Process for preparing (s)-5-benzyl-n-(5-methyl-4-OXO-2,3,4,5- tetrahydropyrido[3,2-b][l,4]oxazepin-3-YL)-4h-l,2,4-triazole-3- carboxamide

Abstract

Provided herein are methods for preparing (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide and intermediates useful therein.

Description

Attorney Docket No: 01183-0334-00PCT PROCESS FOR PREPARING (S)-5-BENZYL-N-(5-METHYL-4-OXO-2,3,4,5- TETRAHYDROPYRIDO[3,2-B][1,4]OXAZEPIN-3-YL)-4H-1,2,4-TRIAZOLE-3- CARBOXAMIDE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. provisional application No. 63 / 707,647, filed October 15, 2024, and U.S. provisional application No.63 / 708,132 filed October 16, 2024, each of which is incorporated by reference herein in its entirety for any purpose. FIELD OF THE DISCLOSURE

[0002] The present disclosure relates generally to methods for preparing (S)-5-benzyl-N-(5- methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3- carboxamide and intermediates useful therein. BACKGROUND OF THE DISCLOSURE

[0003] Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation, apoptosis, and necroptosis. RIPK1 has an important role in modulating inflammatory responses mediated by nuclear-factor kappa-light chain enhancer of activated B cells (NF-kB). More recent research has shown that its kinase activity controls necroptosis, a form of necrotic cell death. Further, RIPK1 is part of a pro-apoptotic complex indicating its activity in regulating apoptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death. Research suggests that inhibition of RIPK1 is a potential clinical target for diseases involving inflammation or cell death. RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases.

[0004] The compound of Formula (I), (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5- tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, (hereinafter also referred as “Compound (I)”), depicted below, is a RIPK1 inhibitor:Attorney Docket No: 01183-0334-00PCT and is useful in the treatment of RIPK1 mediated diseases or disorders.

[0005] The method for preparing compound (I) was disclosed in Example 42 of U.S. Patent No.9,896,458 B2, at column 316, line 34 to column 319 line 4. The disclosed synthesis comprises several steps that employ undesirable reagents or solvents, which is not suitable for multi-kilo to commercial scale manufacturing. Accordingly, there is a need for a chemical process for the synthesis of Compound (I) is safe, cost and labor efficient, scalable, environmentally friendly, reproducible, and that allows improved purity, among other considerations.

[0006] Accordingly, provided herein are improved methods for preparing a compound of Formula (I) and intermediates useful therein that may address one or more of these needs. In some embodiments, the compound of Formula (I) (also referred to in the present disclosure as “Compound (I)” and the chemical structure of which is shown below) is prepared in a more efficient process.

[0007] Described herein, in certain embodiments, are methods for preparing Compound (I) and intermediates useful therein, such as Compound (3-b).

[0008] The present disclosure relates to a method of preparing a compound of Formula (I): comprising:adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising a compound of Formula (1-g):Attorney Docket No: 01183-0334-00PCT 1-g and a compound of Formula (1-l): in acetonitrile to form the

[0009] The present disclosure a preparing a compound of Formula (1- l): comprising:adding a base to a mixture comprising a compound of Formula (3-d): in water followed by addition ofof Formula (1-l).

[0010] The present disclosure further relates to a method of preparing a compound of Formula (3-d): comprising:i) reacting a compound of Formula (2-B): wherein R is selected from n-Et, with a compound of FormulaAttorney Docket No: 01183-0334-00PCTin the presence of a base to form a compound of Formula (3-c):wherein the base is and potassium carbonate; wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol; ii) heating a mixture comprising a compound of Formula (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C, to form the compound of Formula (3-d).

[0011] The present disclosure further relates to a method of preparing a compound of Formula (3-b):comprising: adding hydrazine monohydrate to a mixture comprising a compound of Formula (3-A): wherein R is Et or t-Bu, in an organiccompound of Formula (3-b), wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2- methyltetrahydrofuran; optionally wherein the organic solvent is ethanol.Attorney Docket No: 01183-0334-00PCT

[0012] The present disclosure furthermore relates to a method of preparing a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, comprising: adding a compound of Formula (2-a):to a mixture comprising acetyl chloride an solvent to form the compound of Formula (2-B), wherein the organic solvent is selected from ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is n-butanol.

[0013] The present disclosure also relates to a method of preparing a compound of Formula (I):comprising: i) preparing a compound of Formula (1-l): by adding a base to a mixture(3-d):in water followed by addition of an acid to form the compound of Formula (1-l):Attorney Docket No: 01183-0334-00PCT ii) reacting a compound of Formula (1-g):with the compound of Formula (1-l) of Formula (I).

[0014] The present disclosure also relates to a method of preparing a compound of Formula (I):comprising: i) preparing a compound of Formula (1-g):by adding alcoholic hydrochloric acid to a mixture comprising a compound of Formula (1-f):in an organic solvent to form the compound of Formula (1-g), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH; ii) preparing the compound of Formula (I) by adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising the compound of Formula (1-g) and a compound of Formula (1-l):Attorney Docket No: 01183-0334-00PCT 1-l in acetonitrile to form the compound of Formula (I).

[0015] The present disclosure further relates to a method of preparing a compound of Formula (1-f):comprising: adding Formula (1-e):to a mixture of iodomethane and potassium carbonate in MeTHF to form the compound of Formula (1-f).

[0016] The present disclosure also relates to a method of preparing a compound of Formula (I), comprising the following steps:Attorney Docket No: 01183-0334-00PCT .Attorney Docket No: 01183-0334-00PCT

[0018] FIG.1 provides the HPLC plot for Ethyl 2-hydrazineyl-2-oxoacetate (2-d) as prepared according to Example S2.2.

[0019] FIG.2 provides an exemplary reagent stream setup. DETAILED DESCRIPTION OF THE DISCLOSURE Definitions

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed descriptions are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0021] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.

[0022] Reference in the specification to “some embodiments”, “an embodiment”, “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristicAttorney Docket No: 01183-0334-00PCT described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosure.

[0023] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 0 ºC” means “about 0 ºC” and also “0 ºC.” Generally, the term “about” includes an amount that would be expected to be within experimental error, such as for example, within 15%, 10%, or 5%.

[0024] As used herein, the term “salt” refers to an acid or base salt of a compound disclosed herein. In some instances, the salt is a “pharmaceutically acceptable salt”, which is understood to be non-toxic. Non-limiting examples of salts include mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0025] As used herein, reference to a “compound of Formula (X)” is also meant to refer to “Compound (X)”. For example, “a compound of Formula (I)” is used interchangeably with “Compound (I)”. Synthesis of Compounds

[0026] The present disclosure relates to methods of preparing a compound of Formula (I). The present disclosure also relates intermediate compounds useful for the preparation of a compound of Formula (I), as well as the synthesis of such intermediates. An overview of a synthesis of a compound of Formula (I) of the present disclosure is shown in Schemes 1-3.Attorney Docket No: 01183-0334-00PCT Scheme 1.Formula (I): comprising:adding a base to a mixture comprising a compound of Formula (1-k):in water followed by addition of an acid to form a compound of Formula (1-l):Attorney Docket No: 01183-0334-00PCT .

[0028] In some embodiments, of preparing a compound ofFormula (I): comprising:heating a mixture comprising a compound of Formula (1-j):in an organic solvent to form a compound of Formula (1-k):

[0029] In some embodiments,of preparing a compound of Formula (I): comprising:mixing a compound of Formula (1-h):Attorney Docket No: 01183-0334-00PCT and a compound of Formula (1-i):in an organic solvent to form a (1-j):. Compound of Formula (1-l)

[0030] In one aspect, provided are a compound of Formula (1-l): comprising:adding a base to a mixture comprising a compound of Formula (1-k):in water followed by addition of an acid to form the compound of Formula (1-l).

[0031] In some embodiments, the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium phosphate. In some embodiments, the base is sodium hydroxide.

[0032] In some embodiments, the acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid. In some embodiments, the acid is hydrochloric acid. Compound of Formula (1-k)Attorney Docket No: 01183-0334-00PCT

[0033] In another aspect, provided herein are methods of preparing a compound of Formula (1- k):comprising: heating a mixture comprising a compound of Formula (1-j):in an organic solvent to form the compound of Formula (1-k).

[0034] In some embodiments, the mixture is heated to a temperature ranging from 60 to 200 °C. In some embodiments, the mixture is heated to a temperature ranging from 100 to 180 °C. In some embodiments, the mixture is heated to a temperature ranging from 120 to 160 °C.

[0035] In some embodiments, the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, 2-methyltetrahydrofuran, toluene, anisole, m-xylene, p-xylene, o-xylene, chlorobenzene, 1,4-dichlorobenzene, and chloroform. In some embodiments, the organic solvent is selected from ethanol and chlorobenzene. Compound of Formula (1-j)

[0036] In another aspect, provided herein are methods of preparing a compound of Formula (1- j):comprising: mixing a compound of Formula (1-h):Attorney Docket No: 01183-0334-00PCT and a compound of Formula (1-i):in an organic solvent to form the (1-j).

[0037] In some embodiments, the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, 2-methyltetrahydrofuran, toluene, anisole, m-xylene, p-xylene, o-xylene, chlorobenzene, 1,4-dichlorobenzene, and chloroform. In some embodiments, the organic solvent is selected from ethanol and chlorobenzene.Attorney Docket No: 01183-0334-00PCT Scheme 2.Formula (I): comprising:adding an acid to a mixture comprising a compound of Formula (2-f):Attorney Docket No: 01183-0334-00PCTin water to form a compound of .

[0039] In some embodiments, of preparing a compound ofFormula (I):comprising: heating a mixture comprising a compound of Formula (2-e):in an organic solvent to form a compound of Formula (2-f):.

