Process for producing 6-substituted-1-(2H)-isoquinolinone and intermediate compounds

Abstract

The present invention relates to substituted 6-substituted isoquinoline N-oxide compounds of formula (V): [Chemical Formula 1] TIFF2025525162000092.tif20170 (V) and methods for their preparation. The compounds of formula (V) can be used as intermediates for the preparation of 6-substituted-1(2H)-isoquinolinone compounds of formula (I): [Chemical Formula 2] TIFF2025525162000093.tif20170 (I). The compounds of formula (I) are inhibitors of the enzyme Rho kinase or can be used as intermediates in the preparation of further inhibitors of the Rho kinase enzyme.

Description

Technical Field

[0001] The present invention relates to substituted 6-substituted isoquinoline oxide compounds of formula (V) and methods for producing them:

Chem.

Chem.

Background Art

[0002] The present invention relates to a compound of formula (V):

Chem.

[0003] The compound of formula (I) is an inhibitor of Rho kinase enzyme and is particularly useful for the treatment of hypertension, pulmonary hypertension, elevated intraocular pressure, retinopathy and glaucoma, peripheral circulatory disorders, peripheral obstructive arterial disease (PAOD), coronary artery disease, angina pectoris, cardiac hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end-organ damage), fibrotic lung, fibrotic liver, liver failure, hypertensive nephropathy, non-hypertensive nephropathy, diabetic nephropathy, renal failure, fibrotic kidney, glomerulosclerosis, organomegaly, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic diseases, stroke, cerebral vasospasm, cerebral ischemia, pain (e.g., neuropathic pain), neurodegeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunction, arteriosclerosis, benign prostatic hyperplasia, diabetes and diabetic complications, metabolic syndrome, vascular restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, bone diseases such as osteoporosis, gastrointestinal infections caused by bacteria, sepsis, breast cancer, colon cancer, prostate cancer, ovarian cancer, brain cancer, and lung cancer, etc., for the treatment of the occurrence, progression and metastasis thereof. The compound of formula (I) can also be used as an intermediate in the production of further inhibitors of Rho kinase enzyme. The compound of formula (I) and the synthetic route for producing the compound of formula (I) are described, for example, in U.S. Patent Nos. 8,716,481 and 8,785,642.

[0004] There are problems with the current synthetic route for producing the compound of formula (I). One problem is that in the current synthetic route, dimethylamine and pyrrolidine are produced as stoichiometric by-products. Since dimethylamine and pyrrolidine exhibit similar properties to the target compound of formula (I), it may be difficult to remove them to the acceptable levels in the active pharmaceutical ingredient (API). Another problem is that in the current synthetic route, intermediates with poor crystallization properties are produced, which may make isolation and purification difficult.

[0005] Another problem is that in the current synthetic route, 6-(piperidin-4-yloxy)-1H-isochromen-1-one having the following structure is produced:

Chemical formula

[0006] 6-(Piperidin-4-yloxy)-1H-isochromen-1-one shows mutagenicity. Therefore, an object of the present invention is to provide an alternative route for producing a compound of formula (I) that does not produce by-products that may be difficult to remove from the target compound of formula (I), does not produce intermediates with poor crystallization properties, and does not produce by-products having undesirable properties.

[0007] These compounds of formula (I) may be used as Rho kinase inhibitors or as intermediates in the synthesis of further inhibitors.

Summary of the Invention

[0008] The overall process steps for producing substituted 6-substituted isoquinoline oxide compounds of formula (V) and using them as intermediates in the production of compounds of formula (I) are shown in Scheme 1 below.

Chemical

[0009] Each process step of Scheme 1 can further include any step of forming salts of the compound of formula (I), the compound of formula (IV), and the compound of formula (V).

[0010] The compound of formula (I) and its salts can exist in lactam form and / or tautomeric lactim form as shown below:

Chemical

Mode for Carrying Out the Invention

[0011] The method steps for producing a substituted 6-substituted isoquinoline oxide compound of formula (V), and the steps of using them as intermediates in the production of a compound of formula (I) are further described in detail below.

[0012] In one embodiment, the present invention relates to a compound of formula (V):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0013] Step A is shown below.

Chemical formula

[0014] Preferably, R1 is a protecting group. The protecting group of R1 is preferably stable under the reaction conditions used in Step A, Step B, and Step C. Suitable protecting groups R1 include N-alkylenearyls such as benzyl (Bn) group, (diphenyl)methylene group, trityl (triphenylmethyl, Tr) group, or (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, amides such as formyl group, acetyl (Ac) group, or benzoyl (Bz) group, carbamates such as tert-butyloxycarbonyl (BOC) group, carbobenzyloxy (Cbz) group, p-methoxybenzylcarbonyl (Moz) group, or 9-fluorenylmethyloxycarbonyl (Fmoc) group, and N-P and N-sulfonyl protecting groups such as dialkylphosphoramidate group, methanesulfonyl (mesyl, Ms) group, or p-toluenesulfonyl (tosyl, Ts) group.

[0015] The protecting group of R1 can be introduced by methods known in the art, by which a compound of formula (II) where R1 is H is reacted with a corresponding protecting group-providing reagent to generate a protected amine. When R1 is H, a protecting group may be introduced into the compound of formula (IV) by reacting the compound of formula (IV) with a corresponding protecting group-providing reagent to generate a protected amine. When R1 is H, a protecting group may be introduced into the compound of formula (V) by reacting the compound of formula (IV) with a corresponding protecting group-providing reagent to generate a protected amine. Suitable reagents used for introducing the protecting group are known in the art and are commercially available. For example, di-tert-butyl dicarbonate can be used to introduce a tert-butyloxycarbonyl (BOC) group.

[0016] Preferably, the same protecting group R1 is used throughout the synthesis shown in Scheme 1. Therefore, it is preferable to use the protecting group R1 in steps A, B, and C.

[0017] Most suitable are protecting groups that are stable to bases but unstable to acids, such as a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, or a p-toluenesulfonyl (tosyl, Ts) group.

[0018] Preferably, R1 is a C1-C6 alkyl group.

[0019] The C1-C6 alkyl group of R1 can be introduced by methods known in the art, by which a compound of formula (II) in which R1 is H is reacted with a corresponding alkylating reagent to produce an amine alkylated with a C1-C6 alkyl group. In another embodiment, when R1 is H, a C1-C6 alkyl group may be introduced into the compound of formula (IV) by reacting the compound of formula (IV) with a corresponding alkylating reagent to produce an amine alkylated with a C1-C6 alkyl group. In another embodiment, when R1 is H, a C1-C6 alkyl group may be introduced into the compound of formula (V) by reacting the compound of formula (IV) with a corresponding alkylating reagent to produce an amine alkylated with a C1-C6 alkyl group. Suitable reagents used for introducing the C1-C6 alkyl group are known in the art and are commercially available. For example, alkyl halides can be used for introducing a C1-C6 alkyl group.

[0020] Preferably, the same C1-C6 alkyl group R1 is used throughout the synthesis shown in Scheme 1. Therefore, it is preferred to use the same C1-C6 alkyl group R1 in steps A, B, and C.

[0021] The leaving group L1 can be replaced by a nucleophile and can be selected from various groups including but not limited to those containing a weak base. Suitable leaving groups L1 include halides such as fluoride (-F), chloride (-Cl), bromide (-Br), iodide (-I), sulfonates such as p-toluenesulfonate (-TsO) or methanesulfonate (-MsO), perfluoroalkylsulfonates such as trifluoromethanesulfonate (-CF3SO3), nitrate (-ONO2), and phosphate (-OPO(OR2) where R may be an alkyl group).

[0022] The leaving group L2 is replaceable by a nucleophile and can be selected from various groups including, but not limited to, weak bases. Suitable leaving groups L2 include halides such as fluoride (-F), chloride (-Cl), bromide (-Br), iodide (-I), sulfonates such as p-toluenesulfonate (-TsO) or methanesulfonate (-MsO), perfluoroalkylsulfonates such as trifluoromethanesulfonate (-CF3SO3), nitrate (-ONO2), and phosphate (-OPO(OR2) where R may be an alkyl group).

[0023] The leaving group L1 can be introduced by methods known in the art, by which a compound of formula (II) where R2 is -OH is reacted with a corresponding leaving group-providing reagent to generate the leaving group L1.

[0024] The leaving group L2 can be introduced by methods known in the art, by which a compound of formula (III) where R3 is -OH is reacted with a corresponding leaving group-providing reagent to generate the leaving group L2.

[0025] Suitable reagents used to introduce the leaving group are known in the art and are commercially available. For example, methanesulfonyl chloride (MsCl) can be used to introduce the methanesulfonate ( -OMs) leaving group.

[0026] Preferably, R1 is H or a protecting group as defined above.

[0027] Preferably, R1 is a protecting group as defined above.

[0028] Preferably, R1 is a protecting group selected from the group consisting of trityl (triphenylmethyl, Tr) group, (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, tert-butyloxycarbonyl (BOC) group, and p-toluenesulfonyl (tosyl, Ts) group.

[0029] Preferably, R1 is a tert-butyloxycarbonyl (BOC) group.

[0030] Preferably, R1 is a C1-C6 alkyl group.

[0031] Preferably, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0032] Preferably, R2 is -OH or L1, where L1 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3).

[0033] Preferably, R2 is L1, and L1 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3).

[0034] Preferably, R3 is -OH or L2, where L2 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3).

[0035] Preferably, R3 is -OH.

[0036] Preferably, n is 1, 2, or 3.

[0037] Preferably, n is 2 or 3.

[0038] Preferably, n is 3.

[0039] Preferably, step A involves reacting the compound of formula (II) with the compound of formula (III) in the presence of an additional reagent selected from the group consisting of a solvent, a base, and mixtures thereof.

[0040] Solvents suitable for use in step A can be selected from the group consisting of water, ethers, amides, nitriles, and mixtures thereof.

[0041] The solvent used in step A can be an ether selected from the group consisting of diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), dimethoxyethane (DME), methyl tert-butyl ether (MTBE), 1,4-dioxane, and mixtures thereof. and mixtures thereof.

[0042] The solvent used in step A can be an amide selected from the group consisting of dimethylformamide (DMF), dimethylacetamide (DMA), 2-pyrrolidone, and mixtures thereof.

[0043] The solvent used in step A can be a nitrile selected from the group consisting of acetonitrile (MeCN), propionitrile, benzonitrile, and mixtures thereof.

[0044] Preferably, the solvent is selected from the group consisting of water, diethyl ether, THF, MTBE, DMF, MeCN, and mixtures thereof.

[0045] Bases suitable for use in step A can be selected from the group consisting of organic bases, inorganic bases, and mixtures thereof.

[0046] The base used in step A can be an organic base selected from the group consisting of amine bases, alkoxide bases, and mixtures thereof.

[0047] The base used in Step A can be an amine base selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N - diisopropylethylamine, and mixtures thereof.

[0048] The base used in Step A can be an alkoxide salt selected from the group consisting of lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert - butoxide, sodium tert - butoxide, potassium tert - butoxide, and mixtures thereof.

[0049] The base used in Step A can be an inorganic base selected from the group consisting of hydroxide salts, carbonate salts, bicarbonate salts, and mixtures thereof.

[0050] The base used in Step A can be a hydroxide salt selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof.

[0051] The base used in Step A can be a carbonate salt selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.

[0052] The base used in Step A can be a bicarbonate salt selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0053] Preferably, the base is selected from the group consisting of lithium tert - butoxide, sodium tert - butoxide, potassium tert - butoxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.

[0054] Preferably, step A is carried out at about 0 °C to about 150 °C. Preferably, step A is carried out at a temperature of about room temperature to about 125 °C. Preferably, step A is carried out at about 50 °C to about 110 °C. Preferably, step A is carried out at about 55 °C to about 100 °C. Preferably, step A is carried out at about 75 °C to about 105 °C. Preferably, step A is carried out at about 100 °C. Preferably, step A is carried out at about 90 °C. Preferably, step A is carried out at about 65 °C. Preferably , step A is carried out at about 55 °C. Preferably, step A is carried out at about 50 °C to about 145 °C. Preferably, step A is carried out at about 75 °C to about 140 °C. Preferably, step A is carried out at about 100 °C to about 135 °C. Preferably, step A is carried out at about 130 °C.

[0055] Preferably, the amount of the compound of formula (II) relative to the amount of the compound of formula (III) is in the range of 1 to 5 molar equivalents. Preferably, the range is 1.1 to 4 molar equivalents. Preferably, the range is 1.2 to 3 molar equivalents. Preferably, the range is 1.3 to 2 molar equivalents. Preferably, the range is 1.4 to 1.8 molar equivalents. Preferably, the range is 1.5 to 1.7 molar equivalents. Preferably, the amount of the compound of formula (II) relative to the compound of formula (III) is about 1.6 molar equivalents. Preferably, the amount of the compound of formula (II) relative to the amount of the compound of formula (III) is in the range of 1 to 2 molar equivalents. Preferably, the range is 1 to 1.6 molar equivalents. Preferably, the range is 1 to 1.5 molar equivalents. Preferably, the range is 1 to 1.4 molar equivalents. Preferably, the range is 1 to 1.3 molar equivalents. Preferably, the range is 1 to 1.2 molar equivalents. Preferably, the amount of the compound of formula (II) relative to the compound of formula (III) is about 1.1 molar equivalents. Preferably, the amount of the compound of formula (II) relative to the amount of the compound of formula (III) is in the range of 1.5 to 3 molar equivalents. Preferably, the range is 1.75 to 2.75 molar equivalents. Preferably, the range is 2 to 2.5 molar equivalents. Preferably, the range is 2.1 to 2.25 molar equivalents. Preferably, the amount of the compound of formula (II) relative to the compound of formula (III) is about 2.2 molar equivalents.

