Process and intermediate compounds for preparation of 6-substituted-1-(2h)-isoquinolinones

Abstract

The present invention relates to a substituted 6-substituted isoquinoline oxide compound # imgabs0 # of formula (V) and to a process for the preparation thereof. These compounds of formula (V) can be used as intermediates # imgabs 1 # for the preparation of 6-substituted-1-(2H)-isoquinolinone compounds of formula (I) which are inhibitors of the enzyme Rhoo-kinases, or can also be used as intermediates for the preparation of other inhibitors of Rhoo-kinases.

Description

Technical Field

[0001] The present invention relates to substituted 6-substituted isoquinoline oxide compounds of formula (V) The compound of formula (V) can be used as an intermediate for preparing a 6-substituted-1-(2H)-isoquinolinone compound of formula (I) Background Art

[0002] The present invention relates to a compound of formula (V) Wherein n is 1, 2, 3 or 4, and R1 is H, a C1-C6 alkyl group or a protecting group. The protecting group prevents the nitrogen atom to which it is attached from reacting with other molecules (e.g., other reagents) during a chemical reaction, and may be selected from a variety of groups, including but not limited to those mentioned in PGM Wuts and TW Greene, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley and Sons, New York, 2007 ("Greene"), Chapter 7: Protection for the Amino Group. In addition, reference is made to WO 2009 / 080335, which describes suitable groups associated with the synthesis of compounds of formula (I). The present invention also relates to a method for preparing a compound of formula (V). The present invention also relates to the use of a compound of formula (V), i.e., a 6-substituted isoquinoline oxide compound of formula (V), as an intermediate in the preparation of a 6-substituted-1-(2H)-isoquinolinone derivative of formula (I) Wherein n is 1, 2, 3 or 4, and R1 is H, C1-C6 alkyl group or a protecting group as described above. The compound of formula (I) may exist in the lactam form and / or as a tautomeric lactimide form, as shown below:

[0003] The compounds of formula (I) are inhibitors of the enzyme Rho-kinase and are particularly useful in the treatment of hypertension, pulmonary hypertension, ocular hypertension, retinopathy and glaucoma, peripheral circulatory disorders, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina pectoris, cardiac hypertrophy, heart failure, ischemic disease, ischemic organ failure (end organ damage), fibrotic lung, fibrotic liver, liver failure, renal disease (including hypertension-induced, non-hypertension-induced and diabetic nephropathy), renal failure, fibrotic kidney, glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory tract infections, Distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain (e.g., neuropathic pain), neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunction, atherosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, vascular restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, bone diseases such as osteoporosis, bacterial gastrointestinal infections, sepsis, cancer (e.g., breast cancer, colon cancer, prostate cancer, ovarian cancer, brain cancer and lung cancer and their metastases) development and progression. The compounds of formula (I) can also be used as intermediates for the preparation of other inhibitors of Rho-kinase. The compounds of formula (I) and the synthetic routes for preparing the compounds of formula (I) are described in, for example, U.S. Patent Nos. 8,716,481 and 8,785,642.

[0004] There are some problems associated with existing synthetic routes for preparing compounds of formula (I). One problem is that existing synthetic routes produce stoichiometric amounts of dimethylamine and pyrrolidine byproducts. Dimethylamine and pyrrolidine exhibit properties similar to those of the target compound of formula (I), and therefore may ultimately be difficult to remove to acceptable levels in the active pharmaceutical ingredient (API). Another problem is that existing synthetic routes produce intermediates with low crystalline properties, and therefore may result in difficult separation and purification.

[0005] Another problem is that existing synthetic routes produce 6-(piperidin-4-yloxy)-1H-isochromen-1-one with the following structure:

[0006] 6-(Piperidin-4-yloxy)-1H-isochromen-1-one exhibits mutagenic properties. It is therefore an object of the present invention to provide an alternative route for the preparation of compounds of formula (I) which does not produce by-products that may be difficult to remove from the target compound of formula (I), does not produce intermediates with poor crystalline properties, and does not produce by-products with undesirable properties.

[0007] These compounds of formula (I) can be used as Rho-kinase inhibitors, or can be used as intermediates for the synthesis of other inhibitors. Summary of the invention

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

[0009] Each of the process steps in Scheme 1 may further include the optional step of forming a salt of the compound of formula (I), the compound of formula (IV), and the compound of formula (V).