[0040] In some embodiments, provided herein are methods of preparing a compound of Formula (I):Attorney Docket No: 01183-0334-00PCT comprising:adding a compound of :wherein R is selected from n-Bu, iBu, n- to a mixture comprising a compound of Formula (2-d): 2-d and a base in an organic solvent and water followed by addition of an additional base to form a compound of Formula (2-e):.

[0041] In some embodiments, provided herein are methods of preparing a compound of Formula (I):comprising: mixing a compound of Formula (2-c):Attorney Docket No: 01183-0334-00PCTwith hydrazine monohydrate in an a compound of Formula (2-d): .Compound of Formula (1-l)

[0042] In one aspect, provided herein are methods of preparing a compound of Formula (1-l): comprising:adding an acid to a mixture comprising a compound of Formula (2-f):in water to form the compound of Formula (1-l).

[0043] In some embodiments, the acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid. In some embodiments, the acid is hydrochloric acid. Compound of Formula (2-f)

[0044] In another aspect, provided herein are methods of preparing a compound of Formula (2- f):comprising: heating a mixture comprising a compound of Formula (2-e):Attorney Docket No: 01183-0334-00PCT in an organic solvent to form the f).

[0045] In some embodiments, a ranging from 40 to 80 °C. In some embodiments, the mixture is heated to a temperature ranging from 50 to 70 °C.

[0046] In some embodiments, the organic solvent is selected from tetrahydrofuran, 2- methyltetrahydrofuran, methanol, ethanol, 2-propanol, n-butanol, acetonitrile, dichloromethane, dimethyl sulfoxide, toluene, ethyl acetate, iso-propyl acetate, and acetone. In some embodiments, the organic solvent is selected from ethanol and n-butanol. Compound of Formula (2-e)

[0047] In another aspect, provided herein are methods of preparing a compound of Formula (2- e):comprising: adding a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, to a mixture comprising a compound of Formula (2-d): 2-d and a base in an organic solvent followed by addition of an additional base to form the compound of Formula (2-e).Attorney Docket No: 01183-0334-00PCT

[0048] In some embodiments, the base is selected from N-methylimidazole, diisopropylethylamine, pyridine, triethylamine, N-methylmorpholine, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate. In some embodiments, the base is selected from diisopropylethylamine and sodium hydroxide.

[0049] In some embodiments, the organic solvent is selected from tetrahydrofuran, 2- methyltetrahydrofuran, methanol, ethanol, 2-propanol, n-butanol, acetonitrile, dichloromethane, dimethyl sulfoxide, toluene, ethyl acetate, iso-propyl acetate, and acetone. In some embodiments, the organic solvent is selected from ethanol and n-butanol. Compound of Formula (2-d)

[0050] In another aspect, provided herein are methods of preparing a compound of Formula (2- d):comprising: mixing a compound of Formula (2-c):with hydrazine monohydrate in an organic solvent to form the compound of Formula (2-d).

[0051] In some embodiments, the organic solvent is selected from tetrahydrofuran, 2- methyltetrahydrofuran, methanol, ethanol, 2-propanol, n-butanol, acetonitrile, dichloromethane, dimethyl sulfoxide, toluene, ethyl acetate, iso-propyl acetate, and acetone. In some embodiments, the organic solvent is selected from ethanol and n-butanol. Compound of Formula (2-b) and Compound of Formula (2-B)

[0052] In another aspect, provided herein are methods of preparing a compound of Formula (2- b):Attorney Docket No: 01183-0334-00PCTcomprising: adding a compound of Formula (2-a):to a mixture comprising acetyl chloride n- form the compound of Formula (2-b).

[0053] Schemes 2 and 3 illustrate a specific example wherein a compound of Formula (2-B) is the compound of Formula (2-b). However, a person of ordinary skill in the art will understand that any compound within the scope of the compound of Formula 2-B can be used in the procedures described in Schemes 2 and 3.(wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et)

[0054] In another aspect, provided herein are methods of preparing a compound of Formula (2- B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, comprising: adding a compound of Formula (2-a):to a mixture comprising acetyl chloride in an organic solvent, wherein the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, 2-propanol, n- butanol, iso-propyl, iso-butanol.Attorney Docket No: 01183-0334-00PCT Scheme 3.Formula (I): comprising:Attorney Docket No: 01183-0334-00PCT adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising a compound of Formula (1-g): and a compound of Formula (1-l):in acetonitrile to form the

[0056] In some embodiments, provided herein are methods of preparing a compound of Formula (I): comprising:adding a base followed by an amidation reagent to a mixture comprising a compound of Formula (1-g):.Attorney Docket No: 01183-0334-00PCT

[0057] In some embodiments, provided herein are methods of preparing a compound of Formula (I):comprising: adding a base to a mixture comprising a compound of Formula (3-d):in water followed by addition of an acid to form a compound of Formula (1-l): .

[0058] In some embodiments,of preparing a compound of Formula (I):comprising: i) reacting a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, with a compound of Formula (3-b):Attorney Docket No: 01183-0334-00PCTin the presence of a base in form a compound of Formula (3-c):ii) heating a mixture (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C, to form t compound of Formula (3-d).

[0059] In some embodiments, provided herein are methods of preparing a compound of Formula (I): comprising:adding hydrazine monohydrate to a mixture comprising a compound of Formula (3-A):wherein R is Et or t-Bu, in an organic solvent to form a compound of Formula (3-b): 3-b in the presence of a base to form a compound of Formula (3-c):Attorney Docket No: 01183-0334-00PCT

[0060] In some embodiments, of preparing a compound of Formula (I):comprising: adding a compound of Formula (2-a):to a mixture comprising acetyl chloride in an organic solvent to form a compound of Formula (2- B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et.

[0061] In some embodiments, provided herein are methods of preparing a compound of Formula (I): comprising:i. preparing a compound of Formula (1-g):Attorney Docket No: 01183-0334-00PCT by adding alcoholic hydrochloric acida compound of Formula (1-f):in an organic solvent to form the g); ii. preparing the compound of Formula (1-f) by adding a compound of Formula (1-e): in DMSO to a mixture ofin MeTHF to form the compound of Formula (1-f); iii. preparing the compound of Formula (1-e) by adding ethyl chloroformate to a mixture comprising a compound of Formula (1-d):in pyridine to form the compound of Formula (1-e); iv. preparing the compound of Formula (1-d) by adding palladium on carbon to a mixture comprising a compound of Formula (1-c):Attorney Docket No: 01183-0334-00PCT in methanol to form the compound of Formula (1-d); v. preparing the compound of Formula (1-c) by adding sodium hydroxide to a mixture comprising a compound of Formula (1-a): 1-a and a compound of Formula (1-b): 1-b in dimethylformamide to form the compound of Formula (1-c). Compound of Formula (I-g)

[0062] In some embodiments, a compound of Formula (1-g): 1-g is prepared by adding alcoholic hydrochloric acid to a mixture comprising a compound of Formula (1-f): in an organic solvent to form theg).

[0063] In some embodiments, the organic solvent is selected from MeOH, EtOH, and iPrOH. Compound of Formula (I-f)

[0064] In some embodiments, a compound of Formula (1-f):Attorney Docket No: 01183-0334-00PCTis prepared by adding a compoundto a mixture of a methylation agent an

[0065] In some embodiments, the methylation agent is selected from MeI and DMS.

[0066] In some embodiments, the base is selected from potassium carbonate, LiHMDS and NaH.

[0067] In some embodiments, the organic solvent is selected from MeCN, DMF, DMSO, MeTHF, nBuCN and DMSO / MeTHF; optionally wherein the methylation agent is MeI, the base is potassium carbonate and the organic solvent is MeTHF.

[0068] In some embodiments, the compound of Formula (1-f) is prepared by adding Formula (1-e) to a mixture of MeI and potassium carbonate in MeTHF; wherein Formula (1-e) is added slowly to the mixture to keep reaction temperature at around 10°C or below 15°C. Compound of Formula (I-e)

[0069] In some embodiments, a compound of Formula (1-e): is prepared by adding ethyla compound of Formula (1- d):Attorney Docket No: 01183-0334-00PCTin pyridine to form the compound of .

[0070] In some embodiments, the compound of Formula (1-e):is prepared by adding an amide agent to a comprising a compound of Formula (1-d):and a base in an organic solvent to form the compound of Formula (1-e).

[0071] In some embodiments, the amide coupling agent is selected from ethyl chloroformate, HATU, Pyoxim, DPP-Cl, COMU and EDCI.

[0072] In some embodiments, the base is selected from pyridine, DIPEA, NMI, Et3N.

[0073] In some embodiments, the organic solvent is selected from pyridine, MeCN, DMF, DCM, and THF. Compound of Formula (I-d)

[0074] In some embodiments, a compound of Formula (1-d):is prepared by adding palladium on carbon in the presence of hydrogen to a mixture comprising a compound of Formula (1-c):Attorney Docket No: 01183-0334-00PCTin an organic solvent to form the d).

[0075] In some embodiments, the organic solvent is selected from MeOH, EtOH, IPAc, and EtOH / water mixture. Compound of Formula (I-c)

[0076] In some embodiments, the compound of Formula (1-c) is prepared by adding a base to a mixture comprising a compound of Formula (1-a): 1-a and a compound of Formula (1-b): 1-b in an organic solvent to form the compound of Formula (1-c).

[0077] In some embodiments, the base is selected from NaOH, KOH, LiOH, NaH, t-BuOK, potassium t-pentoxide, NaHCO3, K2CO3, and Cs2CO3. In some embodiments, the base is NaOH.

[0078] In some embodiments, the organic solvent is selected from DMF, t-BuOH, t-Amyl alcohol, IPA, MeOH, THF, 2-MeTHF, MeCN, THF / water, t-Amyl alcohol / water, t-BuOH / water, IPA / water, MeCN / water and acetone / water. In some embodiments, the organic solvent is DMF. Compound of Formula (1-l)

[0079] In another aspect, provided herein are methods of preparing a compound of Formula (1- l):Attorney Docket No: 01183-0334-00PCT comprising:adding a base to a mixture a (3-d):in water followed by addition of an of Formula (1-l).