[0056] Preferably, step A is carried out in the presence of a base and a solvent. Preferably, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof, and the solvent is selected from the group consisting of DMF, water, diethyl ether, MTBE, MeCN, and mixtures thereof. Preferably, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof, and the solvent is selected from the group consisting of DMF, water, MTBE, MeCN, and mixtures thereof. Preferably, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, and potassium tert-butoxide, and the solvent is selected from the group consisting of DMF, water, diethyl ether, MeCN, and mixtures thereof. Preferably, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, and potassium tert-butoxide, and the solvent is DMF or MeCN. Preferably, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, and potassium tert-butoxide, and the solvent is a mixture of DMF or MeCN and water. Preferably, the base is potassium hydroxide and the solvent is DMF. Preferably, the base is potassium hydroxide and the solvent is a mixture of DMF and water. Preferably, the base is potassium carbonate and the solvent is DMF. Preferably, the base is potassium carbonate and the solvent is a mixture of DMF and water. Preferably, the base is cesium carbonate and the solvent is DMF. Preferably, the base is cesium carbonate and the solvent is a mixture of DMF and water. Preferably, the base is potassium tert-butoxide and the solvent is DMF. Preferably, the base is potassium tert-butoxide and the solvent is a mixture of DMF and water. Preferably, the base is potassium hydroxide and the solvent is MeCN. Preferably, the base is potassium hydroxide and the solvent is a mixture of MeCN and water. Preferably, the base is potassium carbonate and the solvent is MeCN.Preferably, the base is potassium carbonate, and the solvent is a mixture of MeCN and water. Preferably, the base is cesium carbonate, and the solvent is MeCN. Preferably, the base is cesium carbonate, and the solvent is a mixture of MeCN and water. Preferably, the base is potassium tert-butoxide, and the solvent is MeCN. Preferably, the base is potassium tert-butoxide, and the solvent is a mixture of MeCN and water. Preferably, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, and potassium tert-butoxide, and the solvent is MTBE. Preferably, the base is potassium hydroxide, and the solvent is MTBE. Preferably, the base is potassium carbonate, and the solvent is MTBE. Preferably, the base is cesium carbonate, and the solvent is MTBE. Preferably, the base is potassium tert-butoxide, and the solvent is MTBE.

[0057] Preferably, the amount of the base with respect to the compound of formula (III) is in the range of 1 to 7 molar equivalents. Preferably, the range is 2 to 6 molar equivalents. Preferably, the range is 3 to 5 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 3 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 4 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is in the range of 1 to 3 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 1 molar equivalent. Preferably, the amount of the base with respect to the compound of formula (III) is about 2 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 2.2 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is in the range of 1 to 1.5 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 1.1 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 1.2 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 1.3 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 1.4 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (III) is about 1.5 molar equivalents.

[0058] Step A can be carried out using a compound of formula (II) or a pharmaceutically acceptable salt thereof and a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0059] Examples of Step A are shown in Scheme 2 and Table I below. Scheme 2 shows an example of the reaction of Step A, and Table I shows the reaction conditions used in the reaction shown in Scheme 2.

Chemical formula

[0060]

Table 1-1

[0061]

Table 1-2

[0062] [Table 1-3]

[0063] [Table 1-4]

[0064] [Table 1-5]

[0065] [Table 1-6]

[0066] [Table 1-7]

[0067] The method for producing the compound of formula (V) comprises reacting a compound of formula (IV): [Chemical formula] (IV) to produce a compound of formula (V): [Chemical formula] (V) (wherein R1 is H, a C1-C6 alkyl group, or a protecting group defined above, and n is 1, 2, 3, or 4), and further includes step B of generating the compound.

[0068] Step B is shown below. [Chemical formula] Project B

[0069] Preferably, R1 is H or a protecting group as defined above.

[0070] Preferably, R1 is a protecting group as defined above.

[0071] Preferably, R1 is a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group.

[0072] Preferably, R1 is a tert-butyloxycarbonyl (BOC) group.

[0073] Preferably, R1 is a C1-C6 alkyl group.

[0074] Preferably, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0075] Preferably, n is 1, 2, or 3.

[0076] Preferably, n is 2 or 3.

[0077] Preferably, n is 3.

[0078] Preferably, R4 is -OH, -O - , a p-toluenesulfonate (-TsO), a methanesulfonate (-MsO), a trifluoromethanesulfonate (-CF3SO3), and mixtures thereof.

[0079] Preferably, Project B involves reacting a compound of formula (IV) in the presence of an additional reagent selected from the group consisting of an oxidizing agent, a catalyst, a solvent, a base, and mixtures thereof to form a compound of formula (V).

[0080] The oxidizing agents suitable for use in Process B can be selected from the group consisting of peroxides, oxiranes, oxygen, ozone, oxone (potassium peroxymonosulfate), halogens, metal oxides, permanganates, and perborates.

[0081] Preferably, the oxidizing agent in Process B is a peroxide selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, acetone peroxide, acetylbenzoyl peroxide, benzoyl peroxide, tert-butyl hydroperoxide, diacetyl peroxide, ethyl hydroperoxide, methyl ethyl ketone peroxide, peracetic acid, performic acid, peroxybenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium percarbonate (Na2CO3·1.5H2O2), and mixtures thereof.

[0082] Preferably, the oxidizing agent used in Process B is an oxirane selected from the group consisting of dimethyldioxirane, difluorodioxirane, methyl(trifluoromethyl)dioxirane, 3,3-bis(trifluoromethyl)dioxirane, and mixtures thereof.

[0083] Preferably, the oxidizing agent used in Process B is oxone.

[0084] Preferably, the oxidizing agent used in Process B is a permanganate compound. Preferably, the oxidizing agent used in Process B is potassium permanganate.

[0085] Preferably, the oxidizing agent used in Process B is a perborate selected from the group consisting of lithium perborate, sodium perborate, potassium perborate, and mixtures thereof. The perborate may be in the form of a hydrate such as sodium perborate tetrahydrate.

[0086] Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, acetone peroxide, sodium percarbonate, peracetic acid, performic acid, peroxybenzoic acid, mCPBA, dimethyldioxirane, Oxone, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium perborate, and mixtures thereof.

[0087] The catalyst suitable for use in step B can be selected from the group consisting of organic catalysts, inorganic catalysts, and organometallic catalysts.

[0088] Preferably, the catalyst used in step B is selected from the group consisting of organometallic catalysts such as methyltrioxorhenium(VII) (also abbreviated as MeReO3, MTO), organic acids such as acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof, inorganic acids such as phosphomolybdic acid (PMA), and mixtures thereof.

[0089] The solvent suitable for use in step B can be selected from the group consisting of halogenated alkanes, nitriles, alcohols, organic acids, and mixtures thereof.

[0090] The solvent used in step B can be a halogenated alkane selected from the group consisting of dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0091] The solvent used in step B can be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile, and mixtures thereof.

[0092] The solvent used in step B can be an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol (1-BuOH), sec-butanol, isobutanol, tert-butanol, and mixtures thereof.

[0093] The solvent used in step B can be an organic acid selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof.

[0094] The base suitable for use in Step B is an inorganic base.

[0095] The base used in Step B can be selected from the group consisting of hydroxide salts, bicarbonate salts, and carbonate salts.

[0096] The base used in Step B can be a hydroxide salt selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof.

[0097] The base used in Step B can be a bicarbonate salt selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0098] The base used in Step B can be a carbonate salt selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.

[0099] Preferably, Step B is carried out at about -10°C to about 50°C. Preferably, Step B is carried out at about -5°C to about 40°C. Preferably, Step B is carried out at about 0°C to about 30°C. Preferably, Step B is carried out at about 5°C to about 30°C. Preferably, Step B is carried out at about 0°C to about 25°C. Preferably, Step B is carried out at about 5°C to about 25°C. Preferably, Step B is carried out at about 0°C to about 20°C. Preferably, Step B is carried out at about 5°C to about 20°C. Preferably, Step B is carried out at about 0°C to about 15°C. Preferably, Step B is carried out at about 5°C to about 15°C. Preferably, Step B is carried out at about 0°C to about 10°C. Preferably, Step B is carried out at about 5°C to about 10°C.

[0100] Preferably, step B is carried out at about 25°C to about 150°C. Preferably, step B is carried out at about 30°C to about 135°C. Preferably, step B is carried out at about 35°C to about 120°C. Preferably, step B is carried out at about 40°C to about 105°C. Preferably, step B is carried out at about 45°C to about 100°C. Preferably, step B is carried out at about 45°C to about 95°C. Preferably, step B is carried out at about 45°C to about 90°C. Preferably, step B is carried out at about 45°C to about 80°C. Preferably, step B is carried out at about 45°C to about 70°C. Preferably, step B is carried out at about 45°C to about 60°C. Preferably, step B is carried out at about 45°C to about 55°C. Preferably, step B is carried out at about 55°C to about 75°C. Preferably, step B is carried out at about 55°C to about 70°C. Preferably, step B is carried out at about 55°C to about 65°C. Preferably, step B is carried out at about 65°C to about 95°C. Preferably, step B is carried out at about 70°C to about 90°C. Preferably, step B is carried out at about 75°C to about 85°C. Preferably, step B is carried out at about 80°C to about 90°C. Preferably, step B is carried out at about 50°C. Preferably, step B is carried out at about 55°C. Preferably, step B is carried out at about 60°C. Preferably, step B is carried out at about 65°C. Preferably, step B is carried out at about 70°C. Preferably, step B is carried out at about 75°C. Preferably, step B is carried out at about 80°C. Preferably, step B is carried out at about 85°C. Preferably, step B is carried out at about 90°C.

[0101] Preferably, step B is carried out in the presence of an oxidizing agent. Preferably, the oxidizing agent used in step B is a peroxide selected from the group consisting of peracetic acid, performic acid, and mixtures thereof.

[0102] Preferably, step B is carried out in the presence of an oxidizing agent and a solvent. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, formic acid, sodium perborate, and mixtures thereof, and the solvent is selected from the group consisting of MeCN, ethanol, acetic acid, DCM, chloroform, and mixtures thereof. Preferably, the oxidizing agent is selected from the group consisting of mCPBA, hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, sodium perborate, and mixtures thereof, and the solvent is selected from the group consisting of MeCN, ethanol, acetic acid, DCM, and mixtures thereof. Preferably, the oxidizing agent is selected from the group consisting of mCPBA, hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, and sodium perborate, and the solvent is selected from the group consisting of MeCN, ethanol, acetic acid, and DCM. Preferably, the oxidizing agent is sodium perborate and the solvent is acetic acid. Preferably, the oxidizing agent is hydrogen peroxide and the solvent is acetic acid. Preferably, the oxidizing agent is urea hydrogen peroxide and the solvent is acetic acid. Preferably, the oxidizing agent is sodium perborate and the solvent is MeCN. Preferably, the oxidizing agent is hydrogen peroxide and the solvent is MeCN. Preferably, the oxidizing agent is urea hydrogen peroxide and the solvent is MeCN. Preferably, the oxidizing agent is mCPBA and the solvent is MeCN. Preferably, the oxidizing agent is sodium perborate and the solvent is ethanol. Preferably, the oxidizing agent is hydrogen peroxide and the solvent is ethanol. Preferably, the oxidizing agent is urea hydrogen peroxide and the solvent is ethanol. Preferably, the oxidizing agent is mCPBA and the solvent is ethanol. Preferably, the oxidizing agent is hydrogen peroxide and the solvent is DCM. Preferably, the oxidizing agent is urea hydrogen peroxide and the solvent is DCM. Preferably, the oxidizing agent is mCPBA and the solvent is DCM.

[0103] Preferably, step B is carried out in the presence of an oxidizing agent, a catalyst, and a solvent. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, hydrogen peroxide urea, sodium percarbonate, peracetic acid, performic acid, sodium perborate, mCPBA, and a mixture thereof; the solvent is selected from the group consisting of MeCN, ethanol, acetic acid, DCM, chloroform, and a mixture thereof; and the catalyst is selected from the group consisting of acetic acid, trifluoroacetic acid, formic acid, MTO, PMA, and a mixture thereof. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, hydrogen peroxide urea, sodium percarbonate, peracetic acid, performic acid, sodium perborate, and a mixture thereof; the solvent is selected from the group consisting of MeCN, ethanol, DCM, and a mixture thereof; and the catalyst is selected from the group consisting of acetic acid, formic acid, MTO, PMA, and a mixture thereof. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, hydrogen peroxide urea, sodium percarbonate, and a mixture thereof, the solvent is selected from the group consisting of MeCN, ethanol, DCM, and a mixture thereof, and the catalyst is selected from the group consisting of acetic acid, formic acid, MTO, PMA, and a mixture thereof. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, hydrogen peroxide urea, sodium percarbonate, and a mixture thereof, the solvent is MeCN or MeCN, and the catalyst is selected from the group consisting of acetic acid, MTO, PMA, and a mixture thereof. Preferably, the oxidizing agent is hydrogen peroxide or hydrogen peroxide urea, the solvent is DCM, and the catalyst is MTO or PMA. Preferably, the oxidizing agent is hydrogen peroxide or hydrogen peroxide urea, the solvent is MeCN, and the catalyst is MTO or PMA. Preferably, the oxidizing agent is hydrogen peroxide, the catalyst is PMA, and the solvent is MeCN. Preferably, the oxidizing agent is urea hydrogen peroxide, the catalyst is PMA, and the solvent is MeCN. Preferably, the oxidizing agent is hydrogen peroxide, the catalyst is MTO, and the solvent is MeCN.Preferably, the oxidizing agent is urea hydrogen peroxide, the catalyst is MTO, and the solvent is MeCN. Preferably, the oxidizing agent is sodium percarbonate, the catalyst is MTO, acetic acid, and mixtures thereof, and the solvent is MeCN. Preferably, the oxidizing agent is hydrogen peroxide or urea hydrogen peroxide, the solvent is ethanol, and the catalyst is MTO or PMA. Preferably, the oxidizing agent is hydrogen peroxide, the catalyst is PMA, and the solvent is ethanol. Preferably, the oxidizing agent is urea hydrogen peroxide, the catalyst is PMA, and the solvent is ethanol. Preferably, the oxidizing agent is hydrogen peroxide, the catalyst is MTO, and the solvent is ethanol. Preferably, the oxidizing agent is urea hydrogen peroxide, the catalyst is MTO, and the solvent is ethanol. Preferably, the oxidizing agent is sodium percarbonate. and the catalyst is MTO, acetic acid, and mixtures thereof, and the solvent is ethanol.