[0010] The compounds of formula (I) and their salts may exist in the lactam form and / or as tautomeric lactim form, as shown below: DETAILED DESCRIPTION

[0011] The process steps for preparing substituted 6-substituted isoquinoline oxide compounds of formula (V) and using them as intermediates for preparing compounds of formula (I) are described in more detail below.

[0012] In one embodiment, the invention relates to a process for preparing a compound of formula (V), The method comprises step A: making a compound of formula (II) Reaction with a compound of formula (III) To produce a compound of formula (IV) in, R1 is H, a C1-C6 alkyl group, or a protecting group selected from a variety of groups, including but not limited to those mentioned in Greene, Chapter 7: Protection for the Amino Group. Reference is also made to WO2009 / 080335, which describes suitable groups relevant to the synthesis of compounds of formula (I); n is 1, 2, 3, or 4; R2 is -OH or L1, L1 is a leaving group capable of being displaced by a nucleophile and can be selected from a variety of groups including, but not limited to, weak bases; R3 is -OH or L2, L2 is a leaving group capable of being displaced by a nucleophile and can be selected from a variety of groups including, but not limited to, weak bases; R4 is selected from the group consisting of: -OH, -O - , sulfonates such as toluenesulfonate (-TsO) or methanesulfonate (-MsO), perfluoroalkylsulfonates such as trifluoromethanesulfonate (-CF3SO3), and mixtures thereof.

[0013] Step A is as follows.

[0014] Preferably, R1 is a protecting group. The protecting group in R1 is preferably a protecting group used in steps A, B and C that is stable under the reaction conditions. Suitable protecting groups R1 can be selected from: N-alkylenearyls, such as a benzyl (Bn) group, a (diphenyl)methylene group, a triphenylmethyl (Tr) group or a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group; amides, such as a formyl group, an acetyl (Ac) group or a benzoyl (Bz) group; carbamates, such as a tert-butyloxycarbonyl (BOC) group, a benzyloxycarbonyl (Cbz) group, a p-methoxybenzylcarbonyl (Moz) group or a 9-fluorenylmethoxycarbonyl (Fmoc) group; and NP and N-sulfonyl protecting groups, such as a dialkylphosphoramide group, a mesyl (mesyl, Ms) group or a p-toluenesulfonyl (tosyl, Ts) group.

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

[0016] Preferably, the same protecting group R1 is used throughout the synthesis shown in Scheme 1. Thus, in steps A, B and C, preferably protecting group R1 is used.

[0017] Most suitable are base-stable but acid-labile protecting groups such as a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group or a tosyl (Ts) group.

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

[0019] The C1-C6 alkyl group in R1 can be introduced by methods known in the art, whereby the compound of formula (II) wherein R1 is H reacts with a corresponding alkylating agent to provide an amine alkylated by a C1-C6 alkyl group. In another embodiment, if R1 is H, then the C1-C6 alkyl group is introduced into the compound of formula (IV) by reacting a compound of formula (IV) with a corresponding alkylating agent to provide an amine alkylated by a C1-C6 alkyl group. In another embodiment, if R1 is H, then the C1-C6 alkyl group is introduced into the compound of formula (V) by reacting a compound of formula (IV) with a corresponding alkylating agent to provide an amine alkylated by a C1-C6 alkyl group. Suitable reagents for introducing C1-C6 alkyl groups are known in the art and are commercially available. For example, alkyl halides can be used to introduce C1-C6 alkyl groups.

[0020] Preferably, the same C1-C6 alkyl group R1 is used throughout the synthesis shown in Scheme 1. Thus, in steps A, B and C, preferably the same C1-C6 alkyl group R1 is used.

[0021] Leaving group L1 can be substituted by nucleophile and can be selected from a variety of groups, including but not limited to weak bases. Suitable leaving group L1 can be selected from: halide, such as fluoride (-F), chloride (-Cl), bromide (-Br) or iodide (-I); sulfonate, such as toluenesulfonate (-TsO) or methanesulfonate (-MsO); perfluoroalkylsulfonate, such as trifluoromethanesulfonate (-CF3SO3); nitrate (-ONO2); and phosphate (-OPO(OR2), wherein R can be an alkyl group).

[0022] Leaving group L2 can be substituted by nucleophile and can be selected from various groups, and these groups include but are not limited to weak base.Suitable leaving group L2 can be selected from: halide, such as fluoride (-F), chloride (-Cl), bromide (-Br) or iodide (-I); sulfonate, such as toluenesulfonate (-TsO) or methanesulfonate (-MsO); perfluoroalkyl sulfonate, such as trifluoromethanesulfonate (-CF3SO3); nitrate (-ONO2); and phosphate (-OPO (OR2), wherein R can be an alkyl group).

