Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide and preparation methods thereof

Abstract

The present invention relates to the dihydrochloride and dibenzenesulfonate salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide, and pharmaceutical compositions thereof useful in treating cancer and other diseases associated with dysregulation of kinase pathways. The present invention also relates to methods and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide and its salts.

Description

[0001] This application is a divisional application of invention patent application No. 201810253971.5, whose application date is May 20, 2009 and invention name is "Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide and preparation methods related thereto". Technical Field

[0002] The present invention relates to the dihydrochloride and dibenzenesulfonate of kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, which are used to treat cancer and other diseases associated with dysregulation of kinase pathways. The present invention also relates to methods and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and its salts. Background Art

[0003] Protein kinase (PK) is a group of enzymes that regulate a variety of important biological processes, including cell growth, cell survival and cell differentiation, organ formation and morphogenesis, new blood vessel formation, tissue repair and regeneration. Protein kinases play their physiological functions by catalyzing the phosphorylation of proteins (or substrates) to regulate the cell activity of substrates in a variety of biological contexts. In addition to the function in normal tissues / organs, many protein kinases also play a more specific role in many human diseases including cancer. The subtypes of protein kinases (also called oncogenic protein kinases) can cause tumor formation and growth when they are out of regulation, and also promote tumor maintenance and deterioration (Blume-Jensen P et al., Nature 2001, 411 (6835): 355-365). So far, oncogenic protein kinases represent one of the most and most attractive groups of protein targets for cancer intervention and drug development.

[0004] The proto-oncogene c-Met is a member of a different subfamily of heterodimeric receptor tyrosine kinases, which include Met, Ron and Sea (Birchmeier, C. et al., Nat. Rev. Mol. Cell Biol. 2003, 4(12):915-925; Christensen, JG et al., Cancer Lett. 2005, 225(1):1-26). The only high-affinity ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor (SF). Binding of HGF to c-Met induces activation of the receptor by autophosphorylation, which results in an increase in receptor-dependent signaling. Both c-Met and HGF are widely expressed in a variety of organs, but their expression is usually restricted to cells of epithelial and mesenchymal origin, respectively. The biological functions of c-Met (or the c-Met signaling pathway) in normal tissues and human malignancies such as cancer are well documented (Christensen, JG et al., Cancer Lett. 2005, 225(1): 1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6): 284-292).

[0005] HGF and c-Met are each required for normal mammalian development, and the abnormalities reported in both HGF-null mice and c-Met-null mice are consistent with the approximation of embryonic expression and the loss of epithelial-mesenchymal transition during organ morphogenesis (Christensen, JG et al., Cancer Lett. 2005, 225(1): 1-26). Consistent with these findings, the signal transduction and subsequent biological effects of the HGF / c-Met pathway have been shown to be important for epithelial-mesenchymal interactions during development, and for the regulation of cell migration, invasion, cell proliferation and survival, angiogenesis, morphogenesis and organization of three-dimensional tubular structures (e.g., renal tubular cells, gland formation). The specific outcome of c-Met pathway activation in a given cell / tissue is highly contiguous.

[0006] The dysregulated c-Met pathway plays an important and sometimes decisive (in the case of genetic modification) role in tumor formation, growth, maintenance and progression (Birchmeier, C. et al., Nat. Rev. Mol. Cell. Biol. 2003, 4(12):915-925; Boccaccio, C. et al., Nat. Rev. Cancer 2006, 6(8):637-645; Christensen, JG et al., Cancer Lett. 2005, 225(1):1-26). HGF and / or c-Met are overexpressed in a significant portion of most human cancers and are often associated with poor clinical outcomes such as more aggressive disease, disease progression, tumor metastasis and shortened patient lifespan. Moreover, patients with high levels of HGF / c-Met protein are more resistant to chemotherapy and radiation therapy. In addition to aberrant HGF / c-Met expression, the c-Met receptor can also be activated in cancer patients by gene mutation (both germline and somatic) and gene amplification. Although gene amplification and gene mutation are the most common genetic modifications reported in patients, the receptor can also be activated by deletion, truncation, gene rearrangement, as well as aberrant receptor processing and defective negative regulatory mechanisms.

[0007] The various cancers in which c-Met has been implicated include, but are not limited to, carcinomas (e.g., bladder cancer, breast cancer, cervical cancer, bile duct cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer); musculoskeletal sarcomas (e.g., osteosarcoma, synovial sarcoma, rhabdomyosarcoma); soft tissue sarcomas (e.g., MFH / fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma); hematopoietic malignancies (e.g., multiple myeloma, lymphoma, adult T-cell leukemia, acute myeloid leukemia, chronic myeloid leukemia); and other neoplasms (e.g., glioblastoma, astrocytoma, melanoma, mesothelioma, and Wilms' tumor) (www.vai.org / met / ; Christensen, JG et al., Cancer Lett. 2005, 225(1):1-26).

[0008] Through many preclinical studies, the following concept has been further solidified: the activated c-Met pathway promotes tumor formation and progression and may be a good target for effective cancer intervention (Birchmeier, C. et al., Nat. Rev. Mol. Cell Biol. 2003, 4(12):915-925; Christensen, JG et al., Cancer Lett. 2005, 225(1):1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284-292). For example, studies have shown that the tpr-met fusion gene, overexpression of c-met, and activating c-met mutations all cause oncogenic transformation of various model cell lines and lead to tumor formation and metastasis in mice. More importantly, agents that specifically impair and / or block HGF / c-Met signaling have been demonstrated in vitro and in vivo to have significant anti-tumor (sometimes tumor regression) and anti-metastatic activity. These agents include anti-HGF antibodies and anti-c-Met antibodies, HGF peptide antagonists, decoy c-Met receptors, c-Met peptide antagonists, dominant negative c-Met mutations, c-Met-specific antisense oligonucleotides and ribozymes, and selective small molecule c-Met kinase inhibitors (Christensen, JG et al., Cancer Lett. 2005, 225(1): 1-26).

[0009] In addition to its established role in cancer, aberrant HGF / c-Met signaling has been implicated in atherosclerosis, pulmonary fibrosis, renal fibrosis and regeneration, liver disease, allergic disorders, inflammatory and autoimmune diseases, cerebrovascular disease, cardiovascular disease, and disorders associated with organ transplantation (Ma, H. et al., Atherosclerosis. 2002, 164(1):79-87; Crestani, B. et al., Lab. Invest. 2002, 82(8):1015-1022; Sequra-Flores, AA et al., Rev. Gastroenterol. Mex. 2004, 69(4):243-250; Morishita, R. et al., Curr. Genet. 2003, 114(5):114-115; Morishita, R. et al., Curr. Genet. 2003, 114(5):114-115; Sequra-Flores, AA et al., Rev. Gastroenterol. Mex. 2004 ... Ther. 2004, 4(2): 199-206; Morishita, R. et al., Endocr. J. 2002, 49(3): 273-284; Liu, Y., Curr. Opin. Nephrol. Hypertens. 2002, 11(1): 23-30; Matsumoto, K. et al., Kidney Int. 2001, 59(6): 2023-2038; Balkovetz, DF et al., Int. Rev. Cytol. 1999, 186: 225-250; Miyazawa, T. et al., J. Cereb. Blood Flow Metab. 1998, 18(4): 345-348; Koch, AE et al., Arthritis Rheum. 1996, 39(9): 1566-1575; Futamatsu, H. et al., Circ. Res. 2005, 96(8): 823-830; Eguchi, S. et al., Clin. Transplant. 1999, 13(6): 536-544).

[0010] Inhibitors of c-Met and other kinases are reported in U.S. Patent Serial No. 11 / 942,130, including the compound 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide (I) having the structure indicated below.

[0011]

[0012] In order to develop more effective drugs to treat cancer and other diseases, there is a continuing need for new or improved versions of existing agents that inhibit kinases such as c-Met. The salts, compositions and methods described herein are directed to these needs and other goals. Summary of the invention

[0013] The present invention provides a salt, which is 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide dihydrochloride or a hydrate or solvate thereof.

[0014] The present invention also provides a salt, which is 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide dibenzenesulfonate or its hydrate or solvate.

[0015] The present invention also provides a composition comprising the salt of the present invention or a hydrate or solvate thereof and at least one pharmaceutically acceptable carrier.

[0016] The present invention also provides a method for inhibiting the activity of a receptor or non-receptor tyrosine kinase, which comprises contacting the kinase with a salt of the present invention or a hydrate or solvate thereof.

[0017] The present invention also provides a method for inhibiting the HGF / c-Met kinase signaling pathway in a cell, which comprises contacting the cell with a salt of the present invention or a hydrate or solvate thereof.

[0018] The present invention also provides a method for inhibiting the proliferation activity of cells, which comprises contacting the cells with the salt of the present invention or a hydrate or solvate thereof.

[0019] The present invention also provides a method of inhibiting tumor growth in a patient, which comprises administering to the patient a therapeutically effective amount of a salt of the present invention or a hydrate or solvate thereof.

[0020] The present invention also provides a method for inhibiting tumor metastasis in a patient, which comprises administering to the patient a therapeutically effective amount of a salt of the present invention or a hydrate or solvate thereof.

[0021] The present invention also provides a method for treating a disease in a patient, wherein the disease is associated with dysregulation of the HGF / c-MET signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a salt of the present invention or a hydrate or solvate thereof.

[0022] The present invention also provides a method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a salt of the present invention or a hydrate or solvate thereof.

[0023] The invention also provides a salt of the invention for use in therapy.

[0024] The invention also provides the use of a salt of the invention for the manufacture of a medicament for use in therapy.

[0025] The present invention also provides a method for preparing the dihydrochloride of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide, which comprises:

[0026] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and water with at least two equivalents of hydrochloric acid in a solvent comprising water to form a second mixture; and

[0027] b) combining the second mixture with methyl tert-butyl ether.

[0028] The present invention also provides a method for preparing the dihydrochloride of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide, which comprises:

[0029] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and methanol with at least two equivalents of hydrochloric acid in a solvent comprising isopropanol to form a second mixture; and

[0030] b) combining the second mixture with acetone.

[0031] The present invention also provides a method for preparing dibenzenesulfonate of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide, which comprises:

[0032] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and methanol with at least two equivalents of benzenesulfonic acid in a solvent comprising isopropanol to form a second mixture; and

[0033] b) combining the second mixture with methyl tert-butyl ether.

[0034] The present invention also provides a method for preparing a compound of formula I or a salt thereof:

[0035]

[0036] The method comprises treating a compound of formula II

[0037]

[0038] With the compound of formula III

[0039]

[0040] Reaction to form a compound of formula I or a salt thereof;

[0041] wherein X1 is chlorine, bromine or iodine.

[0042] The present invention also provides a method for preparing a compound of formula I:

[0043]

[0044]

[0045] The method includes:

[0046] a) the compound of formula II

[0047]

[0048] With the compound of formula VII

[0049]

[0050] Reaction to form a compound of formula VI:

[0051] and

[0052] b) reacting a compound of formula VI with Zn(CN)2 and Zn in the presence of a catalyst.

[0053] wherein X6 is chlorine, bromine or iodine.

[0054] The present invention also provides a compound of formula III or a salt thereof:

[0055]

[0056] The present invention also provides a compound of formula II:

[0057]

[0058] wherein X1 is chlorine, bromine or iodine.

[0059] The present invention also relates to the following items 1-83:

[0060] 1. A salt, which is 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide dihydrochloride or a hydrate or solvate thereof.

[0061] 2. A hydrate of the salt described in item 1.

[0062] 3. The hydrate of item 2, characterized in that the melting point is about 220°C to about 224°C.

[0063] 4. The hydrate as described in item 2, characterized in that the melting point is about 222°C.

[0064] 5. The hydrate according to item 2, which is crystalline.

[0065] 6. The hydrate as described in item 2, which has a DSC differential thermogram characterized by an endothermic peak at about 222°C.

[0066] 7. A hydrate as described in item 2, which has substantially Figure 2 DSC thermogram shown.

[0067] 8. A hydrate as described in item 2, which has substantially Figure 3 TGA shown.

[0068] 9. The hydrate as described in item 2, which has an X-ray powder diffraction pattern including a characteristic peak expressed at a 2θ angle of about 26.0.

[0069] 10. The hydrate as described in item 2, which has an X-ray powder diffraction pattern including a characteristic peak expressed at about 24.7 degrees 2θ.

[0070] 11. The hydrate as described in item 2, which has an X-ray powder diffraction pattern including a characteristic peak expressed at a 2θ angle of about 18.2.

[0071] 12. The hydrate as described in item 2, which has an X-ray powder diffraction pattern including a characteristic peak expressed at a 2θ angle of about 29.3.

[0072] 13. The hydrate as described in item 2, which has an X-ray powder diffraction pattern including a characteristic peak expressed at a 2θ angle of about 7.8.

[0073] 14. The hydrate as described in item 2, which has an X-ray powder diffraction pattern including characteristic peaks expressed at about 26.0 and 24.7 in 2θ angle.

[0074] 15. The hydrate as described in item 2, which has an X-ray powder diffraction pattern including characteristic peaks expressed at 2θ angles of about 26.0, 24.7, 18.2, 29.3 and 7.8.

[0075] 16. A salt which is 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide dibenzenesulfonate or a hydrate or solvate thereof.

[0076] 17. The salt according to item 16, wherein the salt is anhydrous.

[0077] 18. The salt of item 16, characterized in that it has a melting point of about 268°C to about 272°C.

[0078] 19. The salt according to item 16, characterized in that the melting point is about 270°C.

[0079] 20. The salt according to item 16, which is crystalline.

[0080] 21. The salt according to item 16, which has a DSC differential thermogram characterized by an endothermic peak at about 270°C.

[0081] 22. The salt according to claim 16, which has substantially Figure 5 DSC thermogram shown.

[0082] 23. The salt of item 16, which has an X-ray powder diffraction pattern including a characteristic peak expressed at about 20.2 degrees 2θ.

[0083] 24. The salt according to item 16, which has an X-ray powder diffraction pattern including a characteristic peak expressed at about 15.0 degrees 2θ.

[0084] 25. The salt according to item 16, which has an X-ray powder diffraction pattern including a characteristic peak expressed at about 16.3 degrees 2θ.

[0085] 26. The salt according to item 16, which has an X-ray powder diffraction pattern including a characteristic peak expressed at about 18.3 degrees 2θ.

[0086] 27. The salt according to item 16, which has an X-ray powder diffraction pattern including a characteristic peak expressed at about 23.8 degrees 2θ.

[0087] 28. The salt according to item 16, which has an X-ray powder diffraction pattern including a characteristic peak expressed at about 4.9 in 2θ degrees.

[0088] 29. The salt of item 16, which has an X-ray powder diffraction pattern comprising characteristic peaks expressed at about 15.0, 16.3, 18.3, 20.2, 23.8 and 4.9 in 2θ degrees.

[0089] 30. A composition comprising the salt according to any one of items 1 to 29 or a hydrate or solvate thereof and at least one pharmaceutically acceptable carrier.

[0090] 31. A method for inhibiting the activity of a receptor or non-receptor tyrosine kinase, the method comprising contacting the kinase with a salt or a hydrate or solvate thereof according to any one of items 1 to 29.

[0091] 32. A method as described in claim 31, wherein the kinase is c-Met.

[0092] 33. A method of inhibiting the HGF / c-Met kinase signaling pathway in a cell, the method comprising contacting the cell with the salt or hydrate or solvate thereof according to any one of items 1 to 29.

[0093] 34. A method for inhibiting the proliferation activity of a cell, the method comprising contacting the cell with the salt or a hydrate or solvate thereof according to any one of items 1 to 29.

[0094] 35. A method of inhibiting tumor growth in a patient, the method comprising administering to the patient a therapeutically effective amount of the salt or hydrate or solvate thereof according to any one of items 1 to 29.

[0095] 36. A method of inhibiting tumor metastasis in a patient, the method comprising administering to the patient a therapeutically effective amount of the salt or a hydrate or solvate thereof according to any one of items 1 to 29.

[0096] 37. A method for treating a disease in a patient, wherein the disease is associated with dysregulation of the HGF / c-MET signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a salt or a hydrate or solvate thereof according to any one of items 1 to 29.

[0097] 38. The method of claim 37, wherein the disease is cancer, atherosclerosis, pulmonary fibrosis, renal fibrosis and regeneration, liver disease, allergic disorders, inflammatory diseases, autoimmune disorders, cerebrovascular diseases, cardiovascular diseases, or symptoms associated with organ transplantation.

[0098] 39. A method of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a salt or a hydrate or solvate thereof according to any one of items 1 to 29.

[0099] 40. The method of claim 39, wherein the cancer is carcinoma, musculoskeletal sarcoma, soft tissue sarcoma, or hematopoietic malignancy.

[0100] 41. The method of claim 39, wherein the cancer is bladder cancer, breast cancer, cervical cancer, bile duct cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH / fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult T-cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma or Wilms' tumor.

[0101] 42. A method for preparing the hydrate described in item 2, the method comprising:

[0102] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and water with at least two equivalents of hydrochloric acid in a solvent comprising water to form a second mixture; and

[0103] b) combining the second mixture with methyl tert-butyl ether.

[0104] 43. The method of item 42, wherein step a) is performed at a temperature of about 20°C to about 30°C.

[0105] 44. The method of item 42, wherein step a) and step b) are performed at about room temperature.

[0106] 45. A method for preparing the hydrate described in item 2, the method comprising:

[0107] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and methanol with at least two equivalents of hydrochloric acid in a solvent comprising isopropanol to form a second mixture; and

[0108] b) combining the second mixture with acetone.

[0109] 46. ​​The method of item 45, wherein steps a) and b) are performed at a temperature of about 50°C to about 60°C.

[0110] 47. The method of item 45, wherein steps a) and b) are performed at a temperature of about 55°C.

[0111] 48. A method for preparing the salt of item 16, the method comprising:

[0112] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and methanol with at least two equivalents of benzenesulfonic acid in a solvent comprising isopropanol to form a second mixture; and

[0113] b) combining the second mixture with methyl tert-butyl ether.

[0114] 49. The method of item 48, wherein steps a) and b) are performed at a temperature of about 50°C to about 60°C.

[0115] 50. The method of item 48, wherein steps a) and b) are performed at a temperature of about 55°C.

[0116] 51. A method for preparing a compound of formula I or a salt thereof:

[0117]

[0118] The method comprises treating a compound of formula II

[0119]

[0120] With the compound of formula III

[0121]

[0122] Reaction to form a compound of formula I or a salt thereof:

[0123] wherein X1 is chlorine, bromine or iodine.

[0124] 52. The method of item 51, further comprising reacting the compound of formula I or its salt with a strong acid to form a compound of formula IV or its salt:

[0125]

[0126] 53. A method as described in item 52, wherein the acid is concentrated hydrochloric acid.