[0104] Preferably, step B is carried out in the presence of an oxidizing agent, a catalyst, a base, and a solvent. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, formic acid, sodium perborate, mCPBA, and mixtures thereof; the solvent is selected from the group consisting of MeCN, ethanol, acetic acid, DCM, chloroform, and mixtures thereof; the catalyst is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, MTO, PMA, and mixtures thereof; and the base is selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, and mixtures thereof; the solvent is selected from the group consisting of MeCN, ethanol, DCM, and mixtures thereof; the catalyst is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, MTO, PMA, and mixtures thereof; and the base is selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, and mixtures thereof; the solvent is selected from the group consisting of MeCN, ethanol, DCM, and mixtures thereof; the catalyst is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, MTO, PMA, and mixtures thereof; and the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, and mixtures thereof. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, and mixtures thereof; the solvent is selected from the group consisting of MeCN, ethanol, DCM, and mixtures thereof; the catalyst is selected from the group consisting of acetic acid, MTO, PMA, and mixtures thereof; and the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, and mixtures thereof.Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, and mixtures thereof, the solvent is MeCN, the catalyst is selected from the group consisting of acetic acid, MTO, and mixtures thereof, and the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, and mixtures thereof. Preferably, the oxidizing agent used in step B is hydrogen peroxide, the solvent is MeCN, the catalyst is a mixture of acetic acid and MTO, and the base is sodium bicarbonate. Preferably, the oxidizing agent used in step B is hydrogen peroxide, the solvent is MeCN, the catalyst is a mixture of acetic acid and MTO, and the base is sodium carbonate. Preferably, the oxidizing agent used in step B is urea hydrogen peroxide, the solvent is MeCN, the catalyst is a mixture of acetic acid and MTO, and the base is sodium bicarbonate. Preferably, the oxidizing agent used in step B is urea hydrogen peroxide, the solvent is MeCN, the catalyst is a mixture of acetic acid and MTO, and the base is sodium carbonate. Preferably, the oxidizing agent used in step B is hydrogen peroxide, the solvent is MeCN, the catalyst is MTO, and the base is sodium bicarbonate. Preferably, the oxidizing agent used in step B is hydrogen peroxide, the solvent is MeCN, the catalyst is MTO, and the base is sodium carbonate. Preferably, the oxidizing agent used in step B is urea hydrogen peroxide, the solvent is MeCN, the catalyst is MTO, and the base is sodium bicarbonate. Preferably, the oxidizing agent used in step B is urea hydrogen peroxide, the solvent is MeCN, the catalyst is MTO, and the base is sodium carbonate. Preferably, the oxidizing agent used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, and mixtures thereof, the solvent is ethanol, and the catalyst is acetic acid, MTO, and mixtures thereof. selected from the group consisting of, and said base is selected from the group consisting of sodium bicarbonate, sodium carbonate, and mixtures thereof. Preferably, said oxidizing agent used in step B is hydrogen peroxide, said solvent is ethanol, said catalyst is a mixture of acetic acid and MTO, and said base is sodium bicarbonate. Preferably, said oxidizing agent used in step B is hydrogen peroxide, said solvent is ethanol, said catalyst is a mixture of acetic acid and MTO, and said base is sodium carbonate. Preferably, said oxidizing agent used in step B is urea hydrogen peroxide, said solvent is ethanol, said catalyst is a mixture of acetic acid and MTO, and said base is sodium bicarbonate. Preferably, said oxidizing agent used in step B is urea hydrogen peroxide, said solvent is ethanol, said catalyst is a mixture of acetic acid and MTO, and said base is sodium carbonate. Preferably, said oxidizing agent used in step B is hydrogen peroxide, said solvent is ethanol, said catalyst is MTO, and said base is sodium bicarbonate. Preferably, said oxidizing agent used in step B is hydrogen peroxide, said solvent is ethanol, said catalyst is MTO, and said base is sodium carbonate. Preferably, said oxidizing agent used in step B is urea hydrogen peroxide, said solvent is ethanol, said catalyst is MTO, and said base is sodium bicarbonate. Preferably, said oxidizing agent used in step B is urea hydrogen peroxide, said solvent is ethanol, said catalyst is MTO, and said base is sodium carbonate.

[0105] Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is in the range of 1 to 10 molar equivalents. Preferably, the range is 1 to 8 molar equivalents. Preferably, the range is 1.1 to 7.5 molar equivalents. Preferably, the range is 1.2 to 6 molar equivalents. Preferably, the range is 1.25 to 5 molar equivalents. Preferably, the range is 1.3 to 4 molar equivalents. Preferably, the range is 1.4 to 3 molar equivalents. Preferably, the range is 1.5 to 2 molar equivalents. Preferably, the range is 1.6 to 1.9 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 1.5 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 1.8 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 2 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 2.2 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 2.5 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 2.8 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 3 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 3.2 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 4 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 5 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 6 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 7 molar equivalents. Preferably, the amount of the oxidizing agent relative to the compound of formula (IV) is about 7.5 molar equivalents.

[0106] Preferably, the amount of the catalyst relative to the compound of formula (IV) is in the range of 0.001 to 1 molar equivalent. Preferably, said range is 0.05 to 0.5 molar equivalent. Preferably, said range is 0.01 to 0.5 molar equivalent. Preferably, the amount of the catalyst relative to the compound of formula (IV) is about 0.005 molar equivalent. Preferably, the amount of the catalyst relative to the compound of formula (IV) is about 0.01 molar equivalent. Preferably, the amount of the catalyst relative to the compound of formula (IV) is about 0.02 molar equivalent. Preferably, the amount of the catalyst relative to the compound of formula (IV) is about 0.03 molar equivalent. Preferably, the amount of the catalyst relative to the compound of formula (IV) is about 0.1 molar equivalent. Preferably, the amount of the catalyst relative to the compound of formula (IV) is about 0.2 molar equivalent. Preferably, the amount of the catalyst relative to the compound of formula (IV) is about 0.3 molar equivalent.

[0107] Preferably, the amount of the base relative to the compound of formula (IV) is in the range of 1 to 10 molar equivalents. Preferably, said range is 1 to 7 molar equivalents. Preferably, said range is 1.1 to 6 molar equivalents. Preferably, said range is 1.2 to 5 molar equivalents. Preferably, said range is 1.3 to 4 molar equivalents. Preferably, said range is 1.4 to 3 molar equivalents. Preferably, said range is 1.5 to 2 molar equivalents. Preferably, the amount of the base relative to the compound of formula (IV) is about 1.5 molar equivalent. Preferably, the amount of the base relative to the compound of formula (IV) is about 2 molar equivalent.

[0108] Without wishing to be bound by theory, step B is considered to be reversible in the presence of water. Thus, without wishing to be bound by theory, the reaction of step B is considered to be optimized by minimizing the amount of water present in step B.

[0109] Step B can be carried out using the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0110] Examples of step B are shown in Scheme 3 and Table II below. Scheme 3 shows an example of the reaction of step B, and Table II shows the reaction conditions used in the reaction shown in Scheme 3. [Chemical formula] Scheme 3 The product of Scheme 3, which is a compound of formula (V), is shown in its zwitterionic N-oxide form, i.e., the form in which R4 is -O - However, it may also be in the form in which the nitrogen atom of the N-oxide is bonded to -OH (i.e., R4 is -OH) or methanesulfonate (-MsO) (i.e., R4 is -MsO). These forms are shown below. [Chemical formula]

[0111] [Table 2-1]

[0112] [Table 2-2]

[0113] [Table 2-3]

[0114] [Table 2-4]

[0115] [Table 2-5]

[0116] [Table 2-6]

[0117] [Table 2-7]

[0118] In one embodiment, the present invention is a method for producing a compound of formula (I) using a compound of formula (V), wherein formula (V):

Chemical formula

Chemical formula

[0119] Step C is shown below.

Chemical formula

[0120] Preferably, R1 is H or a protecting group as defined above.

[0121] Preferably, R1 is a protecting group as defined above.

[0122] Preferably, R1 is a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group.

[0123] Preferably, R1 is a tert-butyloxycarbonyl (BOC) group.

[0124] Preferably, R1 is a C1-C6 alkyl group.

[0125] Preferably, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0126] Preferably, n is 1, 2, or 3.

[0127] Preferably, n is 2 or 3.

[0128] Preferably, n is 3.

[0129] Preferably, step C comprises reacting a compound of formula (V) to form a compound of formula (I) in the presence of an additional reagent selected from the group consisting of an electrophilic reagent, a solvent, a base, a buffer, and mixtures thereof.

[0130] Electrophilic reagents suitable for use in step C can be selected from the group consisting of acyl halides, acid anhydrides, sulfonyl halide reagents, and mixtures thereof.

[0131] Preferably, the electrophilic reagent used in step C is an acyl halide selected from the group consisting of acyl chlorides, acyl bromides, acyl iodides, and mixtures thereof.

[0132] Preferably, the electrophilic reagent used in step C is an acid anhydride selected from the group consisting of acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, and mixtures thereof.

[0133] Preferably, the electrophilic reagent used in step C is a sulfonyl halide reagent selected from the group consisting of benzenesulfonyl chloride, benzenesulfonyl bromide, benzenesulfonyl iodide, methanesulfonyl chloride (mesyl chloride, MsCl), methanesulfonyl bromide, methanesulfonyl iodide, p-toluenesulfonyl chloride (tosyl chloride, TsCl), p-toluenesulfonyl bromide, p-toluenesulfonyl iodide, and mixtures thereof.

[0134] Solvents suitable for use in Step C can be selected from the group consisting of water, amides, ethers, ketones, halogenated alkanes, nitriles, and mixtures thereof.

[0135] The solvent used in Step C can be an amide selected from the group consisting of DMF, DMA, 2-pyrrolidone, and mixtures thereof.

[0136] The solvent used in Step C is diethyl ether, THF, 2-MeTHF, DME, M TBE, 1,4-dioxane, and can be an ether selected from the group consisting of mixtures thereof.

[0137] The solvent used in Step C can be a ketone selected from the group consisting of acetone, methyl ethyl ketone, cyclohexanone, and mixtures thereof.

[0138] The solvent used in Step C can be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0139] The solvent used in Step C can be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile, and mixtures thereof.

[0140] The solvent used in Step C can be a mixture of one or more organic solvents selected from the group consisting of ethers, ketones, halogenated alkanes, and nitriles and water.

[0141] The base suitable for use in Step C can be selected from the group consisting of organic bases, inorganic bases, and mixtures thereof.

[0142] The base used in Step C can be an organic base selected from the group consisting of amine bases, alkoxide salts, and mixtures thereof.

[0143] The base used in Step C can be an amine base selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N - diisopropylethylamine, and mixtures thereof.

[0144] The base used in Step C can be an alkoxide salt selected from the group consisting of lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert - butoxide, sodium tert - butoxide, potassium tert - butoxide, and mixtures thereof.

[0145] The base used in Step C can be an inorganic base selected from the group consisting of hydroxide salts, carbonate salts, bicarbonate salts, phosphate salts, hydrogen phosphate salts, dihydrogen phosphate salts, and mixtures thereof.

[0146] The base used in Step C can be a hydroxide salt selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof.

[0147] The base used in Step C can be a carbonate salt selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.

[0148] The base used in Step C can be a bicarbonate salt selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0149] The base used in Step C can be a phosphate salt selected from the group consisting of lithium phosphate, sodium phosphate, potassium phosphate, and mixtures thereof.

[0150] The base used in Step C can be a hydrogen phosphate salt selected from the group consisting of dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and mixtures thereof.

[0151] The base used in Step C can be a dihydrogen phosphate salt selected from the group consisting of lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof.

[0152] The buffer suitable for use in Step C is a buffer that maintains the pH of the reaction mixture in Step C within the range of pH 4 to pH 10. Without wishing to be bound by theory, it is believed that impurities are formed in Step C in a pH range lower than pH 4. Further, without wishing to be bound by theory, in a pH range higher than pH 10, the hydrolysis rate of the electrophilic reagent is considered to be faster than the rate of Step C. Examples of suitable buffers include acetate buffers such as sodium acetate - acetic acid buffer (pH about 5.2). Further examples of suitable buffers include H3PO4 - Na2HPO4 buffer (about pH 4), Na2HPO4 - NaH2PO4 buffer (about pH 5.8 to about pH 10.0), imidazole - HCl buffer (about pH 6.2 to about pH 7.8), H3PO4 - triethylamine (TEA) buffer (about pH 7), citric acid - triethylamine (TEA) buffer (about pH 7), citric acid - tris(hydroxymethyl)aminomethane (TRIS) buffer (about pH 8), and 3-(N - morpholino)-propanesulfonic acid (MOPS) - triethylamine (TEA) buffer (about pH 7).

[0153] Preferably, step C is carried out in the presence of an electrophilic reagent and a solvent. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, and mixtures thereof, and the solvent is selected from the group consisting of water, DMF, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN, and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, and mixtures thereof, and the solvent is selected from the group consisting of water, DMF, THF, 2-MeTHF, acetone, methyl ethyl ketone, DCM, chloroform, MeCN, and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, and mixtures thereof, and the solvent is selected from the group consisting of water, DMF, THF, 2-MeTHF, acetone, DCM, MeCN, and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, and mixtures thereof, and the solvent is selected from the group consisting of water, THF, 2-MeTHF, acetone, DCM, MeCN, and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, and mixtures thereof, and the solvent is a mixture of at least one organic solvent selected from the group consisting of THF, 2-MeTHF, acetone, DCM, and MeCN and water.Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), and the solvent is a mixture of water and at least one organic solvent selected from the group consisting of THF, 2-MeTHF, acetone, DCM, and MeCN. Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), and the solvent is a mixture of water and THF. Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), and the solvent is a mixture of water and 2-MeTHF. Preferably, the electrophilic reagent is methanesulfonyl chloride ( mesyl chloride, MsCl), and the solvent is a mixture of water and acetone. Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), and the solvent is a mixture of water and DCM. Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), and the solvent is a mixture of water and MeCN.