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

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

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

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

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

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

[0029] Preferably, R1 is a tert-butoxycarbonyl (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, wherein L1 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

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

[0034] Preferably, R3 is -OH or L2, wherein L2 is selected from the group consisting of chloride (-Cl), bromide (-Br), iodide (-I), 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 comprises: reacting a compound of formula (II) with a compound of formula (III) in the presence of an additional reagent selected from the group consisting of a solvent, a base and a mixture thereof.

[0040] Suitable solvents for step A may be selected from the group consisting of water, ethers, amides, nitriles and mixtures thereof.

[0041] The solvent used in step A may 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 a mixture thereof.

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

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

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

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

[0046] The base used in step A may be an organic base selected from the group consisting of an amine base, an alkoxide, and a mixture 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 may be an alkoxide 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 may 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 may 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 may be a carbonate selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof.

[0052] The base used in step A may be a bicarbonate 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 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 ratio of the amount of the compound of formula (II) to the amount of the compound of formula (III) is in the range of 1 molar equivalent to 5 molar equivalents. Preferably, the range is 1.1 molar equivalents to 4 molar equivalents. Preferably, the range is 1.2 molar equivalents to 3 molar equivalents. Preferably, the range is 1.3 molar equivalents to 2 molar equivalents. Preferably, the range is 1.4 molar equivalents to 1.8 molar equivalents. Preferably, the range is 1.5 molar equivalents to 1.7 molar equivalents. Preferably, the ratio of the amount of the compound of formula (II) to the amount of the compound of formula (III) is about 1.6 molar equivalents. Preferably, the ratio of the amount of the compound of formula (II) to the amount of the compound of formula (III) is in the range of 1 molar equivalent to 2 molar equivalents. Preferably, the range is 1 molar equivalent to 1.6 molar equivalents. Preferably, the range is 1 molar equivalent to 1.5 molar equivalents. Preferably, the range is 1 molar equivalent to 1.4 molar equivalents. Preferably, the range is 1 molar equivalent to 1.3 molar equivalents. Preferably, the range is 1 molar equivalent to 1.2 molar equivalents. Preferably, the ratio of the amount of the compound of formula (II) to the amount of the compound of formula (III) is about 1.1 molar equivalents. Preferably, the ratio of the amount of the compound of formula (II) to the amount of the compound of formula (III) is in the range of 1.5 molar equivalents to 3 molar equivalents. Preferably, the range is 1.75 molar equivalents to 2.75 molar equivalents. Preferably, the range is 2 molar equivalents to 2.5 molar equivalents. Preferably, the range is 2.1 molar equivalents to 2.25 molar equivalents. Preferably, the ratio of the amount of the compound of formula (II) to the amount of 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, 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, 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 DMF or a mixture of 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 ratio of the base to the compound of formula (III) is in the range of 1 molar equivalent to 7 molar equivalents. Preferably, the range is 2 molar equivalents to 6 molar equivalents. Preferably, the range is 3 molar equivalents to 5 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (III) is about 3 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (III) is about 4 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (III) is in the range of 1 molar equivalent to 3 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (III) is about 1 molar equivalent. Preferably, the amount ratio of the base to the compound of formula (III) is about 2 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (III) is about 2.2 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (III) is in the range of 1 molar equivalent to 1.5 molar equivalents. Preferably, the base is present in an amount of about 1.1 molar equivalents to the compound of formula (III). Preferably, the base is present in an amount of about 1.2 molar equivalents to the compound of formula (III). Preferably, the base is present in an amount of about 1.3 molar equivalents to the compound of formula (III). Preferably, the base is present in an amount of about 1.4 molar equivalents to the compound of formula (III). Preferably, the base is present in an amount of about 1.5 molar equivalents to the compound of formula (III).

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

[0059] An example of Step A is shown below in Scheme 2 and Table 1. Scheme 2 provides an example of a Step A reaction, and Table 1 provides the reaction conditions used in the reaction shown in Scheme 2: Table I

[0060] The method for preparing the compound of formula (V) further comprises step B: reacting the compound of formula (IV) To produce a compound of formula (V) in, R1 is H, a C1-C6 alkyl group or a protecting group as described above, and n is 1, 2, 3 or 4.

[0061] Step B is as follows.

[0062] Preferably, R1 is H or a protecting group as described above.

[0063] Preferably, R1 is a protecting group as described above.

[0064] Preferably, R1 is a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a tosyl (Ts) group.