[0080] In some embodiments, the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium phosphate. In some embodiments, the base is sodium hydroxide.

[0081] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid. In some embodiments, the acid is hydrochloric acid. Compound of Formula (3-d)

[0082] In another aspect, provided herein are methods of preparing a compound of Formula (3- d):comprising: i) reacting a compound of Formula (2-B):with a compound of Formula (3-b):Attorney Docket No: 01183-0334-00PCTin the presence of a base to form a compound of Formula (3-c):ii) heating a mixture (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C to form the compound of Formula (3-d).

[0083] In some embodiments, the base is selected from triethylamine, diisopropylethylamine, and potassium carbonate.

[0084] In some embodiments, the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2-methyltetrahydrofuran. In some embodiments, the organic solvent is ethanol.

[0085] In some embodiments, the heating ethe Compound of Formula (3-b)

[0086] In another aspect, provided herein are methods of preparing a compound of Formula (3- b):comprising: adding hydrazine monohydrate to a mixture comprising a compound of Formula (3-A):wherein R is Et or t-Bu, in an organic solvent to form the compound of Formula (3-b).Attorney Docket No: 01183-0334-00PCT

[0087] In some embodiments, the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, dichloromethane, and 2-methyltetrahydrofuran. In some embodiments, the organic solvent is ethanol. Compound of Formula (2-b)

[0088] In another aspect, provided herein are methods of preparing a compound of Formula (2- b):comprising: adding a compound of Formula (2-a):to a mixture comprising acetyl chloride in n-butanol to form the compound of Formula (2-b). Compound of Formula (2-B)

[0089] In another aspect, provided herein are methods of preparing a compound of Formula (2- B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, comprising: adding a compound of Formula (2-a):to a mixture comprising acetyl chloride in an organic solvent to form the compound of Formula (2-B), wherein the organic solvent is selected from ethanol, n-propanol, iso-propanol, n-butanol, and iso-butanol. Compound of Formula (3-d), Compound of Formula (3-c), Compound of Formula (2-f)Attorney Docket No: 01183-0334-00PCT

[0090] In some embodiments, provided herein is compound selected from:

[0091] The disclosure presents an improved process of making the compound of Formula (I) as compared to earlier methods using diethyl oxalate as the starting material to make 1, 2, 4- triazole ethyl ester. Using tert-butyl ester (3-d) eliminated the competitive impurity formation, resulting in the successful isolation of the desired tert-butyl ester in high purity. The crystalline tert-butyl ester (3-d) exhibited high stability and purity, making it an excellent control strategy for future manufacturing campaigns. In addition, using n-butyl imidate HCl salt (2-b) unexpectedly improved process control and facilitated downstream transformations.

[0092] In some embodiments, the disclosure presents a process of making the compound of Formula (I) through the T3P-mediated amidation coupling of penultimate compounds (1-g) and (1-l), resulting in one or more improvements, such as the reduction of the use of base, coupling reagent, and solvent volume and thus allowing the process to become more environmentally friendly. EXAMPLES

[0093] The examples and preparations provided below further illustrate and exemplify the compounds and synthetic methods of the present disclosure. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

[0094] Salts of the compounds described herein can be prepared by standard methods, such as stirring the products, with a solution of an acid (for example, aqueous HCl).

[0095] The w / w%, % yield, and purity of the compounds described herein were obtained using HPLC methods unless otherwise described.

[0096] The following abbreviations may be relevant for the application.Attorney Docket No: 01183-0334-00PCT Abbreviations 2-MeTHF: 2-methyltetrahydrofuran AcCl: acetyl chloride AUC: area under the curve aq or aq.: aqueous Boc: tert-butoxycarbonyl Bu: butyl COMU: (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate CDCl3: deterated chloroform CPME: cyclopentyl methyl ether Cs2CO3: caesium carbonate CSTR: continuous stirred-tank reactor d: doublet dd: doublet of doublets d6-DMSO: deuterated dimethyl sulfoxide DCC: N,N'-dicyclohexylcarbodiimide DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMF: N-dimethylformamide DMS: dimethyl sulfide DMSO: dimethyl sulfoxide DPP-Cl: Diphenylphosphonic chloride Et: ethyl ECF: ethyl chloroformate EDCI: N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride Et3N: triethylamine ECF: ethyl chloroformate eq, equiv, or equiv.: equivalents Et: ethylAttorney Docket No: 01183-0334-00PCT EtOAc: ethyl acetate EtOH: ethanol h, hr, or hrs: hour(s) HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HCl: hydrogen chloride HPLC: high-performance liquid chromatography Pr: propyl IPAc: isopropyl acetate iPrOH or IPA: isopropyl alcohol or 2-propanol iPr: isopropyl K2CO3: potassium carbonate KF: Karl Fischer titration KOH: potassium hydroxide t-BuOK: potassium tert-butoxide LCMS: liquid chromatography-mass spectrometry LiHMDS: lithium bis(trimethylsilyl)amide LiOH: lithium hydroxide m: multiplets MeCN or CH3CN: acetonitrile MHz: megahertz KF: Karl Fischer titration MeCN or CH3CN: acetonitrile MeI: methyl iodide MeOH: methanol min or mins: minute(s) mol: mole MsCl: methanesulfonyl chloride MTBE: methyl tertiary butyl ether NMM: N-methylmorpholineAttorney Docket No: 01183-0334-00PCT NMI: 1-methylimidazole NaOH: sodium hydroxide NaHCO3: sodium bicarbonate n-BuOH: n-butanol n-Bu: n-butyl nBuCN: n-butylnitrile NH4OAc: ammonium acetate NMI: 1-methylimidazole NMR: nuclear magnetic resonance NMT: no more than n-Pr: n-propyl o: octet PhCl: chlorobenzene Pyoxim: [Ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate s: singlet t-Amyl alcohol: tert-amyl alcohol t-BuOH: tert-butanol T3P: 1-propanephosphonic acid anhydride THF: tetrahydrofuran TLC: thin layer chromatography UPLC: ultra-performance liquid chromatography V: volume(s) wt%: weight percent δ: chemical shift (ppm)Attorney Docket No: 01183-0334-00PCT Scheme 1. Synthesis of Compound I – Route 1in 9-10V of anhydrous DMF was added NaOH (aq) (11M, 1.7 equiv) at 20°C. The mixture was agitated at 20°C for 1-1.25hrs. To the mixture was added NaOH(aq) (0.3 equiv) every hour for 5 times. The reaction was monitored via HPLC analysis to confirm that 3-F-2-NO2 pyridine content was below 5%. Ethyl acetate (10V) was added and aqueous layer was drained. The combined organic layer was washed with H2O (10V) three times, followed by a brine wash. The final mixture was then dried with Na2SO4. The combined solution was dried down to solid (crude 1-c) at under vacuum to dryness.Attorney Docket No: 01183-0334-00PCT

[0098] 1H NMR (400 MHz CDCl3) δ 8.11 (s, 1H),7.56 (m, 2H), 5.58 (d, 1H), 4.98 (m, 1H), 4.75 (m, 1H), 4.63 (m, 1H), 4.42 (m, 1H), 2.00 (s, 1H), 1.43 (s, 9H), 1,22 (d, 1H). LCMS [M+H] 272.0.

[0099] To the reactor, water (50V) was added at 15°C, dropwise. Dichloromethane (12V) was added, and the organic layer was separated. The aqueous layer was extracted with two additional portions DCM (12V x2), and the organic layers were combined. The pH of the aqueous layer was then adjusted to pH 4-5. To the reactor containing the aqueous layer, EtOAc (10V) was added, and the aqueous layer was drained, and the organic layer was combined with the DCM layer. The combined organic layers was washed with H2O (10V) three times, followed by a brine wash. The final mixture was then dried with Na2SO4. The combined solution was dried down to solid at <45°C. The crude mixture of 1-c was transferred to a pressure reactor and suspended in methanol (10V). The crude solution was bubbled thoroughly with N2 gas, and the pressure reactor was inerted with N2-vacuum cycle three times. The reactor was then charged with 10% Pd / C solution in methanol (0.33kg / L). The N2 / H2 exchange cycle was performed three times with stirring at 30°C. The mixture was stirred for 12 hrs at 4-5 bar H2 at 30°C. The mixture was checked for completion (1-c NMT 2 area%). The mixture was diluted with DCM (10V), filtered through Celite, and washed with 20% MeOH in DCM three times. The crude solution was recharged into a reactor and the solvent was completely removed using rotavap. To the system, methanol (5V) was added, and the content was stirred for 2hrs at room temperature, then cooled down to 10 °C, and aged for additional 2hrs, which resulted in the formation of a slurry. The material was filtered and washed with cold methanol and dried at 40°C under vacuum to afford 1-d as off-white powder in 76% yield.

[0100] 1H NMR (400 MHz d6-DMSO) δ 7.51 (d, 1H), 7.06 (d, 1H), 6.56 (dd, 1H), 4.48 (s, 1H), 4.37 (m, 1H), 4.04 (s, 1H), 1.41 (s, 9H).13CNMR (100 MHz d6-DMSO) δ 171.7, 155.8, 151.1, 140.7, 138.5, 116.2, 111.8, 78.5, 68.3, 53.2, 28.4. Example S1.2. tert-Butyl (S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3- yl)carbamate (1-e)Attorney Docket No: 01183-0334-00PCT

[0101] To a reactor, 1-d was charged and 10V of pyridine was added to dissolve the precursor at 20°C. To the solution, ethyl chloroformate (2 eq) was added dropwise at 0°C. The reaction was warmed up to 25°C and stirred for 2-3 hours, and the reaction was monitored by HPLC (1-d NMT 2%). Once the reaction was complete, the crude solution was cooled to 5°C, and 15V of H2O was charged to the solution to precipitate 1-e. The slurry was filtered, and the mixture was washed with water (5V x3). The wet material was charged back into a reactor; then H2O (10V) was added, and the mixture was stirred for 2 hours, and the solid was filtered. The solid was then vacuum dried at 60°C to afford off-white powder (1-e) in 83% yield.