[0154] Preferably, step C is carried out in the presence of an electrophilic reagent, a solvent, and a base. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, and mixtures thereof; the solvent is selected from the group consisting of water, DMF, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN, and mixtures thereof; and the base is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N-diisopropylethylamine, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, and mixtures thereof; the solvent is selected from the group consisting of water, DMF, THF, 2-MeTHF, acetone, methyl ethyl ketone, DCM, chloroform, MeCN, and mixtures thereof; and the base is selected from the group consisting of trimethylamine, triethylamine, tripropylamine, triisopropylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof.Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, and mixtures thereof; the solvent is selected from the group consisting of water, DMF, THF, 2-MeTHF, acetone, DCM, MeCN, and mixtures thereof; and the base is selected from the group consisting of triethylamine, triisopropylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, and mixtures thereof; the solvent is selected from the group consisting of water, THF, 2-MeTHF, acetone, DCM, MeCN, and mixtures thereof; and the base is selected from the group consisting of triethylamine, triisopropylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, and mixtures thereof; the solvent is selected from the group consisting of THF, 2-MeTHF, acetone, DCM, and MeCN. A mixture of at least one organic solvent and water to be selected, and the base is selected from the group consisting of triethylamine, triisopropylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophile is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of at least one organic solvent selected from the group consisting of THF, 2-MeTHF, acetone, DCM, and MeCN and water, and the base is selected from the group consisting of triethylamine, triisopropylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophile is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and THF, and the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophile is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and 2-MeTHF, and the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof.Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and acetone, and the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and DCM, and the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof. Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and MeCN, and the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof.

[0155] Preferably, step C is carried out in the presence of an electrophilic reagent, a solvent, and a buffer. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, and mixtures thereof, the solvent is selected from the group consisting of water, DMF, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN, and mixtures thereof, and the buffer is a buffer that maintains the pH of the reaction mixture in step C within the range of pH 4 to pH 10. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, and mixtures thereof, the solvent is selected from the group consisting of water, DMF, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN, and those selected from the group consisting of mixtures, and said buffer is selected from the group consisting of sodium acetate - acetic acid buffer, H3PO4 - Na2HPO4 buffer, Na2HPO4 - NaH2PO4 buffer, imidazole - HCl buffer, H3PO4 - triethylamine (TEA) buffer, citric acid - triethylamine (TEA) buffer, citric acid - tris(hydroxymethyl)aminomethane (TRIS) buffer, and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer. Preferably, said electrophile is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chlorides, acyl bromides, acetic anhydride, and mixtures thereof, said solvent is selected from the group consisting of water, DMF, THF, 2-MeTHF, acetone, methyl ethyl ketone, DCM, chloroform, MeCN, and mixtures thereof, and said buffer is selected from the group consisting of sodium acetate - acetic acid buffer, H3PO4 - Na2HPO4 buffer, Na2HPO4 - NaH2PO4 buffer, imidazole - HCl buffer, H3PO4 - triethylamine (TEA) buffer, citric acid - triethylamine (TEA) buffer, citric acid - tris(hydroxymethyl)aminomethane (TRIS) buffer, and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer.Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, and mixtures thereof; the solvent is selected from the group consisting of water, DMF, THF, 2-MeTHF, acetone, DCM, MeCN, and mixtures thereof; and the buffer solution is selected from the group consisting of sodium acetate-acetic acid buffer solution, H3PO4-Na2HPO4 buffer solution, Na2HPO4-NaH2PO4 buffer solution, imidazole-HCl buffer solution, H3PO4-triethylamine (TEA) buffer solution, citric acid-triethylamine (TEA) buffer solution, citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer solution, and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer solution. Preferably, the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, and mixtures thereof; the solvent is selected from the group consisting of water, THF, 2-MeTHF, acetone, DCM, MeCN, and mixtures thereof; and the buffer solution is selected from the group consisting of sodium acetate-acetic acid buffer solution, H3PO4-Na2HPO4 buffer solution, Na2HPO4-NaH2PO4 buffer solution, imidazole-HCl buffer solution, H3PO4-triethylamine (TEA) buffer solution, citric acid-triethylamine (TEA) buffer solution, citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer solution, and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer solution.Preferably, the electrophile is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chlorides, and mixtures thereof, the solvent is a mixture of water and at least one organic solvent selected from the group consisting of THF, 2-MeTHF, acetone, DCM, and MeCN, and the buffer solution is selected from the group consisting of sodium acetate-acetic acid buffer solution, H3PO4-Na2HPO4 buffer solution, Na2HPO4-NaH2PO4 buffer solution, imidazole-HCl buffer solution, H3PO4-triethylamine (TEA) buffer solution, citric acid-triethylamine (TEA) buffer solution, citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer solution, and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer solution. Preferably, the electrophile is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and at least one organic solvent selected from the group consisting of THF, 2-MeTHF, acetone, DCM, and MeCN, and the buffer solution is selected from the group consisting of sodium acetate-acetic acid buffer solution, H3PO4-Na2HPO4 buffer solution, Na2HPO4-NaH2PO4 buffer solution, imidazole-HCl buffer solution, H3PO4-triethylamine (TEA) buffer solution, citric acid-triethylamine (TEA) buffer solution, citric acid-tris(hydroxymethyl... It is selected from the group consisting of tris(hydroxymethyl)aminomethane (TRIS) buffer and 3-(N-morpholino)propanesulfonic acid (MOPS)-triethylamine (TEA) buffer. Preferably, the electrophile is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and THF, and the buffer is selected from the group consisting of sodium acetate-acetic acid buffer, H3PO4-Na2HPO4 buffer, Na2HPO4-NaH2PO4 buffer, imidazole-HCl buffer, H3PO4-triethylamine (TEA) buffer, citric acid-triethylamine (TEA) buffer, citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer, and 3-(N-morpholino)propanesulfonic acid (MOPS)-triethylamine (TEA) buffer. Preferably, the electrophile is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and 2-MeTHF, and the buffer is selected from the group consisting of sodium acetate-acetic acid buffer, H3PO4-Na2HPO4 buffer, Na2HPO4-NaH2PO4 buffer, imidazole-HCl buffer, H3PO4-triethylamine (TEA) buffer, citric acid-triethylamine (TEA) buffer, citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer, and 3-(N-morpholino)propanesulfonic acid (MOPS)-triethylamine (TEA) buffer. Preferably, the electrophile is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and acetone, and the buffer is selected from the group consisting of sodium acetate-acetic acid buffer, H3PO4-Na2HPO4 buffer, Na2HPO4-NaH2PO4 buffer, imidazole-HCl buffer, H3PO4-triethylamine (TEA) buffer, citric acid-triethylamine (TEA) buffer, citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer, and 3-(N-morpholino)propanesulfonic acid (MOPS)-triethylamine (TEA) buffer.Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and DCM, and the buffer solution is selected from the group consisting of sodium acetate - acetic acid buffer solution, H3PO4 - Na2HPO4 buffer solution, Na2HPO4 - NaH2PO4 buffer solution, imidazole - HCl buffer solution, H3PO4 - triethylamine (TEA) buffer solution, citric acid - triethylamine (TEA) buffer solution, citric acid - tris(hydroxymethyl)aminomethane (TRIS) buffer solution, and 3-(N - morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer solution. Preferably, the electrophilic reagent is methanesulfonyl chloride (mesyl chloride, MsCl), the solvent is a mixture of water and MeCN, and the buffer solution is selected from the group consisting of sodium acetate - acetic acid buffer solution, H3PO4 - Na2HPO4 buffer solution, Na2HPO4 - NaH2PO4 buffer solution, imidazole - HCl buffer solution, H3PO4 - triethylamine (TEA) buffer solution, citric acid - triethylamine (TEA) buffer solution, citric acid - tris(hydroxymethyl)aminomethane (TRIS) buffer solution, and 3-(N - morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer solution.

[0156] Preferably, the amount of the electrophilic reagent relative to the compound of formula (V) is in the range of 0.05 to 10 molar equivalents. Preferably, the range is 0.1 to 7 molar equivalents. Preferably, the range is 0.2 to 6 molar equivalents. Preferably, the range is 0.25 to 5 molar equivalents. Preferably, the range is 0.3 to 4 molar equivalents. Preferably, the range is 0.4 to 3 molar equivalents. Preferably, the range is 0.5 to 2.5 molar equivalents. Preferably, the range is 0.6 to 2.25 molar equivalents. Preferably, the range is 0.7 to 2 molar equivalents. Preferably, the range is 0.75 to 1.75 molar equivalents. Preferably, the amount of the electrophilic reagent relative to the compound of formula (V) is about 1.5 molar equivalents. Preferably, the amount of the electrophilic reagent relative to the compound of formula (V) is about 1.6 molar equivalents. Preferably, the amount of the electrophilic reagent relative to the compound of formula (V) is about 1.7 molar equivalents. Preferably, the amount of the electrophilic reagent relative to the compound of formula (V) is about 1.8 molar equivalents. Preferably, the amount of the electrophilic reagent relative to the compound of formula (V) is about 1.9 molar equivalents. Preferably, the compound of formula (V) The amount of the electrophilic reagent with respect to the compound is about 2 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 2.1 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 2.2 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 2.3 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 2.4 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 2.5 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 3 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 3.5 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 4 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 4.5 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 5 molar equivalents. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 0.25 molar equivalent. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 0.5 molar equivalent. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 0.75 molar equivalent. Preferably, the amount of the electrophilic reagent with respect to the compound of formula (V) is about 1 molar equivalent.

[0157] Preferably, the amount of the base with respect to the compound of formula (V) is in the range of 0.1 to 10 molar equivalents. Preferably, the range is 0.5 to 9 molar equivalents. Preferably, the range is 0.75 to 8 molar equivalents. Preferably, the range is 1 to 7 molar equivalents. Preferably, the range is 1.5 to 6 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 0.25 molar equivalent. Preferably, the amount of the base with respect to the compound of formula (V) is about 0.5 molar equivalent. Preferably, the amount of the base with respect to the compound of formula (V) is about 0.75 molar equivalent. Preferably, the amount of the base with respect to the compound of formula (V) is about 1 molar equivalent. Preferably, the amount of the base with respect to the compound of formula (V) is about 1.5 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 2 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 2.5 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 3 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 4 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 5 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 6 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 7 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 7.5 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 8 molar equivalents. Preferably, the amount of the base with respect to the compound of formula (V) is about 9 molar equivalents.

[0158] Preferably, the amount of the buffer solution used in step C is sufficient to maintain the pH within a pH range of pH 4 to pH 10 during the duration of step C.

[0159] Preferably, the amount of the buffer solution relative to the compound of formula (V) is in the range of 1 to 10 molar equivalents. Preferably, said range is 1.5 to 9 molar equivalents. Preferably, said range is 2 to 8 molar equivalents. Preferably, said range is 2.5 to 7 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 2 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 3 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 4 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 5 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 6 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 7 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 7.5 molar equivalents. Preferably, the amount of the buffer solution relative to the compound of formula (V) is about 8 molar equivalents.

[0160] Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:10 to 10:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:9 to 9:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:8 to 8:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:7 to 7:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:6 to 6:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:5 to 5:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:4 to 4:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:3 to 3:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is in the range of 1:2 to 2:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 1:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 2:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 1:2. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 2:3. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 3:2. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 4:3. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 3:4. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 5:3. Preferably, the ratio of the volume of water to the volume of the organic solvent in step C is 3:5.

[0161] Step C can be carried out using the formula (V) or a pharmaceutically acceptable salt thereof.

[0162] Preferably, step C is carried out at about -10°C to about 100°C. Preferably, step C is carried out at about -5°C to about 80°C. Preferably, step C is carried out at about 0°C to about 65°C. Preferably, step C is carried out at about 5°C to about 50°C. Preferably, step C is carried out at about 10°C to about 35°C. Preferably, step C is carried out at about 15°C to about 30°C. Preferably, step C is carried out at about 20°C to about 25°C. Preferably, step C is carried out at about 20°C. Preferably, step C is carried out at about 21°C. Preferably, step C is carried out at about 22°C. Preferably, step C is carried out at about 23°C. Preferably, step C is carried out at about 24°C. Preferably, step C is carried out at about 25°C. Preferably, step C is carried out at about -10°C to about 20°C. Preferably, step C is carried out at about -5°C to about 15°C. Preferably, step C is carried out at about -5°C to about 5°C. Preferably, step C is carried out at about 0°C. Preferably, step C is carried out at about 0°C to about 15°C. Preferably, step C is carried out at about 5°C to about 10°C.

[0163] Examples of step C are shown in Scheme 4 and Table III below. Scheme 4 shows an example of the reaction of step C, and Table III shows the reaction conditions used in the reaction shown in Scheme 4.

Chemical formula

Chemical formula

[0164]

Table 3-1

[0165]

Table 3-2

[0166]

Table 3-3

[0167]

Table 3-4

[0168]

Table 3-5

[0169]

Table 3-6

[0170]

Table 3-7

[0171]

Table 3-8

[0172]

Table 3-9

[0173]

Table 3-10

[0174]

Table 3-11

[0175] Preferably, after step C, any deprotection step D is followed, which comprises removing the protecting group of the compound of formula (I) (wherein R1 is the protecting group defined above), by reacting the compound of formula (I) with at least one deprotecting reagent to produce a compound of formula (I) wherein R1 is H).

[0176] Preferably, step D comprises reacting a compound of formula (I) (wherein R1 is the protecting group defined above) in the presence of a deprotecting reagent and a solvent to form a compound of formula (I) (wherein R1 is H).

[0177] The deprotecting reagent suitable for use in step D can be selected from the group consisting of acyl halides, acid anhydrides, organic acids, inorganic acids, and mixtures thereof.

[0178] The deprotecting reagent used in step D can be an acyl halide selected from the group consisting of acyl chlorides, acyl bromides, acyl iodides, and mixtures thereof.

[0179] The deprotecting reagent used in step D can be an acid anhydride selected from the group consisting of acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, and mixtures thereof.

[0180] The deprotecting reagent used in step D can be an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, and mixtures thereof.

[0181] The deprotecting reagent used in step D can be an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, and mixtures thereof.

[0182] The solvent suitable for use in step D can be selected from the group consisting of alcohols, ethers, nitriles, halogenated alkanes, and mixtures thereof.

[0183] The solvent used in step D can be an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and mixtures thereof.

[0184] The solvent used in step D can be an ether selected from the group consisting of diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof.

[0185] The solvent used in step D can be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile, and mixtures thereof.

[0186] The solvent used in step D can be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0187] Preferably, the deprotection reagent is selected from the group consisting of acyl chlorides, acyl bromides, acetic anhydride, formic anhydride, acetic formic anhydride, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof.

