Methods for the preparation of antibacterial compounds

Abstract

The present invention relates to a method for the manufacture of antibacterial compounds suitable for use in the treatment of infections with, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae and / or the genus Haemophilus.

Description

[Technical field]

[0001] The present invention relates to a process for the manufacture of the antibacterial compounds defined herein. [Background technology]

[0002] New antibacterial compounds are needed to combat the emergence of bacterial pathogens with resistance to existing antibacterial compounds. The increasing occurrence of bacterial resistance to existing antibiotics threatens to lead to multidrug resistance becoming commonplace among many bacterial pathogens, greatly increasing the burden of common infections on society. For example, antibiotic-resistant strains of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species), such as carbapenem-resistant Enterobacteriaceae (CRE), multidrug-resistant (MDR) Acinetobacter, MDR Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), are included in the list of antibiotic-resistant microorganisms identified as posing an immediate or serious threat to human health. Other prominent antibiotic-resistant pathogens include the gram-positive anaerobic bacterium Clostridium difficile, drug-resistant Neisseria gonorrhoeae, and drug-resistant Mycobacterium tuberculosis.

[0003] Specifically, resistance of Gram-negative bacteria, particularly those of the order Enterobacteriale, to existing antibiotic formulations, such as carbapenem (β-lactam) antibiotics, is increasing. Antibiotic-resistant Gram-negative Enterobacteriales strains, such as Escherichia coli NDM-1 (New Delhi metallo-β-lactamase) and carbapenemase-producing Enterobacterales bacteria, such as Klebsiella pneumoniae, are difficult to treat, increasingly prevalent, and increasingly virulent. Furthermore, new emerging hypervirulent, multidrug-resistant, and highly infectious strains of carbapenem-resistant Klebsiella pneumoniae associated with deadly outbreaks, such as the ST11 carbapenem-resistant hypervirulent Klebsiella pneumoniae strain, have been identified. Such strains are resistant to historical and currently recommended antibiotics and currently represent a major public health concern worldwide.

[0004] Currently, Enterobacteriaceae infections suspected to be resistant to carbapenems (CRE) are commonly treated with broad-spectrum agents. Such treatments usually consist of a combination of a β-lactam antibiotic and a β-lactamase inhibitor (BL / BLI) or the use of the antibiotic of last resort, colistin. BL / BLI combinations are effective in the short term but are predicted to eventually succumb to the bacteria's existing resistance mechanisms. Furthermore, these broad-spectrum agents are not active against all Ambler's β-lactamase classes and have no activity against metallo-β-lactamases that confer resistance to a broad range of β-lactam antibiotics, including carbapenems.

[0005] Thus, there is a need for efficient and scalable methods for the production of new antibacterial compounds that can provide reliable and effective treatment for infections, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae that are resistant to known antibiotics, such as carbapenems and other β-lactams, or that are associated with multidrug-resistant infectious agents. Additionally, there is a need to provide antibiotic formulations that can avoid or reduce the side effects associated with known antibacterial compounds.

[0006] It is an object of embodiments of the present invention to provide an effective, scalable method for the formation of antimicrobial compounds that provide solutions to the above-mentioned problems or other problems. Summary of the Invention

[0007] According to a first aspect of the present invention, compound (I)

[0008] [ka] 2-Amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-Amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a pharma- ceutically acceptable salt thereof, comprising

[0009] [ka] The method includes deprotecting the compound according to the present invention.

[0010] According to a second aspect of the present invention, compound (I)

[0011] [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: coupling 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) with 4-bromo-3-methylpyridine (6) or a salt thereof in the presence of a metal catalyst to form 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A);

[0012] [ka] Preferably, herein provided is a method comprising the step of subjecting 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to a metal scavenging treatment, the metal scavenging treatment comprising treatment with a metal scavenger.

[0013] According to a third aspect of the present invention, compound (I)

[0014] [ka] or a pharma- ceutical acceptable salt thereof, the method comprising coupling 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) with 4-bromo-3-methylpyridine (6) or a salt thereof in the presence of a metal catalyst to produce 1-(6-(3-(3-methylpyridine-4 forming 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A),

[0015] [ka] Here, a use is provided which comprises treating 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) with a metal scavenger.

[0016] According to a fourth aspect of the present invention, compound (I)

[0017] [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: amino acid coupling of 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor.

[0018] [ka] The present invention provides a method comprising:

[0019] definition As used herein, the term "disease" or "bacterial disease" is used to define an abnormal condition that impairs physiological function and is associated with a specific symptom. The term is used broadly to encompass any disorder, disease, abnormality, lesion, disorder, condition, or syndrome in which physiological function is impaired, regardless of the nature of the etiology (or indeed whether the etiological basis of the disease has been established). Thus, the term encompasses conditions resulting from trauma, injury, surgery, radiation ablation, poisoning, or nutritional deficiency. The term refers to any disease that involves (e.g., is caused by, exacerbated by, associated with, or characterized by) bacteria present and / or replicating in the body and / or cells of a subject. Thus, the term includes diseases caused or exacerbated by bacterial toxins (sometimes referred to herein as "bacterial poisoning").

[0020] As used herein, the term "infection" or "bacterial infection" is used to define a condition in which a subject is infected with bacteria. Infection can be symptomatic or asymptomatic. If symptomatic, the subject can be identified as infected based on established diagnostic criteria. If asymptomatic, the subject can be identified as infected based on various tests, including, for example, biochemical tests, serological tests, microbial culture methods and / or microscopic observation. Thus, the present invention typically finds use in treating subjects in which bacterial infection has been diagnosed or detected.

[0021] As used herein, the term "treatment" or "treating" refers to an intervention (e.g., administration of a drug to a subject) that cures, alleviates, or reduces the symptoms of a disease, or eliminates (or reduces the effects of) its cause (e.g., a causative bacterium). In this case, the term is used synonymously with the term "therapy". Thus, treatment of infection according to the present invention can be characterized by the bactericidal action (direct or indirect) of the compounds of the present invention. Thus, the compounds of the present invention find use in methods of killing or preventing the growth of bacterial cells.

[0022] Additionally, the term "treatment" or "treating" refers to an intervention (e.g., administration of an agent to a subject) that prevents or delays the onset or progression of a disease or reduces its incidence (or eradicates) in a treated population. In this instance, the term treatment is used synonymously with the term "prophylaxis."

[0023] The term "subject" (which should be interpreted as including "individual", "animal", "patient" or "mammal" as the context allows) defines any subject for which treatment is indicated, particularly a mammalian subject. Mammalian subjects include, but are not limited to, humans, farm animals, livestock, zoo animals, sport animals, pet animals, such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, and cows; primates, such as apes, monkeys, orangutans, and chimpanzees; canines, such as dogs and wolves; felines, such as cats, lions, and tigers; equines, such as horses, donkeys, and zebras; food animals, such as cows, pigs, and sheep; ungulates, such as deer and giraffes; rodents, such as mice, rats, hamsters, and guinea pigs; and the like. Preferably, the subject is a human.

[0024] The terms "gram-negative" and "gram-positive" are terms of art that define two different classes of bacteria based on certain cell wall staining characteristics.

[0025] The term "effective" includes beneficial effects such as additivity, synergy, reduced side effects, reduced toxicity, improved performance, reduced bacterial load during an infection, or activity.

[0026] The term "pharmaceutically acceptable salt" as applied to compound (I) of the present invention defines any organic or inorganic acid addition salt of the free base that is suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response, and is commensurate with a reasonable benefit / risk ratio. Suitable pharmaceutically acceptable salts are well known in the art. Examples include salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid), organic carboxylic acids (e.g., acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and mandelic acid), and organic sulfonic acids (e.g., methanesulfonic acid and p-toluenesulfonic acid).

[0027] In its broadest aspect, the present invention contemplates the preparation of all optical isomers of Compound (I) or pharma- ceutically acceptable salts.

[0028] In cases where the stereochemical form of Compound (I) or a pharma- ceutically acceptable salt thereof is important to pharmaceutical utility, the present invention contemplates the formulation of the isolated eutomer.

[0029] The term "resistant strain" as used herein refers to such strains that have shown resistance or insensitivity to one or more known antibacterial agents, particularly those that are widely considered to be the standard of care in the treatment of infections caused by bacterial strains. A "non-susceptible strain" is a strain in which the MIC (minimum inhibitory concentration) of a given compound or class of compounds for that strain has shifted to a value higher than the MIC for the corresponding susceptible strain. For example, a non-susceptible strain may refer to a strain that is insensitive to β-lactam antibiotics, a strain that is insensitive to one or more fluoroquinolones, and / or a strain that is insensitive to one or more other antibiotics (i.e., antibiotics other than β-lactams and fluoroquinolones). In some cases, the term "resistant" may refer to a strain in which the MIC of a given compound or class of compounds for that strain has shifted to a value significantly higher than the MIC for the corresponding susceptible strain. A bacterial strain may be said to be resistant to a given antibiotic if it is inhibited in vitro by a certain concentration of this agent, which is associated with a high probability of treatment failure.

[0030] As used herein, the term "multidrug-resistant" or "multidrug-resistant" refers to organisms, such as highly resistant Gram-negative bacteria (e.g., carbapenemase-producing Klebsiella pneumoniae), that exhibit in vitro and / or in vivo resistance to two or more antibacterial agents. Such organisms may be resistant to all currently available antibacterial agents or may remain susceptible only to older, potentially more toxic antibacterial agents.

[0031] As used herein, the term "hypervirulent" refers to an exceptionally highly virulent organism, generally as a result of the acquisition of a hypervirulence plasmid. Such organisms are capable of causing severe disease. For completeness, "hypervirulent" refers to organisms that are capable of causing extremely severe or deleterious effects and disease.

[0032] As used herein, the term "antibacterial treatment" refers to the treatment of an infection or disease in a subject with an antibacterial agent other than Compound (I) or a pharma- ceutically acceptable salt thereof. Typically, in the context of the present invention, this is with a known antibiotic or treatment method, including a carbapenem or other β-lactam antibiotic, other than Compound (I) or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0033] [Figure 1-1] Figures 1a to 1c show the results of in vitro pharmacological binding assays for Compound (I), Comparative Compound (II) and Comparative Compound (III) for all 44 ligands tested. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] FIG. 1d shows only those results of the in vitro pharmacological binding assay for compound (I), comparative compound (II) and comparative compound (III) that show greater than 50% inhibition. [Diagram 2] FIG. 2 shows the results of evaluating compound (I) and comparative compound (III) in a proof-of-concept study in a mouse model for the treatment of respiratory infection with gram-negative bacteria of the order Enterobacteriaceae. [Diagram 3] FIG. 3 shows the results of evaluating compound (I) and comparative compound (III) in a proof-of-concept study in a mouse model for the treatment of bacteremia or bloodstream infection with gram-negative bacteria of the order Enterobacteriaceae. [Figure 4-1] 4a-c show the results of evaluating compound (I) and comparative compound (III) in a proof-of-concept study in a mouse model for the treatment of urinary tract infection due to gram-negative bacteria of the order Enterobacteriaceae. [Figure 4-2] Same as above. [Figure 4-3] Same as above. [Diagram 5] FIG. 5 shows the results of compound (I) being further evaluated in a proof-of-concept study in a mouse model for the treatment of respiratory infection with gram-negative bacteria of the order Enterobacteriaceae. [Figure 6-1] 6a to 6c show the results of compound (I) being further evaluated in a proof-of-concept study in a mouse model for the treatment of urinary tract infection due to gram-negative bacteria of the order Enterobacteriaceae. [Figure 6-2] Same as above. [Figure 6-3] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Detailed Description of the Invention The present invention provides a solution to a previously unmet clinical need with respect to the treatment of infections with, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae, in particular Carbapenem-Resistant Enterobacteriaceae (CRE) and Extended-Spectrum β-Lactamase (ESBL) Enterobacteriaceae bacteria, and the treatment of infections with, or diseases caused or exacerbated by, Gram-negative bacteria of the genus Haemophilus.

[0035] Surprisingly and advantageously, it has been found that compound (I) or a pharma- ceutically acceptable salt thereof allows the treatment of infections or diseases caused or exacerbated by gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, such as gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, which are resistant to known β-lactam antibiotics and which are a major cause of death.

[0036] Compound (I) or a pharmaceutically acceptable salt thereof may be particularly advantageous in treating multi-site infections, i.e. infections caused by gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, occurring at different infection sites (intracellular sites in tissues and / or organs) in a subject (as shown by the data provided in the Examples section of the present invention). Compound (I) or a pharmaceutically acceptable salt thereof may be further advantageously utilized in treating infections caused or exacerbated by gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, when antibacterial treatment of a disease or infection in a subject in need of treatment has failed, or when the subject is allergic or otherwise contraindicated to an agent used or contemplated for use in antibacterial treatment.

[0037] Compound (I) or a pharma- ceutically acceptable salt thereof appears to have rapid bactericidal action and is believed to be highly active against all currently tested clinical resistance mechanisms, including all Ambler beta-lactamase classes (including metallo-beta-lactams). Compound (I) or a pharma-ceutically acceptable salt thereof appears to be immune to inactivation by the full range of carbapenem metabolizing enzymes and has demonstrated activity against all currently tested CRE, independent of carbapenemase or other resistance characteristics. In contrast to known BL / BLI combination treatments, Compound (I) or a pharma-ceutically acceptable salt thereof has shown a low propensity for resistance development when tested in vitro.

[0038] Furthermore, compound (I) or its pharma- ceutically acceptable salts show no cross-resistance with currently tested classes of antibiotics, and no contraindications have been observed. Compound (I) or its pharma- ceutically acceptable salts have also demonstrated both in vitro and in vivo safety in pharmacological studies.

[0039] Thus, compound (I) or a pharmaceutically acceptable salt thereof can be used to treat bacterial infections or diseases caused or exacerbated by bacteria resistant to known antibiotics, such as gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, in particular bacteria resistant to known antibiotics, such as carbapenem-resistant Enterobacteriale bacteria (CRE) and extended-spectrum β-lactamase (ESBL) Enterobacteriale bacteria. Compound (I) or a pharmaceutically acceptable salt thereof has bactericidal activity against bacteria resistant to known antibiotics, such as gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, in particular bacteria resistant to known antibiotics, such as carbapenem-resistant Enterobacteriale bacteria (CRE) and extended-spectrum β-lactamase (ESBL) Enterobacteriale bacteria.

[0040] The present invention relates to a method for the preparation of Compound (I) or a pharma- ceutically acceptable salt thereof. The method is effective and scalable. It is a synthetic route that can advantageously use commercially available starting materials, can be tailored to largely avoid purification by column chromatography, and produces Compound (I) or a pharma- ceutically acceptable salt thereof in high yield and purity. Any harmful reagents, such as metal ions of metal catalysts utilized in the method, can be advantageously removed in subsequent steps of the method so that they are present only at trace levels in the final product.

[0041] The process for the preparation of compound (I) or a pharma- ceutically acceptable salt thereof comprises the steps of: 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof.

[0042] [ka] This includes deprotection of the above.

[0043] In this method, compound (I) or a pharma- ceutically acceptable salt thereof is isolated in high yield and purity.

[0044] The method may include deprotecting 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A).

[0045] Generally, the positional isomers 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (11) are When a mixture of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is used in the process, the regioisomer 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) predominates.

[0046] The positional isomers 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (11) When one of the dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-ones (10A) is used in the process, the regioisomer 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) is generally selected.

[0047] Alternatively, the method may comprise deprotecting a salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or a salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A).

[0048] Generally, salts of the positional isomers 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (11) are used. When a mixture of salts of 3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is used in the process, the salt of the regioisomer 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) predominates.

[0049] A salt of the positional isomer 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) or a salt of the positional isomer 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3 When one of the salts of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is used in the process, the salt of the regioisomer 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) is generally selected.

[0050] Preferably, the salts of the two positional isomers (10) and (10A) are the same salt.

[0051] When the method includes deprotecting the salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or the salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), each of the salts of (10) and (10A) may be a hydrochloride salt, such as a dihydrochloride salt (bishydrochloride). It is understood that the salts of the two positional isomers (10) and (10A) are the same hydrochloride salt, and may, for example, both be dihydrochlorides. Thus, the method may comprise deprotecting the hydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or the hydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A).

[0052] Generally, the hydrochloride salts of the positional isomers 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3 When a mixture of hydrochlorides of the regioisomers 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is used in the process, the hydrochloride salt of the regioisomer 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) predominates.

[0053] The hydrochloride salt of the positional isomer 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) or the hydrochloride salt of the positional isomer 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (11) When one of the hydrochlorides of dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is used in the process, the hydrochloride of the regioisomer 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) is generally selected.

[0054] Preferably, when the method comprises deprotection of the salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or the salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), the deprotection is carried out by deprotection of the salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A). Dihydrochloride (bishydrochloride) of amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) and / or dihydrochloride (bishydrochloride) of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D).

[0055] [ka] The deprotection of

[0056] Generally, the dihydrochloride (bishydrochloride) salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) and the dihydrochloride (bishydrochloride) salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D) are When a mixture of the dihydrochloride salts (bishydrochloride) of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D) is used in the process, the dihydrochloride salt (bishydrochloride) of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) predominates. 2-Amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one dihydrochloride (bishydrochloride) (10C) or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo When one of the dihydrochloride salts (bishydrochloride) of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D) is used in the method, the dihydrochloride salt (bishydrochloride) of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) is generally selected.

[0057] The method preferably comprises deprotection of the dihydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) and / or the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D).

[0058] Deprotection of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one dihydrochloride (10C) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one dihydrochloride (10D) readily affords compound (I) or a pharma- ceutically acceptable salt thereof in high yield.

[0059] The deprotection can be base or acid catalyzed, preferably base catalyzed.

[0060] Suitable deprotection reagents include, but are not limited to, NH2OH.HCl (hydroxylamine hydrochloride) and NH2NH2 (hydrazine) or its hydrate. Preferably, the deprotection reagent is NH2OH.HCl (hydroxylamine hydrochloride). Surprisingly and advantageously, it has been found that the use of NH2OH.HCl (hydroxylamine hydrochloride) for deprotection advantageously improves the yield of compound (I) or its pharma- ceutically acceptable salt.