[0102] 1H NMR (400 MHz d6-DMSO) δ 10.4 (s, 1H), 8.16 (d, 1H), 7.56 (d, 1H), 7.17 (m, 2H), 4.33 (m, 3H), 1.36 (s, 9H).13C NMR (100 MHz d6-DMSO) δ 170.5, 155.4, 145.3, 144.3, 143.6, 130.3, 120.9, 78.8, 74.0, 52.1, 28.3. LCMS [M+H] 298.1 Example S1.3. tert-Butyl (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin- 3-yl)carbamate (1-f)

[0103] A solution of 1-e (1 eq) in DMF (9v / w) was transferred to a round bottom flask at 25°C and cooled to 0°C. A pre-cooled solution of methyl iodide (1.1 eq) in DMF (1V) was added into the reaction flask at 0°C (the internal temperature was kept below 5°C during the addition). Potassium carbonate (2 equiv) was added in 4 lots (4x0.5 eq) to the reaction flask at 0°C in 10-15 minute intervals in between the addition of each K2CO3portion. After completing the addition, the reaction mixture was stirred at 0°C for 5-6 hrs, and the reaction was monitored by UPLC. After the completion of the reaction, the reaction mixture was diluted with cold water (20V) at 0°C over a period of 30-60 minutes. The reaction mixture was stirred at 0°C for 1h, and theAttorney Docket No: 01183-0334-00PCT obtained solid was filtered and dried in vacuo. The obtained wet compound was stirred with water (10V) at 30°C for 1h, and then filtered and dried at 60°C for 8-10hrs to afford 1-f as off- white powder in 80% yield.

[0104] 1H NMR (400 MHz d6-DMSO) δ 8.35 (d, 1H), 7.67 (d, 1H), 7.32 (m, 2H), 4.42 (m, 3H), 3.32 (s, 1H), 1.35 (s, 9H).13CNMR (100 MHz d6-DMSO) δ 170.1, 155.3, 149.7, 145.1, 144.6, 131.4, 122.2, 78.9, 76.2, 50.9, 32.7, 28.3. LCMS [M+H] 280.0. Example S1.4. (S)-3-Amino-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one (1- g)

[0105] of 1-f (1 eq) in methanol (7V) at 15°C. The reaction temperature was raised to 30°C, and the mixture was stirred for 14hrs. The reaction was monitored by HPLC / TLC. After completion of the reaction, the reaction mixture was distilled until the volume reached 2-3V under vacuum at a temperature below 40°C. MTBE (8V) was added to the crude mixture at 0°C and the mixture was stirred for 1-2hrs. The obtained solid was filtered and washed with MTBE (2V). The solid was dried under vacuum at 50°C to afford 1-g in 95% yield.

[0106] 1H NMR (400 MHz d6-DMSO) δ 9.55 (s, 1H), 8.81 (s, 3H), 8.39 (d, 1H), 7.76 (d, 1H), 7.38 (m, 2H), 4.77 (m, 1H), 4.58 (m, 1H), 4.43 (m, 1H) 3.39 (s, 3H).13CNMR (100 MHz d6- DMSO) δ 167.2, 148.4, 145.3, 145.1, 131.8, 122.9, 74.9, 49.6, 32.9. Example S1.5. Ethyl 5-benzyl-4H-1,2,4-triazole-3-carboxylate (1-k)were transferred to a round-bottom flask, to which ethanol (10 V) was added at 30°C. TheAttorney Docket No: 01183-0334-00PCT reaction mixture was stirred at 30°C for 30 hours, and the reaction progress was monitored by HPLC. After completion of the reaction, the solid was filtered and washed with ethanol (5 V). The crude solid was then dried for 2-3 hours. The obtained solid was suspended in chlorobenzene (12 V) in a round-bottom flask. The reaction mixture was heated to reflux using dean-stark apparatus and stirred for 24 hours. After completion of the reaction, the reaction mixture was cooled to 5°C. The obtained solid was filtered and washed with chlorobenzene (3V). The wet cake was re-slurred in cyclohexane (10V), and the mixture was stirred for 2-3 hours. The solid was filtered and washed with cyclohexane (4 V), and the product was dried under vacuum at 60°C for 16 hrs to afford an off-white solid (1-k) in 74% yield.

[0108] 1H NMR (400 MHz d6-DMSO) δ 14.4 (br, 1H), 7.35 (m, 5H), 4.33 (m, 2H), 4.12 (s, 2H), 1.33 (t, 3H)13CNMR (100 MHz d6-DMSO) δ 159.9, 158.1, 153.3, 137.2, 128.8, 128.5, 126.8, 60.9, 45.9, 32.4, 14.3, 11.6. Example S1.6.5-Benzyl-4H-1,2,4-triazole-3-carboxylic acid (1-l)

[0109] 5-benzyl-4H-[1, 2, 4] triazole-3-carboxylic acid ethyl ester (1-k, 1.0 equiv) was charged in a round-bottom flask, and water was added at 0°C. To the stirred solution, NaOH in water (4 equiv, 3.5 M) was added dropwise while maintaining the temperature at <5°C. The reaction mixture was then stirred for 3 hours at 25°C. After completion of the reaction was confirmed by HPLC, the reaction was cooled back to 0°C, and the pH was adjusted to 2 using 6N HCl (aq.). The obtained solid was filtered and washed with water (5V). The wet solid was then re-loaded to the flask and was suspended in water (10V) at 25°C. The content was stirred for 1hour, filtered, and dried at 50°C to afford white powder (1-l) in 74% yield.

[0110] 1H NMR (400 MHz d6-DMSO) δ 14.3 (br, 1H), 7.35 (m, 5H), 4.11 (m, 2H).13CNMR (100 MHz d6-DMSO) δ 161.1, 160.5, 154.3, 138.5, 128.9, 128.4, 126.3, 45.9, 8.49. Example S1.7. (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (I)Attorney Docket No: 01183-0334-00PCTand were was propanephosphonic acid anhydride (50% in EtOAc; 1.25 eq) was added at 5°C under N2 atmosphere. The reaction was warmed to 25°C and stirred for 3-4 hrs. The reaction was monitored by HPLC (1-g NMT 2 area%). After the completion of the reaction, the reaction crude was cooled to 0°C, and water (10V) was added slowly. The resulting mixture was concentrated down to 9-10v / w. The reaction mixture was then diluted with EtOH (5V) and 3V of water at 30°C. Then the reaction crude was heated to 70°C and maintained for 2-3hrs. The reaction crude was cooled slowly to 10°C over a period of 15 hrs and aged for 2 hrs. The obtained solid was filtered and washed with 5V H2O twice. To further purify the material to remove inorganic impurities, the reaction crude was re-dissolved into DCM (15V) and washed with H2O (10V). The organic layer was further washed with saturated sodium bicarbonate (2x 10V), followed by water (2x10V). The organic layer was treated with charcoal and stirred for 30-40 minutes. The organic layer was filtered through Celite and washed with additional dichloromethane. The filtrate was concentrated, and 5V of ethanol was added. Recrystallization was performed by heating the mixture to 70°C and slowly cooling it down to 10°C over 10-12hrs. The resulting solid was then filtered and washed with the 2V of ethanol and dried under the vacuum at 50°C to afford Compound I in 78% yield.

[0112] 1H NMR (400 MHz d6-DMSO) δ 14.35-14.82 (br, 1H), 8.51-8.93 (br, 1H), 8.35-8.37 (dd, 1H), 7.69 (dd, 1H), 7.26-7.35 (m, 6H), 4.67-4.73 (t, 1H), 4.49-4.54 (dd, 1H), 4.82-4.90 (m, 1H), 4.15 (s, 2H), 3.36 (s, 3H).13CNMR (100 MHz d6-DMSO) δ 169.1, 158.3, 149.3, 145.2, 144.7, 137.2, 128.8, 128.7, 126.8, 122.4, 76.0, 49.4, 32.8, 32.6. LCMS [M+H] 379.2 Scheme 2. Synthesis of Compound I – Route 2Attorney Docket No: 01183-0334-00PCTExample S2.1. Butyl 2-phenylacetimidate hydrochloride (2-b)

[0114] In a round-The reaction vessel was cooled to 0 °C, and acetyl chloride (2.2 equiv.) was added dropwise while maintaining the internal temperature to <10°C. To the mixture, benzyl cyanide (2-a, 1.0 equiv) was added via a syringe dropwise. The reaction was stirred at 23°C for 16 hours, and 2-MeTHFAttorney Docket No: 01183-0334-00PCT (5V) was added and the stirring was continued for 2 hours at 5°C. The slurry was filtered and washed with 2-MeTHF (2V) twice. The filter cake was dried, which afforded white crystalline powder (2-b) in 85% yield.

[0115] 1H NMR (400 MHz, CDCl3) δ ppm 12.73 (s, 1H), 11.68 (s, 1H), 7.47 – 7.40 (m, 2H), 7.38 – 7.30 (m, 3H), 4.55 (t, J = 6.3 Hz, 2H), 4.04 (s, 2H), 1.81 – 1.70 (m, 2H), 1.37 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, CDCl3) δ ppm 177.38, 131.42, 129.70, 129.23, 128.46, 74.92, 39.46, 29.85, 18.78, 13.56. HRMS calcd. for C12H18ClNO m / z [M- HCl+H]+: calculated: 192.1383, found: 192.1378. Example S2.2. Ethyl 2-hydrazineyl-2-oxoacetate (2-d)

[0116] Media bottles forwith ethanol and flushing with dry N2. Four jacketed continuous-stirrered tank reactor (CSTR) vessels were equipped with a over-head stirrer and a collection bottle. In the starting material bottle, diethyl oxalate (1.5kg, 1 equiv) was diluted with 15L anhydrous EtOH. In the second bottle, hydrazine monohydrate (605g, 1.0 equiv) was added and diluted with EtOH (15L). The tubing at the first section before CSTR1 was equipped with a static mixer and pre-cooled to -78°C. The CSTR vessels CSTR2, CSTR3, and CSTR4 were pre-cooled to -30C°. The flow rates of 2-c and the hydrazine monohydrate solution was adjusted to such that residence time of each vessel was the following: the static mixer (6 seconds), CSTR1 (10 minutes), CSTR2 (30 minutes), CSTR3 (30 minutes), and CSTR4 (30 minutes). The CSTR system was run, and the effluent was continuously filtered, wherein the collected filtrate contained the desired product 2-d (4.7 wt%, 86.6% assay yield), which was used for the next step without further purification.