[0188] Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, diethyl ether, THF, 2-MeTHF, MeCN, DCM, chloroform, and mixtures thereof.

[0189] Preferably, the deprotection reagent is acyl chloride and the solvent is isopropanol. Preferably, the deprotection reagent is hydrochloric acid and the solvent is THF. Preferably, the deprotection reagent is trifluoroacetic acid and the solvent is DCM.

[0190] Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is in the range of 1 to 20 molar equivalents. Preferably, said range is 2 to 17.5 molar equivalents. Preferably, said range is 3 to 15 molar equivalents. Preferably, said range is 4 to 12.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 7.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 8 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 9 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 10 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 12.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is in the range of 1 to 10 molar equivalents. Preferably, said range is 1.5 to 7.5 molar equivalents. Preferably, said range is 2 to 5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 2 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 2.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 3 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 4 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 10 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 12.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is in the range of 1 to 10 molar equivalents. Preferably, said range is 1.5 to 7.5 molar equivalents. Preferably, said range is 2 to 5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 2 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 2.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 3 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (I) wherein R1 is the protecting group defined above is about 4 molar equivalents.

[0191] Step D can be carried out using the compound of formula (I) or a pharmaceutically acceptable salt thereof. By Step D, a compound of formula (I) wherein R1 is H or a pharmaceutically acceptable salt thereof is obtained.

[0192] Preferably, step D is carried out at about -10°C to about 70°C. Preferably, step D is carried out at about -5°C to about 60°C. Preferably, step D is carried out at about 0°C to about 50°C. Preferably, step D is carried out at about 5°C to about 40°C. Preferably, step D is carried out at about 10°C to about 35°C. Preferably, step D is carried out at about 15°C to about 30°C. Preferably, step D is carried out at room temperature.

[0193] Examples of step D are shown in Scheme 5 and Table IV below. Scheme 5 shows an example of the reaction of step D, and Table IV shows the reaction conditions used in the reaction shown in Scheme 5.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0194]

Table 4-1

[0195]

Table 4-2

[0196]

Table 4-3

[0197] Preferably, after step A, optionally, a deprotection step E is followed, which comprises removing the protecting group of the compound of formula (IV) (wherein R1 is the protecting group defined above, and reacting the compound of formula (IV) with at least one deprotecting reagent to produce a compound of formula (IV) wherein R1 is H).

[0198] Preferably, step E comprises reacting a compound of formula (IV) (wherein R1 is the protecting group defined above) in the presence of a deprotecting reagent and a solvent to form a compound of formula (IV) (wherein R1 is H).

[0199] The deprotecting reagent suitable for use in step E can be selected from the group consisting of acyl halides, acid anhydrides, organic acids, inorganic acids, and mixtures thereof.

[0200] The deprotecting reagent used in step E can be an acyl halide selected from the group consisting of acyl chlorides, acyl bromides, acyl iodides, and mixtures thereof.

[0201] The deprotecting reagent used in step E can be an acid anhydride selected from the group consisting of acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, and mixtures thereof.

[0202] The deprotection reagent used in step E can be an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, and mixtures thereof.

[0203] The deprotection reagent used in step E can be an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, and mixtures thereof.

[0204] Solvents suitable for use in step E can be selected from the group consisting of alcohols, ethers, nitriles, halogenated alkanes, and mixtures thereof.

[0205] The solvent used in step E can be an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and mixtures thereof.

[0206] The solvent used in step E can be an ether selected from the group consisting of diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof.

[0207] The solvent used in step E can be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile, and mixtures thereof.

[0208] The solvent used in step E can be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0209] Preferably, the deprotection reagent is selected from the group consisting of acyl chlorides, acyl bromides, acetic anhydride, formic anhydride, acetic formic anhydride, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof.

[0210] ​Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, diethyl ether, THF, 2-MeTHF, MeCN, DCM, chloroform, and mixtures thereof.

[0211] Preferably, the deprotecting reagent is an acyl chloride, and the solvent is isopropanol. Preferably, the deprotecting reagent is hydrochloric acid, and the solvent is THF. Preferably, the deprotecting reagent is trifluoroacetic acid, and the solvent is DCM.

[0212] According to a preferred embodiment of the present invention, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is in the range of 1 to 20 molar equivalents. Preferably, the range is 2 to 17.5 molar equivalents. Preferably, the range is 3 to 15 molar equivalents. Preferably, the range is 4 to 12.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 7.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 8 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 9 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 10 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 12.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is in the range of 1 to 10 molar equivalents. Preferably, the range is 1.5 to 7.5 molar equivalents. Preferably, the range is 2 to 5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 2 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 2.5 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 3 molar equivalents. Preferably, the amount of the deprotecting reagent for the compound of formula (IV) (wherein R1 is the protecting group defined above) is about 4 molar equivalents.

[0213] Step E can be carried out using the compound of formula (IV) or a pharmaceutically acceptable salt thereof. By step E, a compound of formula (IV) wherein R1 is H or a pharmaceutically acceptable salt thereof is obtained.

[0214] Preferably, step E is carried out at about -10°C to about 70°C. Preferably, step E is carried out at about -5°C to about 60°C. Preferably, step E is carried out at about 0°C to about 50°C. Preferably, step E is carried out at about 5°C to about 40°C. Preferably, step E is carried out at about 10°C to about 35°C. Preferably, step E is carried out at about 15°C to about 30°C. Preferably, step E is carried out at room temperature.

[0215] Preferably, after step B, optionally, a deprotection step F is included which involves removing the protecting group of the compound of formula (V) (wherein R1 is the protecting group defined above, reacting the compound of formula (V) with at least one deprotecting reagent to produce a compound of formula (V) wherein R1 is H).

[0216] Preferably, step F involves reacting a compound of formula (V) (wherein R1 is the protecting group defined above) in the presence of a deprotecting reagent and a solvent to form a compound of formula (V) (wherein R1 is H).

[0217] The deprotecting reagent suitable for use in step F can be selected from the group consisting of acyl halides, acid anhydrides, organic acids, inorganic acids, and mixtures thereof.

[0218] The deprotecting reagent used in step F can be an acyl halide selected from the group consisting of acyl chlorides, acyl bromides, acyl iodides, and mixtures thereof.

[0219] The deprotecting reagent used in step F can be an acid anhydride selected from the group consisting of acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, and mixtures thereof.

[0220] The deprotecting reagent used in step F can be an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, and mixtures thereof.

[0221] The deprotection reagent used in step F can be an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, and mixtures thereof.

[0222] Solvents suitable for use in step F can be selected from the group consisting of alcohols, ethers, nitriles, halogenated alkanes, and mixtures thereof.

[0223] The solvent used in step F can be an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and mixtures thereof.

[0224] The solvent used in step F can be an ether selected from the group consisting of diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof.

[0225] The solvent used in step F can be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile, and mixtures thereof.

[0226] The solvent used in step F can be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof. The solvent used in step F can be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0227] Preferably, the deprotection reagent is selected from the group consisting of acyl chlorides, acyl bromides, acetic anhydride, formic anhydride, acetic formic anhydride, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof.

[0228] The solvent is selected from the group consisting of methanol, ethanol, isopropanol, diethyl ether, THF, 2-MeTHF, MeCN, DCM, chloroform, and mixtures thereof.

[0229] Preferably, the deprotection reagent is an acyl chloride and the solvent is isopropanol. Preferably, the deprotection reagent is hydrochloric acid and the solvent is THF. Preferably, the deprotection reagent is trifluoroacetic acid and the solvent is DCM.

[0230] According to a preferred embodiment of the present invention, the amount of the deprotection reagent for the compound of formula (V) (wherein R1 is the protecting group defined above) is from 1 to 20 molar equivalents, preferably from 2 to 17.5 molar equivalents, more preferably from 3 to 15 molar equivalents, still more preferably from 4 to 12.5 molar equivalents, for example in the range of about 5, about 7.5, about 8, about 9, about 10, or about 12.5 molar equivalents. Still more preferably, the amount of the deprotection reagent for the compound of formula (V) (wherein R1 is the protecting group defined above) is in the range of 1 to 10, 1.5 to 7.5, or 2 to 5 molar equivalents. The amount of the deprotection reagent for the compound of formula (V) (R1 is the protecting group defined above) can be about 2, about 2.5, about 3, or about 4 molar equivalents.

[0231] Step F can be carried out using the compound of formula (V) or a pharmaceutically acceptable salt thereof. By Step F, a compound of formula (V) wherein R1 is H or a pharmaceutically acceptable salt thereof is obtained.

[0232] Preferably, Step F is carried out at about -10°C to about 70°C. Preferably, Step F is carried out at about -5°C to about 60°C. Preferably, Step F is carried out at about 0°C to about 50°C. Preferably, Step F is carried out at about 5°C to about 40°C. Preferably, Step F is carried out at about 10°C to about 35°C. Preferably, Step F is carried out at about 15°C to about 30°C. Preferably, Step F is carried out at room temperature.

[0233] The compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V) may exist as pharmaceutically acceptable salts.

[0234] Pharmaceutically acceptable salts of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V) can be prepared by methods known in the art from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid, and organic acids, for example, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, and tartaric acid. In the pharmaceutically acceptable salts of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), the ratio of the inorganic acid or organic acid to the compound of formula (I), formula (II), formula (III), formula (IV), or formula (V) is 1 to 5 molar equivalents of the inorganic acid or organic acid per 1 molar equivalent of the compound of formula (I), formula (II), formula (III), formula (IV), or formula (V). Preferably, the ratio of the inorganic acid or organic acid to the compound of formula (I), formula (II), formula (III), formula (IV), or formula (V) is 1 molar equivalent of the inorganic acid or organic acid per 1 molar equivalent of the compound of formula (I), formula (II), formula (III), formula (IV), or formula (V). Preferably, the ratio of the inorganic acid or organic acid to the compound of formula (I), formula (II), formula (III), formula (IV), or formula (V) is 2 molar equivalents of the inorganic acid or organic acid per 1 molar equivalent of the compound of formula (I), formula (II), formula (III), formula (IV), or formula (V).

[0235] The pharmaceutically acceptable salts of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V) may exist as hydrates. The stoichiometry of water molecules to the salt molecules of the pharmaceutically acceptable salts of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V) depends on how strongly the water is bound to each salt and on the humidity.

[0236] Preferably, the hydrates of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), or pharmaceutically acceptable salts thereof, can be formed in any step G by dissolving or suspending the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or pharmaceutically acceptable salts thereof in water or a mixture of water and an organic solvent.

[0237] Preferably, the hydrates of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), or pharmaceutically acceptable salts thereof, are formed in step G by dissolving or suspending the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or pharmaceutically acceptable salts thereof in water.

[0238] Preferably, the hydrates of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), or pharmaceutically acceptable salts thereof, are formed in step G by dissolving or suspending the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or pharmaceutically acceptable salts thereof in a mixture of water and an organic solvent.

[0239] Organic solvents suitable for use in step G are nitriles such as MeCN or propionitrile, ketones such as acetone, ethers such as THF, and alcohols such as methanol, ethanol, n - propanol, and isopropanol.

[0240] Preferably, the hydrates of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), or pharmaceutically acceptable salts thereof, are formed in step G by dissolving or suspending the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or pharmaceutically acceptable salts thereof in a mixture of water and MeCN, acetone, THF, methanol, ethanol, n - propanol, or isopropanol.

[0241] Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:10 to 10:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:9 to 9:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:8 to 8:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:7 to 7:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:6 to 6:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:5 to 5:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:4 to 4:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:3 to 3:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is in the range of 1:2 to 2:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 1:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 2:1. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 1:2. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 2:3. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 3:2. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 4:3. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 3:4. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 5:3. Preferably, the ratio of the volume of water to the volume of the organic solvent in step G is 3:5.

[0242] Preferably, step G is carried out at about -10°C to about 100°C. Preferably, step G is carried out at about -5°C to about 90°C. Preferably, step G is carried out at about 0°C to about 80°C. Preferably, step G is carried out at about 5°C to about 75°C. Preferably, step G is carried out at about 10°C to about 70°C. Preferably, step G is carried out at about 15°C to about 65°C. Preferably, step G is carried out at about 20°C to about 60°C. Preferably, step G is carried out at about 25°C to about 55°C. Preferably, step G is carried out at about 65°C. Preferably, step G is carried out at about 60°C. Preferably, step G is carried out at about 55°C. Preferably, step G is carried out at about 50°C. Preferably, step G is carried out at about 45°C. Preferably, step G is carried out at about 40°C. Preferably, step G is carried out at about 35°C. Preferably, step G is carried out at about 30°C. Preferably, step G is carried out at about 25°C. Preferably, step G is carried out at about 20°C.

[0243] Examples of step G are shown in Scheme 6 and Table V below. Scheme 6 shows an example of the reaction of step G, and Table V shows the reaction conditions used in the reaction shown in Scheme 6. [Chemical formula] Scheme 6 The reactants of Scheme 6 are shown in the lactam form, but as shown below, they may be in the lactim form or in an equilibrium state of both forms. [Chemical formula] Furthermore, the products of Scheme 6 are shown in the lactam form, but as shown below, they may be in the lactim form or in an equilibrium state of both forms. [Chemical formula] [Table 5]

[0244] The entire reaction process is carried out until it is determined to be completed by standard experimental techniques. For example, when at least one reagent is no longer detected in the reaction mixture, it may be determined that the process is complete. Alternatively, when no change is detected in the concentration of the reagent, reaction product, or both in the reaction mixture, it may be determined that the process is complete. The detection of the reagent, product, or both can be performed using standard experimental techniques and equipment. For example, the reagent, product, and both can be monitored using thin-layer chromatography, gas chromatography, or liquid chromatography.

[0245] The product obtained from each reaction step can be isolated by standard synthetic techniques and further purified. For example, the reaction mixture can be evaporated, followed by normal aqueous treatment, and then isolation can be performed by purification by chromatography or crystallization of the product. Alternatively, the product contained in the reaction mixture may be directly precipitated from the reaction mixture by adding a suitable antisolvent such as water and / or alcohol.

[0246] The amount of solvent used in any step is determined by standard experimental techniques. For example, the solvent may be used in an amount such that all the reagents in a step are dissolved in the solvent. Alternatively, a certain amount of solvent may be used to control the reaction rate of the step.