[0127] 54. The method of item 52 or 53, further comprising reacting the compound of formula IV or its salt with CH3NH2 in the presence of at least one coupling agent to form a compound of formula V or its salt:

[0128]

[0129] 55. A method as described in item 54, wherein the coupling agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxybenzotriazole, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and its salts.

[0130] 56. The method according to item 52 or 53, further comprising:

[0131] a) the compound of formula IV or its salt

[0132]

[0133] Reaction with a halogenating agent to form a compound of formula VI or a salt thereof:

[0134] and

[0135] b) reacting the compound of formula VI or a salt thereof with CH3NH2 to form a compound of formula V or a salt thereof:

[0136]

[0137] wherein X2 is a halogen.

[0138] 57. The method of item 56, wherein the halogenating agent is thionyl chloride.

[0139] 58. The method of any one of items 51-57, further comprising:

[0140]

[0141] With the compound of formula IIb

[0142]

[0143] The method for preparing the compound of formula II is as follows:

[0144]

[0145] wherein X1 is chlorine, bromine or iodine.

[0146] 59. The method of item 58, wherein the reaction of the compound of formula IIa with the compound of formula IIb is carried out in the presence of proline.

[0147] 60. A method as described in any of items 58-59, wherein X1 is chlorine.

[0148] 61. The method of item 58 or 59, further comprising reacting a compound of formula IIc in the presence of a palladium catalyst and a base.

[0149]

[0150] The compound of formula IIa is prepared by reacting with prop-2-en-1-ol:

[0151]

[0152] wherein X3 is chlorine, bromine or iodine.

[0153] 62. The method of item 61, further comprising:

[0154]

[0155] The compound of formula IIa is prepared by reacting with an acid of formula HX':

[0156]

[0157] wherein X' is chlorine, bromine or iodine.

[0158] 63. The method of item 62, further comprising reducing the compound of formula IIe with hydrogen in the presence of a hydrogenation catalyst:

[0159]

[0160] The compound of formula IId is prepared by the method of:

[0161]

[0162] 64. A method as described in item 63, wherein the hydrogenation catalyst is palladium on carbon.

[0163] 65. The method of item 63 or 64, further comprising reacting a compound of formula IIc with a compound of formula IIf in the presence of a coupling catalyst and a base.

[0164]

[0165] The method of the reaction is to prepare the compound of formula IIe.

[0166] 66. The method of item 65, wherein the catalyst is a mixture of palladium acetate and CuI.

[0167] 67. The method of item 63, further comprising:

[0168]

[0169] Reaction with 9-boranebicyclo[3.3.1]nonane, followed by reaction with a compound of formula IIc in the presence of a coupling catalyst

[0170]

[0171] Reaction to prepare the compound of formula IId by a method of forming a compound of formula IId

[0172]

[0173] wherein X3 is chlorine, bromine or iodine.

[0174] 68. A method as described in item 67, wherein the coupling catalyst is palladium (II) diacetate.

[0175] 69. A method as described in any one of items 51 to 68, which further comprises reacting a compound of formula IIIa in the presence of a palladium catalyst and a base.

[0176]

[0177] With the compound of formula IIIb

[0178]

[0179] The compound of formula III is prepared by a reaction method; wherein:

[0180] X4 is chlorine, bromine or iodine; and

[0181] Every R a Independently C 1-6 Alkyl; or

[0182] Every R a Together with two oxygen atoms and a boron atom, it forms a 5-membered heterocyclic ring or a 6-membered heterocyclic ring; wherein the heterocyclic ring is optionally substituted by 1, 2, 3 or 4 independently selected C 1-4 Alkyl substitution.

[0183] 70. The method of item 69, wherein the compound of formula IIIb has formula IIIb-1:

[0184]

[0185] 71. The method of item 69 or 70, further comprising preparing the compound of formula IIIa by reacting 1,2,4-triazine-3-amine with a halogenating agent.

[0186] 72. The method of item 70, further comprising preparing the compound of formula IIIb-1 by a method comprising:

[0187] a) the compound of formula IIIc

[0188]

[0189] Reaction with a reagent of formula R1MgY followed by reaction with a compound of formula B(OR2)3 to form a compound of formula IIId:

[0190] and

[0191] b) after the reaction in step a), reacting the compound of formula IIId with an acid, and then reacting with pinacol to form a compound of formula IIIb-1;

[0192] in:

[0193] R1 is C 1-6 alkyl;

[0194] Each R2 is independently C 1-6 alkyl; and

[0195] X5 is chlorine, bromine or iodine.

[0196] 73. A method for preparing a compound of formula I:

[0197]

[0198] The method comprises:

[0199] a) the compound of formula II

[0200]

[0201] With the compound of formula VII

[0202]

[0203] Reaction to form a compound of formula VIa:

[0204] and

[0205] b) reacting the compound of formula VIa with Zn(CN)2 and Zn in the presence of a catalyst;

[0206] wherein X6 is chlorine, bromine or iodine.

[0207] 74. A method as described in item 73, wherein the catalyst is 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)2Cl2).

[0208] 75. The method of item 73 or 74, further comprising:

[0209]

[0210] The compound of formula VII is prepared by reacting with aminoguanidine or its salt and a base;

[0211] wherein X6 is chlorine, bromine or iodine.

[0212] 76. A method as described in item 75, wherein the base is potassium hydroxide.

[0213] 77. The method of item 75 or 76, further comprising reacting a compound of formula IX in the presence of an acid

[0214]

[0215] The compound of formula VIII is prepared by reacting with triethyl orthoformate to form the compound of formula VIII;

[0216] wherein X6 is chlorine, bromine or iodine.

[0217] 78. A method as described in item 77, wherein the acid is p-toluenesulfonic acid.

[0218] 79. The method of item 77 or 78, further comprising:

[0219]

[0220] The compound of formula IX is prepared by reacting with a strong acid to form the compound of formula IX:

[0221] wherein X6 is chlorine, bromine or iodine.

[0222] 80. The method of item 79, further comprising:

[0223]

[0224] The compound of formula X is prepared by reacting with CH3MgBr to form a compound of formula X

[0225] wherein X6 is chlorine, bromine or iodine.

[0226] 81. The method of item 80, further comprising:

[0227]

[0228] The compound of formula XI is prepared by reacting with oxalyl chloride or thionyl chloride followed by treatment with dimethylhydroxylamine or a salt thereof to form a compound of formula XI;

[0229] wherein X6 is chlorine, bromine or iodine.

[0230] 82. A compound of formula III or a salt thereof:

[0231]

[0232] 83. A compound of formula II:

[0233]

[0234] Among them, X 1 It is chlorine, iodine or bromine. BRIEF DESCRIPTION OF THE DRAWINGS

[0235] Figure 1 The X-ray powder diffraction (XRPD) pattern characteristics of the dihydrochloride salt of the present invention prepared according to the method of Example 1 are shown.

[0236] Figure 2 The differential scanning calorimetry (DSC) microcharacteristics of the dihydrochloride salt of the present invention prepared according to the method of Example 1 are shown.

[0237] Figure 3 The differential thermogram characteristic of the thermogravimetric analysis (TGA) of the dihydrochloride salt of the present invention prepared according to the method of Example 1 is shown.

[0238] Figure 4 The X-ray powder diffraction (XRPD) pattern characteristics of the dibenzenesulfonate of the present invention prepared according to the method of Example 5 are shown.

[0239] Figure 5 The differential scanning calorimetry (DSC) microcharacteristics of the dibenzenesulfonate salt of the present invention prepared according to the method of Example 5 are shown. DETAILED DESCRIPTION

[0240] The present invention provides, inter alia, the dihydrochloride and dibenzenesulfonate salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide (see formula I above). The salts of the present invention have the advantage that they can be obtained in crystalline form, which makes them particularly suitable for use in pharmaceutical formulations.

[0241] Dihydrochloride

[0242] The dihydrochloride salt can be prepared by combining 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide with a molar excess of hydrochloric acid as described in Example 1 below. The dihydrochloride salt can be obtained as a crystalline solid, such as Figure 1As shown in the XRPD pattern shown in (see also Example 2 below). A hydrate of the dihydrochloride salt can also be obtained, based on Figure 3 The TGA results are shown in (see also Example 4 below). DSC shows that the dihydrochloride salt melts at about 220°C to about 224°C, or more specifically at about 222°C (see Figure 2 and Example 3). The solubility of the dihydrochloride salt at 25°C was found to be: about 4.5 mg / mL in water; 0.002 mg / mL in pH 7.4 buffer; 0.002 mg / mL in pH 8.0 buffer; and about 24 mg / mL in 0.1N aqueous HCl. The salt prepared by the method of Example 1 was found to have good solubility characteristics and was desirably reproducible.

[0243] In some embodiments, the X-ray powder diffraction pattern of the dihydrochloride salt includes a characteristic peak expressed at about 26.0 at 2θ angles. In some embodiments, the X-ray powder diffraction pattern of the dihydrochloride salt includes a characteristic peak expressed at about 24.7 at 2θ angles. In some embodiments, the X-ray powder diffraction pattern of the dihydrochloride salt includes a characteristic peak expressed at about 18.2 at 2θ angles. In some embodiments, the X-ray powder diffraction pattern of the dihydrochloride salt includes a characteristic peak expressed at about 29.3 at 2θ angles. In some embodiments, the X-ray powder diffraction pattern of the dihydrochloride salt includes characteristic peaks expressed at about 26.0 and 24.7 at 2θ angles. In some embodiments, the X-ray powder diffraction pattern of the dihydrochloride salt includes a characteristic peak expressed at about 7.8 at 2θ angles. In some embodiments, the X-ray powder diffraction pattern of the dihydrochloride salt includes characteristic peaks expressed at about 26.0, 24.7, 18.2 and 29.3 at 2θ angles. In some embodiments, the dihydrochloride salt has an X-ray powder diffraction pattern comprising characteristic peaks expressed at degrees 2θ at about 7.8, 26.0, 24.7, 18.2, and 29.3.

[0244] Dibenzenesulfonate

[0245] Dibenzenesulfonic acid salts (di-besylate salts) can be prepared by combining 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide with a molar excess of benzenesulfonic acid, as described in Example 5 below. A crystalline solid of the di-besylate salt can be obtained, such as Figure 4 As shown in the XRPD pattern shown in (see also Example 5 below). DSC shows that the dibenzenesulfonate salt melts at about 268°C to about 272°C, or more specifically at about 270°C (see Figure 5and Example 7). The solubility of the dibenzenesulfonate salt at 25°C was found to be: about 3.9 mg / mL in water; 0.003 mg / mL in pH 7.4 buffer; 0.003 mg / mL in pH 8.0 buffer; and at least 29 mg / mL in 0.1 N aqueous HCl.

[0246] In some embodiments, the present invention provides a specific form of a dibenzenesulfonate salt, the X-ray powder diffraction pattern of which includes a characteristic peak expressed at about 20.2 at a 2θ angle. In some embodiments, the X-ray powder diffraction pattern of a dibenzenesulfonate salt includes a characteristic peak expressed at about 15.0 at a 2θ angle. In some embodiments, the X-ray powder diffraction pattern of a dibenzenesulfonate salt includes a characteristic peak expressed at about 16.3 at a 2θ angle. In some embodiments, the X-ray powder diffraction pattern of a dibenzenesulfonate salt includes a characteristic peak expressed at about 18.3 at a 2θ angle. In some embodiments, the X-ray powder diffraction pattern of a dibenzenesulfonate salt includes a characteristic peak expressed at about 23.8 at a 2θ angle. In some embodiments, the X-ray powder diffraction pattern of a dibenzenesulfonate salt includes a characteristic peak expressed at about 4.9 at a 2θ angle. In some embodiments, the X-ray powder diffraction pattern of a dibenzenesulfonate salt includes characteristic peaks expressed at about 15.0, 16.3, 18.3, 20.2 and 23.8 at 2θ angles. In some embodiments, the dibenzenesulfonate salt has an X-ray powder diffraction pattern comprising characteristic peaks expressed at degrees 2θ at about 15.0, 16.3, 18.3, 20.2, 23.8, and 4.9.

[0247] Definitions and Alternative Embodiments

[0248] The present invention includes hydrates or solvates of the above salts. Solvates refer to salts in which the solvent is contained within the crystal lattice or as a component of the crystal lattice. The term "hydrate" as used herein is a specific solvate in which the solvent is water and is intended to refer to a substance having water of hydration. Examples of hydrates include hemihydrates, monohydrates, dihydrates, and the like.

[0249] In some embodiments, the salt of the present invention is crystalline. As used herein, "crystalline" material refers to a material comprising at least some crystalline materials. The presence of crystalline materials can be detected by methods such as XRPD. The salt of the present invention can be crystallized in different crystalline forms, and different crystalline forms have different lattices, and therefore have different physical properties. Some crystalline forms can have different water contents or solvent contents. Different lattices can be identified by solid-state characterization methods, such as by X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor absorption (DVS) and similar methods further assist in identifying crystalline forms and assist in determining stability and solvent / water content.

[0250] Different crystalline forms of a particular substance, such as a salt of the invention, may include both an anhydrous form of the substance and a solvate / hydrate form of the substance, wherein each of the anhydrous form and the solvate / hydrate form is distinguished from each other by a different XRPD pattern and thereby represents a different crystal lattice. In some examples, a single crystalline form (e.g., identified by a single XRPD pattern) may have a variable water content or solvent content, wherein, except for changes in composition relative to water and / or solvent, the crystal lattice remains essentially unchanged (as represented by the XRPD pattern).

[0251] The XRPD image of reflection (peak) is generally considered to be the fingerprint of a specific crystalline form. It is well known that the relative intensity of XRPD peaks can vary widely, depending on the sample preparation technique, crystal size distribution, various filters used, sample determination procedures and the specific instrument used. In some instances, new peaks may be observed, or existing peaks may disappear, depending on the type or setting of the instrument. The term "peak" as used herein refers to a reflection with a relative height / intensity of at least about 4% of the maximum peak height / intensity. In addition, instrument changes and other factors can affect 2θ values. Therefore, the peak arrangements as reported herein may vary by plus or minus about 0.2° (2θ), and the term "substantially" as used in the context of XRPD herein refers to including the above-mentioned changes.

[0252] In the same manner, temperature readings associated with DSC, TGA or other thermal experiments may vary by about ±3°C, depending on the instrument, specific settings, sample preparation, etc. Therefore, solid forms or crystalline forms reported herein as having a DSC thermogram "substantially" as shown in any of the accompanying drawings should be understood to accommodate such variations.

[0253] The salts of the present invention may also include all isotopes of atoms present in the salt. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0254] Salt of the present invention and solid form thereof can be found together with other materials, or can be separated.In some embodiments, salt of the present invention or its solid form are separated substantially. " substantially separation " refers to that salt is separated at least partially or substantially from the environment in which it is formed or detected. Partial separation can include, for example, a composition rich in salt of the present invention. Substantially separation can include comprising the following composition: at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% salt of the present invention by weight. The method for separating compounds and their salts is a conventional method in the art.

[0255] method

[0256] Treatment of cells expressing protein kinases with salts of the invention (in vivo or in vitro) can result in inhibition of ligand / kinase signaling pathways and inhibition of downstream events associated with the signaling pathways, such as cell proliferation and increased cell motility. For example, the salts of the invention can block and / or impair biochemical and biological processes resulting from c-Met pathway activation, including but not limited to: c-Met kinase activation (e.g., c-Met phosphorylation) and signaling (activation and recruitment of cellular substrates such as Gab1, Grb2, Shc, and c-Cb1, and subsequent activation of multiple signal transducers including PI-3 kinase, PLC-γ, STAT, ERK1 / 2, and FAK), cell proliferation and survival, cell motility, cell migration and invasion, metastasis, angiogenesis, and the like. Thus, the present invention also provides methods for inhibiting ligand / kinase signaling pathways, such as the HGF / c-Met kinase signaling pathway in cells, by contacting cells with salts of the invention. The present invention also provides methods for inhibiting the proliferative activity of cells or inhibiting cell motility by contacting cells with salts of the invention.

[0257] The present invention also provides a method for treating a disease associated with a dysregulated kinase signaling pathway in an individual (e.g., a patient), the dysregulated kinase signaling pathway comprising abnormal activity and / or overexpression of a protein kinase, by administering a therapeutically effective amount or dose of a salt of the present invention or a pharmaceutical composition thereof to an individual in need of such treatment. In some embodiments, the dysregulated kinase is of the Met family (e.g., c-Met, Ron, or Sea). In some embodiments, the dysregulated kinase is overexpressed in the patient's diseased tissue. In some embodiments, the dysregulated kinase is abnormally active in the patient's diseased tissue. The dysregulation of c-Met and HGF / c-Met signaling pathways is intended to include activation of enzymes by a variety of mechanisms, including, but not limited to: HGF-dependent autocrine and paracrine activation, c-met gene overexpression and amplification, point mutations, deletions, truncations, rearrangements, and abnormal c-Met receptor processing and defective negative regulatory mechanisms.

[0258] In some embodiments, the salts of the invention are used to treat diseases such as cancer, atherosclerosis, pulmonary fibrosis, renal fibrosis and regeneration, liver disease, allergic disorders, inflammatory diseases, autoimmune disorders, cerebrovascular disease, cardiovascular disease, or disorders associated with organ transplantation. In other embodiments, the compounds of the invention can be used in methods of inhibiting tumor growth or tumor metastasis in patients.

[0259] Examples of cancers treatable by the methods herein include bladder cancer, breast cancer, cervical cancer, bile duct cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH / fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult T-cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma or Wilms' tumor, and the like.

[0260] As used herein, the term "cell" means a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be a part of a tissue sample removed from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that survives in an organism such as a mammal.

[0261] As used herein, the term "contacting" refers to bringing the referred moieties together in an in vitro system or an in vivo system. For example, "contacting" a compound of the invention with a protein kinase includes administering the compound of the invention to an individual or patient such as a human, and, for example, introducing the compound of the invention into a sample of a cell preparation or purified preparation containing the protein kinase.

[0262] As used herein, the terms "subject" or "patient" used interchangeably refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0263] As used herein, the terms "treating" or "treatment" refer to one or more of the following: (1) preventing a disease; e.g., preventing a disease, disorder or condition in an individual who may be susceptible to the disease, disorder or condition but does not yet experience or display the pathology or symptoms of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, disorder or condition in an individual who experiences or displays the pathology or symptoms of the disease, disorder or condition; and (3) ameliorating a disease; e.g., ameliorating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease, in an individual who experiences or displays the pathology or symptoms of the disease, disorder or condition.