[0117] The crude product was analyzed by HPLC instrument and Waters Xselect HSS T3 column (4.6 x 150 mm, 3.5 um). Two mobile phases were used for a 23 minute gradient program, wherein the mobile phase A was 10 mM NH4OAc in H2O: CH3CN (95:5) and B was acetonitrile. The detection wavelength was 200 nm, column oven temperature was 2.5 C°, and flow rate was 1.0 mL / min. Within the total run time of 23 minutes, the desired product eluted at 3.1 minutes. The obtained HPLC plot is shown in Figure 1.Attorney Docket No: 01183-0334-00PCT

[0118] 1H NMR (400 MHz, d6-DMSO) δ ppm 4.60 (s 2H), 4.22 (q, 2H), 1.20 (t, 3H).

[0119] A schematic of an exemplary reagent stream setup is shown in Figure 2. Example S2.3. Sodium 5-benzyl-4H-1,2,4-triazole-3-carboxylate (2-f)temperature of the solution was adjusted to 5°C under stirring. At 5°C, DIPEA (3.0 equiv) and EtOH (4V) was charged. To the mixture, under stirring, the imidate salt (2-b) was added portion wise while maintaining the internal temperature at <10°C. The mixture was stirred for 16 hours at 5°C. The reaction progress was monitored by HPLC. Once the 2-d was no more than 1% AUC, water (5V) was charged followed by dropwise addition of 30% NaOH in water (2.7 equiv) at 5°C. The reaction mixture was stirred for 3 hours at 5°C. The reaction mixture was warmed to 60°C and stirred for 16 hours. Once the reaction reached completion, the mixture was concentrated to 5V at a temperature below 50°C in vacuo. To the reactor vessel, 5V of acetonitrile was added, and the mixture was concentrated to 5V. This process was repeated 2 additional times, and the reactor vessel temperature was adjusted to 5°C. The mixture was stirred for an additional 2 hours. The slurry was filtered and dried to afford white solid (2-f) in 64% yield (over the 3 steps) with 62% assay, which was used in the next step without further purification.

[0121] 1H NMR (400 MHz,D2O) δ ppm 7.2-7.4 (m 5H), 4.2 (s, 2H),

[0122] LCMS MS+ 223.1 Example S2.4.5-Benzyl-4H-1,2,4-triazole-3-carboxylic acid (1-l)Attorney Docket No: 01183-0334-00PCT

[0123] To a 2-f (1.0 equiv, 24kg, corrected) wassuspended in water (17V), and the suspension was stirred at 5-10 hours until all the solid dissolved. To the solution, 1M HCl (aq) was charged dropwise while maintaining the internal temperature at 20°C. The suspension was stirred for another 10-20 hours at 20°C, and the progress was monitored by HPLC (the reaction continued until the supernatant concentration of 1-l was NMT 1 weight %). The suspension was filtered through centrifugal filtration, and the filter cake was washed with water (10V) twice. The wet-cake was then re-loaded onto a reactor and suspended in 10V of water. The slurry was stirred for 15 hours to remove excess acid retained in the wet-cake. The suspension was filtered through centrifugal filtration, and the filter cake was washed again with water (10V) twice and dried at 50°C for 40 hours to afford off-white powder 1-l (19.5kg, 88% yield).

[0124] 1H NMR (400 MHz d6-DMSO) δ 14.3 (br, 1H), 7.35 (m, 5H), 4.11 (m, 2H).13CNMR (100 MHz d6-DMSO) δ 161.1, 160.5, 154.3, 138.5, 128.9, 128.4, 126.3, 45.9, 8.49. Example S2.5. (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (I)at 25°C. To the reaction suspension, 3.18V of N,N-diisopropylethylamine (3.9 equiv) was added over 30 mins, and the mixture was stirred for 30 min at 25 °C. To the stirred mixture, 3.31V of T3P (1.05 equiv 50 wt% in acetonitrile) was added over 30min, and the resulting mixture was stirred for 2 hrs at 25°C. Upon completion of the reaction, the mixture was quenched with 4.0V of water. The crude solution was filtered, and the filtrate was collected (the assay yield and the API concentration was measured). The crude solution was distilled to 7.1 V at 35 °C underAttorney Docket No: 01183-0334-00PCT vacuum. To the reactor was added 5V of ethanol followed by 0.87V 6N HCl (aq). Then 4.35V of water was added, and the reaction mixture was heated to 70°C. To the reaction mixture, 2 wt% of Compound I seed in EtOH (0.3V), prepared according to the procedure described in US patent 11,999,750, was added into the reactor, and the mixture was aged for 2 hours at 70°C. The slurry was then cooled at 10°C / h to 10°C and aged for >16 hours. The slurry was filtered and washed with 4V of 5:8 ethanol / water followed by 4V of 1:3 ethanol / water and then dried under vacuum at 50°C to afford Compound I as white crystalline powder (83.7% yield), wherein the characterization data was consistent with Example S1.7. Recrystallization was performed on this powder. The powder was dissolved in THF (25V) and filtration was performed through a 0.45 micron cartridge. The filter was rinsed with 1V THF, and the mixture was concentrated to 13 V. EtOH (13V) was charged, and the final volume was adjusted to 18V. The mixture was heated to reflux until complete dissolution of the powder, then the mixture was cooled to 70°C and seeded (3 weight% with respect to the compound I). The slurry was stirred for 1 hour at 70 °C and then cooled to 40°C in 3 hours. The mixture was heated to 55 °C and stirred for an hour. The mixture was cooled to 10°C over 4.5 hours and stirred for 1 hour before wet milling the mixture at 10 °C. The cake was filtered, and the cake was rinsed with ethanol (2V) at 10 °C. The cake was dried at 50°C to afford 93% yield of compound I.Attorney Docket No: 01183-0334-00PCT Scheme 3. Synthesis of Compound I – Route 3

[0126] Di-a 2000 mL reactor with an overhead stirrer. Ethanol (800 mL; 8V) was added to the reactor, and the stirring speed was set to 350 rpm. The jacket temperature was adjusted to 10 °C. A double syringe pump with 2-100 mL syringes was set up and was primed with ethanol. A solution of hydrazineAttorney Docket No: 01183-0334-00PCT hydrate (41.63 g; 0.832 mol) diluted in ethanol (166.40 g; 3.61 mol) were separately prepared in a graduated cylinder and the final volume was recorded (final volume 250 mL, Density of Hydrazine: 0.167 g / mL). A portion of the hydrazine hydrate and ethanol solution (206.3mL) that corresponds to the desired loading (34.5 g; 0.44 mol; 1.10 eq) was transferred to the reactor via syringe pump over 2h. The reactor was stirred overnight while maintaining the jacketed temperature at 10 °C and IPC samples were collected throughout the process. Once the reaction was complete, the heterogeneous solution was filtered into a frit funnel, and the filtrate was analyzed for 3-b weight% and assay yield (62.3% assay yield), which was used without further purification.

[0127] 1H NMR (400 MHz, CDCl3) δ 8.14 (br, 1H), 1.51 (s, 9H) (note: in-situ NMR was performed and some protons were not observed)

[0128] Alternatively, tert-butyl 2-hydrazineyl-2-oxoacetate (3-b) was prepared from tert-butyl ethyl oxalate, as shown below.

[0129] Awas combined with a solution of 82% hydrazine monohydride (1.0 equiv) in EtOH (5V) at a temperature ranging from of -20 to -10 °C in a plug flow reactor with flow rates such that a total residence time of 10 min was achieved. The resulting effluent stream was collected in a media bottle to afford a 9.65 wt% solution of tert-butyl 2-hydrazineyl-2-oxoacetate (3-b) (93.3% yield). The effluent was taken directly to the next step without further purification. Example S3.2. tert-butyl 5-benzyl-4H-1,2,4-triazole-3-carboxylate (3-d)Attorney Docket No: 01183-0334-00PCT

[0130] To a reactor, 35 g of 3-b (in an ethanol solution, mass of 3-b was calculated based on weight%) was charged, and the temperature was adjusted to 5°C. To the solution, N,N- diisopropylethylamine (3.0 equiv, 85g) was charged at 5 °C over 0.5 hours under N2. The mixture was then stirred for 1 hour at 5 °C.2-b (1.5 equiv, 149.29g) was added portion wise to the mixture while maintaining the temperature at 0-10°C. The mixture was stirred for 20 hr at 5 °C until 3-b was fully consumed. Once the full consumption of the hydrazide was confirmed, the reaction temperature was raised to 60 °C and the mixture was stirred for 3 hours at 60 °C until the intermediate fully cyclized to 3-d (monitored by HPLC). The solution was distilled under vacuum at an internal temperature of below 60 °C until the solvent volume was 6-7V. The solution was then cooled to 35 °C and hydrochloric acid 35% (12.5 g) was added to the reactor to adjust the pH to 5 at 35 °C. Water (1V, 100g) was charged into the reactor at 35 °C, and a 3-d seed (1 weight%; prepared by isolating a small amount of crude product and purifying it via silica chromatography) was charged into the mixture, and the mixture was stirred for 2 hours. To this mixture, additional water (6V) was added dropwise over 4 hours. The resulting slurry was stirred for 2 hours at 30 °C, and the jacket temperature was cooled to 5 °C over 6 hours. The slurry was stirred for another 9 hr at 5 °C. The slurry was then filtered, and the filter cake was washed with a pre-cooled water:ethanol mixture (5V, 7:6 ratio) twice. The wet cake was dried at 45 °C for 22 hrs to obtain white powder (3-d) in 72.7%