[0065] Preferably, R1 is a tert-butoxycarbonyl (BOC) group.

[0066] Preferably, R1 is a C1-C6 alkyl group.

[0067] Preferably, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0068] Preferably, n is 1, 2 or 3.

[0069] Preferably, n is 2 or 3.

[0070] Preferably, n is 3.

[0071] Preferably, R4 is selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO), trifluoromethanesulfonate (-CF3SO3) and mixtures thereof.

[0072] Preferably, step B comprises reacting a compound of formula (IV) to form a compound of formula (V) 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.

[0073] Suitable oxidizing agents for use in step B may be selected from the group consisting of peroxides, ethylene oxide, oxygen, ozone, potassium persulfate (potassium peroxymonosulfate), halogens, metal oxides, permanganate compounds and perborates.

[0074] Preferably, the oxidant used in step B is a peroxide selected from the following: 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-chloroperbenzoic acid (mCPBA), peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium percarbonate (Na2CO3·1.5H2O2) and mixtures thereof.

[0075] Preferably, the oxidant used in step B is an oxirane selected from the group consisting of dimethyldioxirane, difluorodioxirane, methyl(trifluoromethyl)dioxirane, 3,3-Bis(trifluoromethyl)dioxirane and mixtures thereof.

[0076] Preferably, the oxidizing agent used in step B is potassium persulfate.

[0077] Preferably, the oxidant used in step B is a permanganate compound. Preferably, the oxidant used in step B is potassium permanganate.

[0078] Preferably, the oxidizing agent used in step 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.

[0079] Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, acetone peroxide, sodium percarbonate, peracetic acid, performic acid, perbenzoic acid, mCPBA, dimethyldioxirane, potassium persulfate, peroxymonosulfuric acid, peroxynitric acid, peroxymonophosphoric acid, sodium perborate and mixtures thereof.

[0080] Suitable catalysts for step B may be selected from the group consisting of organic catalysts, inorganic catalysts and organometallic catalysts.

[0081] Preferably, the catalyst used in step B is selected from the group consisting of: an organometallic catalyst, such as methylrhenium trioxide (VII) (MeReO3, also abbreviated as MTO); an organic acid, such as acetic acid, formic acid, trifluoroacetic acid and mixtures thereof; an inorganic acid, such as phosphomolybdic acid (PMA); and mixtures thereof.

[0082] Suitable solvents for step B may be selected from the group consisting of halogenated alkanes, nitriles, alcohols, organic acids and mixtures thereof.

[0083] 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.

[0084] The solvent used in step B may be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile and mixtures thereof.

[0085] The solvent used in step B may 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.

[0086] The solvent used in step B may be an organic acid selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, and a mixture thereof.

[0087] Suitable bases used in Step B are inorganic bases.

[0088] The base used in step B may be selected from the group consisting of hydroxide salts, bicarbonate salts and carbonate salts.

[0089] The base used in step B may be a hydroxide salt selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof.

[0090] The base used in step B may be a bicarbonate selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof.

[0091] The base used in step B may be a carbonate selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] Preferably, step B is carried out in the presence of an oxidant and a solvent. Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic 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 oxidant 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 oxidant 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 oxidant is sodium perborate, and the solvent is acetic acid. Preferably, the oxidant is hydrogen peroxide, and the solvent is acetic acid. Preferably, the oxidant is urea hydrogen peroxide, and the solvent is acetic acid. Preferably, the oxidant is urea hydrogen peroxide, and the solvent is acetic acid. Preferably, the oxidant is sodium perborate, and the solvent is MeCN. Preferably, the oxidant is hydrogen peroxide, and the solvent is MeCN. Preferably, the oxidant is urea peroxide, and the solvent is MeCN. Preferably, the oxidant is mCPBA, and the solvent is MeCN. Preferably, the oxidant is sodium perborate, and the solvent is ethanol. Preferably, the oxidant is hydrogen peroxide, and the solvent is ethanol. Preferably, the oxidant is urea peroxide, and the solvent is ethanol. Preferably, the oxidant is mCPBA, and the solvent is ethanol. Preferably, the oxidant is hydrogen peroxide, and the solvent is DCM. Preferably, the oxidant is urea peroxide, and the solvent is DCM. Preferably, the oxidant is mCPBA, and the solvent is DCM.