[0264] Combination therapy

[0265] One or more additional agents or treatments, such as, for example, chemotherapy, anticancer agents, cytotoxic agents, or anticancer therapies (e.g., radiation, hormones, etc.), can be used in combination with the salts of the invention for the treatment of the diseases, disorders, or conditions described herein. The agents or therapies can be administered together with the salts of the invention (e.g., combined into a single dosage form), or the agents or therapies can be administered simultaneously or sequentially via different routes of administration.

[0266] Suitable anticancer agents include kinase inhibitors, including trastuzumab (Herceptin), imatinib (Gleevec), gefitinib (Iressa), erlotinib hydrochloride (Tarceva), cetuximab (Erbitux), bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), and RTK inhibitors described in, for example, WO 2005 / 004808, WO 2005 / 004607, WO 2005 / 005378, WO 2004 / 076412, WO 2005 / 121125, WO 2005 / 039586, WO 2005 / 028475, WO 2005 / 040345, WO 2005 / 039586, WO 2003 / 097641, WO 2003 / 087026, WO 2005 / 040154, WO 2005 / 030140, WO 2006 / 014325, WO 2005 / 070891, WO 2005 / 073224, WO 2005 / 113494 and U.S. Patent Application Publication Nos. 2005 / 0085473, 2006 / 0046991 and 2005 / 0075340.

[0267] Suitable chemotherapeutic agents or other anticancer agents also include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes), such as uracil mustard, nitrogen mustard, cyclophosphamide (Cytoxan TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0268] Suitable chemotherapeutic agents or other anticancer agents also include, for example, antimetabolites (including but not limited to folate antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine.

[0269] Suitable chemotherapeutic agents or other anticancer agents also include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytosine arabinoside, paclitaxel, TM), plicamycin, deoxycoformycin, mitomycin C, L-asparaginase, interferon (especially IFN-a), etoposide and teniposide.

[0270] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, cyclophosphamide, ifosfamide, and droloxifene.

[0271] Also suitable are cytotoxic agents such as epididymoxin; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes, such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutics; leucovorin; tegafur; and hematopoietic growth factors.

[0272] Other anticancer agents include antibody therapeutics, such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.). Additional antibody therapeutics include antibodies to tyrosine kinases and / or their ligands, such as anti-HGF antibodies and / or anti-c-Met antibodies. The term "antibody" is meant to include all antibodies (e.g., monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, etc.), and antigen-binding fragments thereof.

[0273] Other anticancer agents include those that block the migration of immune cells, such as antibodies to chemokine receptors including CCR2 and CCR4.

[0274] Other anticancer agents include those that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0275] Other anticancer agents include anticancer vaccines, such as dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0276] Methods for safe and effective administration of most of the above-mentioned agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of various chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is hereby incorporated by reference as if listed in its entirety.

[0277] Intermediates and methods

[0278] In some embodiments, the present invention provides a method of preparing a particular form of the dihydrochloride salt by a method comprising:

[0279] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and water with at least two equivalents of hydrochloric acid in a solvent comprising water to form a second mixture; and

[0280] b) combining the second mixture with methyl tert-butyl ether.

[0281] In some embodiments, step a) is performed at a temperature of about 20°C to about 30°C.

[0282] In some embodiments, steps a) and b) are performed at about room temperature.

[0283] In some embodiments, the present invention provides a method of preparing a particular form of the dihydrochloride salt by a method comprising:

[0284] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and methanol with at least two equivalents of hydrochloric acid in a solvent comprising isopropanol to form a second mixture; and

[0285] b) combining the second mixture with acetone.

[0286] In some embodiments, steps a) and b) are performed at a temperature of about 50°C to about 60°C.

[0287] In some embodiments, steps a) and b) are performed at a temperature of about 55°C.

[0288] In some embodiments, the present invention provides a method for preparing a specific form of dibenzenesulfonate, comprising:

[0289] a) reacting a first mixture comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and methanol with at least two equivalents of benzenesulfonic acid in a solvent comprising isopropanol; and

[0290] b) combining the second mixture with methyl tert-butyl ether.

[0291] In some embodiments, steps a) and b) are performed at a temperature of about 50°C to about 60°C. In some embodiments, steps a) and b) are performed at a temperature of about 55°C.

[0292] The present invention also provides methods and intermediates useful, inter alia, for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and its salts, including the salts of the present invention.

[0293] For example, in some embodiments, the present invention provides a compound of Formula III or a salt thereof:

[0294]

[0295] The present invention also provides a compound of formula II:

[0296]

[0297] wherein X1 is chlorine, iodine or bromine.

[0298] In some embodiments, X1 is chloro.

[0299] The present invention also provides a method for preparing a compound of formula I or a salt thereof:

[0300]

[0301] The method comprises treating a compound of formula II

[0302]

[0303] With the compound of formula III

[0304]

[0305] Reaction to form a compound of formula I or a salt thereof;

[0306] wherein X1 is chlorine, bromine or iodine.

[0307] In some embodiments, X1 is chloro.

[0308] In some embodiments, the reaction is carried out in a solvent such as ethylene glycol. In some embodiments, the reaction is carried out at a temperature from about 120° C. to about 150° C., or from about 130° C. to about 140° C. In some embodiments, the reaction is carried out for about three hours to about four hours.

[0309] In some embodiments, the method further comprises reacting the compound of Formula I or a salt thereof with a strong acid to form a compound of Formula IV or a salt thereof:

[0310]

[0311] In some embodiments, the acid is hydrochloric acid or hydrobromic acid. In some embodiments, the acid is concentrated hydrochloric acid.

[0312] In some embodiments, the reaction of the compound of Formula I with the strong acid is carried out at a temperature of from about 80° C. to about 120° C., from about 90° C. to about 110° C., or about 100° C. In some embodiments, the reaction is carried out for about 15 hours to about 24 hours, or about 18 hours.

[0313] In some embodiments, the method further comprises reacting a compound of Formula IV or a salt thereof with CH3NH2 in the presence of at least one coupling agent to form a compound of Formula V or a salt thereof:

[0314]

[0315] In some embodiments, the coupling agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxybenzotriazole (HOBt), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and salts thereof.

[0316] In some embodiments, the reaction of the compound of formula IV with CH3NH2 is carried out at a temperature from about 15°C to about 40°C, from about 15°C to about 25°C, about 30°C, or about room temperature. In some embodiments, the reaction is carried out in a solvent including but not limited to acetonitrile. In some embodiments, the reaction is carried out in the presence of a base including but not limited to a tertiary amine such as triethylamine. In some embodiments, CH3NH2 is present in an amount of about 1 equivalent to about 10 equivalents, about 2 equivalents to about 8 equivalents, or about 3 equivalents to about 6 equivalents.

[0317] In some embodiments, the method further comprises:

[0318] a) a compound of formula IV or a salt thereof

[0319]

[0320] Reaction with a halogenating agent to form a compound of formula VI or a salt thereof

[0321] and

[0322] b) reacting a compound of formula VI or a salt thereof with CH3NH2 to form a compound of formula V or a salt thereof

[0323]

[0324] wherein X2 is a halogen.

[0325] In some embodiments, X2 is chlorine. In some embodiments, the halogenating agent is thionyl chloride. In some embodiments, the halogenating agent is oxalyl chloride.

[0326] In some embodiments, the reaction of the compound of formula IV with the halogenating agent is carried out at a temperature of from about 50° C. to about 80° C., from about 60° C. to about 75° C., or about 72° C. In some embodiments, the reaction is carried out in a solvent including but not limited to toluene. In some embodiments, the halogenating agent is present in an amount of about 1 equivalent to about 20 equivalents, about 8 equivalents to about 12 equivalents, or about 10 equivalents.

[0327] In some embodiments, the reaction of the compound of Formula VI with CH3NH2 is carried out at a temperature from about 0°C to about 35°C, from about 0°C to about 10°C, or about room temperature. In some embodiments, the reaction is carried out in a solvent including but not limited to tetrahydrofuran. In some embodiments, CH3NH2 is present in an amount of about 1 equivalent to about 20 equivalents, about 8 equivalents to about 12 equivalents, or about 10 equivalents.

[0328] In some embodiments, step b) is performed in the presence of a base (eg, a tertiary amine).

[0329] In some embodiments, the method further comprises the step of:

[0330]

[0331] With the compound of formula IIb

[0332]

[0333] The method for preparing the compound of formula II

[0334]

[0335] wherein X1 is chlorine, bromine or iodine.

[0336] In some embodiments, X1 is chloro.

[0337] In some embodiments, the reaction is carried out in the presence of proline. In some embodiments, the reaction is carried out in the presence of proline and benzoic acid. In some embodiments, the reaction of the compound of formula IIa with the compound of formula IIb is carried out at a temperature of from about 0°C to about 50°C, from about 20°C to about 40°C, or about 20°C. In some embodiments, the reaction is carried out in a solvent including but not limited to dichloromethane. In some embodiments, the compound of formula IIb is present in an amount of about 1 equivalent to about 2 equivalents, about 1 equivalent to about 1.5 equivalents, about 1 equivalent to about 1.2 equivalents, or about 1.05 equivalents. In some embodiments, proline is present in an amount of about 0.1 equivalent to about 0.5 equivalents or about 0.1 equivalent to about 0.2 equivalents. In some embodiments, proline is present in an amount of about 0.1 equivalents, and benzoic acid is present in an amount of about 0.1 equivalents.

[0338] In some embodiments, the method further comprises preparing a compound of Formula IIa by a method comprising reacting a compound of Formula IIc with prop-2-en-1-ol in the presence of a palladium catalyst and a base:

[0339]

[0340] wherein X3 is chlorine, bromine or iodine.

[0341] In some embodiments, X3 is bromo.

[0342] In some embodiments, the conditions of the Heck coupling reaction are used, using a palladium (0) or palladium (II) catalyst, and carried out under conditions known in the art (see, for example, Melpolder and Heck, J. Org. Chem. 1976, 41, 265-272, or Littke and Fu, J. Am. Chem. Soc. 2001, 123, 6989-7000, both of which are incorporated herein in their entirety). In some embodiments, the palladium catalyst is Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)).

[0343] In some embodiments, the palladium catalyst is present in an amount of about 0.01 equivalent to about 0.1 equivalent, about 0.01 equivalent to about 0.05 equivalent, about 0.01 equivalent to about 0.02 equivalent, or about 0.015 equivalent. In some embodiments, the reaction also includes reacting in the presence of a phosphine ligand or a salt thereof. In some embodiments, the phosphine ligand or a salt thereof is tri(tert-butyl)phosphine tetrafluoroborate.

[0344] In some embodiments, the ligand is present in an amount of about 0.01 equivalents to about 0.05 equivalents or about 0.03 equivalents.

[0345] In some embodiments, the base is an inorganic base. In some embodiments, the base is an organic base. In some embodiments, the base is a tertiary amine, including but not limited to N-methyl-N-cyclohexylcyclohexylamine. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is present in an amount of about 1 equivalent to about 5 equivalents, about 1 equivalent to about 2 equivalents, about 1 equivalent to about 1.5 equivalents, or about 1.2 equivalents.

[0346] In some embodiments, the reaction of the compound of Formula IIc with prop-2-en-1-ol is carried out at a temperature of from about 40° C. to about 80° C., from about 50° C. to about 70° C., or from about 50° C. to about 55° C. In some embodiments, the reaction is carried out in a solvent including but not limited to dioxane. In some embodiments, prop-2-en-1-ol is present in an amount of about 1 equivalent to about 3 equivalents, or about 2 equivalents.

[0347] In some embodiments, the method further comprises preparing a compound of Formula IIa by a process comprising reacting a compound of Formula IId with an acid of Formula HX':

[0348]

[0349] wherein X' is chlorine, bromine or iodine.

[0350] In some embodiments, X' is chloro.

[0351] In some embodiments, the reaction of the compound of Formula IId with the acid is carried out at a temperature of from about 0° C. to about 20° C., from about 0° C. to about 10° C., or from about 0° C. to about 5° C. In some embodiments, the reaction is carried out in a solvent including but not limited to ethyl acetate.

[0352] In some embodiments, the method further comprises preparing a compound of Formula IId by a process comprising reducing a compound of Formula IIe with hydrogen in the presence of a hydrogenation catalyst:

[0353]

[0354] In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments, the hydrogen is at a pressure of about 1 atmosphere. In some embodiments, the reaction of the compound of Formula IIe with hydrogen is carried out at about room temperature.

[0355] In some embodiments, the method further comprises preparing a compound of formula IIe by a method comprising reacting a compound of formula IIc with a compound of formula IIf in the presence of a coupling catalyst and a base (Sonogashira coupling using, for example, the method of Ziesel or Kelly, Suffert and Ziesel, Tetrahedron Lett. 1991, 32, 757; Kelly, Lee and Mears, J Org. Chem. 1997, 62, 2774):

[0356]

[0357] In some embodiments, the coupling catalyst is a palladium catalyst, including but not limited to palladium acetate. In some embodiments, the catalyst is a mixture of palladium acetate and CuI. In some embodiments, the base is an inorganic base. In some embodiments, the base is an organic base. In some embodiments, the base is a tertiary amine, including but not limited to triethylamine. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is present in an amount of about 2 equivalents to about 10 equivalents, about 4 equivalents to about 9 equivalents, about 6 equivalents to about 8 equivalents, or about 7.2 equivalents.

[0358] In some embodiments, the reaction further comprises reacting in the presence of a phosphine ligand or a salt thereof, including but not limited to triphenylphosphine. In some embodiments, palladium acetate is present in an amount of about 0.01 equivalent to about 0.05 equivalent or about 0.03 equivalent. In some embodiments, copper (I) iodide is present in an amount of about 0.005 equivalent to about 0.2 equivalent or about 0.01 equivalent. In some embodiments, the phosphine ligand or a salt thereof is present in an amount of about 0.005 equivalent to about 0.2 equivalent or about 0.012 equivalent.

[0359] In some embodiments, the reaction is carried out at a temperature of from about 70° C. to about 100° C., from about 80° C. to about 100° C., or about 90° C. In some embodiments, the reaction is carried out in a solvent including but not limited to dimethylformamide. In some embodiments, the compound of Formula IIf is present in an amount of about 1 equivalent to about 3 equivalents or about 2 equivalents.

[0360] In some embodiments, the method further comprises preparing a compound of Formula IId by a process comprising:

[0361]

[0362] The compound of formula IIg

[0363]

[0364] Reaction with 9-borabicyclo[3.3.1]nonane (9-BBN) followed by reaction with a compound of formula IIc

[0365]

[0366] The reaction is carried out in the presence of a coupling catalyst to form a compound of formula IId, wherein X3 is chlorine, bromine or iodine.

[0367] In some embodiments, X3 is chloro.

[0368] In some embodiments, 9-BBN is added directly. In some embodiments, 9-BBN is generated in situ (Soderquist and Negron, J. Org. Chem., 1987, 52, 3441-3442). In some embodiments, the compound of formula IIg is present in an amount of about 1 equivalent to about 3 equivalents, or about 1.5 equivalents to about 2.5 equivalents, or about 1.75 equivalents.

[0369] In some embodiments, coupling reaction conditions are utilized, using a palladium(0) or palladium(II) catalyst, and carried out under conditions known in the art (see, e.g., Miyaura and Suzuki, Chem . Rev.1995, 95, 2457-2483, which is hereby incorporated in its entirety). In some embodiments, the palladium catalyst is palladium (II) acetate. In some embodiments, the palladium catalyst is present in an amount of about 0.01 equivalent to about 0.1 equivalent, about 0.01 equivalent to about 0.1 equivalent, about 0.02 equivalent to about 0.07 equivalent, or about 0.05 equivalent.

[0370] In some embodiments, the reaction further comprises reacting in the presence of a phosphine ligand or a salt thereof. In some embodiments, the phosphine ligand is tricyclohexylphosphine. In some embodiments, the phosphine ligand or a salt thereof is present in an amount of about 0.05 equivalents to about 0.2 equivalents, or about 0.1 equivalents.

[0371] In some embodiments, the second step is performed in a solvent including, but not limited to, tetrahydrofuran, water, or a mixture thereof.

[0372] In some embodiments, the second step is performed at reflux temperature.

[0373] In some embodiments, the method further comprises preparing a compound of formula III by a method comprising: reacting a compound of formula IIIa in the presence of a palladium catalyst and a base.

[0374]

[0375] Reaction with a compound of formula IIIb

[0376]

[0377] wherein X4 is chlorine, bromine or iodine; and

[0378] Every R a Independently C 1-6 Alkyl; or

[0379] Every R a Together with two oxygen atoms and a boron atom, it forms a 5-membered heterocyclic ring or a 6-membered heterocyclic ring; wherein the heterocyclic ring is optionally substituted by 1, 2, 3 or 4 independently selected C 1-4 Alkyl substitution.

[0380] In some embodiments, X4 is bromo.

[0381] In some embodiments, the compound of Formula IIIb has Formula IIIb-1:

[0382]

[0383] In some embodiments, X4 is bromo.

[0384] In some embodiments, Suzuki coupling reaction conditions are used, using a palladium (0) or palladium (II) catalyst, and carried out under conditions known in the art (see, e.g., Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483, which is incorporated herein in its entirety). In some embodiments, the palladium catalyst is 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride (Pd (dppf) 2 Cl 2). In some embodiments, the palladium catalyst is present in an amount of about 0.1 equivalents to about 0.5 equivalents, about 0.2 equivalents to about 0.4 equivalents, or about 0.3 equivalents.

[0385] In some embodiments, the base is an inorganic base. In some embodiments, the base is an organic base. In some embodiments, the base is a tertiary amine. In some embodiments, the base is an alkali metal carbonate (e.g., potassium carbonate or sodium carbonate).

[0386] In some embodiments, the reaction is carried out at a temperature of from about 60° C. to about 100° C., from about 70° C. to about 90° C., from about 80° C. to about 90° C., or about 86° C. In some embodiments, the reaction is carried out in a solvent including but not limited to dioxane. In some embodiments, the compound of formula IIIb or IIIb-1 is present in an amount of about 1 equivalent to about 2 equivalents, or about 1.3 equivalents.

[0387] In some embodiments, the method further comprises preparing a compound of Formula IIIa by reacting 1,2,4-triazine-3-amine with a halogenating agent.

[0388] In some embodiments, X4 is bromine; and the halogenating agent is N-bromosuccinimide. In some embodiments, the halogenating agent is present in an amount of about 1 equivalent to about 2 equivalents, or about 1 equivalent to about 1.1 equivalents.

[0389] In some embodiments, the method further comprises preparing 1,2,4-triazine-3-amine by a process comprising reacting glyoxal with aminoguanidine or a salt thereof.