[0061] Preferably, the deprotection is carried out by removing a salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or a salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)propan-1-one (11). 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably the hydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10), e.g. dihydrochloride of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D), In the case of deprotection of hydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), for example, dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D), the deprotection reagent may be accompanied by a base. Suitable bases include 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), piperidine, morpholine, pyrrolidine, and triethylamine (TEA). Preferably, the base is selected from 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA) and triethylamine (TEA). More preferably, the base is selected to be triethylamine (TEA).

[0062] The solvent for deprotection can be selected from any suitable solvent or combination thereof, such as isopropyl alcohol (IPA), ethanol (EtOH), dichloromethane (DCM), methanol (MeOH), toluene, tetrahydrofuran (THF), methyl tert-butyl ether (TBME), and acetonitrile (CH3CN). Preferably, the solvent is selected from methanol, dichloromethane, and isopropyl alcohol (IPA). More preferably, the solvent is selected to be isopropyl alcohol (IPA).

[0063] Preferably, the deprotection is carried out by removing 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro -4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably the hydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10), e.g. 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10). dihydrochloride of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan In the case of deprotection of a hydrochloride salt of 1-propan-1-one (10A), for example, the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D), the deprotection can be carried out at a temperature of 30 to 80°C, for example, 40 to 70°C, preferably 40 to 60°C.

[0064] Preferably, when the deprotection is of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), the deprotection reagent is selected to be NH2OH.HCl (hydroxylamine hydrochloride) and the solvent is selected to be isopropyl alcohol (IPA).

[0065] Preferably, the deprotection is carried out by the addition of a salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or a salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[ 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably the hydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10), e.g. dihydrochloride of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or hydrochloride of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), e.g. In the case of deprotection of the dihydrochloride salt of 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D), the deprotection reagent is selected to be NHOH.HCl (hydroxylamine hydrochloride) in isopropyl alcohol (IPA) as solvent and using triethylamine (TEA) as base.

[0066] Preferably, the deprotection is of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), and when NH2OH.HCl (hydroxylamine hydrochloride) is utilized, the deprotection may provide the hydrochloride salt of compound (I). Compound (I), or a pharma- ceutically acceptable salt thereof, may be obtained from the hydrochloride salt by a suitable extraction method known to the skilled artisan. Compound (I) or a pharma- ceutically acceptable salt thereof can be prepared by treating the hydrochloride of compound (I) under basic conditions. Such treatment can include the use of a base, for example, sodium bicarbonate. Compound (I) or a pharma- ceutically acceptable salt thereof can be obtained using 10% methanol / DCM.

[0067] Preferably, the deprotection is carried out by removing 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H- Salts of benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably the hydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10), e.g., 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10). dihydrochloride of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or a salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A). and deprotection of a hydrochloride salt, e.g., the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D), where NH2OH.HCl (hydroxylamine hydrochloride) is utilized, the deprotection may provide a hydrochloride salt, e.g., the dihydrochloride salt, of compound (I). Compound (I) or a pharma- ceutically acceptable salt thereof may be prepared by treating the hydrochloride salt of compound (I) under basic conditions.Compound (I) or a pharma- ceutically acceptable salt thereof can be prepared by treating the hydrochloride of compound (I) with an ion exchange resin, such as Amberlite IRN78 and MP-carbonate; adding a base such as potassium carbonate or sodium bicarbonate; adding ammonia in a solvent such as methanol or isopropyl alcohol (IPA); or adding ammonium hydroxide (NH4OH). Preferably, compound (I) or a pharma- ceutically acceptable salt thereof is produced by treating the dihydrochloride of compound (I) with ammonium hydroxide (NH4OH). Optionally, the dihydrochloride of compound (I) may be neutralized in water before adding ammonium hydroxide. Optionally, dichloromethane may be introduced to aid in the formation of compound (I). Such treatment of the dihydrochloride of compound (I) facilitates the provision of compound (I) or a pharma- ceutically acceptable salt thereof in high yield and purity.

[0068] The process for the preparation of compound (I) or a pharma- ceutically acceptable salt thereof may further comprise a preceding step to facilitate the formation of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof.

[0069] Thus, a method for preparing compound (I) or a pharma- ceutically acceptable salt thereof comprises the steps of: 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A)

[0070] [ka] to form 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof.

[0071] Generally, when a mixture of the positional isomers 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) is used in the process, the positional isomer 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) predominates.

[0072] When the positional isomers 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) are used in the method, the positional isomer 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) is generally selected.

[0073] The salts of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) are as described above, and the salts of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) are as described above, It may be the dihydrochloride (bishydrochloride) salt of (6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) and / or the dihydrochloride (bishydrochloride) salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D).

[0074] 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) are reacted with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor to give 2-amino-2-methyl-1- (6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof, can be formed.

[0075] Preferably, in the amino acid coupling step, a salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (11) is used. 2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10). Acid salts, such as the dihydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D). 3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), for example the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D).

[0076] Preferably, 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) are reacted with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor to give 2-amino-2-methyl- Salts of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or salts of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably 2-amino-2-methyl -hydrochlorides of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10), for example the dihydrochloride of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or 2-amino -2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) hydrochloride, for example, 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one dihydrochloride (10D).

[0077] Preferably, when formation of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is desired, suitable coupling agents or coupling agent precursors include, but are not limited to, thionyl chloride, (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-(3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr)4 and B(OCH2CF3)3. Preferably, the coupling agent or coupling agent precursor is thionyl chloride (SOCl2). Suitable solvents for this amino acid coupling reaction include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or combinations thereof. The solvent can be selected from N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA). Preferably, the solvent is selected from acetonitrile, N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA), or combinations thereof. More preferably, the solvent is selected from acetonitrile and hexamethylphosphoramide (HMPA), or combinations thereof.

[0078] If formation of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is desired, N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) can be used in combination with thionyl chloride.

[0079] Preferably, when formation of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) is desired, thionyl chloride (SOCl2) is utilized as a coupling agent or coupling agent precursor in either DMPU and acetonitrile (CH3CN), or HMPU and acetonitrile.

[0080] Preferably, the salts of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) ), preferably the hydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10), for example 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or the hydrochloride salts of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), e.g. 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) When formation of the dihydrochloride salt of propan-1-one (10D) is desired, suitable coupling agents or coupling agent precursors include, but are not limited to, thionyl chloride (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-(3'-dimethylaminopropyl)carbodiimide.These include HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), hydroxybenzotriazole, fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr) and B(OCHCF). Preferably, the coupling agent or coupling agent precursor is selected from hydroxybenzotriazole, 1-ethyl-2-)3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), propanephosphonic anhydride (T3P), and thionyl chloride (SOCl2). More preferably, the coupling agent or coupling agent precursor is thionyl chloride. Suitable solvents for this amino acid coupling reaction include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA), acetonitrile (ACN), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), gamma-valerolactone (GVL), N-methylmorpholine (NMM), sulfolane, dichloromethane (DCM), or combinations thereof. Preferably, the solvent is selected from N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), gamma-valerolactone (GVL), N-methylmorpholine (NMM), sulfolane, dichloromethane (DCM) and acetonitrile, or combinations thereof. More preferably, the solvent is selected from acetonitrile or sulfolane, most preferably acetonitrile. Preferably, the amino acid coupling reaction is carried out in the presence of a base such as pyridine or other tertiary amines, preferably pyridine.

[0081] Preferably, the salts of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b] [1,4]oxazin-4-yl)propan-1-one (10A), preferably the hydrochloride salt of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10), e.g., 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2 dihydrochloride of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C), and / or hydrochloride of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), e.g. When formation of the dihydrochloride salt of -2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D) is desired, the coupling agent or coupling agent precursor is thionyl chloride, the solvent is acetonitrile or sulfolane, preferably acetonitrile, and the reaction is carried out in pyridine.

[0082] The method may further comprise an additional preceding step to produce 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A).

[0083] This additional step is consistent with the subsequent reaction step used to form compound (I), i.e., reacting 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) with 2-amino-2-methyl-1-(6-(3-( 3-Methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof, whether or not formed, can be utilized.

[0084] Thus, the method includes the step of preparing 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (8) The process may include an additional preliminary step of deacylation of -one (7A) to form 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A).

[0085] Typically, a mixture of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is used in the process.

[0086] Generally, when a mixture of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is used in the process, the positional isomer 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) predominates.

[0087] When one of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is used in the method, the positional isomer 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) is generally selected.

[0088] The deacylation can be acid or base catalyzed, preferably base catalyzed. Suitable acid catalysts for deacylation include, but are not limited to, HCl, e.g., 6.0N HCl, while suitable base catalysts include, but are not limited to, NaOH. NaOH can be used in either organic or aqueous form, such as 2.0M NaOH or 30% NaOH solution. Preferably, the deacylation is base catalyzed using NaOH, more preferably 30% NaOH solution. Deacylation using a base catalyst, particularly NaOH, e.g., 30% NaOH solution, advantageously allows for easier isolation of the desired 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) products.

[0089] Preferably, the deacylation is carried out in a solvent such as methanol.

[0090] Preferably, the deacylation is carried out using a base catalyst, preferably NaOH in methanol, more preferably 30% NaOH in water.

[0091] Preferably, the deacylation is carried out at a temperature of 50 to 80° C., for example 60 to 80° C., or 60 to 75° C. The deacylation is preferably carried out for 4 to 8 hours, for example 5 to 6 hours.

[0092] In the context of the process according to the first aspect, 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), preferably 1-(6-(3 -(3-Methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (a mixture of regioisomers (7) and (7A)) can be produced by any suitable synthetic route. 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be prepared according to the coupling reaction defined in the second aspect of the invention. 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be produced according to steps 1 to 4 of method 1, 2, 4 or 5, or steps 1 to 3 of method 3 or 6, or a combination thereof, preferably steps 1 to 3 of method 3 or 6.

[0093] According to a second aspect of the present invention, compound (I)

[0094] [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: coupling 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) with 4-bromo-3-methylpyridine (6) or a salt thereof in the presence of a metal catalyst to form 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A);

[0095] [ka] Preferably, herein provided is a method comprising the step of subjecting 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to a metal capture treatment, the metal capture treatment comprising treatment with a metal capture agent.

[0096] In the process according to the second aspect of the invention, 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can then be used in a deacylation and subsequent reaction step to achieve the formation of compound (I) or a pharma- ceutically acceptable salt thereof, as described above in relation to the first aspect of the invention, or in a deprotection and subsequent reaction step to achieve the formation of compound (I) or a pharma- ceutically acceptable salt thereof, as described below in relation to the fourth aspect of the invention.

[0097] It will be appreciated that the coupling steps outlined in the method of the second aspect of the invention may be utilized in the method according to the first or fourth aspects of the invention, as detailed therein, to form 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A). Thus, the coupling steps defined in the second aspect of the invention may be combined with the steps described for the preparation of compound (I) or a pharma-ceutically acceptable salt thereof according to the first or fourth aspects of the invention to achieve compound (I) or a pharma-ceutically acceptable salt thereof.

[0098] Thus, all features of the second aspect of the invention described herein, whether preferred or optional, are applicable to the first or fourth aspects of the invention, and vice versa.

[0099] Generally, a mixture of the regioisomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is formed.

[0100] Generally, when a mixture of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is used in the process, the positional isomer 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) predominates.

[0101] When one of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is used in the method, the positional isomer 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) is generally selected.

[0102] Surprisingly and advantageously, it has been found that the method of the second aspect of the present invention facilitates the formation of the favored regioisomer of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) over 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) by 98% versus 2%, respectively.

[0103] In the coupling reaction, 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) can be reacted with 4-bromo-3-methylpyridine (6) or a salt thereof, such as 4-bromo-3-methylpyridine hydrochloride (6A). Preferably, 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) is reacted with a salt of 4-bromo-3-methylpyridine (6). Preferably, 4-bromo-3-methylpyridine hydrochloride (6A) is utilized. Preferably, 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) is reacted with 4-bromo-3-methylpyridine hydrochloride (6A).

[0104] [ka] and react with.

[0105] Suitable metal catalysts for the coupling reaction include, but are not limited to, transition metal catalysts, such as platinum, palladium, and iridium catalysts. Typically, the transition metal catalysts are used in combination with a base. Suitable bases include, but are not limited to, potassium salts, such as potassium acetate or potassium carbonate, or cesium salts, such as cesium carbonate. Preferably, the metal catalyst is a palladium catalyst, more preferably palladium(II) acetate. Palladium is particularly effective as a catalyst in this coupling reaction. Preferably, the metal catalyst is a palladium catalyst used in combination with a base, more preferably a palladium catalyst used in combination with potassium carbonate, more preferably palladium(II) acetate used in combination with potassium carbonate.

[0106] The coupling reaction was carried out using pivalic acid and tricyclohexylphosphine tetrafluoroborate ((CH 11 The reaction may be carried out in the presence of a homogeneous catalytic system comprising 3P.HBF4) (ligand).

[0107] Suitable solvents for the coupling reaction include dimethylacetamide (DMA), sulfolane, N,N-dimethylformamide (DMF), dimethyl carbonate, gamma-valerolactone, and acetonitrile (ACN). Preferably, the solvent is selected from sulfolane and N-N-dimethylformamide (DMF). More preferably, the solvent is selected to be dimethylformamide (DMF).

[0108] Such coupling reactions may require control of residual metal from the metal catalyst in the products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A). This level of residual metals in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is preferably reduced as far as possible, preferably to less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. Thus, when formed from 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), there may be only trace levels of residual metals in compound (I) or a pharma- ceutically acceptable salt thereof.

[0109] After using metal catalysts, the residual level of metal present in the coupling reaction products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is controlled. To achieve this, a metal scavenging treatment can be utilized following production of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to reduce the metal content. Suitable metal scavenging treatments include, but are not limited to, charcoal absorption; absorption on various grades of silica columns or silica plug filtration; acid treatment; and treatment with a metal scavenger such as trithiocyanuric acid, silamate thiol resin, neutral alumina, florocil, quadrasil, and 10% cysteine ​​in water, or a combination thereof; and combinations thereof.Preferably, the metal scavenging treatment includes treatment with a metal scavenger.Preferably, the metal scavenger is trithiocyanuric acid.

[0110] Trithiocyanuric acid has the CAS number 638-16-4 and is also known in the art as trimercaptotriazine (TMT) or 1,3,5-triazine-2,4,6-trithiol.

[0111] It will be appreciated that when a metal scavenger is utilized, the metal scavenger may be used in excess relative to the amount of metal in the metal catalyst used in the process, and therefore, it is preferred that the level of residual metal be reduced as much as possible, as discussed above.

[0112] Preferably, the metal catalyst is a palladium-based catalyst, more preferably palladium(II) acetate. Thus, the metal capture treatment is preferably capable of capturing palladium. Preferably, the metal capture treatment includes treatment with a palladium capture agent. Preferably, the palladium capture agent is trithiocyanuric acid.

[0113] The treatment with trithiocyanuric acid as a metal capture agent can be carried out once or multiple times, preferably twice. Preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to absorption on a silica column or silica plug filtration and charcoal absorption. More preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to silica plug filtration and charcoal absorption. Typically, silica plug filtration is carried out first, and 10% MeOH / DCM may be used. Typically, the treatment with trithiocyanuric acid is carried out simultaneously with charcoal absorption. The treatment with trithiocyanuric acid can be carried out in a solvent selected from dichloromethane, methanol, ethanol, IPA and water, or a combination thereof. In this method, a palladium catalyst is preferably utilized, so the metal to be captured is preferably palladium.

[0114] Solvents such as dichloromethane, methanol, ethanol, IPA, and water, or combinations thereof, may be used during the metal capture process.

[0115] After metal scavenging, the level of metal, preferably palladium, in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. When the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is subsequently utilized in further reactions, such as those described in connection with the first or fourth aspects of the present invention, to produce compound (I) or a pharma- ceutically acceptable salt thereof, the level of metal, preferably palladium, in compound (I) or a pharma- ceutically acceptable salt thereof may be less than 10 ppm, for example less than 5 ppm. Such an amount is considered to be an acceptable trace amount.

[0116] The level of residual metals in compound (I) or other intermediates in the preparation process, such as 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be measured by inductively coupled plasma mass spectrometry (ICP-MS).

[0117] Preferably, the coupling reaction is carried out under an argon atmosphere.

[0118] Preferably, the reagents used in the coupling reaction are pivalic acid, tricyclohexylphosphine tetrafluoroborate ((CH 11 )3P.HBF4), and N,N-dimethylformamide (DMF). Preferably, the metal scavenger is trithiocyanuric acid.

[0119] In the context of the process according to the second aspect, 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) (starting point of the coupling reaction) can be produced by any suitable synthetic route. Preferably, 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) is produced according to steps 1 to 3 of process 1, 2, 4 or 5, or steps 1 to 2 of process 3 or 6, or a combination thereof, preferably steps 1 and 2 of process 3 or 6.

[0120] Step 4 of Methods 1, 2, 4 and 5, and step 3 of Methods 3 and 6 detailed below disclose preferred reaction conditions for the coupling reactions detailed below in the method of the second aspect of the invention.

[0121] Therefore, compound (I)

[0122] [ka] or a pharma- ceutical acceptable salt thereof, the method comprising coupling 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) with 4-bromo-3-methylpyridine (6) or a salt thereof in the presence of a metal catalyst to produce 1-(6-(3-(3-methylpyridine-4 forming 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A),

[0123] [ka] Here, a use is provided which comprises treating 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) with a metal scavenger.

[0124] All features of the second aspect of the invention described herein, whether preferred or optional, are applicable to use in the third aspect of the invention, and vice versa.

[0125] According to a fourth aspect of the present invention, compound (I)

[0126] [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: amino acid coupling of 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor;

[0127] [ka] The present invention provides a method comprising:

[0128] The coupling agent or coupling agent precursor may be selected from thionyl chloride (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-)3'-dimethylaminopropyl) carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr)4 and B(OCH2CF3)3. Preferably, the coupling agent or coupling agent precursor is thionyl chloride (SOCl2). Suitable solvents for the amino acid coupling reaction include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or combinations thereof. The solvent can be selected from N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA). Preferably, the solvent is selected from acetonitrile, N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA), or combinations thereof. More preferably, the solvent is selected from acetonitrile and hexamethylphosphoramide (HMPA), or combinations thereof.

