Slow evaporation screening

[0535] Solutions of the hydrochloride salt of compound of structure (I) in different solvents or solvent mixtures (Table 26) were prepared at room temperature, and then the solutions were allowed to evaporate naturally (i.e., by slow evaporation while the drug substance solution was left open to air) at room temperature. The resulting solids were characterized by XRPD. The results are shown in Figures 17, 18 and Table 26. An amorphous form was found in MeOH by slow evaporation from the solution. [Table 26] [Example 13] Manufacturing of API

[0536] Form 1 of the hydrochloride salt of the compound of structure (I) was prepared according to the following procedure. 6.00 kg of the free base of the compound of structure (I) and 157 kg of THF were added to a reactor. The resulting mixture was heated to about 55-65° C. to dissolve the free base and obtain a homogeneous mixture which was subsequently filtered. The filtrate was concentrated under reduced pressure and solvent switched to methanol to obtain a volume of about 12 L. 27 kg of ethyl acetate was added to the methanol mixture and the resulting mixture was heated to obtain a homogeneous solution. 8.15 kg of 5 mol / L hydrochloric acid in ethyl acetate and 0.520 kg of seed crystals (Form 1 of the hydrochloride salt of the compound of structure (I)) were added to the homogeneous solution followed by 24 kg of ethyl acetate and the resulting reaction mixture was cooled to 4° C. and filtered. The filtered solid was washed with ethyl acetate and then dried at about 60° C. to obtain 5.56 kg of Form 1 of the hydrochloride salt of the compound of structure (I). [Example 14] Salt Screening 【053...

Claims

1. The following structure (I): 【Chemistry 64】 3. A crystalline hydrochloride salt of the compound of formula (I), characterized by an X-ray powder diffraction pattern containing peaks at 21.5±0.2°, 19.9±0.2° and 17.8±0.2° in terms of 2θ, and a differential scanning calorimetry thermogram containing an endothermic event at 226.9±3° C.

2. 2. The crystal of claim 1, further characterized by an X-ray powder diffraction pattern including a peak at 19.3±0.2 degrees 2θ.

3. 3. The crystal of claim 2, further characterized by an X-ray powder diffraction pattern including a peak at 24.4±0.2 degrees 2θ.

4. The crystal of claim 3, further characterized by an X-ray powder diffraction pattern including a peak at 16.3±0.2 degrees 2θ.

5. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern comprising at least three peaks at 2θ angles selected from the group consisting of 24.4±0.2°, 21.5±0.2°, 19.9±0.2°, 19.3±0.2°, 17.8±0.2° and 16.3±0.2°.

6. 6. The crystal of claim 5, further characterized by an X-ray powder diffraction pattern lacking a peak at 15.7±0.2 degrees 2θ.

7. 7. The crystal of claim 6, further characterized by an X-ray powder diffraction pattern lacking a peak at 17.0±0.2 degrees 2θ.

8. 8. The crystal of claim 7, further characterized by an X-ray powder diffraction pattern lacking a peak at 19.0±0.2 degrees 2θ.

9. Figure 1 below: The crystal of claim 1 having an X-ray powder diffraction pattern shown in

10. Figure 2 below:

2. The crystal of claim 1 having a differential scanning calorimetry thermogram shown in

11. Figure 3 below: The crystal of claim 1 having a thermogravimetric analysis diagram shown in:

12. The crystal according to any one of claims 1 to 11, having a melting temperature of 226±3°C.

13. 5. The crystal of claim 4, wherein the crystal has a purity of greater than 90% by weight.

14. A composition comprising the crystal of claim 4 and a pharma- ceutically acceptable carrier.

15. Polyglycolized glycerides; The following structure (I): 【Chemistry 65】 or a pharma- ceutically acceptable salt thereof.

16. 16. The composition of claim 15, wherein the polyglycolized glyceride has a melting point in the range of 30°C to 50°C.

17. 16. The composition of claim 15, wherein the polyglycolized glyceride has a hydrophilic / lipophilic balance (HLB) value in the range of 8 to 18.

18. 16. The composition of claim 15, wherein the polyglycolized glyceride comprises lauroyl polyoxy-32 glyceride.

19. 16. The composition of claim 15, wherein said composition comprises said compound of structure (I) or a pharma- ceutically acceptable salt thereof in a concentration ranging from 10 weight percent (wt%) to 40 wt%, as determined using the molecular weight of said compound of structure (I) as the hydrochloride salt.

20. 16. The composition of claim 15, wherein the composition comprises the polyglycolized glyceride at a concentration ranging from 50 wt% to 90 wt%.

21. 16. The composition of claim 15, wherein said composition comprises said compound of structure (I) or a pharma- ceutically acceptable salt thereof and said polyglycolized glyceride in a weight ratio ranging from 1:1 to 1:10 as determined using the molecular weight of said compound of structure (I) as a free base.

22. 16. A unit dosage form comprising a therapeutically effective amount of the composition of claim 15.

23. A unit dose form comprising a composition, said composition comprising: polyglycolized glycerides in an amount of 560 mg to 600 mg; an amount of 115 mg to 125 mg of the following structure (I): 【Chemistry 66】 or a pharma- ceutically acceptable salt thereof.

24. 14. A method for preparing the crystals of any one of claims 1 to 13, comprising precipitating said crystals from a solution or suspension comprising the hydrochloride salt of 2-((1R,4R)-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol and a non-aqueous medium, wherein the non-aqueous medium is a mixture of MeOH and EtOAc.

25. 25. The method of claim 24, further comprising contacting said solution or suspension with a seed crystal of said crystal.

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