[0390] In some embodiments, the method further comprises preparing a compound of Formula IIIb-1 by a process comprising:

[0391] a) the compound of formula IIIc

[0392]

[0393] Reaction with a reagent of formula R1MgY followed by reaction with a compound of formula B(OR2)3 to form a compound of formula IIId:

[0394] and

[0395] b) after the reaction in step a), reacting the compound of formula IIId with an acid and then with pinacol to form a compound of formula IIIb-1;

[0396] in

[0397] R1 is C 1-6 alkyl;

[0398] Each R2 is independently C 1-6 alkyl; and

[0399] X5 is chlorine, bromine or iodine.

[0400] In some embodiments, X5 is bromine. In some embodiments, R1 is isopropyl. In some embodiments, R2 is methyl. In some embodiments, B(OR2)3 is present in an amount of about 1 equivalent to about 2 equivalents, or about 1.4 equivalents. In some embodiments, step a) is carried out at a temperature of from about 0°C to about 25°C, or from about 7°C to about 16°C.

[0401] In some embodiments, pinacol is present in an amount of about 1 equivalent to about 3 equivalents, or about 2 equivalents. In some embodiments, step b) is performed at a temperature from about room temperature to about 50° C. In some embodiments, step b) is performed in a solvent including but not limited to cyclohexane.

[0402] The present invention also provides a method for preparing a compound of formula I or a salt thereof:

[0403]

[0404] The method includes:

[0405] a) the compound of formula II

[0406]

[0407] With the compound of formula VII

[0408]

[0409] Reaction to form a compound of formula VIa:

[0410] and

[0411] b) reacting a compound of formula VIa with Zn(CN)2 and Zn in the presence of a catalyst to form a compound of formula I or a salt thereof;

[0412] wherein X6 is chlorine, bromine or iodine.

[0413] In some embodiments, the compound of formula I is converted to the compound of formula V by the above-described method steps.

[0414] In some embodiments, X6 is bromo.

[0415] In some embodiments, the compound of formula II and the compound of formula VII are present in about 1.1 equivalents to about 0.67 equivalents, respectively. In some embodiments, step a) is carried out in a solvent including but not limited to 1-butanol. In some embodiments, step a) is carried out at a temperature of about 100° C. to about 120° C., or about 110° C.

[0416] In some embodiments, the catalyst is a palladium (II) or palladium (0) catalyst. In some embodiments, the catalyst further comprises a phosphine ligand. In some embodiments, the catalyst is 1,1'-bis (diphenylphosphino) ferrocene palladium dichloride (II) (Pd (dppf) 2Cl2). In some embodiments, Zn is present in an amount of about 0.1 equivalent to about 0.3 equivalent, or about 0.2 equivalent. In some embodiments, Zn (CN) 2 is present in an amount of about 0.5 equivalent to about 1 equivalent, or about 0.6 equivalent. In some embodiments, the catalyst is present in an amount of about 0.03 equivalent to about 0.1 equivalent, or about 0.06 equivalent. In some embodiments, step b) is carried out in a solvent including but not limited to dimethylacetamide, water, or a mixture thereof. In some embodiments, step b) is carried out at a temperature of about 100 ° C to about 120 ° C, or about 110 ° C.

[0417] In some embodiments, the method further comprises preparing the compound of formula VII by a process comprising reacting a compound of formula VIII with aminoguanidine or a salt thereof and a base:

[0418]

[0419] wherein X6 is chlorine, bromine or iodine.

[0420] In some embodiments, X6 is bromo.

[0421] In some embodiments, the base is an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide). In some embodiments, the base is potassium hydroxide. In some embodiments, aminoguanidine or its salt is present in an amount of about 1 equivalent to about 3 equivalents, or about 2 equivalents. In some embodiments, the base is present in an amount of about 3 equivalents to about 5 equivalents, or about 4 equivalents. In some embodiments, the reaction is carried out at a temperature of from about 60°C to about 80°C, or about 75°C.

[0422] In some embodiments, the method further comprises forming a compound of Formula VIII by a process comprising reacting a compound of Formula IX with triethyl orthoformate in the presence of an acid to form a compound of Formula VIII:

[0423]

[0424] wherein X6 is chlorine, bromine or iodine.

[0425] In some embodiments, X6 is bromo.

[0426] In some embodiments, the acid is p-toluenesulfonic acid. In some embodiments, the reaction is carried out at a temperature of from about 100° C. to about 120° C., or about 110° C. In some embodiments, triethyl orthoformate is present in an amount of about 1 equivalent to about 4 equivalents, about 2 equivalents to about 3 equivalents, or about 2.5 equivalents. In some embodiments, the acid is present in an amount of about 0.1 equivalent to about 1 equivalent, about 0.2 equivalent to about 0.6 equivalent, or about 0.4 equivalent.

[0427] In some embodiments, the method further comprises preparing a compound of Formula IX by a process comprising reacting a compound of Formula X with a strong acid to form a compound of Formula IX:

[0428]

[0429] wherein X6 is chlorine, bromine or iodine.

[0430] In some embodiments, X6 is bromine. In some embodiments, the acid has the formula HX', wherein X' is chlorine, bromine or iodine. In some embodiments, X' is bromine. In some embodiments, the reaction is carried out in a solvent including but not limited to dimethyl sulfoxide. In some embodiments, the acid is HBr combined with DMSO, as described in Floyd, Du, Fabio, Jacob and Johnson J. Org, Chem., 1985, 50, 5022-5027. In some embodiments, the addition of a strong acid is carried out at about room temperature, and the reaction mixture is then heated to a temperature from about 50°C to about 70°C, or about 60°C.

[0431] In some embodiments, the method further comprises preparing a compound of formula X by a method comprising reacting a compound of formula XI with CH3MgBr to form a compound of formula X:

[0432]

[0433] wherein X6 is chlorine, bromine or iodine.

[0434] In some embodiments, CH3MgBr is present in an amount of about 1 equivalent to about 3 equivalents, or about 1.7 equivalents. In some embodiments, the reaction is carried out at a temperature of about 0°C to about 15°C, about 0°C to about 5°C, or about 0°C.

[0435] In some embodiments, the method further comprises preparing a compound of formula XI by a process comprising reacting a compound of formula XII with oxalyl chloride or thionyl chloride followed by treatment with dimethylhydroxylamine or a salt thereof to form a compound of formula XI:

[0436]

[0437] In some embodiments, the reaction is carried out with oxalyl chloride. In some embodiments, oxalyl chloride is present in an amount of about 1 equivalent to about 2 equivalents or about 1.4 equivalents to about 1.5 equivalents. In some embodiments, the reaction is carried out in a solvent including but not limited to dichloromethane. In some embodiments, the reaction is carried out at a temperature of about room temperature.

[0438] In some embodiments, any of the intermediates described in the embodiments herein can exist as free radicals. In some embodiments, any of the intermediates described in the embodiments herein can exist as salts. In some embodiments, the intermediates described herein are in the form of hydrates or solvates.

[0439] In some embodiments, the invention provides any of the above-described individual method steps or intermediate compounds.

[0440] At various locations in this specification, substituents of compounds are disclosed in groups or ranges. It is particularly noted that the compounds include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0441] It should also be understood that specific features described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features described for convenience in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0442] As used herein, the phrase "optionally substituted" refers to unsubstituted or substituted. As used herein, the term "substituted" refers to hydrogen atoms being removed and replaced by substituents. It is understood that valence is limited to substitutions on given atoms.

[0443] As used herein, the term "Cn-m "Alkyl" refers to a saturated hydrocarbon which may be straight or branched chain having n to m carbon atoms. In some embodiments, the alkyl group contains 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, n-octyl, and the like.

[0444] As used herein, in the formula -B (OR a The term "5-membered heterocycle or 6-membered heterocycle" in the context of part 2 of the present invention refers to a saturated monocyclic ring having 5 ring members or 6 ring members, including two oxygen atoms and one boron atom, wherein the remaining 2 ring members or 3 ring members are carbon atoms.

[0445] As used herein, the term "about" refers to plus or minus 10% of a value.

[0446] The expression "ambient temperature" as used herein and the expression "room temperature" as used herein are known in the art and generally refer to temperatures such as reaction temperatures, i.e., the reaction is carried out at about room temperature, for example a temperature from about 20°C to about 30°C.

[0447] The methods described herein can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy or spectrophotometry (e.g., UV-visible); or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0448] The term "reaction" as used herein is used as known in the art and generally refers to chemical reagents being brought together in such a manner as to allow for their interaction at the molecular level to obtain a chemical or physical transformation. In some embodiments, the reaction comprises two reagents, wherein one or more equivalents of the second reagent are used relative to the first reagent. The reaction steps of the methods described herein may be carried out for a period of time under conditions suitable for preparing the determined product.

[0449] Compounds may also include salt forms of the compounds and intermediates described herein. Examples of salts (or salt forms) include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Typically, salt forms can be prepared by reacting a free base or free acid with a stoichiometric amount or excess of a desired inorganic or organic acid or base to form a salt in a suitable solvent or various combinations of solvents.

[0450] Compounds and intermediates also include pharmaceutically acceptable salts of compounds disclosed herein. As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by adding a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the term "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications and does not interact adversely with the active ingredient from a toxicological point of view. Pharmaceutically acceptable salts, including monosalts and disalts, include but are not limited to those derived from organic and inorganic acids, such as but not limited to acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid and similarly known acceptable acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), both of which are incorporated herein by reference in their entirety.

[0451] The preparation of compounds may include the protection and deprotection of a variety of chemical groups. Those skilled in the art can easily determine the need for protection and deprotection and the selection of suitable protecting groups. The chemistry of protecting groups can be found in, for example, Greene et al., Protective Groups in Organic Synthesis, 4th edition, Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. The adjustment and formation methods and splitting methods of protecting groups described herein can be adjusted according to the needs of various substituents.

[0452] The reaction of the method described herein can be carried out in an appropriate solvent, and the technician in the field of organic synthesis can easily select the solvent. Suitable solvents can be substantially unreactive with starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, a temperature in the range from the solidification temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to the specific reaction steps, a solvent suitable for the specific reaction steps can be selected. In some embodiments, the reaction can be carried out in the absence of a solvent, for example, when at least one of the reagents is a liquid or a gas.

[0453] Suitable solvents may include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, chlorobutane, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof, and the like.

[0454] Suitable ether solvents include dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether, mixtures thereof, and the like.

[0455] Suitable protic solvents may include, by way of example but not limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol or 3-pentanol, neopentyl alcohol, tert-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol or glycerol.

[0456] Suitable aprotic solvents may include, by way of example but not limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, methyl ethyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

[0457] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o- or p-xylene, octane, indane, nonane or naphthalene.

[0458] Supercritical carbon dioxide and ionic liquids can also be used as solvents.

[0459] The reactions of the methods described herein can be carried out at a suitable temperature, which can be readily determined by one skilled in the art. The reaction temperature will depend on, for example: the melting and boiling points of the reagents and solvents (if any); the thermodynamics of the reaction (e.g., strongly exothermic reactions may require a reduced temperature); and the kinetics of the reaction (e.g., a high activation barrier may require an elevated temperature). "Elevated temperature" refers to a temperature above room temperature (about 22°C).

[0460] The reactions of the methods described herein can be carried out in air or under an inert atmosphere. Generally, reactions involving reagents or products that react substantially with air can be carried out using air-sensitive synthesis techniques well known to those skilled in the art.

[0461] In some embodiments, preparation of the compounds may include the addition of an acid or base to effect, for example, catalysis of a desired reaction or the formation of a salt form such as an acid addition salt.

[0462] Example acids can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, 4-nitrobenzoic acid, methylsulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinylacetic acid, valeric acid, caproic acid, enanthic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0463] Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some example strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, wherein: alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and tert-butyl oxides; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl, and cyclohexyl substituted amides.

[0464] Once the compounds are prepared according to the methods described herein, conventional separation and purification procedures such as concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography and the like can be used to isolate the desired product.

[0465] Drug preparations and dosage forms

[0466] When used as a medicament, the salt of the present invention can be administered in the form of a pharmaceutical composition, such as a salt of the present invention in combination with at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local treatment or systemic treatment is required and on the area to be treated. Administration can be topical (including eye and application to mucous membranes, including nasal administration, vaginal administration and rectal administration), pulmonary (e.g., by inhalation or insufflation of powders, or aerosols, including through a nebulizer; breathing tube, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods of ocular administration may include topical administration (eye drops), subconjunctival, periocular or vitreous injection, or introduction by surgical placement of a balloon catheter or eye insert in the conjunctival sac. Parenteral administration includes intravenous, arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial administration, such as intrathecal administration or intraventricular administration. Parenteral administration can be in the form of rapid infusion administration, or can be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0467] The present invention also includes pharmaceutical compositions comprising the above-mentioned salt of the present invention in combination with one or more pharmaceutically acceptable carriers as active ingredients. In the manufacture of the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient, or loaded into a carrier in the form of, for example, a capsule, a saccharide, paper, or other container. When an excipient is used as a diluent, it can be a solid, semisolid, or liquid substance, which is used as a vehicle, carrier, or medium for the active ingredient. Therefore, the composition can be a tablet, a pill, a powder, a lozenge, a capsule, a formulation, a suspension, an emulsion, a solution, a syrup, an aerosol (as a solid or in a liquid medium), an ointment containing, for example, up to 10% by weight of an active compound, a soft gelatin capsule, and a hard gelatin capsule, a suppository, a sterile injectable solution, and a sterile packaged powder.

[0468] In preparing the formulation, the active compound may be milled to provide a suitable particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[0469] The salt of the present invention can be milled using known milling procedures such as wet milling to obtain a particle size suitable for tablet formation and for other formulation types. Finely divided (nanoparticle) preparations of the salt of the present invention can be prepared by methods known in the art, for example, see International Patent Application No. WO 2002 / 000196.

[0470] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. The compositions of the present invention can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient using procedures known in the art.

[0471] The compositions can be formulated in unit dosage form, each dosage containing from about 5 mg to about 100 mg of active ingredient, more usually about 10 mg to about 30 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable for use as single dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical excipient.

[0472] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will generally be determined by a physician based on the relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0473] For preparing solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is usually evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the above type, comprising from, for example, 0.1 mg to about 500 mg of the active ingredient of the present invention.

[0474] Tablets or pills of the present invention can be coated or additionally mixed to provide a dosage form that provides an advantage of prolonged action. For example, tablets or pills can include an internal formulation component and an external formulation component, the latter being an encapsulated form on a precursor. The two components can be separated by an enteric layer, which is used to resist the decomposition in the stomach and allows the internal component to pass completely through the duodenum or to release over time. Various materials can be used for such enteric layers or enteric coatings, including a mixture of various polymeric acids and polymeric acids with materials such as shellac, hexadecanol, and cellulose acetate.

[0475] Liquid forms for oral administration or by injection into which the compounds and compositions of the present invention may be incorporated include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, and formulations and similar pharmaceutical vehicles.

[0476] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition may be administered by oral or nasal respiratory route for local or systemic effect. The composition may be atomized by the use of an inert gas. The atomized solution may be breathed in directly from the atomizing device, or the atomizing device may be connected to a mask curtain or intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0477] The amount of the compound or composition administered to a patient will vary depending on the substance being administered, the purpose of the administration, such as prevention or treatment, the patient's condition, the mode of administration, and the like. In therapeutic applications, the composition may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially inhibit the symptoms of the disease and the complications of the disease. The effective dose will depend on the disease condition being treated, as well as at the discretion of the attending physician based on factors such as the severity of the disease, the patient's age, weight and general condition, and the like.

[0478] The composition administered to the patient can be in the form of the above-mentioned pharmaceutical composition. These compositions can be sterilized by conventional sterilization techniques, or can be aseptically filtered. For use, the aqueous solution can be packaged or lyophilized, and the lyophilized preparation is combined with a sterile water carrier before administration. The pH of the compound preparation will generally be between 3 and 11, more preferably from 5 to 9, and most preferably from 7 to 8. It should be understood that the use of specific aforementioned excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

[0479] The therapeutic dose of the salt of the present invention may vary according to, for example, the specific use for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the salt of the present invention in the pharmaceutical composition may vary according to a variety of factors, including dosage, chemical characteristics (such as hydrophobicity), and route of administration. For example, the salt of the present invention may be provided in a physiological buffered aqueous solution containing about 0.1% to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and degree of progression of the disease or illness, the overall health of the specific patient, the corresponding biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dosage can be inferred from the dose-response curve obtained from an in vitro or animal model test system.

[0480] The salts of the present invention may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent, such as an antiviral agent, a vaccine, an antibody, an immunopotentiator, an immunosuppressant, an anti-inflammatory agent, and the like.

[0481] Labeled compounds and assays

[0482] Another aspect of the invention relates to fluorescent dyes, spin labels, heavy metal or radiolabeled salts of the invention for use in imaging and in both in vitro and in vivo assays to localize and quantify protein kinase targets in tissue samples, including humans, and for determining kinase ligands by inhibiting the binding of labeled compounds. Thus, the invention includes kinase assays containing labeled salts.

[0483] The present invention also includes isotopically labeled compounds of the compounds of the present invention. An "isotopically" or "radiolabeled" compound is a compound of the present invention in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present invention include, but are not limited to 2 H (also written as deuterium D), 3 H (also written as tritium T), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 18 F. 35 S. 36 Cl, 82 Br,75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I and 131 I. The radionuclide incorporated into the instant radiolabeled compound will depend on the specific application of the radiolabeled compound. For example, for in vitro labeling and competition assays, incorporation of 3 H. 14 C. 82 Br, 125 I. 131 I or 35 Compounds containing S will generally be the most useful. For radiographic applications, 11 C. 18 F. 125 I. 123 I. 124 I. 131 I. 75 Br, 76 Br or 77 Br will usually be the most useful.

[0484] It is understood that a "radiolabeled" or "labeled compound" is a compound into which at least one radionuclide has been incorporated. In some embodiments, the radionuclide is selected from 3 H. 14 C. 125 I. 35 S and 82 The group composed of Br.

[0485] Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the invention and are well known in the art.

[0486] The radiolabeled salts of the present invention can be used in screening assays to identify / evaluate compounds. In general, the ability of a newly synthesized or established compound (i.e., a test compound) to reduce the binding of a radiolabeled salt of the present invention to an enzyme can be evaluated. Thus, the ability of a test compound to compete with a radiolabeled salt to bind to an enzyme is directly related to its binding affinity.

[0487] Pill Box

[0488] The present invention also includes a pharmaceutical kit, which is used, for example, to treat or prevent a disease, such as cancer and other diseases noted herein, and which includes one or more containers containing a pharmaceutical composition, the pharmaceutical composition including a therapeutically effective amount of a salt of the present invention. Such a kit, if necessary, may also include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, another container, etc., which is obvious to those skilled in the art. Instructions for the amount of components to be administered, instructions for administration, and / or instructions for mixing the components as inserts or markers may also be included in the kit.