[0129] For amino acid coupling, N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) can be used in combination with thionyl chloride.

[0130] Preferably, thionyl chloride (SOCl2) is utilized as a coupling agent or coupling agent precursor in either DMPU and acetonitrile (CH3CN) or HMPU and acetonitrile (CH3CN).

[0131] The process according to the fourth aspect of the invention may further comprise a preliminary step to form compound (12).

[0132] The method comprises deacylating 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) to form 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12).

[0133] [ka] It may further include.

[0134] The deacylation can be base-catalyzed or acid-catalyzed, preferably acid-catalyzed. Suitable acid catalysts for deacylation include, but are not limited to, HCl, e.g., 6.0N HCl, while suitable base catalysts include, but are not limited to, NaOH, e.g., 2.0M NaOH. Preferably, the deacylation is acid-catalyzed using HCl, preferably 6.0N HCl, preferably in the presence of methanol (MeOH).

[0135] The process according to the fourth aspect of the invention may further comprise an additional preliminary step to form 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11).

[0136] The method may further comprise deprotecting 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to form 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11).

[0137] Typically, a mixture of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (a mixture of positional isomers 7 and 7A) is used.

[0138] Generally, when a mixture of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is used in the process, the positional isomer 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) predominates.

[0139] When one of the positional isomers 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is used in the method, the positional isomer 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) is generally selected.

[0140] The deprotection can be base or acid catalyzed, preferably base catalyzed.

[0141] Suitable deprotection reagents include, but are not limited to, NH2OH.HCl (hydroxylamine hydrochloride), and NH2NH2 (hydrazine) or its hydrate. Preferably, the deprotection reagent is NH2OH.HCl (hydroxylamine hydrochloride).

[0142] The solvent for deprotection can be selected from any suitable solvent or combination thereof, such as isopropyl alcohol (IPA), ethanol (EtOH), dichloromethane (DCM), methanol (MeOH), and acetonitrile (CH3CN). Preferably, the solvent is selected from methanol, dichloromethane, and isopropyl alcohol (IPA). More preferably, the solvent is selected to be isopropyl alcohol (IPA).

[0143] Preferably, the deprotection reagent is NH2OH.HCl (hydroxylamine hydrochloride) in isopropyl alcohol (IPA) as the solvent.

[0144] In the context of the process according to the fourth aspect, 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be produced by any suitable synthetic route. 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be prepared according to the coupling reaction defined in the second aspect of the invention. 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be produced according to steps 1 to 4 of method 1, 2, 4 or 5, or steps 1 to 3 of method 3 or 6, or a combination thereof, preferably steps 1 to 3 of method 3 or 6.

[0145] It will therefore be appreciated that the fourth aspect presents an alternative route of formation from 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to produce compound (I) or a pharma- ceutically acceptable salt thereof, relative to that provided in the first aspect of the invention. As described above, the preparation of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be achieved by an alternative synthesis which results in the formation of compound (I) or a pharma- ceutically acceptable salt thereof. Both the first and fourth embodiments can be prepared in the same manner, with only the steps following the preparation of (6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) differing.

[0146] According to a further aspect of the present invention, compound (I)

[0147] [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of deacylating 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) to form 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12).

[0148] [ka] The present invention provides a method comprising:

[0149] The deacylation can be base-catalyzed or acid-catalyzed, preferably acid-catalyzed. Suitable acid catalysts for deacylation include, but are not limited to, HCl, e.g., 6.0N HCl, while suitable base catalysts include, but are not limited to, NaOH, e.g., 2.0M NaOH. Preferably, the deacylation is acid-catalyzed using HCl, preferably 6.0N HCl, preferably in the presence of methanol (MeOH).

[0150] Suitable methods for synthesizing compound (I) include, but are not limited to, the following methods 1, 2 and 3. Methods 1, 2 and 3 represent preferred methods for synthesizing compound (I), and the methods include the preferred linking step detailed below. However, in the context of the present invention, it will be understood that these preferred steps are separable, and one or more of the steps can be replaced with any other suitable step identified by a person skilled in the art. Among methods 1, 2 and 3, compound (I) is preferably formed by method 3.

[0151] Method 1 Compound (I) can be synthesized according to the following method:

[0152] Step 1

[0153] [ka] Bromination of 1-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethan-1-one (1) to form 2-bromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-one hydrobromide (2) and 2,2-dibromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin)-6-yl)ethan-1-one (2A) (by-product).

[0154] Preferably, the reagents used for the bromination in step 1 are selected to be hydrogen bromide (HBr) in acetic acid (AcOH), preferably a 33% solution, and Br2 in glacial acetic acid.

[0155] Step 2

[0156] [ka] Acylation of 2-bromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-one hydrobromide (2) and 2,2-dibromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-one (2A) with an acylating agent to form 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-bromoethan-1-one (3) and 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A).

[0157] Suitable acylating agents for step 2 include, but are not limited to, acyl halides such as acetyl chloride; and anhydrides of carboxylic acids. Preferably, the acylating agent is acetyl chloride (CH3COCl).

[0158] Preferably, the reagent used for the acylation in step 2 is acetyl chloride (CH3COCl) as the acylating agent in THF (tetrahydrofuran).

[0159] Step 3

[0160] [ka] Cyclization of 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-bromoethan-1-one (3) and 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) with pyrimidin-2-amines (4) to form 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5).

[0161] Preferably, the solvent used in the cyclization in step 3 is ethanol (EtOH).

[0162] Preferably, the cyclization is carried out at a temperature of 60-85° C., for example 75-85° C., for a period of 12-36 hours, for example 18-30 hours.

[0163] Step 4

[0164] [ka] 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) and 4-bromo-3-methylpyridine (6) are coupled in the presence of a metal catalyst to give 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)- To form 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (a mixture of regioisomers 7 and 7A).

[0165] Suitable metal catalysts for step 4 include, but are not limited to, transition metal-based catalysts, such as platinum-based catalysts, palladium-based catalysts, and iridium-based catalysts. Typically, the transition metal-based catalysts are used in combination with a base. Suitable bases include, but are not limited to, potassium salts, such as potassium acetate or potassium carbonate, or cesium salts, such as cesium carbonate. Preferably, the metal catalyst is a palladium-based catalyst, more preferably palladium(II) acetate. Preferably, the metal catalyst is a palladium-based catalyst used in combination with a base, more preferably a palladium-based catalyst used in combination with potassium carbonate, more preferably palladium(II) acetate used in combination with potassium carbonate.

[0166] The coupling reaction in step 4 is carried out using pivalic acid and tricyclohexylphosphine tetrafluoroborate ((CH 11 The reaction may be carried out in the presence of a homogeneous catalytic system comprising 3P.HBF4) (ligand).

[0167] Suitable solvents for the coupling reaction include dimethylacetamide (DMA), sulfolane, N,N-dimethylformamide (DMF), dimethyl carbonate, gamma-valerolactone, and acetonitrile (ACN). Preferably, the solvent is selected to be dimethylacetamide (DMA).

[0168] Preferably, the reagents used in the coupling reaction in step 4 are pivalic acid, tricyclohexylphosphine tetrafluoroborate ((CH 11 ) 3P.HBF4), and palladium(II) acetate (Pd(OAc)2) and potassium carbonate (K2CO3) in the presence of dimethylacetamide (DMA).

[0169] In such coupling reactions, control of residual metal from the metal catalyst in the products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one) (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be required. This level of residual metals in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is preferably reduced as far as possible, preferably to less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. Thus, 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one When formed from 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one) (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), only trace levels of residual metals may be present in compound (I) or a pharma- ceutically acceptable salt thereof.

[0170] After using metal catalysts, the residual level of metal present in the coupling reaction products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is controlled. To achieve this, a metal scavenging treatment can be utilized following production of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to reduce the metal content. Suitable metal scavenging treatments include, but are not limited to, charcoal absorption; absorption on various grades of silica columns or silica plug filtration; acid treatment; and treatment with a metal scavenger such as trithiocyanuric acid, silamate thiol resin, neutral alumina, florisil, quadrasil, and 10% cysteine ​​aqueous solution, or combinations thereof; and combinations thereof.Preferably, the metal scavenging treatment includes treatment with a metal scavenger.Preferably, the metal scavenger is trithiocyanuric acid.

[0171] It will be understood that when a metal scavenger is utilized, the metal scavenger can be used in excess relative to the amount of metal in the metal catalyst used in the process. It is then preferred that the level of residual metal be reduced as much as possible as discussed above.

[0172] Preferably, the metal catalyst is a palladium-based catalyst, more preferably palladium(II) acetate. Thus, the metal capture treatment is preferably capable of capturing palladium. Preferably, the metal capture treatment includes treatment with a palladium capture agent. Preferably, the palladium capture agent is trithiocyanuric acid.

[0173] The treatment with trithiocyanuric acid as a metal capture agent can be carried out once or multiple times, preferably twice. Preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to absorption on a silica column or silica plug filtration and charcoal absorption. More preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to silica plug filtration and charcoal absorption. Typically, silica plug filtration is carried out first, and 10% MeOH / DCM may be used. Typically, the treatment with trithiocyanuric acid is carried out simultaneously with charcoal absorption. The treatment with trithiocyanuric acid can be carried out in a solvent selected from dichloromethane, methanol, ethanol, IPA and water, or a combination thereof. In this method, a palladium catalyst is preferably utilized, so the metal to be captured is preferably palladium.

[0174] Solvents such as dichloromethane, methanol, ethanol, IPA, and water, or combinations thereof, may be used during the metal capture process.

[0175] After metal scavenging, the level of metal, preferably palladium, in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. When the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is subsequently utilized in further reactions, such as those described in connection with the first or fourth aspects of the present invention, the level of metal, preferably palladium, in compound (I) or a pharma- ceutically acceptable salt thereof may be less than 10 ppm, for example less than 5 ppm. Such an amount is considered to be an acceptable trace amount.

[0176] The level of residual metals in compound (I) or other intermediates in the preparation process, such as 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be measured by inductively coupled plasma mass spectrometry (ICP-MS).

[0177] Preferably, the coupling reaction is carried out under an argon atmosphere.

[0178] Preferably, the reagents used in the coupling reaction in step 4 are pivalic acid, tricyclohexylphosphine tetrafluoroborate ((CH 11 )3P.HBF4), and N,N-dimethylformamide (DMF). Preferably, the metal scavenger is trithiocyanuric acid.

[0179] Step 5

[0180] [ka] 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (regioisotopic Deacylation of the regioisomers 7 and 7A to form 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) (a mixture of regioisomers 8 and 8A).

[0181] The deacylation in step 5 can be acid or base catalyzed, preferably base catalyzed. Suitable acid catalysts for the deacylation in step 5 include, but are not limited to, HCl, e.g., 6.0 N HCl, while suitable base catalysts include, but are not limited to, NaOH, e.g., 2.0 M NaOH. Preferably, the deacylation is base catalyzed using NaOH, more preferably 2.0 M NaOH.

[0182] Step 6

[0183] [ka] The amino acid coupling of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) (a mixture of regioisomers 8 and 8A) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor gave 2-amino-2-methylpropanoic acid (10). Formation of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) (mixture of regioisomers 10 and 10A).

[0184] Suitable coupling agents or coupling agent precursors for step 6 include, but are not limited to, thionyl chloride (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-)3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr)4, and B(OCH2CF3)3. Preferably, the coupling agent or coupling agent precursor is thionyl chloride (SOCl2).

[0185] Suitable solvents for step 6 include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or a combination thereof. The solvent can be selected from N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA). Preferably, the solvent is selected from acetonitrile, N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA), or a combination thereof. More preferably, the solvent is selected from acetonitrile and hexamethylphosphoramide (HMPA), or a combination thereof.

[0186] For the amino acid coupling in step 6, N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) can be used in combination with thionyl chloride.

[0187] Preferably, in step 6, thionyl chloride (SOCl2) is utilized as a coupling agent or coupling agent precursor in either DMPU and acetonitrile (CH3CN), or HMPU and acetonitrile.

[0188] Step 7

[0189] [ka] Deprotection of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) (mixture of regioisomers 10 and 10A) to form compound (I).

[0190] The deprotection in step 7 can be base or acid catalyzed, preferably base catalyzed.

[0191] Suitable deprotection reagents include, but are not limited to, NH2OH.HCl (hydroxylamine hydrochloride), and NH2NH2 (hydrazine) or its hydrate. Preferably, the deprotection reagent is NH2OH.HCl (hydroxylamine hydrochloride).

[0192] The solvent for the deprotection of step 7 can be selected from any suitable solvent, such as isopropyl alcohol (IPA), ethanol (EtOH), dichloromethane (DCM), methanol (MeOH), and acetonitrile (CH3CN). Preferably, the solvent is selected to be isopropyl alcohol (IPA).

[0193] Preferably, the deprotection reagent in step 7 is selected to be NH2OH.HCl (hydroxylamine hydrochloride) in isopropyl alcohol (IPA).

[0194] It will be appreciated that when NH2OH.HCl (hydroxylamine hydrochloride) is utilized, deprotection may provide the hydrochloride salt of compound (I). Compound (I) can be prepared by treating the hydrochloride salt of compound (I) under basic conditions. Such treatment may include the use of a base, for example, sodium bicarbonate. Compound (I) or a pharma- ceutically acceptable salt thereof can be obtained using 10% methanol / DCM.

[0195] Method 2 Compound (I) can be synthesized according to the following method:

[0196] Step 1

[0197] [ka] Bromination of 1-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethan-1-one (1) to form 2-bromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-one hydrobromide (2) and 2,2-dibromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin)-6-yl)ethan-1-one (2A) by-product.

[0198] Preferably, the reagents used for the bromination in step 1 are selected to be hydrogen bromide (HBr) in acetic acid (AcOH), preferably a 33% solution, and Br2 in glacial acetic acid.

[0199] Step 2

[0200] [ka] Acylation of 2-bromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-one hydrobromide (2) and 2,2-dibromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-one (2A) by-products with an acylating agent to form 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-bromoethan-1-one (3) and 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A).

[0201] Suitable acylating agents for step 2 include, but are not limited to, acyl halides such as acetyl chloride; and anhydrides of carboxylic acids. Preferably, the acylating agent is acetyl chloride (CH3COCl).

[0202] Preferably, the reagent used for the acylation in step 2 is acetyl chloride (CH3COCl) as the acylating agent in THF (tetrahydrofuran).

[0203] Step 3

[0204] [ka] Cyclization of 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-bromoethan-1-one (3) and 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) with pyrimidin-2-amines (4) to form 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5).

[0205] Preferably, the solvent used in the cyclization in step 3 is ethanol (EtOH).

[0206] Preferably, the cyclization is carried out at a temperature of 60-85° C., for example 75-85° C., for a period of 12-36 hours, for example 18-30 hours.

[0207] Step 4

[0208] [ka] Coupling of 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) with 4-bromo-3-methylpyridine (6) in the presence of a metal catalyst to give 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl) )-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (mixture of regioisomers 7 and 7A).

[0209] Suitable metal catalysts for step 4 include, but are not limited to, transition metal-based catalysts, such as platinum-based catalysts, palladium-based catalysts, and iridium-based catalysts. Typically, the transition metal-based catalysts are used in combination with a base. Suitable bases include, but are not limited to, potassium salts, such as potassium acetate or potassium carbonate, or cesium salts, such as cesium carbonate. Preferably, the metal catalyst is a palladium-based catalyst, more preferably palladium(II) acetate. Preferably, the metal catalyst is a palladium-based catalyst used in combination with a base, more preferably a palladium-based catalyst used in combination with potassium carbonate, more preferably palladium(II) acetate used in combination with potassium carbonate.

[0210] The coupling reaction in step 4 is carried out using pivalic acid and tricyclohexylphosphine tetrafluoroborate ((CH11 The reaction may be carried out in the presence of a homogeneous catalytic system comprising 3P.HBF4) (ligand).

[0211] Suitable solvents for the coupling reaction include dimethylacetamide (DMA), sulfolane, N,N-dimethylformamide (DMF), dimethyl carbonate, gamma-valerolactone, and acetonitrile (ACN). Preferably, the solvent is selected to be dimethylacetamide (DMA).

[0212] Preferably, the reagents used in the coupling reaction in step 4 are pivalic acid, tricyclohexylphosphine tetrafluoroborate ((CH 11 ) 3P.HBF4), and palladium(II) acetate (Pd(OAc)2) and potassium carbonate (K2CO3) in the presence of dimethylacetamide (DMA).

[0213] In such coupling reactions, control of residual metal from the metal catalyst in the products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one) (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be required. This level of residual metals in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is preferably reduced as far as possible, preferably to less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. Thus, 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one When formed from 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one) (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), only trace levels of residual metals may be present in compound (I) or a pharma- ceutically acceptable salt thereof.

[0214] After using metal catalysts, the residual level of metal present in the coupling reaction products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is controlled. To achieve this, a metal scavenging treatment can be utilized following production of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to reduce the metal content. Suitable metal scavenging treatments include, but are not limited to, charcoal absorption; absorption on various grades of silica columns or silica plug filtration; acid treatment; and treatment with a metal scavenger such as trithiocyanuric acid, silamate thiol resin, neutral alumina, florisil, quadrasil, and 10% cysteine ​​aqueous solution, or combinations thereof; and combinations thereof.Preferably, the metal scavenging treatment includes treatment with a metal scavenger.Preferably, the metal scavenger is trithiocyanuric acid.

[0215] It will be appreciated that when a metal scavenger is utilized, the metal scavenger may be used in excess relative to the amount of metal in the metal catalyst used in the process, and therefore, it is preferred that the level of residual metal be reduced as much as possible, as discussed above.

[0216] Preferably, the metal catalyst is a palladium-based catalyst, more preferably palladium(II) acetate. Thus, the metal capture treatment is preferably capable of capturing palladium. Preferably, the metal capture treatment includes treatment with a palladium capture agent. Preferably, the palladium capture agent is trithiocyanuric acid.