[0096] Preferably, step B is carried out in the presence of an oxidant, a catalyst and a solvent. Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic 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; and the catalyst is selected from the group consisting of acetic acid, trifluoroacetic acid, formic acid, MTO, PMA and mixtures thereof. Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, sodium perborate and mixtures thereof; the solvent is selected from the group consisting of MeCN, ethanol, DCM and mixtures thereof; and the catalyst is selected from the group consisting of acetic acid, formic acid, MTO, PMA and mixtures thereof. Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea hydroperoxide, sodium percarbonate and mixtures thereof; the solvent is selected from the group consisting of MeCN, ethanol, DCM and mixtures thereof; and the catalyst is selected from the group consisting of acetic acid, formic acid, MTO, PMA and mixtures thereof. Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea hydroperoxide, sodium percarbonate and mixtures thereof; the solvent is MeCN or MeCN; and the catalyst is selected from the group consisting of acetic acid, MTO, PMA and mixtures thereof. Preferably, the oxidant is hydrogen peroxide or urea hydroperoxide, the solvent is DCM, and the catalyst is MTO or PMA. Preferably, the oxidant is hydrogen peroxide or urea hydroperoxide, the solvent is MeCN, and the catalyst is MTO or PMA. Preferably, the oxidant is hydrogen peroxide; the catalyst is PMA; and the solvent is MeCN. Preferably, the oxidant is urea hydroperoxide; the catalyst is PMA; and the solvent is MeCN. Preferably, the oxidant is hydrogen peroxide; the catalyst is MTO; and the solvent is MeCN. Preferably, the oxidant is urea peroxide; the catalyst is MTO; and the solvent is MeCN. Preferably, the oxidant is sodium percarbonate; the catalyst is MTO, acetic acid and mixtures thereof; and the solvent is MeCN. Preferably, the oxidant is hydrogen peroxide or urea peroxide, the solvent is ethanol, and the catalyst is MTO or PMA. Preferably, the oxidant is hydrogen peroxide; the catalyst is PMA; and the solvent is ethanol. Preferably, the oxidant is urea peroxide; the catalyst is PMA; and the solvent is ethanol. Preferably, the oxidant is hydrogen peroxide; the catalyst is MTO; and the solvent is ethanol. Preferably, the oxidant is hydrogen peroxide; the catalyst is MTO; and the solvent is ethanol. Preferably, the oxidant is urea peroxide; the catalyst is MTO; and the solvent is ethanol. Preferably, the oxidant is sodium percarbonate; the catalyst is MTO, acetic acid and mixtures thereof; and the solvent is ethanol.

[0097] Preferably, step B is carried out in the presence of an oxidant, a catalyst, a base and a solvent. Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic 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 oxidant 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 oxidant 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 oxidant 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 oxidant 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 oxidant 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 oxidant 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 oxidant 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 oxidant 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 oxidant used in step B is hydrogen peroxide; the solvent is MeCN; the catalyst is MTO; and the base is sodium bicarbonate. Preferably, the oxidant used in step B is hydrogen peroxide; the solvent is MeCN; the catalyst is MTO; and the base is sodium carbonate. Preferably, the oxidant used in step B is urea peroxide; the solvent is MeCN; the catalyst is MTO; and the base is sodium bicarbonate. Preferably, the oxidant used in step B is urea peroxide; the solvent is MeCN; the catalyst is MTO; and the base is sodium carbonate. Preferably, the oxidant used in step B is selected from the group consisting of hydrogen peroxide, urea peroxide, sodium percarbonate and mixtures thereof; the solvent is ethanol; 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 oxidant used in step B is hydrogen peroxide; the solvent is ethanol; the catalyst is a mixture of acetic acid and MTO; and the base is sodium bicarbonate. Preferably, the oxidant used in step B is hydrogen peroxide; the solvent is ethanol; the catalyst is a mixture of acetic acid and MTO; and the base is sodium carbonate. Preferably, the oxidant used in step B is urea hydrogen peroxide; the solvent is ethanol; the catalyst is a mixture of acetic acid and MTO; and the base is sodium bicarbonate. Preferably, the oxidant used in step B is urea hydrogen peroxide; the solvent is ethanol; the catalyst is a mixture of acetic acid and MTO; and the base is sodium carbonate. Preferably, the oxidant used in step B is hydrogen peroxide; the solvent is ethanol; the catalyst is MTO; and the base is sodium bicarbonate. Preferably, the oxidant used in step B is hydrogen peroxide; the solvent is ethanol; the catalyst is MTO; and the base is sodium carbonate. Preferably, the oxidant used in step B is urea hydrogen peroxide; the solvent is ethanol; the catalyst is MTO; and the base is sodium carbonate. Preferably, the oxidant used in step B is urea hydrogen peroxide; the solvent is ethanol; the catalyst is MTO; and the base is sodium bicarbonate. Preferably, the oxidant used in step B is urea hydrogen peroxide; the solvent is ethanol; the catalyst is MTO; and the base is sodium carbonate.