[0489] The present invention will be described in more detail by specific examples. The following examples are provided for exemplary purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily appreciate that a variety of non-critical parameters can be changed or modified to produce substantially the same results.

[0490] Example

[0491] Example 1

[0492] Preparation of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide dihydrochloride

[0493] A suspension of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide (421.2 g, 1.021 mol) (see the preparation of U.S. Serial No. 11 / 942,130, the disclosure of which is hereby incorporated by reference in its entirety) in methanol (MeOH, 6600 mL) was heated to 55° C., and then a premixed solution of concentrated aqueous hydrochloric acid (conc. HCl, 37 wt.%, 12 M, 420 mL, 5.10 mol, 5.0 equiv.) in isopropanol (IPA, 1510 mL) was added dropwise at 55° C. The resulting solution was stirred at 55° C. for 30 min, and then methyl tert-butyl ether (MTBE, 6750 mL) was added via an addition funnel over 30 min. After the addition of methyl tert-butyl ether, a solid was slowly precipitated out. The resulting mixture was stirred at 55 °C for an additional 1 h and then allowed to gradually cool to room temperature. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with methyl tert-butyl ether (MTBE, 3×500 mL) and dried in a vacuum oven at 45-55 °C to constant weight. The desired 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide dihydrochloride (470.7 g, 495.5 g theoretical, 95% yield) was obtained as an off-white to pale yellow crystalline solid: melting point (decomposition) 222 °C;1 H NMR(400MHz,DMSO-d6)δppm 9.46(s,1H),9.25(dd,1H,J=5.4Hz,1.4Hz),9.12(d,1H,J=8.3Hz),8.51(m,1H),8.47(d,1H,J=0.9Hz),8.34(d,1H,J=1.3Hz),8. 23(s,1H),8.21(dd,1H,J=9.0Hz,1.8Hz),8.09-8.02(m,3H),7.79(dd,1H,J=7.5Hz,8.3Hz),4.77(s,2H),2.78(s,3H,J=4.5Hz); 13 C NMR(100MHz,DMSO-d6)δppm 163.4,159.4(d,J=249.9Hz),145.8,145.4,144.5,143.8,140.4,138.8,136.8,135.9,135.7(J=8.6Hz),131.2(J= 3.1Hz), 130.7, 128.7, 128.2, 126.2 (J = 14.9Hz), 126.0, 123.1 (J = 3Hz), 122.5, 121.0, 114.9 (J = 5.6Hz), 28.4, 26.3; 19 F NMR (376.3MHz, DMSO-d6) δppm-113.2; C 23 H 17 FN6O (free base, molecular weight 412.42), LCMS (EI) m / e 413.1 (M + +H) and 435.0(M + +Na).

[0494] Example 2

[0495] X-ray powder diffraction of dihydrochloride

[0496] XRPD was performed using a Rigaku MiniFlex X-ray powder diffractometer (X-ray radiation from Copper (Cu), Kβ filter, start angle -3; end angle -45; sampling -0.02; scanning speed -2). The sample powder was dispersed on the zero background sample holder. Figure 1 An XRPD pattern of the dihydrochloride salt prepared by the method of Example 1 is provided in . The 2θ peaks are provided in Table 1 below.

[0497] Table 1

[0498]

[0499]

[0500] Example 3

[0501] Differential Scanning Calorimetry of the Dihydrochloride Salt

[0502] By Figure 2 The DSC trace shown in Figure 1 characterizes the dihydrochloride salt prepared by the method of Example 1. The DSC thermogram shows an endothermic event with a peak onset at 216.1° C. and a peak at 221.91° C. The experiment was performed on a Mettler Toledo Differential Scanning Calorimetry (DSC) 822 instrument using an aluminum sample pan (40 μL) using a heating rate of 10° C. / min from a starting temperature of 30° C. to a final temperature of 280° C.

[0503] Example 4

[0504] Thermogravimetric analysis of the dihydrochloride salt

[0505] By Figure 3 The TGA shown in Figure 1 characterizes the dihydrochloride salt prepared by the method of Example 1. The TGA shows that when the sample is heated from 20°C to 600°C at a heating rate of 20°C / min, a significant weight loss begins at 150°C. This is followed by an exothermic event with a peak at 221.9°C, which is considered to be a melting peak. The experiments were performed on a TA Instruments Q500.

[0506] Example 5

[0507] Preparation of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide dibenzenesulfonate

[0508] A suspension of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide (500 mg, 1.212 mmol) in methanol (MeOH, 12 mL) was heated to 55°C, and then a premixed solution of benzenesulfonic acid (578 mg, 3.65 mmol, 3.01 equiv) in isopropanol (IPA, 3.66 mL) was added dropwise at 55°C. The resulting solution was stirred at 55°C for 30 min, and then methyl tert-butyl ether (MTBE, 12 mL) was added dropwise via an addition funnel. After the addition of methyl tert-butyl ether, solids were slowly precipitated out. The resulting mixture was stirred at 55°C for an additional hour, and then allowed to gradually cool to room temperature. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with methyl tert-butyl ether (MTBE, 2×10 mL) and dried in a vacuum oven at 45-55° C. to constant weight. The desired dibenzenesulfonic acid product (848 mg, 883.3 mg theoretical, 96% yield) was obtained as an off-white crystalline solid: melting point (decomposition) 270.5° C.; 1 H NMR(400MHz,DMSO-d6)δppm 9.51(s,1H),9.30(dd,1H,J=5.4Hz,1.4Hz),9.13(d,1H,J=8.3Hz),8.45(m,1H),8.36(d,1H,J=0.9Hz),8.30(s,1H),8.21(dd,2H,J=9.0 Hz,1.8Hz),8.10-8.04(m,3H),7.80(dd,1H,J=7.5Hz,8.3Hz),7.62-7.56(m,4H),7.33-7.27(m,6H),4.79(s,2H),2.78(d,3H,J=4.5Hz); 19 F NMR (376.3MHz, DMSO-d6) δppm-113.2; C 23 H 17 FN6O (free base, molecular weight 412.42), LCMS (EI) m / e 413.0 (M + +H) and 435.0(M + +Na).

[0509] Example 6

[0510] X-ray Powder Diffraction of Dibenzenesulfonate

[0511] XRPD was performed using a Rigaku MiniFlex X-ray powder diffractometer (X-ray radiation from copper (Cu), Kβ filter, starting angle -3; ending angle -45; sampling -0.02; scanning speed -2). Figure 4 An XRPD pattern of the salt prepared by the method of Example 5 is provided in . The 2θ peaks are provided in Table 2 below.

[0512] Table 2

[0513]

[0514]

[0515] Example 7

[0516] Differential Scanning Calorimetry of Dibenzenesulfonate

[0517] By Figure 5 The DSC trace shown in Figure 5 characterizes the dibenzenesulfonate salt prepared by the method of Example 5. The DSC thermogram shows an endothermic event starting at 269.4°C, followed by an exothermic event with a peak at 270.45°C. The experiment was performed on a Mettler Toledo Differential Scanning Calorimetry (DSC) 822 instrument using a heating rate of 10°C / min from a starting temperature of 30°C to a final temperature of 280°C.

[0518] Example 7A

[0519] Physical Characteristics of Dibenzenesulfonate

[0520] The dibenzenesulfonate salt is usually visually detected as an off-white to pale yellow powder against a white background.

[0521] Example 7B

[0522] Solubility of dibenzenesulfonate

[0523] The dibenzenesulfonate salt is generally obtained as an off-white to pale yellow powder visually inspected against a white background. The solubility of the dibenzenesulfonate salt at 25°C was found to be about 3.9 mg / mL in water; 0.003 mg / mL in a pH 7.4 buffer; 0.003 mg / mL in a pH 8.0 buffer; and at least 29 mg / mL in a 0.1 N aqueous HCl solution.

[0524] Equilibrium solubility was determined by mixing samples in selected aqueous solvents (0.1 N HCl, water, pH 7.4 buffer, and pH 8.0 buffer) for at least 12 hours. Sample concentrations were then determined by HPLC using a single point calibration.

[0525] Example 8

[0526] 4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide (3)

[0527] A solution of oxalyl chloride ((COCl)2, 560 mL, 6.4 mol, 1.45 equiv) in dichloromethane (520 mL) was slowly added to a suspension of 4-bromo-3-fluorobenzoic acid (1, 967.9 g, 4.4 mol) in dichloromethane (5.9 L) at room temperature. The resulting reaction mixture was stirred at room temperature for 20 h and then cooled to 0 ° C by an ice-water bath. N, O-dimethylhydroxylamine hydrochloride (826 g, 8.4 mol, 1.9 equiv) was added, followed by the slow addition of triethylamine (TEA, 2.5 L, 17.7 mol, 4.0 equiv) at 0 ° C. The reaction mixture was then slowly warmed to room temperature, and the reaction mixture was stirred at room temperature overnight. After the coupling reaction was complete, the reaction mixture was washed with saturated sodium bicarbonate aqueous solution (NaHCO3, 2 L). The aqueous phase was stripped with dichloromethane (1 L). The combined organic phases were washed with water (1 L), brine (1 L), and concentrated under reduced pressure. The resulting solid residue was dissolved in methyl tert-butyl ether (MTBE, 5 L), washed successively with water (5×1 L), brine (1 L), and dried over anhydrous sodium sulfate (Na2SO4). The filtered solution was concentrated under reduced pressure, and the resulting solid was dried in a vacuum oven at 45°C to provide 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3,1106 g, 1153 g theoretical value, 95.9% yield) for subsequent reactions without further purification. For 3: 1 H NMR (400 MHz, DMSO-d6) δppm 7.78 (t, 1H, J = 7.47 Hz), 7.56 (dd, 1H, J = 9.3, 1.6 Hz), 7.18 (d, 1H, J = 8.1 Hz), 3.53 (s, 3H), 3.25 (s, 3H); C9H9BrFNO2 (molecular weight 262.08), LCMS (EI) m / e 262.0 / 264.0 (M + +H).

[0528] Scheme 1 (Examples 8-14)

[0529]

[0530] Example 9

[0531] 1-(4-Bromo-3-fluorophenyl)ethanone (4)

[0532] A 3.0 M solution of methylmagnesium chloride (MeMgCl, 2.5 L, 7.5 mol, 1.7 equiv) in THF was slowly added to a solution of crude 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3, 1106 g, 4.2 mol) in anhydrous tetrahydrofuran (THF, 11 L) at 0°C. The resulting reaction mixture was stirred for 2 h at 0°C and then very carefully quenched with saturated aqueous ammonium chloride (NH4Cl, 1.5 L). The resulting solution was concentrated under reduced pressure to remove most of the THF. The residue was then diluted with ethyl acetate (EtOAc, 5 L) and the resulting solution was washed with water (2 L). The aqueous phase was extracted with ethyl acetate (EtOAc, 2×2 L). The combined organic phases were washed with water (2 L), brine (2 L) and dried over anhydrous sodium sulfate (Na2SO4). The filtered solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45°C to provide solid 1-(4-bromo-3-fluorophenyl)ethanone (4, 890.8 g, 911.6 g theoretical, 97.7% yield), which was used in subsequent reactions without further purification. For 4: 1 H NMR (400MHz, DMSO-d6) δppm 7.89-7.84 (m, 2H), 7.71 (dd, 1H, J=8.30, 1.87Hz), 2.57 (s, 3H).

[0533] Example 10

[0534] 2-(4-Bromo-3-fluorophenyl)-2-oxoacetaldehyde (5)

[0535] 48% aqueous hydrogen bromide (HBr, 1420 mL, 12.5 mol, 3.0 equiv) was slowly added to a solution of 1-(4-bromo-3-fluorophenyl)ethanone (4, 890.8 g, 4.1 mol) in DMSO (4 L). During the addition, the reaction temperature was gradually increased from 20° C. to 50° C. The reaction mixture was then heated to 60° C. and stirred at 60° C. overnight. The resulting dimethyl sulfide was removed by distillation and the residue was poured into ice water (28 L). The resulting yellow precipitate was collected by filtration (retaining the filtrate) and washed with water (5 L). The yellow solid was dissolved in ethyl acetate (EtOAc, 5 L), washed with brine (1 L) and dried over anhydrous sodium sulfate (Na2SO4). The solution was then concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45°C to provide the desired product, 2-(4-bromo-3-fluorophenyl)-2-oxoacetaldehyde hydrate (hydrate of 5, 730.6 g, 1020.9 g theoretical, 71.6% yield). The aqueous phase (filtrate) was extracted with ethyl acetate (3×5 L), and the combined organic phases were washed with water (2×2 L), brine (2 L), and dried over anhydrous sodium sulfate (Na2SO4). The solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45°C to provide a second crop of 2-(4-bromo-3-fluorophenyl)-2-oxoacetaldehyde hydrate (hydrate of 5, 289.4 g, 1020.9 g theoretical, 28.3% yield; total 1020 g, 1020.9 g theoretical, 99.9% yield), which was used in subsequent reactions without further purification. For the hydrate of 5: 1 H NMR (400MHz, DMSO-d6) δppm 8.00-7.70 (m, 3H), 6.69 (br s, 2H), 5.59 (s, 1H).

[0536] Embodiment 11

[0537] 1-(4-Bromo-3-fluorophenyl)-2,2-diethoxyethanone(6)

[0538] At room temperature, a 22 L flask was charged with a hydrate of (4-bromo-3-fluorophenyl)-2-oxoacetaldehyde (5, 1020 g, 4.41 mol), toluene (7.5 L), triethyl orthoformate (1633 g, 1.8 L, 11.04 mol, 2.5 equivalents), p-toluenesulfonic acid (33.5 g, 0.176 mol, 0.4 equivalents), and the resulting reaction mixture was heated to 110 ° C and stirred at 110 ° C for 6 h. When HPLC showed that the reaction was complete, the reaction mixture was cooled to room temperature and then poured into a 50 L separatory funnel with ethyl acetate (7.5 L) and saturated sodium bicarbonate aqueous solution (NaHCO , 3 L). The mixture was stirred and separated. The aqueous layer was extracted with ethyl acetate (2 L). The combined organic layers were washed with brine (4 L), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (6, 1240 g, 1345.7 g theoretical, 92.1% yield), which was used in subsequent reactions without further purification. For 6: 1 H NMR (400MHz, DMSO-d6) δppm 7.94-7.94 (m, 2H), 7.78 (dd, 1H, J = 8.51, 2.08Hz), 5.40 (s, 1H), 3.77-3.60 (m, 4H), 1.16-1.14 (m, 6H).

[0539] Example 12

[0540] 6-(4-Bromo-3-fluorophenyl)-1,2,4-triazine-3-amine (7)

[0541] At room temperature, a 22L flask was charged with 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (6, 1240 g, 4.07 mol), ethanol (11 L), water (1.4 L), potassium hydroxide (KOH, 910 g, 16.3 mol, 4.0 equivalents) and aminoguanidine bicarbonate (1105 g, 8.13 mol, 2.0 equivalents). Then, the resulting reaction mixture was heated to 75 ° C for 14 h. When HPLC showed that the condensation reaction was considered to be complete, the reaction mixture was cooled to room temperature and then filtered. Then, the filtrate was concentrated under reduced pressure to remove most of the solvent. The residual aqueous solution was extracted with ethyl acetate (EtOAc, 3×6 L). The organic layers were combined and concentrated under reduced pressure to provide a dark brown solid. The solid was dissolved in ethanol (4 L), and the resulting solution was treated with a solution of 0.2 M aqueous hydrochloric acid solution (4 L). Subsequently, the obtained slurry is heated to 50 DEG C for 6h, then allowed to cool to room temperature. The solution of saturated sodium bicarbonate aqueous solution (NaHCO3, 2L) is slowly added to the slurry, then, the obtained mixture is concentrated under reduced pressure to remove most of the solvent. Then, the residual aqueous solution is treated with ethyl acetate (20L) to dissolve the solid. Separate the two layers, and extract the aqueous layer with ethyl acetate (2×2L). The combined organic layer is concentrated under reduced pressure. The dark brown solid is treated with methyl tert-butyl ether (MTBE, 4L), and the obtained slurry is heated to 30 DEG C, and stirred at 30 DEG C for 30min. The mixture is filtered and the solid (green to orange) is collected (retaining the filtrate), and the solid is washed with methyl tert-butyl ether (MTBE, 2L) to obtain the first batch of collections of the crude desired product (7). The filtrate is evaporated under reduced pressure, and the obtained dark brown solid is treated with methyl tert-butyl ether (MTBE, 2L). The obtained slurry is heated to 30 DEG C, and stirred at 30 DEG C for 30min. The mixture was filtered to give a second crop of the crude desired product (7), which was washed with MTBE (1 L). The combined solids were dried in vacuo at 40-45°C to provide 6-(4-bromo-3-fluorophenyl)-1,2,4-triazine-3-amine (7, 585 g, 1095.1 g theoretical, 53.4% ​​yield), which was used in subsequent reactions without further purification. For 7: 1 H NMR (400 MHz, DMSO-d6) δppm 8.86 (s, 1H), 7.97 (d, 1H, J = 10.79 Hz), 7.81 (m, 2H), 7.52 (br s, 2H); C9H6BrFN4 (molecular weight 269.07), LCMS (EI) m / e 269.0 / 271.1 (M + +H).

[0542] Example 13

[0543] 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline(12)

[0544] 1-(2-Chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11,228 g, 0.74 mol, 1.1 equiv) and 6-(4-bromo-3-fluorophenyl)-1,2,4-triazine-3-amine (7,181 g, 0.673 mol) were suspended in 1-butanol (1800 mL), and the resulting suspension was heated to 110° C. and stirred at 110° C. for 18 h (the reaction mixture became homogeneous at this time). The reaction mixture was then allowed to gradually cool to room temperature and then further cooled to 10° C. in an ice bath. The resulting yellow solid was collected by filtration (retaining the 1-butanol filtrate), washed with cold 1-butanol (3×100 mL) and dried by suction. The solid was then suspended in a saturated aqueous sodium bicarbonate solution (NaHCO 3 , 500 mL), and the resulting suspension was stirred at room temperature for 1 h to neutralize the corresponding hydrochloride. The free base was then filtered, washed with water (500 mL) and dried in a vacuum oven at 45 °C for 18 h to provide the first crop of crude 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 125.1 g, 292.3 g theoretical, 42.8% yield). The 1-butanol filtrate was then concentrated under reduced pressure and the resulting solid was dissolved in dichloromethane (CH2Cl2, 2 L). The solution was washed with saturated aqueous sodium bicarbonate solution (NaHCO3, 1 L), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was then purified by flash column chromatography (SiO2, 0-10% MeOH-CH2Cl2 gradient elution) to provide a second crop of 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 19.7 g, 292.3 g theoretical, 6.7% yield; total 144.8 g, 292.3 g theoretical, 49.5% yield) as a yellow solid. For 12: 1 H NMR (400MHz, DMSO-d6) δppm C 21 H 13 BrFN5 (molecular weight 434.26), LCMS (EI) m / e 434.00 / 435.95 (M+ +H).