[0217] The treatment with trithiocyanuric acid as a metal capture agent can be carried out once or multiple times, preferably twice. Preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to absorption on a silica column or silica plug filtration and charcoal absorption. More preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to silica plug filtration and charcoal absorption. Typically, silica plug filtration is carried out first, and 10% MeOH / DCM may be used. Typically, the treatment with trithiocyanuric acid is carried out simultaneously with charcoal absorption. The treatment with trithiocyanuric acid can be carried out in a solvent selected from dichloromethane, methanol, ethanol, IPA and water, or a combination thereof. In this method, a palladium catalyst is preferably utilized, so the metal to be captured is preferably palladium.

[0218] Solvents such as dichloromethane, methanol, ethanol, IPA, and water, or combinations thereof, may be used during the metal capture process.

[0219] After metal scavenging, the level of metal, preferably palladium, in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. When the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is subsequently utilized in further reactions, such as those described in connection with the first or fourth aspects of the present invention, the level of metal, preferably palladium, in compound (I) or a pharma- ceutically acceptable salt thereof may be less than 10 ppm, for example less than 5 ppm. Such an amount is considered to be an acceptable trace amount.

[0220] The level of residual metals in compound (I) or other intermediates in the preparation process, such as 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be measured by inductively coupled plasma mass spectrometry (ICP-MS).

[0221] Preferably, the coupling reaction is carried out under an argon atmosphere.

[0222] Preferably, the reagents used in the coupling reaction in step 4 are pivalic acid, tricyclohexylphosphine tetrafluoroborate ((CH 11 )3P.HBF4), and N,N-dimethylformamide (DMF). Preferably, the metal scavenger is trithiocyanuric acid.

[0223] Step 5

[0224] [ka] Deprotection of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (mixture of regioisomers 7 and 7A) to form 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11).

[0225] The deprotection in step 5 can be base-catalyzed or acid-catalyzed, preferably base-catalyzed.

[0226] Suitable deprotection reagents include, but are not limited to, NH2OH.HCl (hydroxylamine hydrochloride), and NH2NH2 (hydrazine) or its hydrate. Preferably, the deprotection reagent is NH2OH.HCl (hydroxylamine hydrochloride).

[0227] The solvent for the deprotection in step 5 can be selected from any suitable solvent, such as isopropyl alcohol (IPA), ethanol (EtOH), dichloromethane (DCM), methanol (MeOH), and acetonitrile (CH3CN). Preferably, the solvent is isopropyl alcohol (IPA).

[0228] Preferably, the deprotection reagent for the deprotection in step 5 is selected to be NH2OH.HCl (hydroxylamine hydrochloride) in isopropyl alcohol (IPA).

[0229] Step 6

[0230] [ka] Deacylation of 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) to form 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12).

[0231] The deacylation in step 6 can be base-catalyzed or acid-catalyzed, preferably acid-catalyzed. Suitable acid catalysts for the deacylation in step 6 of method 2 include, but are not limited to, HCl, e.g., 6.0 N HCl, while suitable base catalysts include, but are not limited to, NaOH, e.g., 2.0 M NaOH. Preferably, the deacylation is acid-catalyzed using HCl, preferably 6.0 N HCl, preferably in the presence of methanol (MeOH).

[0232] Step 7

[0233] [ka] Amino acid coupling of 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor to form compound (1).

[0234] Suitable coupling agents or coupling agent precursors for step 7 include, but are not limited to, thionyl chloride (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-)3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr)4, and B(OCH2CF3)3. Preferably, the coupling agent or coupling agent precursor is thionyl chloride (SOCl2).

[0235] Suitable solvents for step 7 include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or combinations thereof. The solvent can be selected from N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA). Preferably, the solvent is selected from acetonitrile, N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA), or combinations thereof. More preferably, the solvent is selected from acetonitrile and hexamethylphosphoramide (HMPA), or combinations thereof.

[0236] For the amino acid coupling in step 7, N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) can be used in combination with thionyl chloride.

[0237] Preferably, the reagents for amino acid coupling in step 7 are selected to be thionyl chloride (SOCl2) as the coupling agent or coupling agent precursor in either DMPU and acetonitrile (CH3CN), or HMPU and acetonitrile.

[0238] For Methods 1 and 2, it has surprisingly and advantageously been found that step 4 facilitates the formation of the favored regioisomer of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) over 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) by 98% versus 2%, respectively.

[0239] Thus, a method for the synthesis of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (mixture of regioisomers 7 and 7A), i.e., step 4 of methods 1 and 2, comprising the steps of:

[0240] [ka] 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) and 4-bromo-3-methylpyridine (6) are coupled in the presence of a metal catalyst to give 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro Also encompassed by the present invention is a process for forming 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (a mixture of regioisomers 7 and 7A).

[0241] Preferably, the metal catalyst is a palladium-based catalyst. More preferably, the metal catalyst is utilized in combination with a base, said base being selected from potassium salts or cesium salts, preferably potassium salts. More preferably, the metal catalyst is a palladium-based catalyst and utilized in combination with potassium carbonate or potassium acetate. More preferably, the metal catalyst is a palladium-based catalyst and utilized in combination with potassium carbonate. More preferably, the metal catalyst is palladium (II) acetate and utilized in combination with potassium carbonate.

[0242] Preferably, the reagents used in the displacement in step 4 of methods 1 and 2 are pivalic acid, tricyclohexylphosphine tetrafluoroborate ((CH 11 ) 3P.HBF4), and palladium(II) acetate (Pd(OAc)2) and potassium carbonate (K2CO3) in the presence of dimethylacetamide (DMA).

[0243] In such coupling reactions, control of residual metal from the metal catalyst in the products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one) (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be required. This can be by the methods discussed above in step 4 of methods 1 and 2, such as using a metal scavenger such as trithiocyanuric acid.

[0244] In addition, for Methods 1 and 2, it has been surprisingly and advantageously discovered that the use of NHOH.HCl (hydroxylamine hydrochloride) for the deprotection in step 7 of Method 1 and step 5 of Method 2 advantageously improves yields.

[0245] Thus, a method for the synthesis of compound (I) from 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), i.e. step 7 of method 1, comprising:

[0246] [ka] Also encompassed by the present invention is a process comprising the step of deprotecting 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) (a mixture of regioisomers 10 and 10A) to form compound (1).

[0247] Preferably, the deprotecting reagent is NH2OH.HCl (hydroxylamine hydrochloride).

[0248] Any suitable solvent can be utilized in step 7 of method 1, for example, the solvent can be selected from isopropyl alcohol (IPA), ethanol (EtOH), methanol (MeOH), dichloromethane (DCM), and acetonitrile (CH3CN). Preferably, the solvent is isopropyl alcohol (IPA).

[0249] Preferably, the deprotection reagent for the deprotection in step 7 of method 1 is NH2OH.HCl (hydroxylamine hydrochloride) in isopropyl alcohol (IPA).

[0250] Thus, a method for the synthesis of 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) from 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), i.e., step 5 of method 2, comprising:

[0251] [ka] 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (8) Also encompassed by the present invention is a process comprising the step of deprotecting 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (a mixture of regioisomers 7 and 7A) to form 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11).

[0252] Preferably, the deprotecting reagent is NH2OH.HCl (hydroxylamine hydrochloride).

[0253] In step 5 of method 2, any suitable solvent can be utilized, for example, the solvent can be selected from isopropyl alcohol (IPA), ethanol (EtOH), methanol (MeOH), and acetonitrile (CH3CN). Preferably, the solvent is isopropyl alcohol (IPA).

[0254] Preferably, the deprotection reagent for the deprotection in step 5 of method 2 is NH2OH.HCl (hydroxylamine hydrochloride) in isopropyl alcohol (IPA).

[0255] A method for synthesizing compound (I) from 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12), i.e., step 7 of method 2, comprising:

[0256] [ka] Also encompassed by the present invention is a method comprising the step of amino acid coupling of 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor to form compound (1).

[0257] Suitable coupling agents or coupling agent precursors for step 7 of method 2 include, but are not limited to, thionyl chloride (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-)3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr)4, and B(OCH2CF3)3. Preferably, the coupling agent or coupling agent precursor is thionyl chloride (SOCl2).

[0258] Suitable solvents for step 7 of method 2 include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or combinations thereof. The solvent can be selected from N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA). Preferably, the solvent is selected from acetonitrile, N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA), or combinations thereof. More preferably, the solvent is selected from acetonitrile and hexamethylphosphoramide (HMPA), or combinations thereof.

[0259] For the amino acid coupling in step 7 of Method 2, N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) can be used in combination with thionyl chloride.

[0260] Preferably, the reagents for amino acid coupling in step 7 of method 2 are selected to be thionyl chloride (SOCl2) as the coupling agent or coupling agent precursor in either DMPU and acetonitrile (CH3CN), or HMPU and acetonitrile.

[0261] Thus, in a method for synthesizing compound (I) from 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11), step 6 of method 2 comprises:

[0262] [ka] Also encompassed by the present invention is a method comprising deacylation of 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) to form 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) and amino acid coupling of 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or coupling agent precursor to form compound (1).

[0263] The deacylation in step 6 of method 2 can be base-catalyzed or acid-catalyzed, preferably acid-catalyzed. Suitable acid catalysts for the deacylation in step 6 of method 2 include, but are not limited to, HCl, e.g., 6.0 N HCl, while suitable base catalysts include, but are not limited to, NaOH, e.g., 2.0 M NaOH. Preferably, the deacylation is acid-catalyzed using HCl, preferably 6.0 N HCl, preferably in the presence of methanol (MeOH).

[0264] Suitable coupling agents or coupling agent precursors for step 7 of method 2 include, but are not limited to, thionyl chloride (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-)3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr)4, and B(OCH2CF3)3. Preferably, the coupling agent or coupling agent precursor is thionyl chloride (SOCl2).

[0265] Suitable solvents for step 7 of method 2 include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or combinations thereof. The solvent can be selected from N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA). Preferably, the solvent is selected from acetonitrile, N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA), or combinations thereof. More preferably, the solvent is selected from acetonitrile and hexamethylphosphoramide (HMPA), or combinations thereof.

[0266] For the amino acid coupling in step 7 of Method 2, N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) can be used in combination with thionyl chloride.

[0267] Preferably, the reagents for amino acid coupling in step 7 of method 2 are selected to be thionyl chloride (SOCl2) as the coupling agent or coupling agent precursor in either DMPU and acetonitrile (CH3CN), or HMPU and acetonitrile.

[0268] Method 3 Compound (I) can be synthesized according to the following method:

[0269] Step 1

[0270] [ka] Acylation of 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (1A) to form 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A).

[0271] The acylation reaction of step 1 may be Friedel-Crafts acylation. Suitable acylating agents for step 1 include, but are not limited to, acyl halides, for example, acyl chlorides such as acetyl chloride, or chlorinated acyl chlorides such as chloroacetyl chloride; and anhydrides of carboxylic acids. Preferably, the acylation agent is an acyl halide, for example, acyl chloride, more preferably chloroacetyl chloride.

[0272] An additional reagent can be utilized for the acylation in step 1. The additional reagent can be selected from aluminum chloride, zinc chloride, boron trichloride, titanium chloride. Preferably, aluminum chloride is selected as the additional reagent.

[0273] The acylation in step 1 is carried out in a suitable solvent. The solvent for the acylation in step 1 can be dichloromethane (DCM).

[0274] Preferably, the reagent used for acylation in step 1 is chloroacetyl chloride as the acylation agent in dichloromethane (DCM) using aluminum chloride (AlCl3).

[0275] Step 2

[0276] [ka] Cyclization of 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) with pyrimidin-2-amine (4) to form 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5).

[0277] Suitable solvents for use in the cyclization of step 2 include ethanol, methanol, 2-isopropyl alcohol (IPA), acetone and dichloromethane. Preferably, the solvent is selected to be ethanol.

[0278] Step 3

[0279] [ka] Coupling of 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) with 4-bromo-3-methylpyridine HCl (6A) in the presence of a metal catalyst to form 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A).

[0280] Suitable metal catalysts for the coupling reaction of step 3 include, but are not limited to, transition metal-based catalysts, such as platinum-based catalysts, palladium-based catalysts, and iridium-based catalysts. Typically, the transition metal-based catalysts are utilized in combination with a base. Suitable bases include, but are not limited to, potassium salts, such as potassium acetate or potassium carbonate, or cesium salts, such as cesium carbonate. Preferably, the metal catalyst is a palladium-based catalyst, more preferably palladium(II) acetate. Palladium is particularly effective as a catalyst in this coupling reaction. Preferably, the metal catalyst is a palladium-based catalyst utilized in combination with a base, more preferably a palladium-based catalyst utilized in combination with potassium carbonate, more preferably palladium(II) acetate utilized in combination with potassium carbonate.

[0281] The coupling reaction in step 3 is carried out using pivalic acid and tricyclohexylphosphine tetrafluoroborate ((CH 11 The reaction may be carried out in the presence of a homogeneous catalytic system comprising 3P.HBF4) (ligand).

[0282] Suitable solvents for the coupling reaction of step 3 include dimethylacetamide (DMA), sulfolane, N,N-dimethylformamide (DMF), dimethyl carbonate, gamma-valerolactone, and acetonitrile (ACN). Preferably, the solvent is selected from sulfolane and N-N-dimethylformamide (DMF). More preferably, the solvent is dimethylformamide (DMF).

[0283] In such coupling reactions, control of residual metal from the metal catalyst in the products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one) (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be required. This level of residual metal in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is preferably reduced as far as possible, preferably to less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. Thus, 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one When formed from 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one) (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), only trace levels of residual metals may be present in compound (I) or a pharma- ceutically acceptable salt thereof.

[0284] After using metal catalysts, the residual level of metal present in the coupling reaction products 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is controlled. To achieve this, a metal scavenging treatment can be utilized following production of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) to reduce the metal content. Suitable metal scavenging treatments include, but are not limited to, charcoal absorption; absorption on various grades of silica columns or silica plug filtration; acid treatment; and treatment with a metal scavenger such as trithiocyanuric acid, silamate thiol resin, neutral alumina, florisil, quadrasil, and 10% cysteine ​​aqueous solution, or combinations thereof; and combinations thereof.Preferably, the metal scavenging treatment includes treatment with a metal scavenger.Preferably, the metal scavenger is trithiocyanuric acid.

[0285] It will be appreciated that when a metal scavenger is utilized, the metal scavenger may be used in excess relative to the amount of metal in the metal catalyst used in the process, and therefore, it is preferred that the level of residual metal be reduced as much as possible, as discussed above.

[0286] Preferably, the metal catalyst is a palladium-based catalyst, more preferably palladium(II) acetate. Thus, the metal capture treatment is preferably capable of capturing palladium. Preferably, the metal capture treatment includes treatment with a palladium capture agent. Preferably, the palladium capture agent is trithiocyanuric acid.

[0287] The treatment with trithiocyanuric acid as a metal capture agent can be carried out once or multiple times, preferably twice. Preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to absorption on a silica column or silica plug filtration and charcoal absorption. More preferably, the metal capture treatment includes treatment with trithiocyanuric acid in addition to silica plug filtration and charcoal absorption. Typically, silica plug filtration is carried out first, and 10% MeOH / DCM may be used. Typically, the treatment with trithiocyanuric acid is carried out simultaneously with charcoal absorption. The treatment with trithiocyanuric acid can be carried out in a solvent selected from dichloromethane, methanol, ethanol, IPA and water, or a combination thereof. In this method, a palladium catalyst is preferably utilized, so the metal to be captured is preferably palladium.

[0288] Solvents such as dichloromethane, methanol, ethanol, IPA, and water, or combinations thereof, may be used during the metal capture process.

[0289] After metal scavenging, the level of metal, preferably palladium, in the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) may be less than 150 ppm, or less than 120 ppm, for example less than 100 ppm, or less than 80 ppm, or less than 50 ppm. When the product 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is subsequently utilized in further reactions, such as those described in connection with the first or fourth aspects of the present invention, the level of metal, preferably palladium, in compound (I) or a pharma- ceutically acceptable salt thereof may be less than 10 ppm, for example less than 5 ppm. Such an amount is considered to be an acceptable trace amount.

[0290] The level of residual metals in compound (I) or other intermediates in the preparation process, such as 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) can be measured by inductively coupled plasma mass spectrometry (ICP-MS).

[0291] Preferably, the coupling reaction is carried out under an argon atmosphere.

[0292] Preferably, the reagents used in the coupling reaction in step 3 are pivalic acid, tricyclohexylphosphine tetrafluoroborate ((CH 11 )3P.HBF4), and N,N-dimethylformamide (DMF). Preferably, the metal scavenger is trithiocyanuric acid.

[0293] Step 4

[0294] [ka] 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (8) Deacylation of tan-1-one (7A) to form 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A).

[0295] The deacylation in step 4 can be acid or base catalyzed, preferably by base catalysis. Suitable acid catalysts for deacylation include, but are not limited to, HCl, e.g., 6.0 N HCl, while suitable base catalysts include, but are not limited to, NaOH. NaOH can be used in either organic or aqueous form, such as 2.0 M NaOH or 30% NaOH solution. Preferably, the deacylation is base catalyzed using NaOH, more preferably 30% NaOH solution.

[0296] Preferably, the deacylation in step 4 is carried out in a solvent such as methanol.

[0297] Preferably, the deacylation in step 4 is carried out using a base catalyst, preferably NaOH in methanol, more preferably 30% NaOH in water.

[0298] Preferably, the deacylation in step 4 is carried out at a temperature of 50 to 80° C., for example 60 to 80° C., or 60 to 75° C. The deacylation is preferably carried out for 4 to 8 hours, for example 5 to 6 hours.

[0299] Step 5

[0300] [ka] 2-amino-2-methylpropanoic acid (9) by amino acid coupling of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor. Formation of the dihydrochloride salt of 2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) and / or the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D).

[0301] Suitable coupling agents or coupling agent precursors for step 5 include thionyl chloride (SOCl2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-(3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazoline. Examples of suitable fluorocarbons include, but are not limited to, chloroform (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), hydroxybenzotriazole, fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr) and B(OCHCF). Preferably, the coupling agent or coupling agent precursor is selected from hydroxybenzotriazole, 1-ethyl-2-)3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), propanephosphonic anhydride (T3P), and thionyl chloride (SOCl2). More preferably, the coupling agent or coupling agent precursor is thionyl chloride.