[0131] 1H NMR (400 MHz d6-DMSO) δ 7.21-7.31 (o, 5H), 4.10 (s, 2H), 1.49 (s, 9H).13C NMR (100 MHz d6-DMSO) δ 158.7, 158.0, 153.5, 137.0, 128.9, 128.8, 127.0, 82.2, 32.3, 27.9. HRMS calcd. for C14H17N3O2 m / z [M + H]+: calculated:260.1321, found: 260.1397. Example S3.3.5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (1-l)

[0132] To a reactor, 3-d (100g, 1 equiv) was charged with 10V water. The jacket temperature was adjusted to 5°C, and the mixture was stirred for 30 minutes. To the resulting suspension, NaOH (39g, 2.5 equiv) was charged slowly while maintaining the temperature below 50°C. The jacket temperature was heated to 50°C, and the mixture was stirred for 15-40 hours until the reaction reached completion (3-d / 1-l ≤ 0.3%). In a separate container, hydrochloric acid (35Attorney Docket No: 01183-0334-00PCT weight%) was diluted in water to prepare a 6M HCl solution. The reaction mixture was cooled to 5°C, and then 6M HCl (aq) was dropwise added to adjust the pH ≤ 2.0 at 5°C. The mixture was stirred for 2 hours at 5°C. The wet-cake was filtered and washed with 5V of water twice. The wet-cake was re-loaded to the reactor and 10V of water was charged. The mixture was stirred for an additional 18 hours, filtered, and washed with 5V of water twice. The wet cake was dried at 50°C for 16-24 hours to afford the off-white powder product (1-l) in 95% yield, wherein the characterization data was consistent with Example S1.6 and Example S2.4. Example S3.4. tert-Butyl (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin- 3-yl)carbamate (1-f)

[0133] A solution of 1-e (40g, 1 eq) in DMSO (5V) was transferred to a round bottom flask at 25°C and cooled to 10°C. In a separate vessel, methyl iodide (22.4g, 1.1 eq) and K2CO3(29.7g, 1.5 equiv) in MeTHF (2.5V) were mixed and pre-cooled to 10°C. To this solution, the 1-e solution was added dropwise. After completing the addition, the reaction mixture was stirred at 10°C for 5-6 hrs, and the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was diluted with cold water (15V) at 20°C over a period of 30-60 minutes. The reaction mixture was stirred at 10°C for 2hrs, and the obtained solid was filtered and washed with water (5V x2). The obtained wet compound was dried at 60°C for 8-10hrs in vacuum to afford 1-f as off-white powder in 89.9% yield.

[0134] 1H NMR (400 MHz d6-DMSO) δ 8.35 (d, 1H), 7.67 (d, 1H), 7.32 (m, 2H), 4.42 (m, 3H), 3.32 (s, 1H), 1.35 (s, 9H).13C NMR (100 MHz d6-DMSO) δ 170.1, 155.3, 149.7, 145.1, 144.6, 131.4, 122.2, 78.9, 76.2, 50.9, 32.7, 28.3. LCMS [M+H] 280.0. Example S3.5. (S)-3-Amino-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one (1- g)Attorney Docket No: 01183-0334-00PCT

[0135] In 2-propanol(238.0mL) were was at acid in 2-propanol (69.95g, 5.53M) was added, and the mixture was stirred until completion, monitored by HPLC / TLC. After completion of the reaction, the reaction mixture was distilled until the volume reached 6V under vacuum at a temperature below 60°C. The concentrate was cooled to 20°C. CPME (6V) was added to the crude mixture at 20°C, and the mixture was cooled to 0°C and stirred for 1-2hrs. The obtained solid was filtered and washed with 2-propanol:CPME (1:2 ratio) (2V), followed by MeCN (2V). The solid was dried under vacuum at 50°C to afford 1-g in 98.5% yield.

[0136] 1H NMR (400 MHz d6-DMSO) δ 9.55 (s, 1H), 8.81 (s, 3H), 8.39 (d, 1H), 7.76 (d, 1H), 7.38 (m, 2H), 4.77 (m, 1H), 4.58 (m, 1H), 4.43 (m, 1H) 3.39 (s, 3H).13C NMR (100 MHz d6- DMSO) δ 167.2, 148.4, 145.3, 145.1, 131.8, 122.9, 74.9, 49.6, 32.9. Example S3.6. (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (I)at Tr=25 ± 5 °C. To the reaction suspension, 3.18V of N,N-diisopropylethylamine (3.9 equiv) was added over 30 mins, and the mixture was stirred for 30 min at 25± 5 °C. To the stirred mixture, 3.31V of T3P (1.08 equiv, 50 wt% in acetonitrile) was added over 30 min (Tr<40°C), and the resultant mixture was stirred for 2 hrs at 25 ± 5 °C. Upon the completion of the reaction, the mixture was quenched with 4.0V of water. The crude solution was filtered, and the mass was measured (the assay yield and the API concentration were determined). The crude solution was then distilled to 7.1 V of the solution at Tj = 35 °C at 100 torr, to which 5V of ethanol followedAttorney Docket No: 01183-0334-00PCT by 0.87V 6N HCl (aq) were added. After charging 4.35V of water, the reaction mixture was then heated to Tr=70°C. To the reaction mixture, 2 wt% of Compound I seed in EtOH (0.3V) , prepared according to the procedure described in US patent 11,999,750, was added into the reactor, and the mixture was aged for 2 hours. The slurry was then cooled at 10°C / h to 10°C and aged for >16 hours. The slurry was filtered and washed with 4V of 5:8 ethanol / water followed by 4V of 1:3 ethanol / water and then dried under vacuum at 50°C to afford Compound I as white crystalline powder (83.7% yield), wherein the characterization data was consistent with Example S1.7. The crude is dissolved in THF (25V) and filtration was performed through 0.45 micron cartridge. The filter was rinsed with 1V of THF and the mixture was concentrated to 13 V. EtOH (13V) was charged and adjust the final volume to 18V. The mixture is heated to reflux until the complete dissolution, then the mixture was cooled to 70°C and seed (3 weight% with respect to the compound I). The slurry was stirred at 1 hour at 70 °C and then cooled to 40°C in 3 hours. The mixture was heated to 55 °C and stirred for an hour. The mixture was cooled to 10°C over 4.5 hours and stirred for 1 hour before wet mill the mixture at 10 °C. The cake was filtered and rinse the cake with ethanol (2V) at 10 °C. Dry the cake at 50°C to afford 93% yield of compound I.

[0138] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following embodiments define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference. To the extent that any incorporated material is inconsistent with the express content of this disclosure, the express content controls.

[0139] Embodiments:

[0140] Non-limiting embodiments of the disclosure include:

[0141] Embodiment 1. A method of preparing a compound of Formula (I):Attorney Docket No: 01183-0334-00PCT comprising:adding diisopropylethylamine acid anhydride to a mixture comprising a compound of Formula (1-g):and a compound of Formula (1-l):in acetonitrile to form the

[0142] Embodiment 2. The method of embodiment 1, wherein the compound of Formula (1-l) is prepared by adding a base to a mixture comprising a compound of Formula (3-d):in water followed by addition of an acid to form the compound of Formula (1-l).

[0143] Embodiment 3. A method of preparing a compound of Formula (1-l): comprising:adding a base to a mixture comprising a compound of Formula (3-d):Attorney Docket No: 01183-0334-00PCT in water followed by addition ofof Formula (1-l).

[0144] Embodiment 4. The method of embodiment 2 or 3, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, lithium hydroxide, and potassium phosphate; optionally wherein the base is sodium hydroxide; and wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid; optionally wherein the acid is hydrochloric acid.

[0145] Embodiment 5. The method of any one of embodiments 2-4, wherein the compound of Formula (3-d) is prepared i) reacting a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, with a compound of Formula (3-b):in the presence of a base in an organic solvent to form a compound of Formula (3-c):wherein the base is selected from triethylamine, diisopropylethylamine, and potassium carbonate; wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol;Attorney Docket No: 01183-0334-00PCT ii) heating a mixture comprising the compound of Formula (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C to form the compound of Formula (3-d).

[0146] Embodiment 6. A method of preparing a compound of Formula (3-d):comprising: i) reacting a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, with a compound of Formula (3-b):in the presence of a base in an organic solvent to form a compound of Formula (3-c):wherein the base is selected from triethylamine, diisopropylethylamine, and potassium carbonate; wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol;Attorney Docket No: 01183-0334-00PCT ii) heating a mixture comprising the compound of Formula (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C to form the compound of Formula (3-d).

[0147] Embodiment 7. The method of embodiment 5 or 6, wherein the compound of Formula (3-b) is prepared by adding hydrazine monohydrate to a mixture comprising a compound of Formula (3-A):wherein R is Et or t-Bu, in an organic to compound of Formula (3-b), wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, butanol, dichloromethane, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol.

[0148] Embodiment 8. A method of preparing a compound of Formula (3-b):comprising: adding hydrazine monohydrate to a mixture comprising a compound of Formula (3-A):wherein R is Et or t-Bu, in an organic solvent to form the compound of Formula (3-b), wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2- methyltetrahydrofuran; optionally wherein the organic solvent is ethanol.

[0149] Embodiment 9. The method of embodiment 7 or 8, wherein the compound of Formula (2-B) is prepared by adding a compound of Formula (2-a):Attorney Docket No: 01183-0334-00PCT to a mixture comprising acetyl chloridesolvent to form the compound of Formula (2-B), wherein the organic solvent is selected from n-butanol, iso-butanol, n-propanol, iso- propanol, and ethanol, optionally the organic solvent is n-butanol.