[0545] Embodiment 14

[0546] 2-Fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzonitrile(13)

[0547] 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 200 g, 0.461 mol), zinc cyanide (ZnCN2, 32.7 g, 0.277 mol, 0.6 eq.), zinc powder (Zn, 6.0 g, 0.093 mol, 0.2 eq.), and Pd(dppf)2Cl2 (22.6 g, 0.028 mol, 0.06 eq.) were suspended in a premixed solution of N,N-dimethylacetamide (DMAC, 2000 mL) and water (H2O, 40 mL). The resulting suspension was then degassed with a stream of nitrogen for 20 min and then heated to 110° C. and stirred at 110° C. for 1-2 h (a homogeneous solution was observed). When LC / MS indicated that the reaction was considered complete, the reaction mixture was first cooled to room temperature and then cooled to 5°C in an ice bath. The cooled reaction mixture was diluted with a mixture of saturated aqueous ammonium chloride solution (NH4Cl aqueous solution), concentrated aqueous ammonium hydroxide solution (NH4OH aqueous solution) and water (volume ratio 4:1:4, 8.1 L), and the resulting mixture was stirred at room temperature for 30 min. The resulting solid was collected by filtration and dried overnight in a vacuum oven at 45°C to provide the crude desired product (13). The crude material was then purified by flash chromatography (SiO2, gradient elution with 1% triethylamine in dichloromethane, 2.5% acetone and 1% triethylamine in dichloromethane, 5.0% acetone and 1% triethylamine in dichloromethane, and 10.0% acetone and 1% triethylamine in dichloromethane successively) to afford pure 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzonitrile (13, 127.4 g, 175.4 g theoretical, 72.6% yield) as a yellow solid. For 13: 1 H NMR (400MHz, DMSO-d6) δppm 9.24(s,1H),8.81(dd,1H,J=4.15,1.66Hz),8.26-8.12(m,4H),8.02(s,1H),7.95-7.9 3(m,2H),7.76(dd,1H,J=8.71,2.08Hz),7.47(dd,1H,J=8.70,4.15Hz),4.62(s,2H); C 22 H 13FN6 (molecular weight 380.38), LCMS (EI) m / e 381.0 (M + +H).

[0548] Embodiment 15

[0549] 6-(3,3-Diethoxyprop-1-ynyl)quinoline(22)

[0550] A mixture of 6-bromoquinoline (8, 2.63 g, 12.6 mmol), propiolic aldehyde diethyl acetal (3.73 mL, 25.2 mmol, 2.0 equiv), triethylamine (TEA, 12.7 mL, 90.8 mmol, 7.2 equiv), copper (I) iodide (CuI, 24.0 mg, 0.126 mmol, 0.01 equiv) and triphenylphosphine (PPh3, 0.39716 g, 1.5142 mmol, 0.12 equiv) in N,N-dimethylformamide (DMF, 15.6 mL, 202 mmol) was degassed with nitrogen bubbling for 5 min. Palladium acetate (Pd(OAc)2, 0.08499 g, 0.3786 mmol, 0.03 equiv) was added, and the mixture was degassed with nitrogen bubbling for 5 min. The reaction mixture was heated to 90°C under nitrogen and stirring. After 3 hours and 10 minutes, HPLC showed that the reaction was complete. The reaction mixture was diluted with ethyl acetate (EtOAc, 100mL), and the reaction mixture was washed with water (H2O, 2×100mL). The aqueous layer was extracted with ethyl acetate (EtOAc, 20mL). Then, the combined organic extracts were concentrated under reduced pressure to obtain a black oily crude product. The crude product was purified by flash column chromatography (SiO2, eluted with 0%-40% EtOAc in n-hexane) to provide colorless oily 6- (3,3-diethoxyprop-1-ynyl) quinoline (22, 3.2g, 3.22g theoretical value, 99% yield). For 22: 1 H NMR(400MHz,DMSO-d6)δppm 8.92(dd,1H,J=4.35Hz,1.86Hz),8.36(d,1H,J=8.40Hz,1.66Hz),8.20(d,1H,J=1.78Hz),7.99(d,1H,J=8.71Hz),7.76 C 16 H 17 NO2 (molecular weight 255.31), LCMS (EI) m / e 256.0 (M + +H).

[0551] Scheme 2 (Examples 15-18)

[0552]

[0553] Example 16

[0554] 6-(3,3-Diethoxypropyl)quinoline(23)

[0555] Method A: 3,3-diethoxy-1-propene (548 g, 4.2 mol, 1.75 equiv) was added to a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (9-BBN in THF, 8.4 L, 4.2 mol, 1.75 equiv) in a 22 L flask at room temperature (internal temperature raised to 40 °C) over 1 h. The resulting reaction mixture was stirred at room temperature overnight. At this time, an aliquot of the reaction mixture was added. 1 H NMR indicated that all 3,3-diethoxy-1-propene was consumed. 6-Bromoquinoline (8, 500 g, 2.4 mol, 1.0 equiv), potassium carbonate (K2CO3, 662 g, 4.8 mol, 2.0 equiv), tricyclohexylphosphine (67.4 g, 0.24 mol, 0.1 equiv), palladium acetate (Pd(OAc)2, 27 g, 0.12 mol, 0.05 equiv) and water (90 mL) were added to the reaction mixture in sequence, followed by degassing with nitrogen for 0.5 h. The reaction mixture was then heated to reflux for 4 h. After TLC and LC / MS indicated that the starting material had been consumed, the reaction mixture was cooled to room temperature with stirring and then quenched with water (7.5 L) and ethyl acetate (EtOAc, 7.5 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc, 4 L). The combined organic layers were washed with saturated saline solution (NaCl, 4 L), dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 10%-60% ethyl acetate gradient elution in heptane) to provide a colorless oil 6-(3,3-diethoxypropyl)quinoline (23, 520 g, 622.4 g theoretical value, 83.5% yield). For 23: 1H NMR(DMSO-d6,300MHz)δppm 8.81(dd,1H,J=4.23Hz,1.73Hz),8.28(d,1H,J=8.07Hz),7.91(d,1H,J=8.62Hz),7.75(s,1H),7.61(dd,1H,J=8.63Hz,1.92Hz),7.46(dd C 16 H 21 NO2 (molecular weight 259.34), LCMS (EI) m / e 260.2 (M + +H).

[0556] Method A - Optional: 9-BBN was generated in situ and used to prepare compound 23 as follows: Under nitrogen atmosphere, anhydrous 1,2-diethoxyethane (DME, 47.0 mL) was charged into a 500 mL 3-necked flask equipped with a distillation apparatus. Borane-dimethyl sulfide complex (12.1 g, 151 mmol, 2 eq) was added, and the solution temperature was increased from 20°C to 22°C. During the period when a small amount of dimethyl sulfide was collected by the distillation apparatus, 1,5-cyclooctadiene (16.3 g, 151 mmol, 2 eq) was added dropwise to the solution over 30 min to maintain a reaction temperature of 50°C-60°C. The reaction mixture was then distilled under nitrogen until the distillate temperature reached 84°C. The collected distillate had a volume of ~21 mL. The oil bath was removed, and anhydrous THF (49 mL) was added. A small sample of the reaction mixture was subjected to 1 H NMR analysis showed that the paraffin was consumed. The 9-BBN solution was used directly in the next step.

[0557] 3,3-Diethoxy-1-propene (19.3 g, 142 mmol, 1.89 equiv) was added dropwise to the above 9-BBN solution while maintaining the temperature below 30°C. The reaction was slightly exothermic and the white precipitate dissolved slowly. The reaction mixture was then stirred at room temperature for 18 h.

[0558] 6-Bromoquinoline (8, 15.7 g, 75.4 mmol, 1 eq.), tricyclohexylphosphine (1.27 g, 4.52 mmol, 0.06 eq.), potassium carbonate (20.8 g, 151 mmol, 2 eq.) and water (0.421 mL, 23.4 mmol) were added to the above prepared solution. The mixture was degassed with nitrogen bubbling for 10-15 min. Palladium acetate (Pd(OAc)2, 0.508 g, 2.26 mmol, 0.03 eq.) was added, and nitrogen bubbling was continued for another 10 min. The reaction mixture was heated to 75 °C, and maintained at 75 °C-78 °C for 2h-3h. When HPLC showed that the reaction was complete, heating was stopped and the reaction mixture was cooled to room temperature. Ethyl acetate (EtOAc, 162 mL) and water (H2O, 162 mL) were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (EtOAc, 2×60 mL), and the combined organic extracts were dried over sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-40% EtOAc gradient elution in n-hexane) to provide 6-(3,3-diethoxypropyl)quinoline (23, 17.6 g, 19.6 g theoretical, 90% yield) as a clear oil, which was found to be identical to the material prepared from Method A in every comparable aspect.

[0559] Method B: A mixture of 6-(3,3-diethoxyprop-1-yn-1-yl)quinoline (22, 56 mg, 0.22 mmol) and palladium on carbon (5 mg) in THF (5 mL) was hydrogenated under 1 atm of H2 for 6 h. The reaction mixture was filtered through a bed of celite and the celite bed was washed with THF (2 x 2 mL). The combined filtrates were concentrated under reduced pressure to provide a clear oily 6-(3,3-diethoxypropyl)quinoline (23, 56 mg, 57 mg theoretical, 98% yield), which was found to be sufficiently pure to be used in subsequent reactions without further purification and was identical in every comparable aspect to the material obtained from Method A.

[0560] Embodiment 17

[0561] 3-(Quinolin-6-yl)propanal (9)

[0562] Method 1: A 22 L flask was charged with tris(dibenzylideneacetone)dipalladium(0) (70.0 g, 0.076 mol, 0.015 equiv), tri-tert-butylphosphine tetrafluoroborate (44 g, 0.152 mol, 0.03 equiv) and dioxane (12 L) at room temperature. The resulting solution was then degassed with a steady stream of nitrogen for 20 min, and then 6-bromoquinoline (8, 1055 g, 5.07 mol, 1.0 equiv), allyl alcohol (588 g, 10.1 mol, 2.0 equiv) and N-methyl-N-cyclohexylcyclohexylamine (1186 g, 6.08 mol, 1.2 equiv) were added at room temperature. The resulting reaction mixture was stirred at 50° C. to 55° C. for 8 h-12 h. When TLC and LC / MS indicated that the reaction was considered complete, the reaction mixture was allowed to cool to room temperature, and then methyl tert-butyl ether (MTBE, 10 L) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 10 min and then filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (SiO2, gradient elution of 20%-80% ethyl acetate in heptane) to provide 3-(quinolin-6-yl)propanal (9, 495 g, 939.1 g theoretical, 52.7% yield) as a yellow oil which partially solidified on standing at 0°C-5°C. For 9: 1 H NMR(400MHz,DMSO-d6)δppm 9.75(t,1H,J=1.24Hz),8.83(dd,1H,J=4.15Hz,1.66Hz),8.25(dd,1H,J=8.3,1.03Hz),7.93(d,1H,J=8.71Hz),7.76(d,1H,J= C 12 H 11 NO (molecular weight 185.22), LCMS (EI) m / e 186 (M + +H).

[0563] Method 2: A solution of 6-(3,3-diethoxypropyl)quinoline (23, Method A of Example 16, 520 g, 2.08 mol, 1.0 equiv) in ethyl acetate (EtOAc, 2.2 L) was cooled to 0°C and then 2N aqueous hydrochloric acid (HCl) solution (2.2 L) was added over 1 h while maintaining the reaction temperature below 5°C. The resulting reaction mixture was stirred at 0°C-5°C for an additional 2 h. When TLC and HPLC / MS indicated the reaction was complete, the reaction was quenched with 0°C ice-cold 3N aqueous sodium hydroxide (NaOH) solution until the pH was between 8 and 9. The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc, 2 L). The combined organic layers were washed with brine (2 L), dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to provide crude 3-(quinolin-6-yl)propanal (9, 385.3 g, 385.3 g theoretical, 100%) as a yellow oil, which was found to be identical in every comparable aspect to that obtained from Method 1. Because the material was found to be sufficiently pure, it was used directly in the subsequent reaction without further purification.

[0564] Method 3: A 22 L flask was charged with a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (9-BBN, 5.75 L, 2.89 mol, 2.0 equiv), and tetrahydrofuran (THF, 6 L) was treated with 3,3-diethoxy-1-propene (393 g, 3.02 mol, 2.10 equiv) at 0°C-5°C, and then the resulting reaction mixture was warmed to room temperature and stirred at room temperature for 14 h. 6-Bromoquinoline (8, 300 g, 1.44 mol, 1.0 equiv), palladium acetate (Pd(OAc)2, 16.1 g, 0.072 mol, 0.05 equiv), potassium carbonate (K2CO3, 398 g, 2.89 mol, 2.0 equiv), tricyclohexylphosphine (22.3 g, 0.079 mol, 0.055 equiv) and water (52 g, 2.8 mol) were added to the reaction mixture at room temperature, which was then degassed with nitrogen for 1 h. The resulting reaction mixture was heated to 75 °C for 1 h. When TLC and LC / MS showed that the reaction was considered complete, the reaction mixture was cooled to room temperature, and water (2 L) was added to dissolve the salts. The resulting mixture was then concentrated to a volume of about 4 L under reduced pressure and then filtered through a plug of celite. The celite plug was washed with ethyl acetate (EtOAc, 2 L). The filtrate was concentrated to a volume of about 2 L under reduced pressure, and then the residue solution was slowly added to a flask containing 2.0 M aqueous hydrochloric acid (HCl) solution (2 L) at 0° C.-5° C. over 5 min. The resulting solution was stirred at 0° C.-5° C. for 14 h, then quenched with saturated aqueous sodium bicarbonate (NaHCO 3 ) solution at 0° C. until the pH was between 8 and 9. The layers were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 2 L). The combined organic layers were washed with brine (1 L), dried with sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure. The residue containing crude 3-(quinolin-6-yl)propanal (9) was purified by flash column chromatography (SiO2, gradient elution with 20-80% ethyl acetate in heptane) to afford 3-(quinolin-6-yl)propanal (9, 139 g, 266.7 g theoretical, 52.1%) as a yellow oil which was found to be identical to that obtained from Methods 1 and 2.

[0565] Embodiment 18

[0566] 1-(2-Chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11)

[0567] Method I: A solution of 3-(quinolin-6-yl)propanal (9, 407 g, 2.2 mol, 1.0 equiv) in chloroform (CHCl3, 1700 mL) was cooled to 0°C, and then proline (52 g, 0.44 mol, 0.2 equiv) and N-chlorosuccinimide (NCS, 303 g, 2.31 mol, 1.05 equiv) were added. The resulting reaction mixture was allowed to slowly warm to room temperature (becoming homogeneous) and the reaction mixture was stirred at room temperature overnight. The reaction exothermed to about 40°C, it reached room temperature, and a precipitate formed at this time. After TLC and LC / MS indicated that the reaction was complete, the reaction mixture was diluted with ethyl acetate (EtOAc, 1700 mL), and the resulting mixture was cooled to 0°C. The solid was collected by filtration, and the collected wet solid mass was placed in a flask and triturated with water (750 mL). The resulting suspension was stirred at room temperature for 30 min, and then the solid was collected by filtration. The collected solid was washed with water (250 mL) and methyl tert-butyl ether (MTBE, 500 mL) and dried in a vacuum oven at 45 °C to constant weight to provide 1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 378.7 g, 701.3 g theoretical, 54% yield) as an off-white powder. For 11: 1 H NMR(DMSO-d6,400MHz)δppm 8.86(dd,1H,J=4.15Hz,1.66Hz),8.33(dd,1H,J=8.51Hz,1.04Hz),7.98(d,1H,J=8.72Hz ),7.85(d,1H,J=1.66Hz),7.68(dd,1H,J=8.51Hz,1.87Hz),7.51(dd,1H,J=8.29Hz,4.15H z),7.36(d,1H,J=7.05Hz),5.28(dd,1H,J=9.54Hz,6.85Hz),5.07(dt,1H,J=9.75Hz,2.7 0Hz), 3.65 (dd, 1H, J = 14.52Hz, 2.49Hz), 3.09 (dd, 1H, J = 14.52Hz, 9.75Hz), 2.64 (s, 4H); C 16 H 15 ClN2O3 (molecular weight 318.75), LCMS (EI) m / e 319.2 (M + +H).

[0568] Method II: A solution of 3-(quinolin-6-yl)propanal (9, 74.8 g, 0.404 mol) in acetonitrile (202 mL, 3.87 mol) was cooled to 0°C, then L-proline (4.70 g, 0.0404 mol, 0.10 equiv), benzoic acid (4.96 g, 0.0404 mol, 0.10 equiv) and N-chlorosuccinimide (NCS, 57.8 g, 0.424 mol, 1.05 equiv) were added at 0°C. The reaction mixture was stirred at 0°C for 3 h, and the resulting clear solution was allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction mixture became a thick suspension, and LC / MS indicated that the reaction was complete. Ethyl acetate (EtOAc, 202 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 h. The solid was collected by filtration, washed with ethyl acetate (EtOAc, 100 mL) and dried under vacuum at 40-45°C to constant weight to provide 1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 88.8 g, 128.8 g theoretical, 69% yield) as an off-white powder which was found to be identical in every comparable aspect to the material prepared from Method I.

[0569] Scheme 3 (Examples 19-21)

[0570]

[0571] Embodiment 19

[0572] 2-Fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14)

[0573] A suspension of 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzonitrile (13, 277.5 g, 0.73 mol, 1.0 equiv) in concentrated hydrochloric acid (2500 mL) and water (250 mL) was heated to 100° C. (homogeneous at this point) and stirred at about 100° C. for 18 h. When LC / MS indicated the reaction was complete, the reaction mixture was cooled to 70° C.-80° C. and then diluted with water (2500 mL). The resulting diluted reaction mixture was then cooled to room temperature (a yellow solid formed at 40° C.-50° C.) and then cooled to 0° C.-5° C. The solid was then collected by filtration, washed with a small amount of 1N aqueous HCl (100 mL) and dried in a vacuum oven at 45°C to constant weight to provide 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14, 271 g, 291.5 g theoretical, 93% yield) as a yellow to bright yellow powder. For 14: 1 H NMR(400MHz,DMSO-d6)δppm 9.34(s,1H),9.23(dd,1H,J=5.19Hz,1.45Hz),9.08(d,1H,J=8.29Hz),8.38(d,1H,J=8.92Hz),8.30 (d,1H,J=1.24Hz),8.18(dd,1H,J=8.72Hz,1.87Hz),8.12(s,1H),8.08-8.00(m,4H),4.75(s,2H);C 22 H 16 Cl2FN5O2 (molecular weight 472.30), C 22 H 14 FN5O2 (free base: molecular weight 399.38), LCMS (EI) m / e 400.0 (M + +H).