[0302] Suitable solvents for step 5 include, but are not limited to, N,N' dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA), acetonitrile (ACN), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), gamma-valerolactone (GVL), N-methylmorpholine (NMM), sulfolane, dichloromethane (DCM), or combinations thereof. Preferably, the solvent is selected from N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), gamma-valerolactone (GVL), N-methylmorpholine (NMM), sulfolane, dichloromethane (DCM), and acetonitrile, or combinations thereof. More preferably, the solvent is selected from acetonitrile or sulfolane, most preferably acetonitrile.

[0303] Preferably, the reaction of step 5 is carried out in the presence of a base, such as pyridine or other tertiary amine, preferably pyridine.

[0304] Preferably, in step 5, the coupling agent or coupling agent precursor is thionyl chloride, the solvent is acetonitrile or sulfolane, preferably acetonitrile, and the reaction is carried out in pyridine.

[0305] Step 6

[0306] [ka] Deprotection of 1-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one dihydrochloride (10C) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one dihydrochloride (10D) to form compound (I).

[0307] The deprotection in step 6 can be base or acid catalyzed, preferably base catalyzed.

[0308] Suitable deprotection reagents for deprotection include, but are not limited to, NH2OH.HCl (hydroxylamine hydrochloride), and NH2NH2 (hydrazine) or its hydrate. Preferably, the deprotection reagent is NH2OH.HCl (hydroxylamine hydrochloride). The deprotection reagent may be accompanied by a base. Suitable bases include 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), piperidine, morpholine, pyrrolidine, and triethylamine (TEA). Preferably, the base is selected from 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA) and triethylamine (TEA). More preferably, the base is selected to be triethylamine (TEA).

[0309] The solvent for the deprotection in step 6 can be selected from any suitable solvent, such as isopropyl alcohol (IPA), ethanol (EtOH), dichloromethane (DCM), methanol (MeOH), and acetonitrile (CH3CN). Preferably, the solvent is selected from methanol, dichloromethane, and isopropyl alcohol (IPA). More preferably, the solvent is isopropyl alcohol (IPA).

[0310] The deprotection in step 6 can be carried out at a temperature of 30 to 80°C, for example 40 to 70°C, preferably 40 to 60°C.

[0311] Preferably, the reagent for deprotection in step 6 is NH2OH.HCl (hydroxylamine hydrochloride) in isopropyl alcohol (IPA) with triethylamine (TEA) as the base.

[0312] It will be appreciated that when NH2OH.HCl (hydroxylamine hydrochloride) is utilized, deprotection may provide the dihydrochloride salt of compound (I). Compound (I) can be prepared by treating the dihydrochloride salt of compound (I) under basic conditions. Compound (I) can be prepared by treating the dihydrochloride salt of compound (I) with an ion exchange resin, such as Amberlite IRN78 and MP-carbonate; adding a base such as potassium carbonate; adding ammonia in a solvent such as methanol or isopropyl alcohol (IPA); or adding ammonium hydroxide (NH4OH). Preferably, compound (I) is formed and isolated by treating the dihydrochloride salt of compound (I) with ammonium hydroxide (NH4OH). Optionally, the dihydrochloride salt of compound (I) may be neutralized in water prior to adding ammonium hydroxide. Optionally, dichloromethane may be introduced to aid in the formation of compound (I).

[0313] Preferably, compound (I) of the present invention is synthesized according to one of the following methods 4, 5, and 6. As with methods 1, 2, and 3, methods 4, 5, and 6 represent preferred methods for synthesizing compound (I), which include the preferred linking step detailed below. Preferably, compound (I) is prepared according to method 6. Method 6 constitutes the best mode currently contemplated for practicing the present invention. However, in the context of the present invention, it will be understood that these preferred steps are separable and one or more of the steps can be replaced with any other suitable step identified by the skilled artisan. In the case of methods 4 and 5, where step X has A and B options, for example step 6A or step 6B, either step XA or XB can be utilized as step X, i.e., either step 6A or 6B can be utilized as step 6.

[0314] As shown in Method 3 above and Method 6 below, compound (I) or a pharma- ceutically acceptable salt thereof can be formed from 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (1A), a commercially available compound.

[0315] Thus, 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (1A)

[0316] [ka] Also incorporated herein is a process for the preparation of Compound (I) or a pharma- ceutically acceptable salt thereof, starting from:

[0317] Method 4 Compound (I) can be synthesized according to the following method:

[0318] Step 1

[0319]

change

[0320] Step 2

[0321]

Chem.

[0322] Step 3

[0323] [ka]

[0324] A 5.0 L 4-neck round bottom flask equipped with a mechanical stirrer was charged with a mixture of EtOH (2.0 L, 3V), 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-bromoethan-1-one (3) and 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) (685 g, 2.30 mol, 92% purity by LCMS), followed by pyrimidin-2-amine (4) (546 g, 5.74 mol) at 20° C. The reaction mixture was further stirred and refluxed for 3 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature (approximately 20° C.) and the resulting precipitated solid was filtered, washed with EtOH (2×250 mL) and dried under vacuum to give 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) as an off-white solid (418 g). MS (ESI+) m / z 295.06 [M+H] for CHNOS. + . 1H NMR (400 MHz, DMSO-d6 + d-TFA): δ 9.27 (d, J = 6.40 Hz, 1H), 8.97 -9.02 (m, 1H), 8.65 (s, 1H), 8.44 (bs, 1H), 7.63-7.69 (m, 2H), 7.10 (d, J = 8.40 Hz, 1H), 4.33-4.36 (m, 2H), 3.89-3.93 (m, 2H), 2.32 (s, 3H). The regioisomeric structures were confirmed by nOe.

[0325] Step 4

[0326] [ka] A 10 L 4-neck round bottom flask equipped with a mechanical stirrer was charged with N,N-dimethylacetamide (2.0 L), 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) (250 g, 849 mmol), 2,2-dimethylpropanoic acid (34.7 g, 340 mmol), potassium carbonate (587 g, 4.25 mol) and 4-bromo-3-methylpyridine (6) (264 g, 1.44 mol) at 20 °C under a N2 atmosphere. The resulting reaction mixture was purged with N2 (gas) for 30 min, followed by the addition of Pd(OAc)2 (19.1 g, 84.9 mmol) and PCy3·HBF4 (31.2 g, 84.9 mmol) under N2 atmosphere. The reaction mixture was again purged with N2 (gas) for another 15 min. The resulting reaction mixture was further stirred at 125 °C for 7 h. The reaction was monitored by LCMS. Crude LCMS confirmed the formation of a regioisomeric mixture of the desired product with a regioisomeric ratio of 98:2. The reaction mixture was filtered through a bed of Celite (height 1.3 cm, diameter 25 cm). The Celite bed was washed with 10% MeOH in DCM (15 L). The filtrate was evaporated under reduced pressure to give the crude residue as a brown liquid. The brown liquid was stirred in heptane (3 x 6.0 L) for 10 h to remove excess DMA. The heptane / DMA mixture was decanted (trace amounts of the desired product were observed in the decanted fractions) to give a waxy solid. The waxy solid was stirred in MTBE (3.0 L) for an additional 15 min. The resulting precipitate was filtered and washed with MTBE (2.0 L) to give the desired product as a brown solid. The brown solid was passed through a small silica plug and eluted with 10% MeOH in DCM (approximately 35 L). The resulting solvent fractions were concentrated to 1 / 10 of their original volume. The concentrated fractions were diluted with MTBE (200 mL) and stirred for 30 min.The resulting precipitate was filtered, washed with MTBE (1.0 L) and dried under vacuum to give a regioisomeric mixture of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) as a light brown solid. Yield: 66% (97% by LCMS, regioisomeric ratio 98:2). MS (ESI+) m / z 386.18 [M+1] for CHNOS. + .1H NMR (400 MHz, DMSO-d6 + d-TFA): δ 9.14 (s, 1H), 9.01-9.04 (m, 2H), 8.86 (d, J = 6.7 Hz, 1H), 8.23 ​​(d, J = 5.8 Hz, 1H), 8.01 (bs, 1H), 7.55-7.58 (m, 1H), 7.41(d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 4.09-4.33 (m, 2H), 3.71-3.92 (m, 2H), 2.17 (s, 3H), 2.11 (bs, 3H).

[0327] Step 5A

[0328] [ka] To a solution of the regioisomeric mixture (97:3) of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (24.0 g, 62.3 mmol) in methanol (150 mL) was added 6.0 N aqueous HCl (62 mL) at room temperature. The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated to ¼ of its original volume. The concentrated reaction mixture was basified to pH 8-9 with saturated aqueous NaHCO3 and extracted with 10% MeOH in DCM (3 x 250 mL). The organic layer was washed with brine (300 mL), dried over (Na2SO4), filtered and concentrated under reduced pressure to 1 / 10 of its original volume. The concentrated mixture was diluted with heptane (100 mL) and stirred for 30 min. The resulting precipitate was filtered, washed with heptane (100 mL) and dried under reduced pressure to give a mixture of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) (20.0 g) as a yellow solid. Yield: 71% (mixture of two regioisomers with a regioisomer ratio of 2:1, 89% by LCMS). LCMS showed two peaks with 56% and 33% of the desired mass, respectively. (ESI+) m / z 344.20 [M+H] for CHNOS + .

[0329] Or step 5B

[0330] [ka] A suspension of the regioisomeric mixture (98:2) of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (10.0 g, 25.9 mmol) in 2.0 M aqueous NaOH solution (52 mL, 104 mmol) was heated at 100° C. for 24 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with water (ca. 500 mL) and dried to give a mixture of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) as a light brown solid. Yield: 8.1 g, 90% (mixture of two regioisomers with a regioisomer ratio of 98:2, 98.7% by LCMS). MS (ESI+) m / z 344.20 [M+H] for CHNOS. + ; 1 H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.54-8.62 (m, 2H), 8.25 (d, J = 6.8 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 6.96-7.03 (m, 2H), 6.46-6.55 (m, 2H), 5.87 (s, 1H), 4.11 (t, J = 4.0 Hz, 2H), 3.25 (bs, 2H), 1.94 (s, 3H).

[0331] Step 6A (HMPA-Mediated Amino Acid Coupling)

[0332] [ka] To a suspension of 2-amino-2-methylpropanoic acid (9) (12 g, 116 mmol) in HMPA (84 mL, 7 V) was added slowly a solution of thionyl chloride (9.29 g, 128 mmol) in ACN (8.4 mL) at 3° C. (external temperature was 0° C.). 10 min after complete addition of the solution of thionyl chloride in ACN, the suspension becomes clear. The resulting reaction mixture was stirred at 0° C. for 20 min, followed by the addition of the regioisomeric mixture of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) (8 g, 23.3 mmol) in portions at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with EtOAc (300 mL). The resulting precipitate was filtered and washed with EtOAc (250 mL). The solid was dissolved in water (50 mL), neutralized to pH 8 with saturated sodium bicarbonate solution, extracted with 10% MeOH in DCM (4×100 mL), and concentrated under reduced pressure to 1 / 10 the original reaction mixture volume. The crude mixture was diluted with MTBE (50 mL) and stirred for 15 min. The resulting precipitate was filtered, washed with MTBE (25 mL) and dried under vacuum to give a regioisomeric mixture of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) as a brown solid. Yield: 66% (97% by LCMS, regioisomeric ratio 98:2). CHNOS MS (ESI+) m / z 429.16 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.54 - 8.62 (m, 2H), 8.29 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 6.98 - 7.05 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 4.45 - 4.67 (m, 2H), 4.30 (bs, 2H), 2.12 (bs, 2H), 1.97 (s, 3H), 1.34 (s, 6H).

[0333] Alternatively, Step 6B (DMPU-mediated amino acid coupling)

[0334]

Chem.

[0335] Step 7

[0336]

Chem.

[0337] In method 4, step 5B is preferably selected.

[0338] Method 5 Compound (I) can be synthesized according to the following method:

[0339] Step 1

[0340] [ka] A 20 L four-neck round bottom flask equipped with a mechanical stirrer was charged with 1-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethan-1-one (1) (300 g, 1.69 mol) at room temperature. A solution of HBr in glacial acetic acid (33% w / w, 2.10 L, 7 V) was added dropwise at 10° C., ideally maintaining the internal temperature below about 12° C. To the resulting reaction mixture was added a solution of bromine (86.7 mL, 1.69 mol) in glacial acetic acid (450 mL, 1.5 V relative to starting material) at 10° C. (internal temperature) slowly (over about 90 min) such that the internal temperature was maintained below 10° C. The reaction was monitored by LCMS. After complete addition of the solution of bromine in glacial acetic acid, crude LCMS confirmed approximately 10% unconsumed starting material (1-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethan-1-one (1)) and approximately 30% conversion to the desired monobrominated product (2) along with approximately 24% dibrominated by-product. The cooling bath was removed and the reaction mixture was gradually warmed to 25° C. (internal temperature) over approximately 1 h. The resulting reaction mixture was further stirred at 40° C. (internal temperature) for 1.5 h [visible precipitation was observed and crude LCMS confirmed unconsumed starting material (1) (approximately 4%) along with the desired monobrominated product (2) (55%) and dibrominated by-product (approximately 18%)]. The reaction mixture was cooled to 10° C., diluted with MTBE (4.9 L, 16 V) and stirred for 1 h. The resulting precipitate was filtered, washed with MTBE (600 mL) and dried under reduced pressure to give 340 g (mixture of mono- and di-brominated products) as an off-white solid. LCMS of the resulting solid confirmed a mixture of 2-bromo-1-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethan-1-one.HBr(2) (ca. 87%, mono-brominated), 2,2-dibromo-1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-one (ca. 5%, di-brominated by-product) and unconsumed 1-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethan-1-one (1) (ca. 1%). This mixture was used in the next step without further purification. The isolated yield, calculated based on the monobrominated product (2) observed by LCMS, was found to be 52%.MS (ESI+) m / z 255.96 [M+H] for CHNOS. + ; 1 1H NMR (400 MHz, DMSO-d6): δ 7.19 - 7.28 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 4.74 (s, 2H), 4.31 (t, J = 4.4 Hz, 2H), and 3.32 (t, J = 4.4 Hz, 2H).

[0341] Step 2

[0342]

Chem.

[0343] Step 3

[0344] [ka] A 5.0 L 4-neck round bottom flask equipped with a mechanical stirrer was charged with a mixture of EtOH (2.0 L, 3V), 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-bromoethan-1-one (3) and 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) (685 g, 2.30 mol, 92% purity by LCMS), followed by pyrimidin-2-amine (4) (546 g, 5.74 mol) at 20° C. The reaction mixture was further stirred and refluxed for 3 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature (approximately 20° C.) and the resulting precipitated solid was filtered, washed with EtOH (2×250 mL) and dried under vacuum to give 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) as an off-white solid (418 g). MS (ESI+) m / z 295.06 [M+H] for CHNOS. + . 1H NMR (400 MHz, DMSO-d6 + d-TFA): δ 9.27 (d, J = 6.40 Hz, 1H), 8.97 -9.02 (m, 1H), 8.65 (s, 1H), 8.44 (bs, 1H), 7.63-7.69 (m, 2H), 7.10 (d, J = 8.40 Hz, 1H), 4.33-4.36 (m, 2H), 3.89-3.93 (m, 2H), 2.32 (s, 3H). The regioisomeric structures were confirmed by nOe.

[0345] Step 4

[0346] [ka] A 10 L 4-neck round bottom flask equipped with a mechanical stirrer was charged with N,N-dimethylacetamide (2.0 L), 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) (250 g, 849 mmol), 2,2-dimethylpropanoic acid (34.7 g, 340 mmol), potassium carbonate (587 g, 4.25 mol) and 4-bromo-3-methylpyridine (6) (264 g, 1.44 mol) at 20 °C under a N atmosphere. The resulting reaction mixture was purged with N2 (gas) for 30 min, followed by the addition of Pd(OAc)2 (19.1 g, 84.9 mmol) and PCy3·HBF4 (31.2 g, 84.9 mmol) under N2 atmosphere. The reaction mixture was again purged with N2 (gas) for another 15 min. The resulting reaction mixture was further stirred at 125 °C for 7 h. The reaction was monitored by LCMS. Crude LCMS confirmed the formation of a regioisomeric mixture of the desired product with a regioisomeric ratio of 98:2. The reaction mixture was filtered through a bed of Celite (height 1.3 cm, diameter 25 cm). The Celite bed was washed with 10% MeOH in DCM (15 L). The filtrate was evaporated under reduced pressure to give the crude residue as a brown liquid. The brown liquid was stirred in heptane (3 x 6.0 L) for 10 h to remove excess DMA. The heptane / DMA mixture was decanted (trace amounts of the desired product were observed in the decanted fractions) to give a waxy solid. The waxy solid was stirred in MTBE (3.0 L) for an additional 15 min. The resulting precipitate was filtered and washed with MTBE (2.0 L) to give the desired product as a brown solid. The brown solid was passed through a small silica plug and eluted with 10% MeOH in DCM (approximately 35 L). The resulting solvent fractions were concentrated to 1 / 10 of their original volume. The concentrated fractions were diluted with MTBE (200 mL) and stirred for 30 min.The resulting precipitate was filtered, washed with MTBE (1.0 L) and dried under vacuum to give a regioisomeric mixture of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) as a light brown solid. Yield: 66% (97% by LCMS, regioisomeric ratio 98:2). MS (ESI+) m / z 386.18 [M+1] for CHNOS. + .1H NMR (400 MHz, DMSO-d6 + d-TFA): δ 9.14 (s, 1H), 9.01-9.04 (m, 2H), 8.86 (d, J = 6.7 Hz, 1H), 8.23 ​​(d, J = 5.8 Hz, 1H), 8.01 (bs, 1H), 7.55-7.58 (m, 1H), 7.41(d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 4.09-4.33 (m, 2H), 3.71-3.92 (m, 2H), 2.17 (s, 3H), 2.11 (bs, 3H).