[0247] Definition The term "alcohol" refers to a compound of the formula: R'-OH. R' can be a substituted or unsubstituted alkyl group such as a C1-C 10 substituted or unsubstituted alkyl group, a substituted or unsubstituted C3-C 10 substituted or unsubstituted cyclic alkyl group such as a cyclic alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol.

[0248] The term "alkane" refers to a straight-chain or branched-chain hydrocarbon having 1 to 20 carbon atoms, and "substituted alkane" refers to a straight-chain or branched-chain hydrocarbon having 1 to 20 carbon atoms and further having one or more substituents.

[0249] The term "alkyl" refers to a straight-chain or branched-chain alkyl radical having 1 to 20 carbon atoms, and "substituted alkyl" refers to an alkyl radical further having one or more substituents.

[0250] The term "amide" refers to a compound of the formula: R'-C(O)-NR''R α wherein R' can be H, a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R'' can be H, a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R α can be H, a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. Two or more of R', R'', and R α may be the same, or all of R', R'', and R α may be different. Two of R', R'', and R α may together form a substituted or unsubstituted cyclic alkyl group such as a substituted or unsubstituted C3-C 10 cyclic alkyl group. Examples of amides include dimethylformamide, dimethylacetamide, and 2-pyrrolidone.

[0251] The term "aryl" refers to an aromatic group having 6 to 24 carbon atoms, and "substituted aryl" refers to an aryl group further having one or more substituents.

[0252] The term "buffer solution" refers to a solution that can withstand changes in pH when an acid or a base is added.

[0253] The term "aqueous solution" refers to a solution containing water and a solute selected from the group consisting of salts, acids, bases, buffers, water-soluble or water-miscible organic solvents, and mixtures thereof.

[0254] The term "catalyst" refers to a reagent that can increase the rate of a chemical reaction and is selected from the group consisting of organic compounds, inorganic compounds, or organometallic compounds. Examples of catalysts include methyltrioxorhenium(VII), phosphomolybdic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, triethylamine, pyridine, 4-dimethylaminopyridine, N,N'-dicyclohexylcarbodiimide, and 4-pyrrolidinylpyridine.

[0255] The term "cycloalkyl" refers to a cyclic ring-containing moiety having 3 to 20 carbon atoms, and "substituted cycloalkyl" refers to a cycloalkyl moiety further having one or more substituents.

[0256] The terms "electrophile" and "electrophilic reagent" refer to Lewis acids. Examples of electrophilic reagents include alkyl halides, acyl halides, acid anhydrides, and sulfonyl halide reagents.

[0257] The term "ester" refers to a compound of the formula: R'-C(O)-O-R". R' can be a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R" can be a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R' and R" may be the same. R' and R" may be different. R' and R", taken together, can form a substituted or unsubstituted C3-C 10A substituted or unsubstituted cyclic alkyl group such as a cyclic alkyl group may be formed. Examples of esters include methyl acetate, ethyl acetate, and mixtures thereof.

[0258] The term "ether" refers to a compound of the formula: R'-O-R". R' can be a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R" can be a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R' and R" may be the same. R' and R" may be different. R' and R", together, may form a substituted or unsubstituted cyclic alkyl group such as a C3-C 10 substituted or unsubstituted cyclic alkyl group. Examples of ethers include THF, 2-MeTHF, MTBE, 1,4-dioxane, DME, and mixtures thereof.

[0259] Halogen means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0260] The term "halogenated alkane" refers to an alkane containing one or more carbon atoms and one or more halogen atoms. A halogenated alkane can contain 1 to 10 carbon atoms and 1 to 10 halogen atoms. Examples of halogenated alkanes include DCM, chloroform, carbon tetrachloride, and 1,2-dichloroethane.

[0261] The term "ketone" refers to a compound of the formula: R'-C(O)-R". R' can be a substituted or unsubstituted alkyl group such as a C1-C 10 alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R" can be a substituted or unsubstituted alkyl group such as a C1-C 10It may be a substituted or unsubstituted alkyl group such as an alkyl group, or a substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. R’ and R” may be the same. R’ and R” may be different. R’ and R” together may form a substituted or unsubstituted C3-C 10 substituted or unsubstituted cyclic alkyl group such as a cyclic alkyl group. Examples of ketones include acetone, methyl ethyl ketone, cyclohexanone, and mixtures thereof.

[0262] The term "nitrile" refers to a compound of the formula: R’-CN. R’ is a substituted or unsubstituted C1-C 10 substituted or unsubstituted alkyl group such as an alkyl group, substituted or unsubstituted C3-C 10 substituted or unsubstituted cyclic alkyl group such as a cyclic alkyl group, substituted or unsubstituted aryl group such as a substituted or unsubstituted phenyl group. Examples of nitriles include MeCN, propionitrile, benzonitrile, and mixtures thereof.

[0263] The terms "nucleophile" and "nucleophilic reagent" refer to Lewis bases. Examples of nucleophilic reagents include ammonia, azide, amine, enol, organolithium reagents, alkylmagnesium halides, allylmagnesium halides, vinylmagnesium halides, arylmagnesium halides, and mixtures thereof.

[0264] The term "oxidizing agent" refers to a compound that acquires electrons and is reduced in a chemical reaction. Examples of oxidizing agents include hydrogen peroxide, urea hydrogen peroxide, acetylbenzoyl peroxide, benzoyl peroxide, tert-butyl hydroperoxide, diacetyl peroxide, ethyl hydroperoxide, methyl ethyl ketone peroxide, sodium percarbonate, and peroxides such as peracids, oxygen, ozone, halogen, metal oxides, permanganate compounds such as potassium permanganate, and perborates such as lithium perborate, sodium perborate, and potassium perborate. Examples of peracids include peracetic acid, performic acid, peroxybenzoic acid, mCPBA, peroxymonosulfuric acid, peroxynitric acid, and peroxymonophosphoric acid. Perborates may take the form of hydrates such as sodium perborate tetrahydrate.

[0265] The term "pharmaceutically acceptable" refers to a non-toxic substance that does not interfere with the effectiveness of the active ingredient.

[0266] The term "reducing agent" refers to a compound that loses electrons and is oxidized in a chemical reaction. Examples of reducing agents include hydrogen, lithium aluminum hydride, sodium borohydride, thiosulfate, hydrazine, and diisobutylaluminum hydride.

[0267] The term "room temperature" refers to a temperature range of 19°C to 26°C.

[0268] The substituted aryl group, substituted alkyl group, and substituted cycloalkyl group are substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, -OR a , -SR b , -NR c R d , -F, -Cl, -Br, -I, -CN, -NO2, phenyl, pyridyl, -CHO, -COORe, and -CO(NRfRg), where R a , R b , R c , R d , R e , R f , and R gEach of them is independently selected from H or C1-C6 alkyl.

[0269] As used herein, "water" refers to tap water, distilled water, and / or deionized water.

[0270] As used herein, the terms formula (I), formula (II), formula (III), formula (IV), and formula (V) are hereinafter sometimes referred to as "the compounds of the present invention", "the present invention", and respectively "the compound of formula (I)", "the compound of formula (II)", "the compound of formula (III)", "the compound of formula (IV)", and "the compound of formula (V)". Such terms are defined to include all forms of the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V) (including their pharmaceutically acceptable salts, hydrates, solvates, isomers, crystalline and amorphous forms, polymorphs, and metabolites). For example, the compounds of the present invention or their pharmaceutically acceptable salts can exist in non-solvated and solvated forms. When a solvent or water is closely bound, the complex has a well-defined stoichiometry regardless of humidity. However, when the binding of the solvent or water is weak, such as in channel solvates and hygroscopic compounds, the water / solvent content depends on humidity and drying conditions. In such cases, non-stoichiometry becomes the norm.

[0271] Examples

[0272] Example 1 - Synthesis of the Compound of Formula (IV)

Chemical formula

[0273] Example 2 - Synthesis of the compound of formula (V) [Chemical formula] To a round-bottomed flask, a DCM solution (15-fold amount) of tert-butyl 4-(isoquinolin-6-yloxy)piperidine-1-carboxylate (90.0 g, 1.0 equivalent), which is a compound of formula (IV), was added, and the mixture was cooled to 5 °C to 10 °C over 30 minutes. mCPBA (1.8 equivalents) was added at 5 °C to 10 °C in lots (4 equal lots). The reaction mixture was returned to room temperature over 2 hours and maintained at room temperature for 1 hour. The reaction was monitored by HPLC. The reaction mixture was diluted with DCM (10-fold amount) and quenched with an aqueous 40% sodium metabisulfite solution (10-fold amount) at room temperature. The resulting aqueous layer and DCM layer were separated, and the DCM layer was washed with a 10% aqueous NaOH solution (10-fold amount), followed by washing with water (10-fold amount). The DCM layer was distilled to 1-fold amount, and MTBE (5-fold amount) was added. The solvent was distilled to 1-fold amount, and the same procedure was repeated once with MTBE (5-fold amount). MTBE (5-fold amount) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and the solid was washed with MTBE (2-fold amount). The wet cake was dried under vacuum at less than 45 °C to a constant weight, and 75.0 g of 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isoquinoline 2-oxide, which is a compound of formula (V), was obtained in a yield of 80%.

[0274] Example 3 - Synthesis of the compound of formula (I) [Chemical formula] Into a round-bottomed flask, 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)oxy)isoquinoline 2-oxide (70.0 g, 1.0 equivalent), which is a compound of formula (V), and water:THF (10-fold amount:10-fold amount) were added at room temperature to form a homogeneous reaction mixture. MsCl (2.0 equivalents) was added to the reaction mixture at room temperature for 30 minutes. The reaction mixture was maintained at room temperature for 2 hours. MTBE (10-fold amount) was added to the reaction mixture, and the aqueous layer was extracted with MTBE (2×10-fold amount). The combined MTBE layers were washed with a 10% aqueous solution of potassium bisulfate (KHSO4) (2×10-fold amount). The solvent was distilled under vacuum at a temperature below 45 °C to a constant weight, and 52.0 g of a crude product with a purity of 95.35% (measured by HPLC) was obtained. Acetone (4-fold amount) was added to the crude product (52.0 g), and the mixture was stirred at room temperature for 3 hours. The solid was filtered and washed with cold acetone (1-fold amount). The obtained solid was dried under vacuum at a temperature below 45 °C to a constant weight, and tert-Butyl 4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)piperidine-1-carboxylate, which is a compound of formula (I), was obtained as an off-white solid in a yield of 47% (33.0 g). The solid obtained was washed with cold acetone (1-fold amount). The obtained solid was dried under vacuum at a temperature below 45 °C to a constant weight, and tert-Butyl 4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)piperidine-1-carboxylate, which is a compound of formula (I), was obtained as an off-white solid in a yield of 47% (33.0 g).

[0275] Example 4 - Deprotection of the compound of formula (I)

Chemical formula

[0276] Example 5 - Synthesis of the compound of formula (IV)

Chemical formula

[0277] Example 6 - Synthesis of the Compound of Formula (V)

Chemical Formula

[0278] Example 7 - Synthesis of the compound of formula (I)

Chemical formula

[0279] Example 8 - Deprotection of the Compound of Formula (I)

Chemical formula

[0280] Example 9 - Formation of Hydrates of Salts of Compounds of Formula (I)

Chemical formula

[0281] Although the preferred embodiments of the present invention are described in detail herein, it will be understood by those skilled in the art that modifications can be made thereto without departing from the spirit of the present invention or the scope of the appended claims.

[0282] The subject matter of the present disclosure may relate, among other things, to the following aspects.

[0283] The first aspect is a method for producing a compound of formula (V): [Chemical formula] or a pharmaceutically acceptable salt thereof, comprising i) a compound of formula (II): [Chemical formula] or a pharmaceutically acceptable salt thereof, with a compound of formula (III): [Chemical formula] react with a compound of formula (IV) or a pharmaceutically acceptable salt thereof to Formula (IV): [Chemical formula] produce a compound of formula (IV) or a pharmaceutically acceptable salt thereof in step A, and ii) reacting the compound of formula (IV): [Chemical formula] react with a compound of formula (V) or a pharmaceutically acceptable salt thereof to produce a compound of formula (V): [Chemical formula] produce a compound of formula (V) or a pharmaceutically acceptable salt thereof in step B, and R1 is H, a C1-C6 alkyl group, or a protecting group that prevents the nitrogen atom to which it is attached during a chemical reaction from reacting with other molecules, and is selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, n is 1, 2, 3, or 4, R2 is -OH or L1, a leaving group that can be substituted by a nucleophile, and is selected from the group consisting of fluoride (-F), chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3), R3 is -OH or L2, a leaving group that can be substituted by a nucleophile, and is selected from the group consisting of fluoride (-F), chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3), R4 is -OH, -O - , selected from the group consisting of p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3), relates to a method.

[0284] A second aspect relates to the method of aspect 1, wherein the C1-C6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl, L1 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3), and L2 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3).

[0285] The third aspect relates to the method of aspect 1 or 2, wherein R1 is a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytriphenylmethyl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, n is 2 or 3, R2 is L1 and R3 is -OH or R2 is -OH and R3 is L2, L1 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3), and L2 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3).

[0286] The fourth aspect relates to the method of any one of aspects 1 to 3, wherein R1 is a tert-butyloxycarbonyl (BOC) group, n is 3, R2 is L1, and L1 is methanesulfonate (-MsO), or R2 is -OH, and L2 is chloride (-Cl), bromide (-Br), or iodide (-I).

[0287] The fifth aspect relates to the method of any one of aspects 1 to 4, wherein step A is carried out at about 0 °C to about 150 °C, and step B is carried out at about -10 °C to about 50 °C or about 25 °C to about 150 °C.

[0288] The sixth aspect relates to the method of any one of aspects 1 to 5, wherein step A is carried out at about 50 °C to about 110 °C, and step B is carried out at about 0 °C to about 25 °C or about 45 °C to about 100 °C.

[0289] The seventh aspect relates to the method of any one of aspects 1 to 6, wherein in step A, 1 to 5 molar equivalents of the compound of formula (II) or a pharmaceutically acceptable salt thereof are used relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0290] The eighth aspect relates to any of the methods of Aspects 1 to 7, wherein Step A is carried out in the presence of a base and a solvent, and Step B is carried out in the presence of an oxidizing agent and a solvent.