[0150] Embodiment 10. A method of preparing a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, adding a compound of Formula (2-a): to a mixture comprising acetyl chloridesolvent to form the compound of Formula (2-B), wherein the organic solvent is selected from n-butanol, iso-butanol, n-propanol, iso- propanol, and ethanol, optionally the organic solvent is n-butanol.

[0151] Embodiment 11. The method of embodiment 9 or 10, wherein the compound of Formula (2-B) is a compound of Formula (2-b):and the organic solvent is n-butanol.

[0152] Embodiment 12. The method of embodiment 1, comprising the following steps: i. preparing the compound of Formula (1-g) by adding alcoholic hydrochloric acid to a mixture comprising a compound of Formula (1-f):Attorney Docket No: 01183-0334-00PCTin an organic solvent to form the g), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH; ii. preparing the compound of Formula (1-f) by adding Formula (1-e):in DMSO to a mixture of iodomethane and potassium carbonate in MeTHF to form the compound of Formula (1-f); iii. preparing the compound of Formula (1-e) by adding an amide coupling agent to a mixture comprising a compound of Formula (1-d):and a base in an organic solvent to form the compound of Formula (1-e); wherein the amide coupling agent is selected from ethyl chloroformate, HATU, Pyoxim, DPP-Cl, COMU, and EDCI; wherein the base is selected from pyridine, DIPEA, NMI, and Et3N; and wherein the organic solvent is selected from pyridine, MeCN, DMF, DCM, and THF; iv. preparing the compound of Formula (1-d) by adding palladium on carbon to a mixture comprising a compound of Formula (1-c): in methanol to form the compoundAttorney Docket No: 01183-0334-00PCT v. preparing the compound of Formula (1-c) by adding a base to a mixture comprising a compound of Formula (1-a): 1-a and a compound of Formula (1-b): 1-b in an organic solvent to form the compound of Formula (1-c), wherein the base is selected from NaOH, KOH, LiOH, NaH, t-BuOK, potassium t-pentoxide, NaHCO3, K2CO3, and Cs2CO3; wherein the organic solvent is selected from DMF, t-BuOH, t-Amyl alcohol, IPA, MeOH, THF, 2-MeTHF, MeCN, THF / Water, t-Amyl alcohol / water, t-BuOH / water, IPA / water, MeCN / water, and acetone / water.

[0153] Embodiment 13. The method of embodiment 12, wherein in step ii, Formula (1-e) in DMSO is added slowly to a mixture of iodomethane and potassium carbonate in MeTHF; optionally Formula (1-e) in DMSO is added slowly to a mixture of iodomethane and potassium carbonate in MeTHF to maintain a reaction temperature to around 10°C, below 15°C, or between 10-15°C.

[0154] Embodiment 14. The method of embodiment 1, comprising the following steps: i. preparing the compound of Formula (1-l) by adding an acid to a mixture comprising a compound of Formula (2-f): 2-f in water to form the compound of Formula (1-l); ii. preparing the compound of Formula (2-f) by heating a mixture comprising a compound of Formula (2-e):Attorney Docket No: 01183-0334-00PCT to a temperature ranging from 40 ranging from 50 to 70 °Cin ethanol to form the compound ; iii. preparing the compound of Formula (2-e) by adding a compound of Formula (2- B): wherein R is selected from n-Bu, iBu, to a mixture comprising a compound ofFormula (2-d): and a base in an organic solventof an additional base to form the compound of Formula (2-e), wherein the base is selected from Et3N, K2CO3, and DIPEA; iv. preparing the compound of Formula (2-d) by mixing a compound of Formula (2- c):with hydrazine monohydrate in an organic solvent to form the compound of Formula (2-d); v. preparing the compound of Formula (2-b) by adding a compound of Formula (2-a):Attorney Docket No: 01183-0334-00PCT to a mixture comprising acetyl chloride solvent to form the compound of Formula(2-b).

[0155] Embodiment 15. The method of embodiment 14, wherein the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, 2-propanol, n- butanol, acetonitrile, dichloromethane, dimethyl sulfoxide, toluene, ethyl acetate, iso-propyl acetate, and acetone; optionally wherein the organic solvent is selected from ethanol and n- butanol.

[0156] Embodiment 16. The method of embodiment 1, comprising the following steps: i. preparing the compound of Formula (1-l) by adding a base to a mixture comprising a compound of Formula (1-k):in water followed by addition of an acid to form the compound of Formula (1-l); ii. preparing the compound of Formula (1-k) by heating a mixture comprising a compound of Formula (1-j):in an organic solvent to form the compound of Formula (1-k); iii. preparing the compound of Formula (1-j) by mixing a compound of Formula (1- h):Attorney Docket No: 01183-0334-00PCTin an organic solvent to form the (1-j).

[0157] Embodiment 17. The method of embodiment 16, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium phosphate; optionally wherein the base is sodium hydroxide.

[0158] Embodiment 18. The method of embodiment 16, wherein the mixture is heated to a temperature ranging from 60 to 200 °C; optionally wherein the mixture is heated to a temperature ranging from 100 to 180 °C; optionally wherein the mixture is heated to a temperature ranging from 120 to 160 °C.

[0159] Embodiment 19. The method of embodiment 16, wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, 2-methyltetrahydrofuran, toluene, anisole, m-xylene, p-xylene, o-xylene, chlorobenzene, 1,4-dichlorobenzene, and chloroform; optionally wherein the organic solvent is selected from ethanol and chlorobenzene.

[0160] Embodiment 20. A method of preparing a compound of Formula (I):comprising: i) preparing a compound of Formula (1-l): by adding a base to a mixture(3-d):Attorney Docket No: 01183-0334-00PCT in water followed by addition ofof Formula (1-l): ii) reacting a compound of Formula (1-g): 1-g with the compound of Formula (1-l) to form the compound of Formula (I)..

[0161] Embodiment 21. The method of claim 20, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium phosphate; optionally wherein the base is sodium hydroxide; wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid; optionally wherein the acid is hydrochloric acid.

[0162] Embodiment 22. The method of embodiment 20, wherein the compound of Formula (3- d) is prepared by i) reacting a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, with a compound of Formula (3-b): 3-b in the presence of a base in an organic solvent to form a compound of Formula (3-c):Attorney Docket No: 01183-0334-00PCT wherein the base is and potassium carbonate;selected from tetrahydrofuran, ethanol, n-butanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol; ii) heating a mixture comprising a compound of Formula (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C to form the compound of Formula (3-d).

[0163] Embodiment 23. The method of embodiment 20, wherein the compound of Formula (1- g) is prepared by adding alcoholic hydrochloric acid to a mixture comprising a compound of Formula (1-f): in an organic solvent to form theg), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH.

[0164] Embodiment 24. The method of embodiment 20 or 23, wherein the compound of Formula (1-f) is prepared by adding a compound of Formula (1-e): to a mixture of iodomethane andto form the compound of Formula (1-f).

[0165] Embodiment 25. A method of preparing a compound of Formula (I):Attorney Docket No: 01183-0334-00PCTcomprising: i) preparing a compound of Formula (1-g):by adding alcoholic hydrochloric acid to a a compound of Formula (1-f):in an organic solvent, to form the compound of Formula (1-g)wherein the organic solvent is selected from MeOH, EtOH, and iPrOH; ii) preparing the compound of Formula (I) by adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising the compound of Formula (1-g) and a compound of Formula (1-l): in acetonitrile to form the

[0166] Embodiment 26. A method of preparing a compound of Formula (1-f): comprising:Attorney Docket No: 01183-0334-00PCT adding Formula (1-e):to a mixture of iodomethane and to form the compound of Formula (1-f).

[0167] Embodiment 27. The method of embodiment 26, wherein the compound of Formula (1- e) is in DMSO and is added slowly to a mixture of iodomethane and potassium carbonate in MeTHF to keep reaction at temperature around 10°C or below 15°C.

[0168] Embodiment 28. The method of embodiment 26 or 27, wherein a compound of Formula (1-g):is prepared by adding alcoholic hydrochloric acid to a mixture comprising the compound of Formula (1-f) in an organic solvent to form the compound of Formula (1-g), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH.

[0169] Embodiment 29. The method of embodiment 28, wherein a compound of Formula (I):is prepared by adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising the compound of Formula (1-g) and a compound of Formula (1-l): in acetonitrile to form the.Attorney Docket No: 01183-0334-00PCT

[0170] Embodiment 30. A method of preparing a compound of Formula (I), comprising the following steps: .Attorney Docket No: 01183-0334-00PCT

[0172] members of agroup are one, more one, or group are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process.

[0173] Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0174] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

Attorney Docket No: 01183-0334-00PCT CLAIMS What is claimed is:

1. A method of preparing a compound of Formula (I):comprising: adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising a compound of Formula (1-g):and a compound of Formula (1-l): in acetonitrile to form the2. The method of claim 1, wherein the compound of Formula (1-l) is prepared by adding a base to a mixture comprising a compound of Formula (3-d):in water followed by addition of an acid to form the compound of Formula (1-l).

3. A method of preparing a compound of Formula (1-l):Attorney Docket No: 01183-0334-00PCT comprising:adding a base to a mixture comprising a compound of Formula (3-d):in water followed by addition of an of Formula (1-l).

4. The method of claim 2 or 3, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, lithium hydroxide, and potassium phosphate; optionally wherein the base is sodium hydroxide; and wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid; optionally wherein the acid is hydrochloric acid.

5. The method of any one of claims 2-4, wherein the compound of Formula (3-d) is prepared by i) reacting a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, with a compound of Formula (3-b):in the presence of a base in an organic solvent, to form a compound of Formula (3-c):Attorney Docket No: 01183-0334-00PCTwherein the base is and potassium carbonate; wherein the organic solvent is selected from tetrahydrofuran, ethanol, n-butanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol; ii) heating a mixture comprising the compound of Formula (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C to form the compound of Formula (3-d).