[0347] Step 5

[0348] [ka] To a suspension of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (10 g, 98% by LCMS, 25.9 mmol) in isopropyl alcohol (70 mL) was added hydroxylamine hydrochloride (4.51 g, 64.9 mmol) at room temperature. The resulting suspension was stirred at 80 °C for 6 h. The suspension gradually solubilized at 80 °C for 2 h, and reprecipitation was observed at 2-3 h. The reaction was monitored by LCMS. The resulting suspension was cooled to room temperature, diluted with acetone (100 mL) and stirred for 1 h. The reaction mixture was concentrated to 20% of the original volume and the precipitate was filtered, washed with acetone (300 mL) and dried under vacuum to give the crude material as the HCl salt. The resulting solid was dissolved in water (10 mL) and basified to pH 8.0 with saturated aqueous NaHCO3 at 10° C. The resulting suspension was stirred at room temperature for 2 h. The resulting precipitate was filtered, washed with water (200 mL) and dried under vacuum to give the crude residue. The crude residue was further stirred in MTBE (100 mL), filtered and dried under vacuum to give 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) as a light brown solid. Yield: 7.5 g, 83% (93% by LCMS). CHNOS m / z 350.30 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.86 (bs, 1H), 8.39 (s, 1H), 8.31 (d, J = 4.8 Hz, 1 H), 7.16 (d, J = 4.8 Hz, 1 H), 6.71-7.09 (m, 2H), 5.37 (bs, 2H), 4.21(bs, 2H), 3.79 (bs, 2H), 1.99 (s, 3H), 1.75 (bs, 3H).

[0349] Step 6

[0350] [ka] To a solution of 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazo-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) (7 g, 20.9 mmol) in methanol (35 mL) was added 6.0 N HCl (28 mL) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to obtain the crude product. The crude product was dissolved in water (20 mL), basified to pH 8.0-9.0 with 6.0 M aqueous NaOH, and extracted with 10% MeOH in DCM (3 x 100 mL). The organic layer was washed with brine (200 mL), filtered, and concentrated under reduced pressure to 1 / 10 of the original reaction mixture volume. The concentrated mixture was diluted with heptane (100 mL) and stirred for 15 min. The resulting precipitate was filtered, washed with heptane (100 mL) and dried under reduced pressure to give 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) as a light brown solid. Yield: 5.1 g, 82% (98% by LCMS). MS (ESI+) m / z 308.14 [M+H] for CHNOS. + . 1 H NMR (400 MHz, DMSO-d6+ d-TFA ): δ 8.88 (s, 1H), 8.82 (d, J = 6.1 Hz, 1 H), 7.94 (d, J = 6.1 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H), 6.49 (d, J = 2.2 Hz, 1 H ), 6.42 (dd, J = 2.2, 8.2 Hz, 1 H), 4.14 (t, J = 4.2 Hz, 2 H), 3.27 (t, J = 4.2 Hz, 2 H), 2.16 (s, 3H).

[0351] Step 7A (HMPA-Mediated Amino Acid Coupling)

[0352] [ka] To a suspension of 2-amino-2-methylpropanoic acid (9) (10) (6.0 g, 58.2 mmol) in HMPA (42 mL) was slowly added a solution of thionyl chloride (4.64 mL, 64.0 mmol) in ACN (3.00 mL) at 3° C. After 10 min from the addition of the solution of thionyl chloride in ACN, the suspension becomes a clear solution. The resulting reaction mixture was stirred at 0° C. for 30 min, followed by the addition of 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) (3.58 g, 11.6 mmol) in portions at 3° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL). The resulting precipitate was filtered and washed with EtOAc (200 mL). The solid was dissolved in water (5 mL), basified with saturated aqueous sodium bicarbonate to pH 8.0 and extracted with 10% MeOH in DCM (5 x 100 mL). The collected organic layers were dried (Na2SO4), concentrated to 1 / 5 of its original volume, diluted with DCM (100 mL) and stirred for 15 min. The resulting precipitate was filtered, triturated with 2% MeOH in DCM (25 mL), subsequently washed with MTBE (50 mL) and dried under vacuum to give 2-amino-1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-methylpropan-1-one (Compound (I)) ((2.4 g, LCMS and NMR (300 MHz, 400 MHz, 800 MHz, 900 MHz, 1H-hexanediol) 1H-dopamine ... 1 96.6% by HNMR) as a pale yellow solid. Yield: (53%); MS (ESI+) m / z 392.8 [M+H] for CHNOS. + . 1 H NMR (400 MHz, DMSO-d6+ d-TFA ): δ 8.78-8.84 (m, 2H), 7.93 (d, J = 6.1 Hz, 1 H), 7.44 (d, J = 2.1 Hz, 1 H), 7.09 (dd, J = 2.1, 8.6 Hz, 1 H), 6.97 (d, J = 8.6 Hz, 1 H), 4.34 (bs, 2H), 3.97 (bs, 2H), 2.16 (s, 3H) and 1.60 (s, 6H).

[0353] Alternatively, Step 7B (DMPU-mediated amino acid coupling)

[0354] [ka] To a solution of 2-amino-2-methylpropanoic acid (9) (3.3 g, 32.0 mmol) in DMPU (23 mL) was slowly added a solution of thionyl chloride (2.55 mL, 35.2 mmol) in ACN (2.5 mL) at 4° C. The resulting reaction mixture was stirred at 0° C. for 20 min, followed by the addition of 4-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) (1.97 g, 6.40 mmol) in portions at 0° C. The reaction mixture was allowed to warm to room temperature and further stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with ACN (50 mL). The resulting precipitated solid was filtered and washed with ACN (100 mL). The solid was dissolved in water (5.0 mL), basified to pH 8.0 with saturated aqueous sodium bicarbonate at 10° C., extracted with 10% MeOH in DCM (5×50 mL) and concentrated under reduced pressure. The crude residue was stirred in EtOAc (20 mL), filtered and dried under reduced pressure to give a light brown solid. The resulting solid was further stirred in EtOH (7 mL), filtered and dried under vacuum to give 2-amino-1-{6-[2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}-2-methylpropan-1-one (compound (I)) as an off-white solid (770 mg, 99.7% by LCMS). Yield: (53%); (ESI+) m / z 392.8 [M+H] for CHNOS.+ .

[0355] For all of the above Methods 1, 2, 4, and 5, 4-bromo-3-methylpyridine (6) was formulated according to step 8 as follows:

[0356] [ka]

[0357] A 20 L four-neck round bottom flask equipped with a mechanical stirrer was charged with 3-methylpyridin-4-amine (25.0 g, 231 mmol) and hydrogen bromide (47% aqueous solution, 360 mL) at -20°C (internal temperature). To the resulting reaction mixture, a solution of sodium nitrite (76.6 g, 1.11 mol) in water (520 mL) was added slowly over approximately 90 minutes at -20°C. The reaction mixture was stirred at -20°C for 1 hour, to which CuBr (7.96 g, 55.5 mmol) was added at -20°C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 16 hours. TLC showed the reaction was complete. The reaction mixture was quenched with 50% aqueous sodium hydroxide solution (100 mL) and filtered through a celite bed. The celite bed was washed and extracted with DCM (100 mL). The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were filtered and concentrated under reduced pressure (keeping the water bath temperature >40° C.) to give a brown liquid. Yield 66% (26 g). MS (ESI+) m / z 172.0 [M+H] for CHNOS. + . 1 H NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.25 (d, J = 5.20 Hz, 1 H), 7.66 (d, J = 5.2 Hz, 1 H), 2.33 (s, 3H).

[0358] In Method 3, the hydrochloride salt of 4-bromo-3-methylpyridine (6A) is commercially available or can be formed by modifying the method in Step 8 for making 4-bromo-3-methylpyridine (6) detailed above.

[0359] In the case of Methods 4 and 5, it has surprisingly and advantageously been found that step 4 facilitates the formation of the favored regioisomer of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) over 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) by 98% versus 2%, respectively.

[0360] Thus, methods for synthesizing 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (a mixture of regioisomers 7 and 7A) according to step 4 of methods 4 and 5 described herein are also encompassed by the present invention.

[0361] In addition, for Methods 4 and 5, it has been surprisingly and advantageously discovered that the use of NHOH.HCl (hydroxylamine hydrochloride) in step 7 of Method 4 and step 5 of Method 5 advantageously improves yields.

[0362] Thus, the present invention also encompasses a method for synthesizing compound (I) from 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) using NH2OH.HCl (hydroxylamine hydrochloride).

[0363] Preferably, the method comprises synthesizing compound (I) from 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) according to step 7 of method 4 described herein.

[0364] Thus, the present invention also encompasses a method for synthesizing 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) from 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) using NH2OH.HCl (hydroxylamine hydrochloride).

[0365] Preferably, the method is to synthesize 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) from 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) according to step 5 of method 5.

[0366] Also encompassed by the present invention is a method for synthesizing compound (I) from 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) using 2-amino-2-methylpropanoic acid (9), preferably according to step 7 of method 5.

[0367] Also encompassed by the present invention is a method for synthesizing compound (I) from 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) using 2-amino-2-methylpropanoic acid (9) via 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-1H-imidazol-2-amine (12), preferably according to steps 6 and 7 of method 5.

[0368] Method 6 Compound (I) can be synthesized according to the following method: Step 1

[0369] [ka]

[0370] A 20 L round bottom flask equipped with a mechanical stirrer was charged with dichloromethane (2.6 L, 13 V) at 25° C.±5° C. under nitrogen atmosphere. Aluminum chloride (AlCl3) (0.752 kg, 4 mol equiv.) was added to the round bottom flask at 25° C.±5° C. under nitrogen atmosphere with stirring. This first reaction mixture was stirred for 20±5 minutes under nitrogen atmosphere. The reaction mixture was cooled to 5±5° C. Separately, a 5 L round bottom flask equipped with a mechanical stirrer was charged with 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (1A) (0.25 kg, 1 mol equiv.) and dichloromethane (0.5 L, 2 V). The second reaction mixture was slowly added to the first reaction mixture in the 20 L round bottom flask through an addition funnel at a temperature of 5±5° C. The combined reaction mixture was stirred for 10±5 minutes at 5±5° C. Chloroacetyl chloride (0.145 L, 1.3 mol equiv.) was added slowly to the combined reaction mixture through an addition funnel at a temperature of 5±5° C. under nitrogen atmosphere. The reaction mixture was heated to 40±5° C. The reaction mixture was stirred at 40±5° C. for 3±1 h. The reaction mixture was then cooled to 25±5° C. and added to another 20 L round bottom flask charged with ice cold water (2.5 L, 10 V) with stirring at 2-5° C. The mixture was stirred at 25±5° C. for 30 min-1 h and then allowed to stand for 30 min to allow phase separation to occur. The aqueous layer (10 V) and organic layer (3.5 L, 14 V) were collected in separate containers and the aqueous layer was transferred back to the 20 L round bottom flask which was further charged with dichloromethane (1.5 L, 6 V) and the mixture was allowed to stand for 30 min. The mixture was then transferred to a separatory funnel and allowed to stand for 30 min. The aqueous and organic layers (1.5 L) were separated again and the combined organic layers were charged into a 20 L round bottom flask along with water (1.25 L, 5 V), stirred for 30 min, allowed to stand for 10-15 min and then separated. The organic layer was washed with water (4 x 5 V) and the aqueous (5 L) and organic layers (5 L) were separated. The organic layer was charged into a Buchi round bottom flask and distilled under reduced pressure at 40°C to obtain the concentrated organic layer. Charcoal (10% w / w with respect to starting material) was introduced into the organic layer and stirred at 25±5°C for 120±10 min. The reaction mass was then filtered through a bed of Celite in a Buchner filter, washed with 50% MeOH in DCM and then the filtrate was collected.The organic layer was loaded onto a rotavapor and the filtrate was evaporated under vacuum at 40° C. until 2 V remained. To the resulting mixture, methyl tert-butyl ether (MTBE) (6 V) was added and stirred at 25±5° C. for 1 h. The resulting solid was filtered through a Buchner funnel under vacuum. The solid material was then washed with MTBE (2 V), dried under vacuum for 30 min, and then further dried in a vacuum oven at 55° C. for 7-8 h to give 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) in 70% yield and 97.97% purity (as determined by LCMS). The compound was used in the next step without further purification.

[0371] Step 2

[0372] [ka] A 2 L round bottom flask equipped with a mechanical stirrer was charged with ethanol (1.0 L, 5V) at 25°C ± 5°C under nitrogen atmosphere. 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) (0.21 kg, 1.0 mol equiv.) was added to the round bottom flask at 25°C ± 5°C under nitrogen atmosphere with stirring. This first reaction mixture was stirred for 10 minutes under nitrogen atmosphere, and then 2-aminopyrimidine (4) (0.197 kg, 2.50 mol equiv.) was added to the first reaction mixture at 25°C ± 5°C under nitrogen atmosphere. The reaction mixture was heated to 75-78°C. The reaction mixture was stirred at 78°C for 16-24 hours. The reaction mixture was then cooled to 25±5°C. The mixture was stirred at 25±5°C for 1 h, then filtered through a Buchner filter, the wet cake was washed with ethanol (0.2 L) at 25±5°C, and dried in vacuum for 30 min. Further drying in a vacuum oven at 65±5°C for 5-6 h gave 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) in 57.6% yield with a purity of 99.52% (determined by LCMS). The compound was used in the next step without further purification.

[0373] Step 3

[0374] [ka] A 3 L round bottom flask equipped with a mechanical stirrer was charged with dimethylformamide (850 mL, 10 V) under a nitrogen atmosphere at 25° C.±5° C. 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) (85 g, 1.0 mol equiv.) was added to the round bottom flask at 25±5° C. under a nitrogen atmosphere with stirring. This first reaction mixture was stirred for 10 minutes under a nitrogen atmosphere. 4-Bromo-3-methyl-pyridine HCl (6A) (72.2 g, 1.20 mol equiv.), potassium carbonate (K2CO3) (199.6 g, 5.0 mol equiv.), pivalic acid (13.03 mL, 0.40 mol equiv.), and tricyclohexylphosphine tetrafluoroborate (PCy3.HBF4) (1.63 g, 0.10 mol equiv.) were added at 25°C ± 5°C under nitrogen atmosphere. The reaction mixture was degassed with argon at 25 ± 5°C for 25-30 minutes. To the reaction mixture was added palladium acetate (Pd(OAc)2) (6.48 g, 0.10 mol equiv.). The combined reaction mixture was heated to 125 ± 5°C. The reaction mixture was stirred at 125 ± 5°C for 2-4 hours. The reaction mixture was then cooled to 30 ± 5°C. The reaction mixture was then filtered through a bed of celite on a Buchner filter, washed with 10% MeOH in DCM, and then the filtrate was collected. A rotavapor was loaded with the organic layer, and the filtrate was distilled under vacuum at 65±5°C until 2V remained. Dichloromethane (DCM) (2V) was added to the resulting mixture, stirred at 25±5°C for 15-20 minutes, then methyl tert-butyl ether (MTBE) (10V) was added, stirred at 25±5°C for 15-20 minutes, and the resulting solid formed was filtered off under vacuum in a Buchner funnel. The solid material was then dried under vacuum and then dried in a vacuum oven at 50±5°C for 3-4 hours to obtain 88% crude material (7 and 7A) with a purity of 77.12% (measured by LCMS). The resulting compounds (7 and 7A) were further subjected to a palladium capture procedure involving a trithiocyanuric acid procedure followed by silica plug filtration. Silica plug filtration was performed using silica 100-200 mesh, 10% MeOH in DCM, then the filtrate was collected.The organic layer was charged to a rotavapor and the filtrate was evaporated under vacuum at 45±5°C to obtain a solid. The solid material was charged to a 3 L round bottom flask and then charged with dichloromethane (10V) with stirring. The mixture was stirred for 10 min and trithiocyanuric acid (6.8 g, 20 mol% w / w), charcoal (14.8 g, 20 mol% w / w), sodium bicarbonate (NaHCO3) (28.22 g, 1.75 equiv.) and water (282 mL) were added. The combined mixture was stirred at 25±5°C for 3 h, filtered through a bed of celite on a Buchner filter, washed with 10% MeOH in DCM and then the filtrate was collected. The filtrate was placed in a separator and allowed to stand for 15-20 min to allow phase separation to occur. The water (0.282 L) and organics (5.18 L) were collected in separate vessels and the organic layer was returned to a 10 L round bottom flask which was further charged with 1N NaOH (20 V) and the mixture was stirred for an additional 20 ± 5 min. The resulting mixture was charged to a 10 L separator and allowed to stand for 10-15 min to allow phase separation to occur. The aqueous layer (1.48 L) and organic layer (5.18 L) were collected in separate vessels. The organic layer (5.18 L) was washed with a brine solution (10 L) and separated (5.18 L). The organic layer was charged to a round bottom flask and evaporated under vacuum at 40 ± 5 °C until 1.5 V remained. To the resulting mixture was added methyl tert-butyl ether (MTBE) (3 V) which was then stirred at 25 ± 5 °C for 30 min. The resulting precipitate was filtered under vacuum through a Büchner funnel. The solid material was then washed with MTBE (1V), dried under vacuum for 30 min, and then further dried in a vacuum oven at 50±5°C for 2-4 h to give (7 and 7A) in 70.06% yield with a purity of 95.21% (as determined by LCMS). Palladium results ranged from 49 to 119 ppm. The trithiocyanuric acid procedure was repeated one more time to obtain less than 100 ppm palladium.

[0375] Step 4

[0376] [ka] A 10 L round-bottom flask equipped with a mechanical stirrer was charged with 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (mixture of regioisomers 7 and 7A) (440 g, 1.0 mol equiv.) at a temperature of 25° C.±5° C. Methanol (4.4 L, 10 V) was added to the round-bottom flask at a temperature of 25±5° C. The reaction mass was stirred at 25±5°C for 10 min (RM is in heterogeneous form) followed by the addition of 30% aqueous NaOH (880 mL, 2V) to the round bottom flask with stirring at 25±5°C. The reaction mass was heated at 70±5°C for 5-6 h. After about 4 h at 65-70°C, precipitation of material is observed. Heating is stopped and reaction mass is allowed to stand till it reaches 25±5°C. Formation of more solids was observed in the reaction mixture at 25±5°C than when heated. The reaction mass was filtered through a Buchner funnel under vacuum. The wet cake was washed with methanol (0.88L, 2V) and dried under vacuum for 30 min. The wet cake was removed from the Buchner filter and added to another 5.0L round bottom flask. Milli-Q water (2.2L, 5V) was added to the 5.0L round bottom flask and the mixture was stirred for another 30 min. The mixture was filtered through a Buchner funnel and washed with water (2.2 L, 5 V). The pH of the filtrate should be approximately 7-8. The material was dried on the Buchner funnel for 30 min and further dried in a vacuum oven at 65 ± 5 °C for 12-14 h to give 66.8% yield of (8 and 8A) with a purity of 98.78% (measured by HPLC). The compounds were used in the next step without further purification. Of the regioisomers (8) and (8A), (8) predominates, with 8A being negligible in some batches.