[0291] The ninth aspect relates to the method of Aspect 8, wherein in Step A, 1 to 5 molar equivalents of the compound of formula (II) or a pharmaceutically acceptable salt thereof are used relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof, and in Step A, 1 to 7 molar equivalents of a base are used relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0292] The tenth aspect relates to the method of Aspect 8 or 9, wherein in Step B, 1 to 10 molar equivalents of an oxidizing agent are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0293] The eleventh aspect relates to any of the methods of aspects 8 to 10, wherein the base in step A is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N - diisopropylethylamine, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert - butoxide, sodium tert - butoxide, potassium tert - butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; the solvent in step A is selected from the group consisting of water, diethyl ether, tetrahydrofuran (THF), 2 - methyltetrahydrofuran (2 - MeTHF), dimethoxyethane (DME), methyl tert - butyl ether (MTBE), 1,4 - dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), 2 - pyrrolidone, acetonitrile (MeCN), propionitrile, benzonitrile, and mixtures thereof; the oxidizing agent in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, acetone peroxide, acetylbenzoyl peroxide, benzoyl peroxide, tert - butyl hydroperoxide, diacetyl peroxide, ethyl hydroperoxide, methyl ethyl ketone peroxide, peracetic acid, performic acid, peroxybenzoic acid, meta - chloroperoxybenzoic acid (mCPBA), dimethyldioxirane, oxone (potassium peroxymonosulfate), peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, potassium permanganate, lithium perborate, sodium perborate, potassium perborate, and mixtures thereof; and the solvent in step B is selected from the group consisting of dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2 - dichloroethane, MeCN, propionitrile, benzonitrile, acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof.

[0294] The twelfth aspect is that the base in step A is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof, and the solvent in step A is selected from the group consisting of DMF, MeCN, water, diethyl ether, MTBE, and mixtures thereof, the oxidizing agent in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, peroxybenzoic acid, mCPBA, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium perborate, and mixtures thereof, and the solvent in step B is selected from the group consisting of DCM, chloroform, MeCN, ethanol, acetic acid, and mixtures thereof, and relates to any of the methods of aspects 8 to 11.

[0295] The thirteenth aspect relates to any of the methods of aspects 1 to 12, wherein step A is carried out in the presence of a base and a solvent, and step B is carried out in the presence of an oxidizing agent, a catalyst, and a solvent.

[0296] The fourteenth aspect relates to the method of aspect 13, wherein in step B, 1 to 10 molar equivalents of an oxidizing agent are used with respect to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, and in step B, 0.001 to 1 molar equivalent of a catalyst is used with respect to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0297] The 15th aspect relates to the method of aspect 13 or 14, wherein the base in step A is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N-diisopropylethylamine, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; the solvent in step A is selected from the group consisting of water, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, DMF, DMA, 2-pyrrolidone, MeCN, propionitrile, benzonitrile, and mixtures thereof; the oxidizing agent in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, acetylbenzoyl peroxide, benzoyl peroxide, tert-butyl hydroperoxide, diacetyl peroxide, ethyl hydroperoxide, methyl ethyl ketone peroxide, peracetic acid, performic acid, peroxybenzoic acid, mCPBA, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, potassium permanganate, lithium perborate, sodium perborate, potassium perborate, and mixtures thereof; the solvent in step B is selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, MeCN, propionitrile, benzonitrile, acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof; and the catalyst in step B is selected from the group consisting of acetic acid, trifluoroacetic acid, formic acid, methyltrioxorhenium(VII) (MeReO3, MTO), phosphomolybdic acid (PMA), and mixtures thereof.

[0298] The 16th aspect relates to any of the methods of aspects 13 to 15, wherein the base in step A is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof; the solvent in step A is selected from the group consisting of DMF, MeCN, water, diethyl ether, MTBE, and mixtures thereof; the oxidizing agent in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, peroxybenzoic acid, mCPBA, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium perborate, and mixtures thereof; the solvent in step B is selected from the group consisting of DCM, chloroform, MeCN, ethanol, acetic acid, and mixtures thereof; and the catalyst in step B is selected from the group consisting of acetic acid, MTO, PMA, and mixtures thereof.

[0299] The 17th aspect relates to any of the methods of aspects 1 to 16, wherein step A is carried out in the presence of a base and a solvent, and step B is carried out in the presence of an oxidizing agent, a catalyst, a base, and a solvent.

[0300] The 18th aspect relates to the method of aspect 17, wherein in step B, 1 to 10 molar equivalents of an oxidizing agent are used with respect to the compound of formula (IV) or a pharmaceutically acceptable salt thereof; in step B, 0.001 to 1 molar equivalent of a catalyst is used with respect to the compound of formula (IV) or a pharmaceutically acceptable salt thereof; and in step B, 1 to 10 molar equivalents of a base are used with respect to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0301] The 19th aspect relates to the method of embodiment 17 or 18, wherein the base in step A is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof; the solvent in step A is selected from the group consisting of DMF, MeCN, water, diethyl ether, MTBE, and mixtures thereof; the oxidizing agent in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, formic acid, sodium perborate, mCPBA, and mixtures thereof; the solvent in step B is selected from the group consisting of MeCN, ethanol, acetic acid, DCM, chloroform, and mixtures thereof; the base in step B is selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; and the catalyst in step B is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, MTO, PMA, and mixtures thereof.

[0302] The 20th aspect is a method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (V):

Chemical formula

Chemical formula

[0303] The 21st aspect relates to the method of aspect 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the lactam form and / or lactim form.

[0304] The 22nd aspect is that R1 is H, or a C1-C6 alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl, or a protecting group selected from the group consisting of trityl (triphenylmethyl, Tr) group, (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, tert-butyloxycarbonyl (BOC) group, and p-toluenesulfonyl (tosyl, Ts) group, n is 1, 2, or 3, and R4 is -OH, -O - It relates to the method of aspect 20 or 21, which is selected from the group consisting of p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3).

[0305] The 23rd aspect is that R1 is a protecting group selected from the group consisting of trityl (triphenylmethyl, Tr) group, (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, tert-butyloxycarbonyl (BOC) group, and p-toluenesulfonyl (tosyl, Ts) group, n is 2 or 3, and R4 is -OH, -O - It relates to the method of aspect 22, which is selected from the group consisting of p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF3SO3).

[0306] The 24th aspect is that R1 is tert-butyloxycarbonyl (BOC) group, n is 23, and R4 is -OH, -O -Relates to any of the methods of embodiments 20 to 23, selected from the group consisting of and methanesulfonate (-MsO).

[0307] The 25th embodiment relates to any of the methods of embodiments 20 to 24, wherein step C is carried out at a temperature of about -10 °C to about 100 °C.

[0308] The 26th embodiment relates to the method of embodiment 25, wherein step C is carried out at a temperature of about 5 °C to about 50 °C.

[0309] The 27th embodiment relates to any of the methods of embodiments 20 to 26, wherein step C is carried out in the presence of an electrophilic reagent, a solvent, and a base.

[0310] The 28th embodiment relates to the method of embodiment 27, wherein in step C, 0.05 to 10 molar equivalents of an electrophilic reagent are used with respect to the compound of formula (V) or a pharmaceutically acceptable salt thereof, and in step C, 0.1 to 10 molar equivalents of a base are used with respect to the compound of formula (V) or a pharmaceutically acceptable salt thereof.

[0311] The 29th embodiment relates to any of the methods of embodiments 20 to 26, wherein step C is carried out in the presence of an electrophilic reagent, a solvent, and a buffer.

[0312] The 30th embodiment relates to the method of embodiment 29, wherein in step C, 0.05 to 10 molar equivalents of an electrophilic reagent are used with respect to the compound of formula (V) or a pharmaceutically acceptable salt thereof, and in step C, 0.1 to 10 molar equivalents of a buffer are used with respect to the compound of formula (V) or a pharmaceutically acceptable salt thereof.

[0313] The 31st embodiment is such that the electrophilic reagent in step C is acyl chloride, acyl bromide, acyl iodide, acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, benzenesulfonyl chloride, benzenesulfonyl bromide, benzenesulfonyl iodide, methanesulfonyl chloride (mesyl chloride Selected from the group consisting of lithium, MsCl), methanesulfonyl bromide, methanesulfonyl iodide, p-toluenesulfonyl chloride (tosyl chloride, TsCl), p-toluenesulfonyl bromide, p-toluenesulfonyl iodide, and mixtures thereof, wherein the solvent in step C is selected from the group consisting of water, DMF, DMA, 2-pyrrolidone, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, MeCN, propionitrile, benzonitrile, and mixtures thereof, and wherein the base in step C is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N-diisopropylethylamine, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, hydroxide salts, carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof, relating to any of the methods of embodiments 27-30.

[0314] The 32nd aspect relates to any one of the methods of aspects 27 to 31, wherein the electrophilic reagent is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, and mixtures thereof; the solvent is a mixture of at least one organic solvent selected from the group consisting of THF, 2-MeTHF, acetone, DCM, and MeCN and water; and the base is selected from the group consisting of triethylamine, triisopropylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof.

[0315] The 33rd aspect relates to the method of aspect 32 or 33, wherein the electrophilic reagent in step C is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p-toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chloride, acyl bromide, acetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, and mixtures thereof; the solvent in step C is selected from the group consisting of water, DMF, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN, and mixtures thereof; and the buffer solution in step C is a buffer solution that maintains the pH of the reaction mixture in step C within the range of pH 4 to pH 10.

[0316] The 34th aspect relates to the method of aspect 33, wherein the buffer solution is selected from the group consisting of sodium acetate - acetic acid buffer solution, H3PO4 - Na2HPO4 buffer solution, Na2HPO4 - NaH2PO4 buffer solution, imidazole - HCl buffer solution, H3PO4 - triethylamine (TEA) buffer solution, citric acid - triethylamine (TEA) buffer solution, citric acid - tris(hydroxymethyl)aminomethane (TRIS) buffer solution, and 3-(N-morpholino)-propanesulfonic acid (MOPS) - triethylamine (TEA) buffer solution.

[0317] The 35th aspect is formula (I): [Chemical formula] (In the formula, R1 is a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytriphenylmethyl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, and n is 1, 2, 3, or 4), reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with a deprotecting agent to produce a compound of formula (I) or a pharmaceutically acceptable salt thereof, further comprising a deprotection step D, Relates to any of the methods of aspects 20 to 34, wherein R1 is H, n is 1, 2, 3, or 4, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a lactam form and / or a lactim form.

[0318] The 36th aspect relates to the method of aspect 35, wherein the protecting group is a tert-butyloxycarbonyl (BOC) group.

[0319] The 37th aspect relates to the method of aspect 35 or 36, wherein the deprotecting reagent is selected from the group consisting of acyl chlorides, acyl bromides, acyl iodides, acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and mixtures thereof.

[0320] The 38th aspect relates to any of the methods of aspects 35 to 37, wherein the protecting group is a tert-butyloxycarbonyl (BOC) group and the deprotecting reagent is selected from the group consisting of acyl chlorides, acyl bromides, acetic anhydride, formic acid, acetic acid, trifluoroacetic acid, and hydrochloric acid.

[0321] The 39th aspect relates to any of the methods of aspects 35 to 38, wherein the protecting group is a tert-butyloxycarbonyl (BOC) group, and the deprotecting agent is selected from the group consisting of acyl chlorides, trifluoroacetic acid, and hydrochloric acid.

[0322] The 40th aspect relates to any of the methods of aspects 35 to 39, wherein step D produces the monohydrochloride or dihydrochloride of the compound of formula (I), and the monohydrochloride or dihydrochloride of the compound of formula (I) is in the lactam form and / or lactim form.

[0323] The 41st aspect relates to any of the methods of aspects 20 to 40, wherein step C produces the monohydrochloride or dihydrochloride of the compound of formula (I), and the monohydrochloride or dihydrochloride of the compound of formula (I) is in the lactam form and / or lactim form.

[0324] The 42nd aspect relates to any of the methods of aspects 35 to 41, wherein in step D, 1 to 20 molar equivalents of a deprotecting reagent are used with respect to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0325] The 43rd aspect relates to a compound of formula (V):

Chemical formula

[0326] The 44th aspect relates to the compound of aspect 43, wherein n is 1, 2, or 3, and the C1-C6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

[0327] The 45th aspect relates to the compound of aspect 43 or 44, wherein n is 2 or 3.

[0328] The 46th aspect relates to the compound of any one of aspects 43 to 45, wherein n is 3, R1 is a tert-butyloxycarbonyl (BOC) group, and R4 is selected from the group consisting of -OH, -O - , and methanesulfonate (-MsO).

[0329] The 47th aspect relates to the compound of any one of aspects 43 to 45, wherein n is 3, R1 is H, and R4 is selected from the group consisting of -OH, -O - , and methanesulfonate salt (-MsO).

[0330] In addition to the features described in each of the independent aspects listed above, in some examples, any feature described in the dependent aspects and / or any feature disclosed in the above description and shown in the figures can be shown alone or in combination.

Claims

1. A process for preparing a compound of formula (V): 【Chemical 1】 (V) or a pharmaceutically acceptable salt thereof, comprising: i) reacting a compound of formula (II): 【Chemical 2】 (II) or a pharmaceutically acceptable salt thereof with a compound of formula (III): [Chemical 3] (III) or a pharmaceutically acceptable salt thereof to produce a compound of formula (IV): 【Chemical 4】 (IV) or a pharmaceutically acceptable salt thereof, which is step A, and ii) reacting a compound of formula (IV): 【Chemical Formula 5】 (IV) or a pharmaceutically acceptable salt thereof to produce a compound of formula (V): 【Chemical Formula 6】 (V) or a pharmaceutically acceptable salt thereof, which is step B, wherein in the formula, R １ is H, C １ -C ６ an alkyl group, or a protecting group that prevents the nitrogen atom to which it is attached during a chemical reaction from reacting with other molecules, and is selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, n is 1, 2, 3, or 4; R ２ is - OH or L １ which is a leaving group replaceable by a nucleophile and is selected from the group consisting of fluoride (-F), chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ 3) R ３ is either -OH or L ２ which is a leaving group replaceable by a nucleophile and is selected from the group consisting of fluoride (-F), chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ 3), R ４ is a method selected from the group consisting of -OH, -O － , p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ ).