[0574] Embodiment 20

[0575] 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15)

[0576] A suspension of 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14, 431.4 g, 0.914 mol, 1.0 equiv) and (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP, 570 g, 1.1 mol, 1.2 equiv) in N,N-dimethylformamide (DMF, 3700 mL) was treated with a 2M solution of methylamine in THF (1830 mL, 3.656 mol, 4.0 equiv) at room temperature over 15 min. During the addition of methylamine, the reaction temperature was increased to 30 °C, and the reaction mixture became homogeneous after the addition of methylamine was complete. Then, triethylamine (TEA, 382mL, 2.742mol, 3.0 equivalents) is added to the reaction mixture, and the reaction mixture obtained is stirred at room temperature for 2h-4h. When LC / MS shows that the coupling reaction is completed, the reaction mixture is treated with water (950mL). The obtained suspension is cooled to 0°C-5°C in an ice bath, and stirred for 30min at 0°C-5°C. Solids are collected by filtration, and washed with water (200mL). Then, the wet solid block is suspended in a mixture of water and acetonitrile (volume ratio 1 / 1, 2000mL), and the obtained suspension is stirred at room temperature for 1h. The solid was collected by filtration, washed with water and acetonitrile, and dried in a vacuum oven at 40-45°C to constant weight to provide 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15, 322 g, 377 g theoretical, 85.4% yield) as a yellow to bright yellow powder. For 15: 1 H NMR (400MHz, DMSO-d6) δppm 9.20 (s, 1H), 8.82 (dd, 1H, J = 4.05, 1.56Hz), 8.38 (br m,1H),8.27(dd,1H,J=8.50Hz,1.25Hz),8.06-7.93(m,5H),7.81-7.74(m,2 H), 7.49 (dd, 1H, J = 8.40Hz, 4.35Hz), 4.62 (s, 2H), 2.78 (d, 3H, J = 4.36Hz); C 23 H 17 FN6O (molecular weight 412.42), LCMS (EI) m / e 413.1 (M + +H).

[0577] Embodiment 21

[0578] 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride (21, dihydrochloride)

[0579] A suspension of 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15, 421.2 g, 1.021 mol) in methanol (MeOH, 6600 mL) was heated to 55°C, and then a premixed solution of concentrated aqueous hydrochloric acid (conc. HCl, 37 wt.%, 12 M, 420 mL, 5.10 mol, 5.0 equiv) in isopropanol (IPA, 1510 mL) was added dropwise at 55°C. The resulting clear solution was stirred at 55°C for 30 min, and then methyl tert-butyl ether (MTBE, 6750 mL) was added via an additional funnel over 30 min. After the addition of methyl tert-butyl ether, a solid slowly precipitated out. The resulting mixture was stirred at 55°C for an additional 1 h, and then the resulting mixture was gradually cooled to room temperature. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with methyl tert-butyl ether (MTBE, 3×500 mL), and dried in a vacuum oven at 45° C.-55° C. to constant weight. The desired 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride (21, dihydrochloride, 470.7 g, 495.5 g theoretical, 95% yield) was obtained as an off-white to pale yellow crystalline solid. For 21 (dihydrochloride): melting point (decomposition) 222° C.; 1 H NMR(400MHz,DMSO-d6)δppm 9.46(s,1H),9.25(dd,1H,J=5.4Hz,1.4Hz),9.12(d,1H,J=8.3Hz),8.51(m,1H),8.47(d,1H,J=0.9Hz),8.34(d,1H,J=1.3Hz),8. 23(s,1H),8.21(dd,1H,J=9.0Hz,1.8Hz),8.09-8.02(m,3H),7.79(dd,1H,J=7.5Hz,8.3Hz),4.77(s,2H),2.78(s,3H,J=4.5Hz); 13C NMR(100MHz,DMSO-d6)δppm 163.4,159.4(d,J=249.9Hz),145.8,145.4,144.5,143.8,140.4,138.8,136.8,135.9,135.7(J=8.6Hz),131.2(J= 3.1Hz), 130.7, 128.7, 128.2, 126.2 (J = 14.9Hz), 126.0, 123.1 (J = 3Hz), 122.5, 121.0, 114.9 (J = 5.6Hz), 28.4, 26.3; 19 F NMR (376.3MHz, DMSO-d6) δppm-113.2; C 23 H 17 FN6O (free base, molecular weight 412.42), LCMS (EI) m / e 413.1 (M + +H) and 435.0(M + +Na).

[0580] Scheme 4 (Examples 22-25)

[0581]

[0582] Embodiment 22

[0583] 1,2,4-Triazine-3-amine(16)

[0584] At room temperature, an aqueous solution of glyoxal (57Kg of a 40wt% aqueous solution, 393mol, 0.73 equivalents) was added to a suspension of aminoguanidine bicarbonate (73Kg, 536.3mol) in water (400L). Carbon dioxide (CO2) began to be generated almost immediately. The reaction mixture was then stirred at room temperature for 18h, and after about 2h, the production of gas had virtually ceased. The reaction mixture was then filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was then extracted with cold methanol (MeOH, 3×120L), and the combined methanol solution was cooled to 0°C-5°C and then filtered to remove the remaining solids. The filtrate was then concentrated under reduced pressure, and the residue was recrystallized in acetonitrile to provide fine white needles 1,2,4-triazine-3-amine (16, 34Kg, 37.76Kg theoretical value, 90% yield). For 16: 1 H NMR (400MHz, DMSO-d6) δppm 8.54 (d, 1H, J = 2.33Hz), 8.20 (d, 1H, J = 2.33Hz), 7.15 (br s, 2H).

[0585] Embodiment 23

[0586] 6-Bromo-1,2,4-triazine-3-amine (17)

[0587] A solution of 1,2,4-triazine-3-amine (16, 33 Kg, 343.4 mol) in water (500 L) was treated with N-bromosuccinimide (NBS, 66 Kg, 370 mol, 1.08 equiv) at 5°C-15°C, and the resulting reaction mixture was stirred at 10°C-15°C for 1 h-4 h. When TLC and LC / MS indicated that the bromination reaction was complete, the reaction mixture was treated with saturated aqueous sodium carbonate (Na2CO3). The resulting solution was then extracted with ethyl acetate (EtOAc, 3×500 L). The combined organic extracts were washed with water (2×100 L), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to provide a yellow to brown powder 6-bromo-1,2,4-triazine-3-amine (17, 10.3 Kg, 60 Kg theoretical, 17.2% yield). For 17: 1 H NMR (400 MHz, DMSO-d6) δppm8.39 (s, 1H), 7.47 (br, 2H); C3H3BrN4 (molecular weight 174.99), LCMS (EI) m / e 175.0 / 176.9 (M + +H).

[0588] Embodiment 24

[0589] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzidine nitrile (19)

[0590] Step 1: A solution of 2-fluoro-4-bromobenzonitrile (18, 12.5 Kg, 62.5 mol) in anhydrous tetrahydrofuran (THF, 30 L) was treated with a solution of isopropylmagnesium chloride generated from magnesium (Mg, 1.8 Kg, 150 mol, 1.2 eq.), 2-chloropropane (7.2 Kg, 92 mol, 1.47 eq.) in THF (20 L) and 2-(2-(dimethylamino)ethoxy)-N,N-dimethylethylamine (11 Kg, 69 mol, 1.1 eq.) at room temperature. The resulting mixture was then stirred at 12°C-20°C for an additional 2 h and then treated with trimethyl borate (9 Kg, 86.7 mol, 1.4 eq.) at 10°C-15°C. The reaction mixture was stirred at 7°C-16°C for 40 min. When TLC and LC / MS showed that the reaction was complete, the reaction mixture was quenched with 1N aqueous hydrochloric acid solution (HCl, 35 Kg) at room temperature. Then, the quenched aqueous reaction mixture was extracted with ethyl acetate (EtOAc, 4×35 L). The combined organic extracts were washed with water (50 L), dried over magnesium sulfate (MgSO 4 ) and concentrated under reduced pressure. Then, the residual solid was recrystallized from acetonitrile (20 L) and n-hexane (45 L) to provide the corresponding crude 3-fluoro-4-cyanophenylboronic acid (5.0 Kg, 48% yield).

[0591] Step 2: A suspension of crude 3-fluoro-4-cyanophenylboronic acid (9.2 Kg, 55.8 mol) in cyclohexane (150 L) was treated with pinacol (13.2 Kg, 111.6 mol, 2.0 equiv) at room temperature, and the resulting reaction mixture was raised to 40 ° C for 4 h. When TLC and LC / MS indicated that the reaction was complete, the reaction mixture was cooled to room temperature and then washed with water (2×75 L). Then, dried over magnesium sulfate (MgSO4), and the organic layer was concentrated under reduced pressure to provide a pale yellow solid 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl cyanide (19, 11.8 Kg, 13.8 Kg theoretical value, 85.6% yield). For 19: 1 H NMR (300MHz, DMSO-d6) δppm 7.92 (t, 1H, J-7.00Hz), 7.62 (m, 2H), 1.29 (s, 12H).

[0592] Embodiment 25

[0593] 4-(3-Amino-1,2,4-triazine-6-yl)-2-fluorobenzonitrile (20)

[0594] A mixture of 6-bromo-1,2,4-triazine-3-amine (17, 100.0 g, 571.47 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 145.43 g, 588.61 mmol, 1.03 equiv) in 1,4-dioxane (1200 mL) was stirred at room temperature for 10 min, and then potassium carbonate (K2CO3, 355.4 g, 2572 mmol) in water (600 mL) was added to give a deep red solution. The mixture was degassed by nitrogen bubbling for 10 min, and then 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)2Cl2, 14.14 g, 17.14 mmol, 0.03 equiv) complexed with dichloromethane (1:1) was added at room temperature. The obtained reaction mixture was degassed by nitrogen bubbling for 10 min, and then heated at 86 ° C under nitrogen. After 2 h, HPLC showed that the reaction was complete, and the reaction mixture was cooled to room temperature, and then cooled to 0 ° C-5 ° C with an ice-water bath. 1,4-dioxane (400 mL) was added to the cooled reaction mixture, and then a solution of 3.3M aqueous hydrochloric acid solution (HCl, 1900 mL) was added dropwise and stirred to adjust the pH to 0.40-0.93. The mixture was stirred at room temperature for 30 min, and filtered. The collected solid was stirred with 1,4-dioxane (260 mL), and then 1N HCl (400 mL) was added. The mixture was stirred at room temperature for 10 min, and filtered. The filtrate was combined with the previously obtained filtrate and washed with ethyl acetate (EtOAc, 2×2L). The combined ethyl acetate extracts were extracted with 1N aqueous hydrochloric acid solution (HCl, 3×200 mL). Then, the combined aqueous solution was treated with activated carbon (20 g) and stirred at room temperature for 30 min. The mixture was filtered through a diatomaceous earth bed, and the filtrate was cooled to 0°C-5°C with an ice-water bath. At 5°C-12°C, a 50% solution of sodium hydroxide in water (NaOH, 240 mL, 4500 mmol) was added dropwise to adjust the pH to 10.6-11.6. The mixture was stirred at 0°C-5°C for 30 min, and then filtered. The collected solids were washed with aqueous ammonium hydroxide solution (1 to 3 times of 28% concentrated NH4OH to water, 1900 mL), and dried under vacuum at 40°C-45°C to constant weight to provide an off-white powder 4-(3-amino-1,2,4-triazine-6-yl)-2-fluorobenzonitrile (20, 101.2 g, 122.9 g theoretical value, 82.3% yield). For 20: 1H NMR (400MHz, DMSO-d6) δppm8.94(s,1H),8.12(d,1H,J=11.41Hz),8.08-8.00(m,2H),7.71(br s,2H); C 10 H6FN5 (molecular weight 215.19), LCMS (EI) m / e 215.9 (M + +H).

[0595] Scheme 5 (Example 26)

[0596]

[0597] Embodiment 26

[0598] 2-Fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzonitrile(13)

[0599] Step 1: A 22 L reactor equipped with an overhead stirrer, thermocouple, distillation apparatus and nitrogen inlet was purged with nitrogen at room temperature, then 4-(3-amino-1,2,4-triazine-6-yl)-2-fluorobenzonitrile (20, 300 g, 1.39 mol), 1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 635 g, 1.99 mol, 1.43 equiv) and ethylene glycol (3.0 L) were charged into the reactor. The resulting reaction mixture was heated to 130°C-140°C and bubbling nitrogen was continuously passed through. The distillate was collected with a distillation apparatus. After 3-4 h, HPLC indicated that the reaction was complete (<1.5% of starting material 20 was present). The reaction mixture was gradually cooled to room temperature. Under stirring within 60 min, 2.5% aqueous sodium carbonate solution (Na2CO3, 14.1 L) was added to the reactor, and the mixture was stirred at room temperature for 1-2 h. The mixture was then filtered, and the solid was washed with water (9.6 L) and dried under vacuum to provide the desired crude product (13, 980.4 g), which was combined with multiple other batches for purification as described below.

[0600] Step 2: A solution of the crude product (13, 2754 g) in dichloromethane (CH2Cl2, 37.8 L) and methanol (0.54 L) was treated with silica gel (SiO2, 2700 g) at room temperature, and the resulting mixture was stirred at room temperature for 90 min. The mixture was filtered and the filter cake was washed with a mixture of CH2Cl2 (18 L) and methanol (0.26 L). The combined filtrate was treated with silica gel (SiO2, 1800 g), and the resulting mixture was stirred at room temperature for 90 min, and then filtered. The filter cake was washed with a mixture of CH2Cl2 (18 L) and methanol (0.26 L). The combined filtrate was concentrated to 8-12 L under reduced pressure at 20°C-60°C. The residue was treated in batches with a mixture of isopropyl alcohol (IPA) and water (1:1, 9 L), and distillation was continued at 1 atm until the temperature reached 68°C-75°C. The mixture was cooled to room temperature, and the solid was collected by filtration. The collected solid was washed with isopropanol (IPA, 3.6 L) and dried under vacuum at 40°C-45°C to constant weight to provide pure bright yellow powder 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl)benzyl nitrile (13, 940.27 g). The above reaction and purification methods provided product 13 in a yield of 59-64%. It was found that the spectral data of compound 13 prepared by this synthetic method were the same as those obtained from the material prepared by cyanation of compound 12 described previously. For 13: 1 H NMR(400MHz,DMSO-d6)δppm 9.24(s,1H),8.81(dd,1H,J=4.15,1.66Hz),8.26-8.12(m,4H),8.02(s,1H),7.95-7.9 3(m,2H),7.76(dd,1H,J=8.71,2.08Hz),7.47(dd,1H,J=8.70,4.15Hz),4.62(s,2H); C 22 H 13 FN6 (molecular weight 380.38), LCMS (EI) m / e 381.0 (M + +H).

[0601] Scheme 6 (Examples 27-29)

[0602]

[0603] Embodiment 27

[0604] 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14)

[0605] Compound 13 (900 g, 2.37 mol), water (0.9 L) and concentrated HCl (9.1 L) were charged into a 22 L reactor equipped with an overhead stirrer, a thermocouple and a nitrogen inlet at room temperature. The resulting reaction mixture was heated to 100 ° C for 12 h. When HPLC indicated that the reaction was complete, the reaction mixture was cooled to 90 ° C, and water (4.9 L) was added over 15 min while maintaining the temperature at 65-90 ° C. The reaction mixture was further cooled to room temperature, and the reaction mixture was stirred at room temperature for 3 h. The solid was collected by filtration, washed with water (1.2 L), and dried in vacuo at 40-45 °C to constant weight to provide 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14, 945 g, 946.5 g theoretical, 99.8% yield) as a pale yellow solid, which was found to be identical to the material prepared by the previous method. For 14: 1 H NMR(400MHz,DMSO-d6)δppm 9.34(s,1H),9.23(dd,1H,J=5.19Hz,1.45Hz),9.08(d,1H,J=8.29Hz),8.38(d,1H,J=8.92Hz),8.30 (d,1H,J=1.24Hz),8.18(dd,1H,J=8.72Hz,1.87Hz),8.12(s,1H),8.08-8.00(m,4H),4.75(s,2H); C 22 H 16 Cl2FN5O2 (molecular weight 472.30), C 22 H 14 FN5O2 (free base: molecular weight 399.38), LCMS (EI) m / e 400.0 (M + +H).

[0606] Embodiment 28

[0607] 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15)

[0608] Method A: HOBt (358 g, 2.65 mol, 1.25 eq) and EDC hydrochloride (508.4 g, 2.65 mol, 1.25 eq) were added to a stirred solution of 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14, 1000 g, 2.12 mol) in acetonitrile (5 L) and CHCl (10 L) at room temperature. Then, another portion of CHCl (10 L) was added to the reaction mixture and the resulting reaction mixture was stirred at room temperature for 20 min. A 2.0 M solution of methylamine (MeNH) in THF (3.44 L, 6.88 mol, 3.25 eq) was added with stirring while maintaining the temperature at 15-30°C. The reaction mixture was stirred at room temperature for 2 h, and then another portion of a 2.0 M solution of methylamine (MeNH2) in THF (1.06 L, 2.12 mol, 1 eq) was added. The reaction mixture was stirred at room temperature for 1 h, and a second portion of EDC hydrochloride (406 g, 2.12 mol, 1 eq) was added, and stirring was continued for 6 h. When HPLC indicated that less than 1% of the starting material (14) remained, the reaction mixture was concentrated under reduced pressure at <50 ° C. During the distillation, acetonitrile (20 L) was added, and distillation was continued until the residual volume was about 20 L. The residue was treated with an aqueous solution of 2.5% sodium carbonate (Na2CO3, 40 L), and the resulting mixture was stirred at room temperature for 30 min. The solid was collected by filtration, washed with water (3×4.0 L), and air-dried by suction vacuum on the filter to provide the crude desired product (15). The crude solid was treated with CH2Cl2 (17.6 L) and MeOH (5.2 L) at room temperature, and the resulting mixture was stirred until a clear solution was obtained. The solution was filtered to remove insoluble material. Under vigorous stirring, a 2.5% aqueous solution of sodium carbonate (Na2CO3, 17.6 L) was added to the filtrate, and the mixture was stirred at room temperature for 60 min to give a suspension. Heptane (20 L) was added, and the mixture was stirred for another 60 min. The mixture was filtered and washed successively with water (3×4.0 L) and heptane (4.0 L), and dried in vacuo to provide a bright yellow solid 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl)benzamide (15, 1095.3 g, 874.3 g theoretical value), which was found not to be completely dry and contained ~25% residual solvent. The wet solid was used directly in the subsequent formation reaction of the dihydrochloride (21) without further drying. A small amount of sample was thoroughly dried for spectral analysis and the data were consistent with those obtained by previous methods: For 15: 11H NMR (400 MHz, DMSO-d6) δ ppm 9.20 (s, 1H), 8.82 (dd, 1H, J = 4.05, 1.56 Hz), 8.38 (br m, 1H), 8.27 (dd, 1H, J = 8.50 Hz, 1.25 Hz), 8.06 - 7.93 (m, 5H), 7.81 - 7.74 (m, 2H), 7.49 (dd, 1H, J = 8.40 Hz, 4.35 Hz), 4.62 (s, 2H), 2.78 (d, 3H, J = 4.36 Hz); C 23 H 17 FN6O (molecular weight 412.42), LCMS (EI) m / e 413.1 (M + + H).