[0377] Step 5

[0378] [ka] A 10 L round bottom flask equipped with a mechanical stirrer was charged with 2-amino-2-methylpropanoic acid (9) (260 g, 3.34 mol equiv.) at 25° C.±5° C. under nitrogen atmosphere. Acetonitrile (3.9 L, 15 V) was added to the round bottom flask and the mixture was stirred at 25° C.±5° C. under nitrogen atmosphere for 10 min. Thionyl chloride (403 mL, 7.34 mol equiv.) was added to the round bottom flask over 10 min (an exotherm of about 2° C. was observed). The resulting mixture was heated at 40° C.±2° C. for 2 h (a white suspension was observed). The mixture was then cooled to 30° C. and then pyridine (792 mL, 13.0 mol equiv.) was added to it over 45 min (an exotherm of 5-7° C. was observed and the mixture became clear). The mixture was further stirred at 35-40 °C for 1 h and then cooled to 30 °C followed by addition of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) (mixture of regioisomers 8 and 8A) (260 g, 1.0 mol equiv.) and an exotherm of 4-5 °C was observed. The reaction mass was further stirred at 30 ± 5 °C for 2-3 h (yellow precipitate was observed after maintaining for 30-45 min). The reaction mass was then filtered on a Buchner funnel under nitrogen atmosphere to obtain a solid product which was then washed with acetonitrile (1.04 L, 4 V). The material was then dried in a vacuum oven at 65 ± 5 °C for 6-8 hours to obtain 320 g of crude material. The resulting crude material was then dissolved in ethanol (960 mL, 3 V on crude material) at 25 ± 5 °C and stirred for 5-10 minutes. The mixture was then heated at 70 ± 5 °C for 30 minutes and then cooled to 40 °C. Isopropyl acetate (4.16 L, 13 V) was added to the mixture and then allowed to cool to 25 ± 5 °C. The mixture was then stirred at 25 ± 5 °C for 3-4 hours and then filtered on a Buchner funnel under reduced pressure. The resulting solid was then washed with isopropyl acetate (640 mL, 2 V).The material was dried on a Büchner funnel and finally in an oven at 65 ± 5 °C for 5-6 h to give 10C and 10D in 65.8% yield with a purity of 99.81% (measured by HPLC). Of the regioisomers 10C and 10D, 10C predominates and in some batches 10D is not observed.

[0379] Step 6

[0380] [ka] A 10.0 L round bottom flask equipped with mechanical stirrer was charged with (10C and 10D) bis-HCl salt (250 g, 0.49 mol equiv.) at 25°C ± 5°C. Isopropanol (1.25 L, 5V) was added to the round bottom flask at 25±5°C. The mixture was stirred under nitrogen atmosphere for 10 minutes followed by the addition of triethylamine (208 mL, 3.0 mol equiv.). The resulting mixture was stirred at 25±5°C for 10 minutes and then at 50°C for 2 hours (heterogeneous reaction mass). Hydroxylamine hydrochloride (104 g, 1.49 mol equiv.) was added to the mixture (an exotherm of 2-3°C was observed). The reaction mass was further stirred at 50°C for 2-3 hours. The reaction became clear after 15-20 minutes and solid started precipitating after 2 hours. The reaction mass was cooled to 25±5°C. Isopropyl acetate (1.25 L, 5 V) was added to the round bottom flask at 25 ± 5 °C and the mixture was stirred for another hour. Isopropyl acetate (2.5 L, 10 V) was further added to the round bottom flask at a temperature of 25 ± 5 °C and stirred for another hour. The solid thus obtained was then filtered on a Büchner funnel under reduced pressure to obtain the crude material under nitrogen atmosphere. The solid material thus obtained was washed with isopropyl acetate (500 mL, 2 V) and dried under vacuum. The solid was further dried in a vacuum oven at 60 ± 5 °C for 4-6 hours to obtain 350 g of crude material. The crude material (350 g) was then refluxed in ethanol (1.75 L, 5 V) for 30 minutes and then cooled to 25 ± 5 °C and filtered under reduced pressure to obtain the desired material. The material was dried on a Buchner funnel and finally dried in a vacuum oven at 60±5°C for 6-8 hours to obtain compound (1) in 84.9% yield as bis-HCl salt with a purity of 99.46% (measured by HPLC). The HCl salt thus obtained was further removed to obtain the free base. In a 10.0 L round bottom flask equipped with a mechanical stirrer and charged with Milli-Q water (1.26 L, 2.4 V) at 25°C±5°C, compound (1) (bis-HCl salt) (525 g) was added to the round bottom flask at 25±5°C. The mixture was stirred for 10 minutes and then cooled to 15±5°C followed by the addition of NH4OH (1.26 L, 2.4 V) over a period of 30-45 minutes. The reaction mass was stirred at 15±5°C for 30-45 minutes. Dichloromethane (2.6 L, 5 V) was added to the reaction mass (addition of DCM aids in the formation of solids).The mixture was stirred for an additional 30-45 min, then filtered through a Büchner funnel under reduced pressure and washed with water (1.05 L, 2 V). The wet solid was returned to the round bottom flask and slurried with water (5.25 L, 10 V) at 25 ± 5 °C for 30-45 min. The solid was then filtered again on the Büchner funnel and washed with DCM (1.05 L, 2 V). The material was dried on the Büchner funnel and finally dried in a vacuum oven at 65 ± 5 °C for 12-14 h to give 421 g of compound (1) with a purity of 99.01% (measured by HPLC).

[0381] Those of skill in the art will appreciate that pharma- ceutically acceptable salts of compound (I) can be readily synthesized, typically using any of the synthetic methods disclosed herein, by forming compound (I) followed by the known additional steps required to form a pharma- ceutically acceptable salt thereof.

[0382] The advantageous properties of compound (I) will now be described with reference to specific examples, which are merely exemplary and are for illustrative purposes only; they are not intended to limit in any way the scope of the claimed exclusivity or the described invention. EXAMPLES

[0383] Comparative compound (II):

[0384] [ka] was synthesized by modifying the method outlined above for compound (I), including the selection of an appropriate pyridyl starting material and the use of glycine as the amino acid.

[0385] Comparative compound (III):

[0386] [ka] was synthesized by modifications that included the selection of an appropriate pyridyl starting material and the use of glycine as the amino acid.

[0387] The minimum inhibitory concentration (MIC) and the minimum inhibitory concentration 90 value (MIC ) were determined for compound (I) and comparative compounds (II) and (III). 90 ) we conducted the following analysis.

[0388] Antimicrobial susceptibility Minimum inhibitory concentrations (MICs) against Escherichia coli (NCTC13441) and Klebsiella pneumoniae (NCTC13438) (planktonic bacteria) were determined by a broth microdilution procedure following the guidelines of the Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eleventh Edition, CLSI document M07, 11 January 2018. The broth dilution method involved two-fold serial dilutions of compounds in 96-well microtiter plates, resulting in a final concentration range of 0.39–200 μM, with a maximum final concentration of 2% DMSO. The bacterial strains tested were Escherichia coli (NCTC 13441) and Klebsiella pneumoniae (NCTC 13438). Strains were grown on cation-adjusted Mueller-Hinton broth or Luria-Bertani agar at 37°C in ambient atmosphere. MICs (μM) were determined as the lowest concentration of compound that inhibited growth after a 20-24 hour incubation period. The results are shown in Table 1.

[0389] [Table 1]

[0390] Using the methodology outlined above, the minimum inhibitory concentration (MIC) versus Proteus mirabilis (DSM4479) was determined for compound (I) and comparison compounds (II) and (III). The results are shown in Table 2. Compound (I) shows superior potency versus comparison compounds (II) and (III).

[0391] [Table 2]

[0392] Minimum inhibitory concentrations (MICs) for 100 isolates of Escherichia coli and Klebsiella pneumoniae 90 The minimum inhibitory concentration (MIC) at which 90% of the isolated bacteria (strains) were inhibited was measured. 90 ) were measured by broth microdilution according to EUCAST susceptibility testing criteria (www.eucast.org). Bacterial inocula were prepared at approximately 1x10^6 CFU / mL by diluting 0.5 McFarland suspensions 100-fold. Antimicrobial panels containing 50 μl of antimicrobial solution at twice the final concentration were diluted 2-fold with 50 μl of inoculum to obtain a final inoculum of approximately 5x10^5 CFU / ml, and the desired test concentrations of antimicrobial agents (0.03-64 μg / mL). Plates were incubated according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eleventh Edition, CLSI document M07, 11 January 2018). MICs 90 (μg / ml) is the MIC value at which 90% or more of the isolates (strains) in the test population are inhibited. The results are shown in Table 3.

[0393] [Table 3]

[0394] Using the methodology outlined above for 100 isolates of Escherichia coli and Klebsiella pneumoniae, the minimum inhibitory concentrations (MICs) were determined for compound (I) as well as comparative compound (III) versus Proteus spp. and Providencia spp. The results are shown in Table 4. Compound (I) shows superior potency versus comparative compound (III).

[0395] [Table 4]

[0396] Compound (I) and comparative compounds (II) and (III) were subjected to the following analyses for lipophilicity and volume of distribution (Vss).

[0397] lipophilic The LogP values ​​of compound (I) and comparative compound (III) were measured by performing an acid-based titration using a Sirius T3 instrument manufactured by Sirius Analytical to measure the shift in pKa when the sample solution was in contact with an immiscible solvent (octanol). The LogP of comparative compound (II) was calculated using Marvin (physical and chemical calculation software). The results are shown in Table 5. The lipophilicity data of compound (I) and comparative compounds (II) and (III) were collected in separate experiments performed on different days and compared in Table 5.

[0398] [Table 5]

[0399] distribution volume The volume of distribution (Vss) of compound (I) and comparative compounds (II) and (III) was determined from the analysis of plasma concentration-time profiles obtained from rodent species (mouse) after IV bolus administration of 5 mg / kg, respectively. The volume of distribution was obtained by analyzing the rodent plasma profiles of compound (I) and comparative compounds (II) and (III) using a two-compartment IV bolus model in PK Solver (Excel). The output Vss values ​​are shown in Table 6. The amount of distribution data of compound (I) and comparative compounds (II) was collected in separate experiments performed on different days and compared in Table 6.

[0400] [Table 6]

[0401] Discussion of results Without being bound by theory, the inventors believe that the above results regarding lipophilicity and volume of distribution demonstrate that compound (I) or a pharmaceutically acceptable salt thereof can be advantageously used to treat infections caused by or diseases caused or exacerbated by gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, in particular, to treat multi-site infections caused by gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus. The inventors believe that the above results demonstrate that compound (I) or a pharmaceutically acceptable salt thereof has the ability to effectively distribute to all sites of infection around the subject's body in sufficient concentrations to allow effective treatment at all sites. As well as having a sufficient amount of compound available to exert a pharmacological effect, a balance should be maintained between ensuring that the distribution of the compound from the plasma is fast enough to allow the drug to act quickly against the infection and avoiding a very rapid release that would prevent the drug from reaching all possible sites of infection in sufficient concentrations.

[0402] Such a balance is believed to be demonstrated by the results presented above, which are discussed in more detail below.

[0403] The LogP value of a compound indicates an index of polarity and therefore the ability of the compound to reach the target tissue of a subject, i.e., the ease with which the drug can cross membrane barriers and distribute to possible intracellular infection sites around the subject's body.

[0404] From Table 5, it can be seen that compound (I) of the present invention has a higher LogP value and therefore a lower polarity compared to both comparative compounds (II) and (III), which indicates improved tissue distribution of compound (I) compared to the more polar comparative compounds (II) and (III). The inventors believe that this improved tissue distribution of compound (I) allows the compound to distribute to all possible sites of infection around the subject's body, with enough drug reaching each of the infection sites to allow treatment. If the drug distribution is ineffective, as seen for comparative compounds (II) and (III) based on the LogP values ​​in Table 5, there will be insufficient drug concentration throughout the infection sites, preventing treatment of the infection. As discussed above, there is a balance to be achieved with regard to the efficiency with which the drug distributes around the subject's body. The LogP values ​​of compound (I) show that compound (I) distributes to multiple infection sites and provides adequate drug concentration at all of these infection sites, relative to comparative compounds (II) and (III).

[0405] The volume of distribution (Vss) provides a measure of the extent to which a compound distributes into the body tissues of a subject rather than into the plasma, ie, the tendency of a compound to leave the plasma and distribute into the body tissues of a subject.

[0406] From Table 6 it can be seen that compound (I) has surprising and unexpectedly superior tissue penetration properties compared to comparative compounds (II) and (III), both of which are structurally very similar to compound (I).

[0407] The inventors have concluded that compound (I) exhibits good permeability. The lipophilicity and permeability of compound (I) allow the compound to reach and penetrate into the target tissue of the subject. The surprising and unexpectedly excellent tissue distribution and permeation properties of compound (I) versus comparative compounds (II) and (III) are due to the favorable lipophilicity and permeability of compound (I).

[0408] In vitro safety pharmacology studies In vitro pharmacological binding assays were performed for compound (I), comparative compound (II) and comparative compound (III) to evaluate the percentage of inhibition against 44 ligands (including receptors, transporters, ion channels, enzymes and kinases) at a concentration of 10 μM for compound (I), comparative compound (II) or comparative compound (III). Compound binding was calculated as the percentage of inhibition of binding of radiolabeled ligands specific to each target. Results showing more than 50% inhibition are considered to represent a discernible effect of compound (I), comparative compound (II) or comparative compound (III). Results for all 44 ligands tested are shown in Figures 1a, 1b, and 1c, while Figure 1d shows only results showing more than 50% inhibition. In vitro pharmacological binding assays for compound (I) and comparative compounds (II) and (III) were performed separately on different days and compared in Figures 1a, 1b, 1c, and 1d.

[0409] From Figures 1a, 1b, 1c, and 1d, it can be seen that compound (I) has a different CEREP profile than both comparative compounds (II) and (III). Compound (I) showed greater than 50% inhibition against only a single ligand, i.e., fewer (and different) ligands than comparative compounds (II) and / or (III).

[0410] Proof-of-concept studies Compound (I) and comparative compound (III) were evaluated in proof-of-concept studies in mouse models for the treatment of respiratory infections with gram-negative bacteria of the order Enterobacteriale, bacteremia or bloodstream infections with gram-negative bacteria of the order Enterobacteriale, and urinary tract infections with gram-negative bacteria of the order Enterobacteriale. The results are shown in Figures 2, 3, and 4a-c. Each dot, triangle, or square indicator represents one mouse. LOD refers to the limit of detection of bacteria. Stasis indicates the level of bacteria (colony forming units (CFU)) in the subject before treatment. Each of the proof-of-concept studies was performed separately. Vehicle means a pharma- ceutically acceptable carrier or excipient.

[0411] For a proof-of-concept study on the treatment of respiratory infections caused or exacerbated by gram-negative bacteria of the order Enterobacteriaceae, CD-1 mice were infected with Klebsiella pneumoniae ATCC 43816. Two hours after infection ("Pretreatment" in FIG. 2), vehicle (20% hydroxypropyl β-cyclodextrin) without Compound (I) or Comparative Compound (III), or vehicle (20% hydroxypropyl β-cyclodextrin) containing Compound (I) or Comparative Compound (III) was administered by IV bolus at 20 mg / kg TID (8 hour intervals) for one day.

[0412] From FIG. 2, it can be seen that at the end of the study (26 hours from initial infection: “Compound (I)” and “Comparative Compound (III)” in FIG. 2), Compound (I) unexpectedly had a significant reduction in colony forming units (CFU) compared to Comparative Compound (III), i.e., the bacterial load was significantly reduced by treatment with Compound (I) vs. Comparative Compound (III) compared to pretreatment and vehicle. In fact, the CFU values ​​for Comparative Compound (III) in FIG. 2 remained relatively close to resting levels, i.e., instances where no bacterial killing occurred. From FIG. 2, it can be seen that at the end of the study (26 hours from initial infection), Compound (I) reduced the bacterial load in the lungs by 6.24 logs compared to vehicle, whereas Comparative Compound (III) only showed a 4.16 log reduction compared to vehicle. Thus, compound (I) is 2 logs more effective than the comparative compound (III) in treating respiratory infections due to Klebsiella pneumonia, particularly multidrug resistant Klebsiella pneumonia.

[0413] For a proof-of-concept study on the treatment of bacteremia or bloodstream infection caused by Gram-negative bacteria of the order Enterobacteriaceae, CD-1 mice were infected with human urine isolate Escherichia coli (E. coli) BAA-2469 (NDM-1 positive). One hour after infection ("Pretreatment" in FIG. 3), vehicle (20% hydroxypropyl β-cyclodextrin) containing no compound (I) or comparative compound (III), or vehicle (20% hydroxypropyl β-cyclodextrin) containing compound (I) or comparative compound (III) was administered as a single IV bolus dose at 20 mg / kg.

[0414] From FIG. 3, it can be seen that at the end of the study (9 hours from initial infection: “Compound (I)” and “Comparative Compound (III)” in FIG. 3), Compound (I) unexpectedly had a significant reduction in colony forming units (CFU) compared to Comparative Compound (III), i.e., bacterial load was significantly reduced by treatment with Compound (I) vs. Comparative Compound (III) compared to pretreatment and vehicle. In fact, the CFU values ​​of Comparative Compound (III) in FIG. 3 remained above resting levels, i.e., instances where no bacterial killing occurred. From FIG. 3, it can be seen that at the end of the study (9 hours from initial infection), Compound (I) reduced the bacterial load in the blood below the limit of detection (LOD), a 7.43 log reduction compared to vehicle. In contrast, Comparative Compound (III) showed only a 4.86 log reduction compared to vehicle. Thus, compound (I) is 2.5 logs more effective than the comparator compound (III) in treating bacteremia or bloodstream infections due to Escherichia Coli, particularly multidrug resistant Escherichia Coli.