2. Said C １ -C ６ The alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl, n is 1, 2, or 3; L １ is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ ), and L ２ is chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ ) selected from the group consisting of, the method according to claim 1.

3. R １ is a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytriphenylmethyl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, n is 2 or 3; R ２ is L １ and R ３ is -OH or R ２ is -OH and R ３ is L ２ and L １ is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ ), and L ２ is chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ ) selected from the group consisting of, the method according to claim 1 or 2.

4. R １ is a tert-butyloxycarbonyl (BOC) group, n is 3, and R ２ is L １ and L １ is methanesulfonate (-MsO), or R ２ is -OH, and L ２ is chloride (-Cl), bromide (-Br), or iodide (-I), the method according to any one of claims 1 to 3.

5. The process according to any one of claims 1 to 4, wherein step A is carried out at about 0 °C to about 150 °C and step B is carried out at about -10 °C to about 50 °C or about 25 °C to about 150 °C.

6. The process according to any one of claims 1 to 5, wherein step A is carried out at about 50 °C to about 110 °C and step B is carried out at about 0 °C to about 25 °C or about 45 °C to about 100 °C.

7. The process according to any one of claims 1 to 6, wherein in step A, 1 to 5 molar equivalents of the compound of formula (II) or a pharmaceutically acceptable salt thereof are used relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof.

8. The process according to any one of claims 1 to 7, wherein step A is carried out in the presence of a base and a solvent, and step B is carried out in the presence of an oxidizing agent and a solvent.

9. The process according to claim 8, wherein in step A, 1 to 5 molar equivalents of the compound of formula (II) or a pharmaceutically acceptable salt thereof are used relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof, and in step A, 1 to 7 molar equivalents of a base are used relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof.

10. The process according to claim 8 or 9, wherein in step B, 1 to 10 molar equivalents of an oxidizing agent are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

11. The base in Step A is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N - diisopropylethylamine, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert - butoxide, sodium tert - butoxide, potassium tert - butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof, The solvent in Step A is selected from the group consisting of water, diethyl ether, tetrahydrofuran (THF), 2 - methyltetrahydrofuran (2 - MeTHF), dimethoxyethane (DME), methyl tert - butyl ether (MTBE), 1,4 - dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), 2 - pyrrolidone, acetonitrile (MeCN), propionitrile, benzonitrile, and mixtures thereof, The oxidizing agent in Step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, acetone peroxide, acetylbenzoyl peroxide, benzoyl peroxide, tert - butyl hydroperoxide, diacetyl peroxide, ethyl hydroperoxide, methyl ethyl ketone peroxide, peracetic acid, performic acid, peroxybenzoic acid, metachloroperoxybenzoic acid (mCPBA), dimethyldioxirane, oxone (potassium peroxymonosulfate), peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, potassium permanganate, lithium perborate, sodium perborate, potassium perborate, and mixtures thereof, and The solvent in Step B is dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2 - dichloroethane, MeCN, propionitrile, benzonitrile, acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof, the method according to any one of claims 8 to 10.

12. The base in Step A is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof, The solvent in Step A is selected from the group consisting of DMF, MeCN, water, diethyl ether, MTBE, and mixtures thereof, The oxidizing agent in Step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, formic acid, peroxybenzoic acid, mCPBA, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium perborate, and mixtures thereof, and The solvent in Step B is selected from the group consisting of DCM, chloroform, MeCN, ethanol, acetic acid, and mixtures thereof, the method according to any one of claims 8 to 11.

13. The method according to any one of claims 1 to 12, wherein Step A is carried out in the presence of a base and a solvent, and Step B is carried out in the presence of an oxidizing agent, a catalyst, and a solvent.

14. In Step B, 1 to 10 molar equivalents of an oxidizing agent are used with respect to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, and in Step B, 0.001 to 1 molar equivalent of a catalyst is used with respect to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, the method according to claim 13.

15. The base in Step A is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N-diisopropylethylamine, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof, The solvent in Step A is selected from the group consisting of water, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, DMF, DMA, 2-pyrrolidone, MeCN, propionitrile, benzonitrile, and mixtures thereof, The oxidizing agent in Step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, acetylbenzoyl peroxide, benzoyl peroxide, tert-butyl hydroperoxide, diacetyl peroxide, ethyl hydroperoxide, methyl ethyl ketone peroxide, peracetic acid, performic acid, peroxybenzoic acid, mCPBA, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, potassium permanganate, lithium perborate, sodium perborate, potassium perborate, and mixtures thereof, The solvent in Step B is selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, MeCN, propionitrile, benzonitrile, acetic acid, formic acid, trifluoroacetic acid, and mixtures thereof, and The catalyst in Step B is selected from the group consisting of acetic acid, trifluoroacetic acid, formic acid, methyltrioxorhenium(VII) (MeReO3, MTO), phosphomolybdic acid (PMA), and mixtures thereof, the method according to claim 13 or 14.

16. The base in Step A is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof, The solvent in Step A is selected from the group consisting of DMF, MeCN, water, diethyl ether, MTBE, and mixtures thereof, The oxidizing agent in Step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, peroxybenzoic acid, mCPBA, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium perborate, and mixtures thereof, The solvent in Step B is selected from the group consisting of DCM, chloroform, MeCN, ethanol, acetic acid, and mixtures thereof, and The catalyst in Step B is selected from the group consisting of acetic acid, MTO, PMA, and mixtures thereof, the method according to any one of claims 13 to 15.

17. The method according to any one of claims 1 to 16, wherein step A is carried out in the presence of a base and a solvent, and step B is carried out in the presence of an oxidizing agent, a catalyst, a base, and a solvent.

18. In step B, 1 to 10 molar equivalents of an oxidizing agent are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof. In step B, 0.001 to 1 molar equivalent of a catalyst is used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof. And in step B, 1 to 10 molar equivalents of a base are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof. The method according to claim 17.

19. The base in step A is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and mixtures thereof. The solvent in step A is selected from the group consisting of DMF, MeCN, water, diethyl ether, MTBE, and mixtures thereof. The oxidizing agent in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, formic acid, sodium perborate, mCPBA, and mixtures thereof. The solvent in step B is selected from the group consisting of MeCN, ethanol, acetic acid, DCM, chloroform, and mixtures thereof. The base in step B is selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. And The catalyst in step B is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, MTO, PMA, and mixtures thereof. The method according to claim 17 or 18.

20. A method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (V): 【Chemical Formula 7】 (V) or a pharmaceutically acceptable salt thereof to produce [[ID=]](I) [Chemical 8] (I) a compound of formula (I) or a pharmaceutically acceptable salt thereof, step C. Wherein R １ is a protecting group selected from the group consisting of H, C １ -C ６ alkyl group, or trityl (triphenylmethyl, Tr) group, (4-methoxyphenyl)diphenylmethylene (methoxytriphenylmethyl, MMT) group, tert-butyloxycarbonyl (BOC) group, and p-toluenesulfonyl (tosyl, Ts) group, n is 1, 2, 3, or 4. And R ４ is selected from the group consisting of -OH, -O － , p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ ), a method.

21. The compound of formula (I) or a pharmaceutically acceptable salt thereof is in lactam form and / or lactim form. The method according to claim 20.

22. R １ is H, or a C selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl １ -C ６ alkyl group, or a protecting group selected from the group consisting of trityl (triphenylmethyl, Tr) group, (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, tert-butyloxycarbonyl (BOC) group, and p-toluenesulfonyl (tosyl, Ts) group, n is 1, 2, or 3. And R ４ is selected from the group consisting of -OH, -O － , p-toluenesulfonate (-TsO), methanesulfonate (-MsO), and trifluoromethanesulfonate (-CF ３ SO ３ ), the method according to claim 20 or 21.

23. R １ is a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytriphenylmethyl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, n is 2 or 3. And R ４ is —OH, —O － , p - toluenesulfonate (—TsO), methanesulfonate (—MsO), and trifluoromethanesulfonate (—CF ３ SO ３ ) and is selected from the group consisting of, the method according to claim 22.

24. R １ is a tert-butyloxycarbonyl (BOC) group, n is 3, and R ４ is selected from the group consisting of -OH, -O － , and methanesulfonate (-MsO), the method according to any one of claims 20 to 23.

25. Step C is carried out at a temperature of about -10°C to about 100°C. The method according to any one of claims 20 to 24.

26. The method according to claim 25, wherein step C is carried out at a temperature of about 5 °C to about 50 °C.

27. The method according to any one of claims 20 to 26, wherein step C is carried out in the presence of an electrophilic reagent, a solvent, and a base.

28. In step C, 0.05 to 10 molar equivalents of an electrophilic reagent are used relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof, and in step C, 0.1 to 10 molar equivalents of a base are used relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof. The method according to claim 2 7.

29. The method according to any one of claims 20 to 26, wherein step C is carried out in the presence of an electrophilic reagent, a solvent, and a buffer solution.

30. In step C, 0.05 to 10 molar equivalents of an electrophilic reagent are used relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof, and in step C, 0.1 to 10 molar equivalents of a buffer solution are used relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof. The method according to claim 29.

31. The electrophilic reagent in step C is selected from the group consisting of acyl chlorides, acyl bromides, acyl iodides, acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, benzenesulfonyl chloride, benzenesulfonyl bromide, benzenesulfonyl iodide, methanesulfonyl chloride (mesyl chloride, MsCl), methanesulfonyl bromide, methanesulfonyl iodide, p-toluenesulfonyl chloride (tosyl chloride, TsCl), p-toluenesulfonyl bromide, p-toluenesulfonyl iodide, and mixtures thereof. The solvent for step C is selected from the group consisting of water, DMF, DMA, 2-pyrrolidone, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, MeCN, propionitrile, benzonitrile, and mixtures thereof. The base in step C is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N,N - diisopropylethylamine, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert - butoxide, sodium tert - butoxide, potassium tert - butoxide, hydroxide salts, carbonate salts, bicarbonate salts, phosphate salts, hydrogen phosphate salts, dihydrogen phosphate salts, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof, according to any one of claims 27 to 30.

32. The electrophile is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p - toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chlorides, and mixtures thereof, the solvent is a mixture of at least one organic solvent selected from the group consisting of THF, 2 - MeTHF, acetone, DCM, and MeCN and water, and the base is selected from the group consisting of triethylamine, triisopropylamine, N,N - diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and mixtures thereof, according to any one of claims 27 to 31.

33. The electrophile in step C is selected from the group consisting of methanesulfonyl chloride (mesyl chloride, MsCl), p - toluenesulfonyl chloride (tosyl chloride, TsCl), acyl chlorides, acyl bromides, acetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, and mixtures thereof. The solvent for step C is selected from the group consisting of water, DMF, diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN, and mixtures thereof, and The method according to claim 29 or 30, wherein the buffer solution for step C is a buffer solution that maintains the pH of the reaction mixture in step C within the range of pH 4 to pH 10.

34. The buffer solution is selected from the group consisting of sodium acetate-acetic acid buffer solution, H ３ PO ４ -Na ２ HPO ４ buffer solution, Na ２ HPO ４ -NaH ２ PO ４ buffer solution, imidazole-HCl buffer solution, H ３ PO ４ -triethylamine (TEA) buffer solution, citric acid-triethylamine (TEA) buffer solution, citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer solution, and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer solution, the method according to claim 33.

35. Formula (I): 【Chemical Formula 9】 (I) (wherein R １ is a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytriphenylmethyl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, and n is 1, 2, 3, or 4), or a pharmaceutically acceptable salt thereof, Further comprising a deprotection step D of reacting with a deprotecting reagent to produce a compound of formula (I) or a pharmaceutically acceptable salt thereof, R １ is H, n is 1, 2, 3, or 4, and The method according to any one of claims 20 to 34, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a lactam form and / or a lactim form.

36. The method according to claim 35, wherein the protecting group is a tert-butyloxycarbonyl (BOC) group.

37. The method according to claim 35 or 36, wherein the deprotecting reagent is selected from the group consisting of acyl chlorides, acyl bromides, acyl iodides, acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and mixtures thereof.

38. The method according to any one of claims 35 to 37, wherein the protecting group is a tert-butyloxycarbonyl (BOC) group and the deprotecting reagent is selected from the group consisting of acyl chlorides, acyl bromides, acetic anhydride, formic acid, acetic acid, trifluoroacetic acid, and hydrochloric acid.

39. The method according to any one of claims 35 to 38, wherein the protecting group is a tert-butyloxycarbonyl (BOC) group and the deprotecting reagent is selected from the group consisting of acyl chlorides, trifluoroacetic acid, and hydrochloric acid.

40. Step D produces a monohydrochloride or dihydrochloride of the compound of formula (I), and the The method according to any one of claims 35 to 39, wherein the monohydrochloride or dihydrochloride of the compound of formula (I) is in a lactam form and / or a lactim form.

41. Step C produces a monohydrochloride or dihydrochloride of the compound of formula (I), and the monohydrochloride or dihydrochloride of the compound of formula (I) is in a lactam form and / or a lactim form. The method according to any one of claims 20 to 40.

42. The method according to any one of claims 35 to 41, wherein in step D, 1 to 20 molar equivalents of a deprotecting reagent are used with respect to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

43. A compound of formula (V) or a pharmaceutically acceptable salt thereof, 【Chemical Formula 10】 (V) wherein n is 1, 2, 3, or 4, R １ is H, C １ -C ６ an alkyl group, or a protecting group that prevents the nitrogen atom to which it is attached during a chemical reaction from reacting with other molecules, and is selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group, and R ４ is —OH, —O － , p-toluenesulfonate (—TsO), methanesulfonate (—MsO), and trifluoromethanesulfonate (—CF ３ SO ３ ), a compound of formula (V) or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

44. n is 1, 2, or 3, and Said C １ -C ６ The compound according to claim 43, wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

45. The compound according to claim 43 or 44, wherein n is 2 or 3.

46. n is 3, and R １ is a tert-butyloxycarbonyl (BOC) group, and also R ４ is selected from the group consisting of -OH, -O － , and methanesulfonate (-MsO), the compound according to any one of claims 43 to 45.

47. n is 3, and R １ is H, and also R ４ is selected from the group consisting of -OH, -O － , and methanesulfonate (-MsO), the compound according to any one of claims 43 to 45.

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