[0609] Method B: To 2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid dihydrochloride (14, 50.00 g, 0.1059 mol) was added toluene (300 mL) and then thionyl chloride (SOCl2, 77.2 mL, 1.06 mol, 10.0 equiv) at room temperature. The resulting reaction mixture was heated at 72°C under N2 and the reaction was followed by HPLC analysis for the disappearance of the starting material benzoic acid (14). After 48 h, HPLC indicated that ~4% starting material remained and the reaction was stopped. The reaction mixture was concentrated to dryness by vacuum distillation at 40-50°C. Toluene (300 mL) was added to the residual solid and the solvent was removed by vacuum distillation at 40-50°C. THF (250 mL) was added and the mixture was cooled with an ice-water bath. 2.0M methylamine (MeNH2) in THF (529mL, 1.06mol, 10 equivalents) was added dropwise. The resulting reaction mixture was allowed to warm to room temperature, and the resulting reaction mixture was stirred at room temperature for 17h. Water (600mL) was added to the reaction mixture, and THF (400-500mL) was removed by vacuum distillation at 40°C. Sodium carbonate (15.60g, 0.147mol) was added, and the mixture was stirred at room temperature for 30min. The mixture was filtered, and the solid was washed with water (3×30mL) and dried. The solid was dissolved in premixed dichloromethane (CH2Cl2, 1000mL) and methanol (MeOH, 300mL). With vigorous stirring, a solution of 0.236M sodium carbonate (Na2CO3) in water (1000mL) was added dropwise. After the addition of an aqueous solution of sodium carbonate (Na2CO3), the solid slowly precipitated out. Then, hexane (1000mL) was added dropwise under stirring. The mixture was stirred at room temperature for 30-40 min, and the solid was collected by filtration. The collected solid was washed with water (3×200 mL) and dried in vacuo at 40-50° C. to constant weight to provide 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15, 42.2 g, 43.67 g theoretical, 96.6% yield) as a bright yellow solid, which was found to be identical to the material prepared by Method A in every comparable aspect. For 15, 1H NMR (400MHz, DMSO-d6) δppm 9.20 (s, 1H), 8.82 (dd, 1H, J = 4.05, 1.56Hz), 8.38 (br m,1H),8.27(dd,1H,J=8.50Hz,1.25Hz),8.06-7.93(m,5H),7.81-7.74(m,2 H), 7.49 (dd, 1H, J = 8.40Hz, 4.35Hz), 4.62 (s, 2H), 2.78 (d, 3H, J = 4.36Hz); C 23 H 17 FN6O (molecular weight 412.42), LCMS (EI) m / e 413.1 (M + +H).

[0610] Embodiment 29

[0611] 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride (21, dihydrochloride)

[0612] A 50 L reactor was charged with 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15, 2100 g, containing -25% residual solvent) and filtered USP water (7.6 L) at room temperature. A 6 M aqueous solution of hydrochloric acid (HCl, 3 L) was added with stirring via an addition funnel. The resulting reaction mixture was stirred at room temperature for 1.5 h. Acetone (30.5 L) was added to the reactor with stirring over a period of 1 h, and the resulting mixture was stirred at room temperature for 2.5 h. The solid was collected by filtration, washed with acetone (2 x 4.3 L), and dried in vacuo to constant weight to provide 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride (21, dihydrochloride, 1629.2 g, 1830.6 g theoretical, 89%) as a pale yellow crystalline powder which was found to be identical in every comparable aspect to the material prepared by the previous method. For 21 (dihydrochloride): 1H NMR(400MHz,DMSO-d6)δppm 9.46(s,1H),9.25(dd,1H,J=5.4Hz,1.4Hz),9.12(d,1H,J=8.3Hz),8.51(m,1H),8.47(d,1H,J=0.9Hz),8.34(d,1H,J=1.3Hz), 8.23(s,1H),8.21(dd,1H,J=9.0,1.8Hz),8.09-8.02(m,3H),7.79(dd,1H,J=7.5,8.3Hz),4.77(s,2H),2.78(s,3H,J=4.5Hz); 13 C NMR(100MHz,DMSO-d6)δppm 163.4,159.4(d,J=249.9Hz),145.8,145.4,144.5,143.8,140.4,138.8,136.8,135.9,135.7(J=8.6Hz),131.2(J= 3.1Hz), 130.7, 128.7, 128.2, 126.2 (J = 14.9Hz), 126.0, 123.1 (J = 3Hz), 122.5, 121.0, 114.9 (J = 5.6Hz), 28.4, 26.3; 19 F NMR (376.3MHz, DMSO-d6) δppm-113.2; C 23 H 17 FN6O (free base, molecular weight 412.42), LCMS (EI) m / e 413.1 (M + +H) and 435.0(M + +Na).

[0613] Embodiment 30

[0614] Physical Characteristics of 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride (21)

[0615] The dihydrochloride salt is an off-white to pale yellow powder as determined by visual inspection against a white background.

[0616] Embodiment 31

[0617] Solubility studies

[0618] The solubility of the dihydrochloride salt (21, see Example 21) at 25°C was found to be about 4.9 mg / mL in water; 0.002 mg / mL in a pH 7.4 buffer; 0.002 mg / mL in a pH 8.0 buffer; and about 24 mg / mL in a 0.1N HCl aqueous solution. The equilibrium solubility was determined by mixing the sample in the selected aqueous solvent (0.1N HCl, water, pH 7.4 buffer, and pH 8.0 buffer) for at least 12 hours. The sample concentration was then determined by HPLC using a single-point calibration.

[0619] Example A

[0620] In vitro c-Met kinase assay

[0621] 2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamides were screened in vitro for their ability to inhibit c-Met kinase activity. The IC for inhibition of c-Met kinase was determined as described in the literature with some modifications. 50 Values ​​(Wang, X. et al., MoI. Cancer Ther. 2003, 2(11): 1085-1092; Calic, M. et al., Croatica Chemical ACTA. 2005, 78(3): 367-374). Briefly, histidine-tagged c-Met catalytic domain fusion protein (Invitrogen, #PV3143) was used for the determination. IC 50The phosphorylation degree of poly-Glu-Tyr (Sigma-Aldrich, #P0275) was measured, and poly-Glu-Tyr was coated on (0.01 mg / well) 96-well microplates (R&D Systems, #DY990). The reaction was carried out in 50 μL of a solution containing 50 mM HEPES (pH 7.5), 10 mM MnCl2, 10 mM MgCl2, 0.5 mM DTT, 100 μM Na3VO4, 5 μM ATP (Cell TechnologyTechnology, #9804) and a serial dilution of the test compound. The reaction lasted for 25 minutes at 30°C. After the reaction was completed, the contents of the plate were discarded. The plate was then washed with TBS-T (250 μL / well, 5x), and then blocked for 2 hours with TBS-T containing 1% BSA. The contents of the plate were discarded, and 100 μL (per well) of peroxidase-labeled anti-phosphotyrosine antibody (Sigma, #A5964) diluted (1:60,000) in TBS-T containing 1% BSA was added and incubated for 1 h. The plate was washed with TBS-T (250 μL / well, 5x), and then the color reaction was developed using 100 μL of H2O2 and tetramethylbenzidine (R&D Systems, #DY999) (1:1 mixture). The reaction was stopped within a few minutes with 100 μL of 2N H2SO4. The optical density was immediately measured using a microplate reader at 450 nm and wavelength corrected at 540 nm. IC was calculated using GraphPad Prism software 50 The linear range of the kinase (i.e., the period of time over which the rate remains equal to the initial rate) is determined, and the IC 50 Determination.

[0622] Wang, X. et al., Potent and selective inhibitors of the Met [hepatocyte growth factor / scatter factor (HGF / SF) receptor] tyrosine kinase block HGF / SF-induced tumor cell growth and invasion. (Potent and selective inhibitors of the Met [hepatocyte growth factor / scatter factor (HGF / SF) receptor] tyrosine kinase block HGF / SF-induced tumor cell growth and invasion) Mol. Cancer Ther. 2003, 2 (11): 1085-1092.

[0623] Calic, M., et al., Flavonoids as inhibitors of Lck and Fyn kinases. Croatian Chemica ACTA. 2005, 78(3): 367-374.

[0624] 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide was found to have an IC of less than 500 nM 50 See, e.g., U.S. Serial No. 11 / 942,130.

[0625] Example B

[0626] Cell proliferation / survival assay

[0627] Cell lines representing a variety of human cancers (SNU-1 and SUN-5 gastric cancer, A549 and NCI-H441 lung cancer, U-87 glioblastoma, HT-29 colon cancer, 786-O kidney cancer, PC-3 pancreatic cancer) are available from the American Type Culture Collection and are typically maintained in culture medium and under conditions recommended by the ATCC. The optimal cell density for use in proliferation / survival assays can be predetermined for individual cell lines. Compounds are screened for their ability to inhibit cell proliferation / survival and the IC 50 Below is a sample protocol for SNU-5 and SNU-1 cell proliferation / survival assays. SNU-5 and SNU-1 cells were seeded at 4000 cells / well and 2000 cells / well, respectively, into 96-well cell culture plates with appropriate culture medium containing 2% FBS and supplemented with serial dilutions of individual compounds in a final volume of 100 μL / well. After 72 hours of incubation, 24 μL of CellTiter AQueous One solution reagent (Promega, #G3581) was added to each well (final concentration = 333 μg / mL), and the plate was incubated for another 2 hours in a 37°C incubator. Optical density in the linear range was measured using a microplate reader at 450 nm and wavelength correction at 650 nm. IC was calculated using GraphPad Prism software 50Proliferation assays were performed using A549, NCI-H441, U-87, HT-29, 786-0, and PC-3 cells. First, cells were starved for 48 hours in low serum conditions (0.1-0.5% FBS in appropriate media) and then treated with different concentrations of compounds for 2 hours. After treating cells with HGF (50 ng / mL) (R&D, #294-HGN) for 24 hours, CellTiter AQueous One solution reagent was added and the plate was incubated for 2 hours. The results were recorded by plate reader.

[0628] Example C

[0629] Cell-based c-Met phosphorylation assay

[0630] Using immunoblot assays and ELISA-based c-Met phosphorylation analysis, the inhibitory effect of compounds on c-Met phosphorylation in relevant cell lines (SUN-5 gastric cancer cell line, A549 and NCI-H441 lung cancer cell lines, U-87 glioblastoma cell line, HT-29 colon cancer cell line, 786-O renal cancer cell line, PC-3 pancreatic cancer cell line, and HUVEC cell line) can be assessed. Cells were grown in appropriate culture media and treated with individual compounds at varying concentrations. For SNU-5, HT-29, 786-0 cells, cells were grown in appropriate culture media supplemented with 0.2% or 2% FBS and treated with compounds for 3-4 hours. Whole cell protein extracts were prepared using reagents and protocols obtained from Biosource International with slight modifications (#FNN0011). Briefly, protein extracts were prepared by incubation in lysis buffer [50 mM HEPES (pH 7.5), 100 mM NaCl, 1.5 mM MgCl2, 10% glycerol, 1% Triton X-100, 1 mM sodium orthovanadate, 1 mM sodium fluoride, aprotinin (2 μg / mL), leupeptin (2 μg / mL), pepstatin A (2 μg / mL), and phenylmethylsulfonyl fluoride (1 mM)] at 4°C. Cell debris was cleared from protein extracts by centrifugation at 14000×g for 20 minutes. For A549, H441, U-87, and PC-3 cells, cells were serum-starved (0.2% FBS) for at least 24 hours and then pretreated with different concentrations of compounds for 1 hour. Whole cell extracts were prepared after treating cells with HGF (50 ng / mL) for 10 minutes.

[0631] Immunoblotting assay

[0632] Relevant antibodies were obtained from commercial sources: rabbit polyclonal antibodies, including anti-human c-Met (Santa Cruz Biotechnology, #sc-161) and anti-phospho-c-Met (Biosource International, pY1230 / 4 / 5 and pY1003). For immunoblotting, 10-20 μg of protein extracts from individual treatment conditions were resolved by electrophoresis on 10% SDS-PAGE gels and electrotransferred to nitrocellulose (or PVDF) membranes. The membranes were blocked in PBS containing 3% milk and 0.1% Tween-20 for 1 hour, then the primary anti-c-Met antibody was incubated in blocking solution for 1 hour. After 3 washes, the membranes were incubated with the appropriate horseradish-conjugated secondary antibody for 1 hour. After the final wash, the blots were incubated with a chemiluminescent detection reagent for 5 minutes and the blots were exposed to X-ray film. Images were scanned, quantified and corrected with total c-Met, and the IC was calculated. 50 With IC values ​​of 10 μM or less 50 The compounds were considered to be active.

[0633] ELISA

[0634] Cell protein extracts were analyzed using a human phospho-c-Met ELISA kit according to the manufacturer's instructions (R&D Systems, #DYC2480). Optimal amounts of protein extracts were predetermined for individual cell lines. Briefly, for the assay, appropriate amounts of protein extracts were captured in 96-well microplates with capture anti-human c-Met antibodies for 2 hours. After washing, detection antibody (HRP-conjugated anti-phosphotyrosine antibody) was added and incubated for 2 hours. After additional washing, 100 μL of substrate solution (1:1 mixture of H2O2 and tetramethylbenzidine) was added to each well and the reaction was stopped with 2N H2SO4 within an appropriate amount of time during color development. Optical density was measured in the linear range using a microplate reader at 450 nm and wavelength corrected at 540 nm. IC was calculated using GraphPad Prism software 50 value.

[0635] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the above description. Such modifications also fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications and publications, is hereby incorporated by reference in its entirety.

Claims

1. A method for preparing a compound of formula V or a salt thereof: The method comprises the following steps: 1) The compound of formula IIa: With a compound of formula IIb: wherein X1 is chlorine, bromine or iodine, Reaction to form a compound of formula II: 2) the compound of formula II and the compound of formula III: reacting to form a compound of formula I or a salt thereof; 3) reacting the compound of formula I or its salt with a strong acid to form a compound of formula IV or its salt: 4a) comprising reacting the compound of formula IV or a salt thereof with CH3NH2 in the presence of at least one coupling agent to form a compound of formula V or a salt thereof: or 4b) reacting the compound of formula IV or a salt thereof with a halogenating agent to form a compound of formula VI or a salt thereof: wherein X2 is a halogen; and The compound of formula VI or a salt thereof is reacted with CH3NH2 to form a compound of formula V or a salt thereof.

2. The method of claim 1, wherein the acid in step 3) is concentrated hydrochloric acid.

3. The method of claim 1, wherein the coupling agent in step 4a) is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxybenzotriazole, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and salts thereof.

4. The process of claim 1, wherein the halogenating agent in step 4b) is thionyl chloride.

5. The method of claim 1, wherein the reaction of the compound of formula IIa with the compound of formula IIb is carried out in the presence of proline.

6. The method of claim 5, wherein X1 is chlorine.

7. The method of claim 1 or 5, further comprising reacting a compound of formula IIc in the presence of a palladium catalyst and a base: The compound of formula IIa is prepared by reaction with prop-2-en-1-ol: wherein X3 is chlorine, bromine or iodine.

8. The method of claim 7, further comprising the step of: The compound of formula IIa is prepared by reacting with an acid of formula HX': wherein X' is chlorine, bromine or iodine.

9. The method of claim 8, further comprising reducing the compound of formula IIe with hydrogen in the presence of a hydrogenation catalyst: The compound of formula IId is prepared by the method of:

10. The process of claim 9, wherein the hydrogenation catalyst is palladium on carbon.

11. The method of claim 9 or 10, further comprising reacting a compound of formula IIc with a compound of formula IIf in the presence of a coupling catalyst and a base: The method of the reaction is to prepare the compound of formula IIe.

12. The method of claim 11, wherein the catalyst is a mixture of palladium acetate and CuI.

13. The method of claim 8, further comprising the step of: Reaction with 9-borahabicyclo[3.3.1]nonane, followed by reaction with a compound of formula IIc in the presence of a coupling catalyst: The compound of formula IId is prepared by reacting to form a compound of formula IId: wherein X3 is chlorine, bromine or iodine.

14. The method of claim 13, wherein the coupling catalyst is palladium (II) diacetate.

15. The method of claim 1, further comprising reacting a compound of formula IIIa in the presence of a palladium catalyst and a base: With a compound of formula IIIb: The method of reaction is to prepare the compound of formula III; wherein X4 is chlorine, bromine or iodine; and Every R a Independently C 1-6 Alkyl; or Every R a Together with two oxygen atoms and a boron atom, it forms a 5-membered heterocyclic ring or a 6-membered heterocyclic ring; wherein the heterocyclic ring is optionally substituted by 1, 2, 3 or 4 independently selected C 1-4 Alkyl substitution.

16. The method of claim 15, wherein the compound of formula IIIb has formula IIIb-1:

17. The method of claim 15 or 16, further comprising preparing the compound of formula IIIa by reacting 1,2,4-triazine-3-amine with a halogenating agent.

18. The method of claim 17, further comprising preparing the compound of formula IIIb-1 by a method comprising: a) a compound of formula IIIc: Reaction with a reagent of formula R1MgY, wherein Y is a halogen, followed by reaction with a compound of formula B(OR2)3 to form a compound of formula IIId: and b) after the reaction in step a), reacting the compound of formula IIId with an acid, and then reacting with pinacol to form a compound of formula IIIb-1; in: R1 is C 1-6 alkyl; Each R2 is independently C 1-6 Alkyl; and X5 is chlorine, bromine or iodine.

19. A compound of formula III or a salt thereof:

20. A compound of formula II: Where X 1 It is chlorine, iodine or bromine.

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