[0415] For a proof-of-concept study on the treatment of urinary tract infections caused by Enterobacteriaceae bacteria, female C3H / HeN mice were infected with Escherichia coli (E. coli) UTI 89. Twenty-four hours post-infection ("Pretreatment" in Figure 4a-c), vehicle (20% hydroxypropyl β-cyclodextrin) containing no Compound (I) or Comparative Compound (III), or vehicle (20% hydroxypropyl β-cyclodextrin) containing Compound (I) or Comparative Compound (III) was administered by IV bolus at 20 mg / kg TID (8 hour intervals) for 3 days.

[0416] Since urinary tract infections can affect the bladder and kidneys, bacterial loads were evaluated in the urine, bladder, and kidneys, respectively (Figures 4a-c). Figures 4a and 4b show that at the end of the study (96 hours after initial infection: "Compound (I)" and "Comparative Compound (III)" in Figures 4a and 4b), Compound (I) unexpectedly had a significant reduction in colony forming units (CFU) compared to Comparative Compound (III), i.e., bacterial load was significantly reduced by treatment with Compound (I) vs. Comparative Compound (III) compared to pretreatment and vehicle. Figure 4c shows that at the end of the study (96 hours after initial infection: "Compound (I)" and "Comparative Compound (III)" in Figure 4c), Compound (I) also had a reduction in colony forming units (CFU) compared to Comparative Compound (III), i.e., bacterial load was reduced by treatment with Compound (I) vs. Comparative Compound (III) compared to pretreatment and vehicle. From FIG. 4a, it can be seen that at the end of the study (96 hours after the initial infection), compound (I) reduced the bacterial load in the urine below the limit of detection (LOD), a 6.59 log reduction compared to vehicle. In contrast, comparative compound (III) showed only a 3.36 log reduction compared to vehicle. Thus, compound (I) is 3 logs more effective than comparative compound (III) in reducing CFU in the urine, thus facilitating the treatment of Escherichia coli urinary tract infection (UTI). From FIG. 4b, it can be seen that at the end of the study (96 hours after the initial infection), compound (I) reduced the bacterial load in the bladder by 5.67 logs compared to vehicle. In comparison, comparative compound (III) showed only a 3.71 log reduction compared to vehicle. Thus, compound (I) is 3 logs more effective than comparative compound (III) in reducing CFU in the bladder, thus facilitating the treatment of Escherichia coli urinary tract infection (UTI). FIG. 4c shows that at the end of the study (96 hours after initial infection), compound (I) reduced bacterial burden in the kidney by 4.73 logs compared to vehicle.

[0417] Compound (I) was further evaluated in proof-of-concept studies in mouse models for the treatment of respiratory infections with gram-negative bacteria of the order Enterobacteriale, and urinary tract infections with gram-negative bacteria of the order Enterobacteriale. The results are shown in Figures 5 and 6a-c. Each dot, triangle, or square indicator represents one mouse. LOD refers to the limit of detection of bacteria. Stasis indicates the level of bacteria (colony forming units (CFU)) in the subject before treatment. Each of the proof-of-concept studies was performed separately. Vehicle means a pharma- ceutically acceptable excipient or carrier.

[0418] For further proof-of-concept studies on the treatment of respiratory infections caused or exacerbated by Gram-negative bacteria of the order Enterobacteriaceae, male CD-1 mice were infected with Klebsiella pneumoniae ATCC 43816.

[0419] Two hours after infection ("Pretreatment" in FIG. 5), mice were treated with either a vehicle control (phosphate buffer) without Compound (I), or vehicle (phosphate buffer) containing Compound (I) administered at a dose of 20 mg / kg by 1-hour (QD) intravenous infusion. Mice receiving the vehicle control without Compound (I), and some mice receiving vehicle containing Compound (I), were administered an additional 1-hour continuous intravenous infusion (BID, 3-hour intervals) 3 hours after the first dose start time.

[0420] From FIG. 5, it can be seen that at the end of the study (26 hours after the initial infection: “Compound (I) QD” and “Compound (I) BID” in FIG. 5), Compound (I) reduced colony forming units (CFU), i.e., bacterial load, compared to pretreatment and vehicle (Vehicle BID in FIG. 5). This was especially seen when Compound (I) was administered twice (BID, 3 hours apart) (P value <0.0001 compared to both pretreatment and vehicle). Compound (I) administered once (QD) had a P value of 0.0042 compared to pretreatment and <0.0001 compared to vehicle. From Figure 5, it can be seen that at the end of the study (26 hours after the initial infection), compound (I) reduced the bacterial burden in the lungs by 4.35 and 5.20 logs compared to vehicle (one dose (QD) and two doses (BID, 3 hours apart), respectively), and by 0.95 and 1.80 logs compared to pre-treatment (resting levels) (one dose (QD) and two doses (BID, 3 hours apart), respectively). Thus, compound (I) is effective in treating respiratory infections caused by Klebsiella pneumonia, especially multi-drug resistant Klebsiella pneumonia.

[0421] For further proof-of-concept studies on the treatment of urinary tract infections due to Enterobacteriaceae bacteria, female C3H / HeN mice were infected with E. coli UTI89.

[0422] Twenty-four hours after infection ("Pretreatment" in Figure 6a-c), mice were treated with either a vehicle control (20% hydroxypropyl β-cyclodextrin) not containing compound (I), or a vehicle (20% hydroxypropyl β-cyclodextrin) containing compound (I) at a dose of 20 mg / kg administered by 1-hour (QD) intravenous infusion. For some mice that received vehicle containing compound (I), an additional 1-hour continuous intravenous infusion (BID, 5-hour intervals) was administered 5 hours after the start time of the first dose. Dosing was continued once or twice daily for 3 days. For QD, dosing was performed between 24-25 hours, 48-49 hours, and 72-73 hours after infection, and for BID, dosing was performed between 24-25 hours, 29-30 hours, 48-49 hours, 53-54 hours, 72-73 hours, and 77-78 hours after infection.

[0423] Since urinary tract infections can affect the bladder and kidneys, the bacterial load in urine, bladder, and kidneys was evaluated (Figures 6a-c, respectively). Figures 6a, 6b, and 6c show that at the end of the study (96 hours after initial infection: "Compound (I) QD" and "Compound (I) BID" in Figures 6a, 6b, and 6c), Compound (I) significantly reduced colony forming units (CFU), i.e., treatment with Compound (I) significantly reduced bacterial load compared to pretreatment and vehicle. This was especially seen when Compound (I) was administered twice daily (BID, 5 hours apart). From Figure 6a, it can be seen that at the end of the study (96 hours after the initial infection), both QD and BID daily administrations reduced the bacterial load in urine below the limit of detection (LOD), with 4.86 and 5.87 log reductions (for once (QD) and twice (BID, 5 hours apart) administration, respectively) compared to vehicle. The P value for compound (I) was <0.0001 compared to vehicle, whether administered once (QD) or twice (BID, 5 hours apart). Thus, compound (I) is effective in reducing CFU in urine, thus facilitating the treatment of Escherichia coli urinary tract infections (UTI). From Figure 6b, it can be seen that at the end of the study (96 hours after the initial infection), both QD and BID daily administrations reduced the bacterial load in the bladder below the limit of detection (LOD), with a 5.01 and 5.84 log reduction (for once daily (QD) and twice daily (BID, 5 hours apart), respectively) compared to vehicle. The P value was 0.001 for once daily administration (QD) and 0.0002 for twice daily administration (BID, 5 hours apart) compared to vehicle. Thus, compound (I) is effective in reducing CFU in the bladder, thus facilitating the treatment of Escherichia coli urinary tract infections (UTI).From Figure 6c, it can be seen that at the end of the study (96 hours after the initial infection), compound (I) reduced the bacterial load in the kidney below the limit of detection (LOD) when administered BID, with a 3.17 and 4.3 log reduction (for administration once daily (QD) and twice daily (BID, 5 hours apart), respectively) compared to vehicle. The P value for once daily administration (QD) was 0.0007 and for twice daily administration (BID, 5 hours apart) was <0.0001 compared to vehicle. Thus, compound (I) is effective in reducing CFU in the kidney, thus facilitating the treatment of Escherichia coli urinary tract infections (UTI).

Claims

1. Compound (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof; 【Chemistry 2】 The method comprises deprotecting the compound of formula (I).

2. The method according to claim 1, which is for producing compound (I).

3. 3. The method of claim 1 or 2, comprising said deprotection of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A).

4. 4. The method of claim 3, comprising said deprotection of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A).

5. Salts of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or salts of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably 2-amino-2-methyl 3. The method of claim 1 or 2, comprising the deprotection of the hydrochloride salt of -1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or the hydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A).

6. 2-Amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one dihydrochloride (10C) 【Chemistry 3】 and / or the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D). 【Chemistry 4】 The method of claim 1 or 2, comprising the deprotection of

7. The method of claim 1 , wherein the deprotection is acid catalyzed using an acid catalyst.

8. 3. The method of claim 1 or 2, wherein the deprotection is base-catalyzed using a base catalyst.

9. A deprotection agent is used to remove NH ２ 3. The method according to claim 1 or 2, wherein the OH.HCl (hydroxylamine hydrochloride) and hydrazine or its hydrate.

10. A deprotecting agent is utilized, the deprotecting agent being NH ２ 3. The method of claim 1 or 2, wherein OH.HCl (hydroxylamine hydrochloride).

11. 3. The method according to claim 1 or 2, wherein a deprotecting agent is utilized, said deprotecting agent being accompanied by a base selected from 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), piperidine, morpholine, pyrrolidine, and triethylamine (TEA), preferably 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), and triethylamine (TEA), more preferably triethylamine (TEA).

12. The deprotection was carried out using isopropyl alcohol (IPA), ethanol (EtOH), dichloromethane (DCM), methanol (MeOH), and acetonitrile (CH ３ 3. The method of claim 1 or 2, comprising a solvent selected from the group consisting of methanol, dichloromethane, and isopropyl alcohol (IPA), more preferably isopropyl alcohol (IPA).

13. The method according to claim 1 or 2, wherein the deprotection can be carried out at a temperature of 30 to 80°C, such as 40 to 70°C, preferably 40 to 60°C.

14. 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) are coupled with an amino acid, 【Chemistry 5】 2. The method of claim 1, further comprising the preceding step of forming 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof.

15. The preceding step is an amino acid coupling reaction between 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) and 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor. 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), or a salt thereof 【Chemistry 6】 The method of claim 14 , comprising forming

16. The preceding step is to couple 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) to 2-amino-2-methyl-1-(6-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8B) by amino acid coupling.

15. The method of claim 14, comprising forming methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A).

17. 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) are formed, and the coupling agent or coupling agent precursor is thionyl chloride (SOCl ２ ), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-(3'-dimethylaminopropyl) carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr) ４ and B(OCH ２ CF ３ ) ３ , and preferably, the coupling agent or coupling agent precursor is selected from thionyl chloride (SOCl ２ 15. The method of claim 7 or 14, wherein

18. 18. The method of claim 17, wherein the amino acid coupling uses a solvent selected from N,N' dimethylpropylene urea (DMPU), dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or a combination thereof, preferably the solvent is selected from acetonitrile, N,N' dimethylpropylene urea (DMPU) and hexamethylphosphoramide (HMPA), or a combination thereof, more preferably the solvent is selected from acetonitrile and hexamethylphosphoramide (HMPA), or a combination thereof.

19. 15. The method of claim 7 or 14, wherein the amino acid coupling of the preceding step uses N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) in combination with thionyl chloride.

20. Salts of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and / or 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H and / or 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably the hydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10). 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A), preferably 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10B). and the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10C) and / or the dihydrochloride salt of 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10D) is formed, and the coupling agent or coupling agent precursor is thionyl chloride (SOCl ２ ), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-)3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), hydroxybenzotriazole, fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr) ４ and B(OCH ２ CF ３ ) ３ Preferably, the coupling agent or coupling agent precursor is selected from hydroxybenzotriazole, 1-ethyl-2-(3'-dimethylaminopropyl)carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), propanephosphonic anhydride (T3P), and thionyl chloride (SOCl ２ 15. The method according to claim 7 or 14, wherein the coupling agent or coupling agent precursor is selected from the group consisting of thionyl chloride.

21. 21. The method of claim 20, wherein the amino acid coupling reaction uses a solvent selected from N,N' dimethylpropyleneurea (DMPU), dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA), acetonitrile (ACN), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), gamma-valerolactone (GVL), N-methylmorpholine (NMM), sulfolane, dichloromethane (DCM), or a combination thereof, preferably the solvent is selected from N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), gamma-valerolactone (GVL), N-methylmorpholine (NMM), sulfolane, dichloromethane (DCM) and acetonitrile, or a combination thereof, more preferably the solvent is selected from acetonitrile or sulfolane, most preferably acetonitrile.

22. 21. The method of claim 20, wherein in the amino acid coupling, a base, preferably a tertiary amine, more preferably pyridine, is also used as a reagent.

23. Deacylation of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), 16. The method of claim 14 or 15, further comprising an additional preceding step comprising forming 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and / or 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A).

24. The additional preceding step is to prepare 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethane- 24. The method of claim 23, comprising deacylating 1-one (7A) to form 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A).

25. 24. The method of claim 23, wherein the additional step is acid or base catalyzed, preferably base catalyzed.

26. 26. The method of claim 25, wherein the additional step is base catalyzed using NaOH, preferably 30% NaOH in water.

27. Compound (I) 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: Steps below: 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) and 4-bromo-3-methylpyridine (6) or a salt thereof are coupled in the presence of a metal catalyst to obtain 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A). 【Chemistry 8】 The method includes forming a

28. Compound (I) 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof, the method comprising coupling 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) with 4-bromo-3-methylpyridine (6) or a salt thereof in the presence of a metal catalyst to obtain 1-(6-(3-(3-methylpyridine- forming 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A), 【Chemistry 10】 wherein the use comprises a step of treating 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) with the metal scavenger.

29. 29. The method or use of claim 27 or 28, wherein compound (I) is formed.

30. 29. The method or use according to claim 27 or 28, wherein 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) are formed.

31. 29. The method or use according to claim 27 or 28, wherein 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) is coupled with 4-bromo-3-methylpyridine (6).

32. 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) is reacted with a salt of 4-bromo-3-methylpyridine (6), preferably 4-bromo-3-methylpyridine hydrochloride (6A). 【Chemistry 11】 29. The method or use of claim 27 or 28, wherein the

33. 28. The method of claim 27, wherein 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is subjected to a metal scavenging treatment, preferably said metal scavenging treatment comprises treatment with a metal scavenger.

34. 34. The method or use of claim 28 or 33, wherein the metal scavenging treatment comprises treatment with a metal scavenger, the metal scavenger being trithiocyanuric acid.

35. 29. The method according to claim 27 or 28, wherein the metal catalyst is a transition metal-based catalyst, such as a platinum-based catalyst, a palladium-based catalyst, and an iridium-based catalyst, preferably the metal catalyst is a palladium-based catalyst, more preferably the metal catalyst is palladium(II) acetate.

36. Compound (I) 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, comprising the steps of amino acid coupling of 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12) with 2-amino-2-methylpropanoic acid (9) in the presence of a coupling agent or a coupling agent precursor. 【Chemistry 13】 The method includes:

37. 37. The method of claim 36, wherein compound (I) is formed.

38. The coupling agent or coupling agent precursor is thionyl chloride (SOCl ２ ), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), propanephosphonic anhydride (T3P), 1-ethyl-2-(3'-dimethylaminopropyl) carbodiimide.HCl, 1,1'-carbonyldiimidazole (CDI), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), Ti(iOPr) ４ and B(OCH ２ CF ３ ) ３ Preferably, the coupling agent or coupling agent precursor is selected from thionyl chloride (SOCl ２ 38. The method of claim 36 or 37, wherein

39. 38. The method of claim 36 or 37, wherein the amino acid coupling uses a solvent selected from N,N' dimethylpropyleneurea (DMPU), dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoramide (HMPA) and acetonitrile (ACN), or a combination thereof, preferably a solvent selected from acetonitrile, N,N' dimethylpropyleneurea (DMPU) and hexamethylphosphoramide (HMPA), or a combination thereof, more preferably a solvent selected from acetonitrile and hexamethylphosphoramide (HMPA), or a combination thereof.

40. 38. The method of claim 36 or 37, wherein the amino acid coupling uses N,N' dimethylpropylene urea (DMPU) or hexamethylphosphoramide (HMPA) in combination with thionyl chloride.

41. A preliminary step for forming compound (12), which is the deacylation of 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) to form 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12). 【Chemistry 14】 37. The method of claim 36, further comprising:

42. A process for the preparation of compound (I), comprising the steps of deacylating 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11) to form 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(3-methylpyridin-4-yl)-1H-imidazol-2-amine (12). 【Chemistry 15】 The method includes:

43. 43. The method of claim 41 or 42, wherein the deacylation can be base- or acid-catalyzed, preferably acid-catalyzed.

44. 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and / or 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) is deacylated to give 1-(6-(2-amino-5-(3 43. The method of claim 41 or 42, further comprising the additional preceding step of forming 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11), forming 1-(6-(2-amino-5-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (11).

45. 45. The method of claim 44, wherein the deprotection is acid catalyzed using an acid catalyst.

46. 45. The method of claim 44, wherein the deprotection is base-catalyzed using a base catalyst.

47. A deprotection agent is used to remove NH ２ 45. The method of claim 44, wherein the OH. is selected from HCl (hydroxylamine hydrochloride) and hydrazine or a hydrate thereof.

48. A deprotection agent is used to remove NH ２ 45. The method of claim 44, wherein OH.HCl (hydroxylamine hydrochloride).

49. The deprotection was carried out using isopropyl alcohol (IPA), ethanol (EtOH), dichloromethane (DCM), methanol (MeOH), and acetonitrile (CH ３ CN), preferably selected from methanol, dichloromethane, and isopropyl alcohol (IPA), more preferably said solvent is isopropyl alcohol (IPA).

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