6. A method of preparing a compound of Formula (3-d):comprising: i) reacting a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, with a compound of Formula (3-b):in the presence of a base in an organic solvent to form a compound of Formula (3-c):Attorney Docket No: 01183-0334-00PCTwherein the base is and potassium carbonate; wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol; ii) heating a mixture comprising the compound of Formula (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C to form the compound of Formula (3-d).

7. The method of claim 5 or 6, wherein the compound of Formula (3-b) is prepared by adding hydrazine monohydrate to a mixture comprising a compound of Formula (3-A):wherein R is Et or t-Bu, in an organic solvent to form the compound of Formula (3-b), wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, butanol, and 2- methyltetrahydrofuran; optionally wherein the organic solvent is ethanol.

8. A method of preparing a compound of Formula (3-b):comprising: adding hydrazine monohydrate to a mixture comprising a compound of Formula (3-A):Attorney Docket No: 01183-0334-00PCT 3-A wherein R is Et or t-Bu, in an organic solvent to form the compound of Formula (3-b), wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2- methyltetrahydrofuran; optionally wherein the organic solvent is ethanol.

9. The method of claims 7 or 8, wherein the compound of Formula (2-B) is prepared by adding a compound of Formula (2-a): 2-a to a mixture comprising acetyl chloride in an organic solvent to form the compound of Formula (2-B), wherein the organic solvent is selected from n-butanol, iso-butanol, n-propanol, iso- propanol, and ethanol, optionally the organic solvent is n-butanol.

10. A method of preparing a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, comprising: adding a compound of Formula (2-a):to a mixture comprising acetyl chloride in an organic solvent to form the compound of Formula (2-B), wherein the organic solvent is selected from n-butanol, iso-butanol, n-propanol, iso- propanol, and ethanol, optionally the organic solvent is n-butanol.

11. The method of claim 9 or 10, wherein the compound of Formula (2-B) is a compound of Formula (2-b):Attorney Docket No: 01183-0334-00PCTand the organic solvent is n-butanol.

12. The method of claim 1, comprising the following steps: i. preparing the compound of Formula (1-g) by adding alcoholic hydrochloric acid to a mixture comprising a compound of Formula (1-f):in an organic solvent to form the compound of Formula (1-g), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH; ii. preparing the compound of Formula (1-f) by adding Formula (1-e):in DMSO to a mixture of iodomethane and potassium carbonate in MeTHF to form the compound of Formula (1-f); iii. preparing the compound of Formula (1-e) by adding an amide coupling agent to a mixture comprising a compound of Formula (1-d):and a base in an organic solvent to form the compound of Formula (1-e); wherein the amide coupling agent is selected from ethyl chloroformate, HATU, Pyoxim, DPP-Cl, COMU, and EDCI; wherein the base is selected from pyridine, DIPEA, NMI, and Et3N; and wherein the organic solvent is selected from pyridine, MeCN, DMF, DCM, and THF;Attorney Docket No: 01183-0334-00PCT iv. preparing the compound of Formula (1-d) by adding palladium on carbon to a mixture comprising a compound of Formula (1-c):in methanol to form the ; v. preparing the compound of Formula (1-c) by adding a base to a mixture comprising a compound of Formula (1-a):and a compound of Formula (1-b):in an organic solvent to form the compound of Formula (1-c), wherein the base is selected from NaOH, KOH, LiOH, NaH, t-BuOK, potassium t-pentoxide, NaHCO3, K2CO3, and Cs2CO3; wherein the organic solvent is selected from DMF, t-BuOH, t-Amyl alcohol, IPA, MeOH, THF, 2-MeTHF, MeCN, THF / water, t-Amyl alcohol / water, t-BuOH / water, IPA / water, MeCN / water, and acetone / water.

13. The method of claim 12, wherein in step ii, Formula (1-e) in DMSO is added slowly to a mixture of iodomethane and potassium carbonate in MeTHF to maintain a reaction temperature to around 10°C, below 15°C, or between 10-15°C.

14. The method of claim 1, comprising the following steps: i. preparing the compound of Formula (1-l) by adding hydrochloric acid to a mixture comprising a compound of Formula (2-f):Attorney Docket No: 01183-0334-00PCTin water to form the compound of ii. preparing the compound of Formula (2-f) by heating a mixture comprising a compound of Formula (2-e):to a temperature ranging from 40 to to a temperature ranging from 50 to 70 °C in ethanol to form the compound of Formula (2-f); iii. preparing the compound of Formula (2-e) by adding a compound of Formula (2- B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, to a mixture comprising a compound of Formula (2-d): 2-d and a base in an organic solvent followed by addition of an additional base to form the compound of Formula (2-e), wherein the base is selected from Et3N, K2CO3, and DIPEA; iv. preparing the compound of Formula (2-d) by mixing a compound of Formula (2- c):Attorney Docket No: 01183-0334-00PCTwith hydrazine monohydrate in ethanol of Formula (2-d); v. preparing the compound of Formula (2-b) by adding a compound of Formula (2-a):to a mixture comprising acetyl chloride an solvent to form the compound of Formula (2-b).

15. The method of claim 14, wherein the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, 2-propanol, n-butanol, acetonitrile, dichloromethane, dimethyl sulfoxide, toluene, ethyl acetate, iso-propyl acetate, and acetone; optionally wherein the organic solvent is selected from ethanol and n-butanol.

16. The method of claim 1, comprising the following steps: i. preparing the compound of Formula (1-l) by adding a base to a mixture comprising a compound of Formula (1-k): in water followed by addition ofof Formula (1-l); ii. preparing the compound of Formula (1-k) by heating a mixture comprising a compound of Formula (1-j):in an organic solvent to form the compound of Formula (1-k);Attorney Docket No: 01183-0334-00PCT iii. preparing the compound of Formula (1-j) by mixing a compound of Formula (1- h):and a compound of Formula (1-i):in an organic solvent to form the (1-j).

17. The method of claim 16, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium phosphate; optionally wherein the base is sodium hydroxide.

18. The method of claim 16, wherein the mixture is heated to a temperature ranging from 60 to 200 °C; optionally wherein the mixture is heated to a temperature ranging from 100 to 180 °C; optionally wherein the mixture is heated to a temperature ranging from 120 to 160 °C.

19. The method of claim 16, wherein the organic solvent in step (ii) and step (iii) is independently selected from tetrahydrofuran, ethanol, methanol, n-butanol, 2- methyltetrahydrofuran, toluene, anisole, m-xylene, p-xylene, o-xylene, chlorobenzene, 1,4- dichlorobenzene, and chloroform; optionally wherein the organic solvent is selected from ethanol and chlorobenzene.

20. A method of preparing a compound of Formula (I):comprising: i) preparing a compound of Formula (1-l):Attorney Docket No: 01183-0334-00PCT by adding a base to a mixture (3-d):in water followed by addition of a of Formula (1-l): ii) reacting a compound of Formula (1-g):with the compound of Formula (1-l) to form the compound of Formula (I).

21. The method of claim 20, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium phosphate; optionally wherein the base is sodium hydroxide; wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid; optionally wherein the acid is hydrochloric acid.

22. The method of claim 20, wherein the compound of Formula (3-d) is prepared by i) reacting a compound of Formula (2-B):wherein R is selected from n-Bu, iBu, n-Pr, i-Pr, and Et, with a compound of Formula (3-b):in the presence of a base in an organic solvent to form a compound of Formula (3-c):Attorney Docket No: 01183-0334-00PCTwherein the base is and potassium carbonate; wherein the organic solvent is selected from tetrahydrofuran, ethanol, methanol, n-butanol, and 2-methyltetrahydrofuran; optionally wherein the organic solvent is ethanol; ii) heating a mixture comprising a compound of Formula (3-c) to a temperature ranging from 40 to 80 °C; optionally to a temperature ranging from 50 to 70 °C to form the compound of Formula (3-d).

23. The method of claim 20, wherein the compound of Formula (1-g) is prepared by adding hydrochloric acid to a mixture comprising a compound of Formula (1-f):in an organic solvent to form the compound of Formula (1-g), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH.

24. The method of claim 20 or 23, wherein the compound of Formula (1-f) is prepared by adding a compound of Formula (1-e):to a mixture of iodomethane and potassium carbonate in MeTHF to form the compound of Formula (1-f).

25. A method of preparing a compound of Formula (I):Attorney Docket No: 01183-0334-00PCT comprising:i) preparing a :by adding alcoholic hydrochloric to a a compound of Formula (1-f):in an organic solvent to form the compound of Formula (1-g), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH; ii) preparing the compound of Formula (I) by adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising the compound of Formula (1-g) and a compound of Formula (1-l): in acetonitrile to form the26. A method of preparing a compound of Formula (1-f):comprising:Attorney Docket No: 01183-0334-00PCT adding Formula (1-e):to a mixture of iodomethane and to form the compound of Formula (1-f).

27. The method of claim 26, wherein Formula (1-e) is in DMSO and is added slowly to a mixture of iodomethane and potassium carbonate in MeTHF to keep reaction temperature at around 10°C or below 15°C.

28. The method of claim 26 or 27, wherein a compound of Formula (1-g): is prepared by adding alcoholic comprising the compound ofFormula (1-f) in an organic solvent to form the compound of Formula (1-g), wherein the organic solvent is selected from MeOH, EtOH, and iPrOH.

29. The method of claim 28, wherein a compound of Formula (I):is prepared by adding diisopropylethylamine followed by 1-propanephosphonic acid anhydride to a mixture comprising the compound of Formula (1-g) and a compound of Formula (1-l): in acetonitrile to form the30. A method of preparing a compound of Formula (I), comprising the following steps:Attorney Docket No: 01183-0334-00PCT .

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