[0098] Preferably, the amount ratio of the oxidant to the compound of formula (IV) is in the range of 1 molar equivalent to 10 molar equivalents. Preferably, the range is 1 molar equivalent to 8 molar equivalents. Preferably, the range is 1.1 molar equivalent to 7.5 molar equivalents. Preferably, the range is 1.2 molar equivalent to 6 molar equivalents. Preferably, the range is 1.25 molar equivalent to 5 molar equivalents. Preferably, the range is 1.3 molar equivalent to 4 molar equivalents. Preferably, the range is 1.4 molar equivalent to 3 molar equivalents. Preferably, the range is 1.5 molar equivalent to 2 molar equivalents. Preferably, the range is 1.6 molar equivalent to 1.9 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 1.5 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 1.8 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 2 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 2.2 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 2.5 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 2.8 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 3 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 3.2 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 4 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 5 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 6 molar equivalents. Preferably, the amount ratio of the oxidant to the compound of formula (IV) is about 7 molar equivalents. Preferably, the ratio of the amount of oxidizing agent to the amount of the compound of formula (IV) is about 7.5 molar equivalents.

[0099] Preferably, the amount ratio of the catalyst to the compound of formula (IV) is in the range of 0.001 molar equivalents to 1 molar equivalent. Preferably, the range is 0.05 molar equivalents to 0.5 molar equivalents. Preferably, the range is 0.01 molar equivalents to 0.5 molar equivalents. Preferably, the amount ratio of the catalyst to the compound of formula (IV) is about 0.005 molar equivalents. Preferably, the amount ratio of the catalyst to the compound of formula (IV) is about 0.01 molar equivalents. Preferably, the amount ratio of the catalyst to the compound of formula (IV) is about 0.02 molar equivalents. Preferably, the amount ratio of the catalyst to the compound of formula (IV) is about 0.03 molar equivalents. Preferably, the amount ratio of the catalyst to the compound of formula (IV) is about 0.1 molar equivalents. Preferably, the amount ratio of the catalyst to the compound of formula (IV) is about 0.2 molar equivalents. Preferably, the ratio of the amount of catalyst to the amount of the compound of formula (IV) is about 0.3 molar equivalents.

[0100] Preferably, the amount ratio of the base to the compound of formula (IV) is in the range of 1 molar equivalent to 10 molar equivalents. Preferably, the range is 1 molar equivalent to 7 molar equivalents. Preferably, the range is 1.1 molar equivalents to 6 molar equivalents. Preferably, the range is 1.2 molar equivalents to 5 molar equivalents. Preferably, the range is 1.3 molar equivalents to 4 molar equivalents. Preferably, the range is 1.4 molar equivalents to 3 molar equivalents. Preferably, the range is 1.5 molar equivalents to 2 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (IV) is about 1.5 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (IV) is about 2 molar equivalents.

[0101] Without wishing to be bound by theory, it is believed that Step B is reversible in the presence of water. Thus, without wishing to be bound by theory, it is believed that the reaction of Step B is optimized by minimizing the amount of water present in Step B.

[0102] Step B can be carried out using the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0103] An example of Step B is shown in Scheme 3 and Table II below. Scheme 3 provides an example of the Step B reaction, and Table II provides the reaction conditions used in the reaction shown in Scheme 3. Although the product of Scheme 3, the compound of formula (V), is in the form of a zwitterionic N-oxide (i.e., wherein R4 is -O - ), but it can also be a form in which the nitrogen atom in the N-oxide is combined with -OH (i.e., wherein R4 is -OH) or with methanesulfonate (-MsO) (i.e., wherein R4 is -MsO). These forms are shown below: Table II

[0104] In one embodiment, the present invention relates to a method for preparing a compound of formula (I) using a compound of formula (V), the method comprising step C: reacting a compound of formula (V) To produce a compound of formula (I) in, R1 is H, a C1-C6 alkyl group or a protecting group as described above, and n is 1, 2, 3 or 4.

[0105] Step C is as follows.

[0106] Preferably, R1 is H or a protecting group as described above.

[0107] Preferably, R1 is a protecting group as described above.

[0108] Preferably, R1 is a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a tosyl (Ts) group.

[0109] Preferably, R1 is a tert-butoxycarbonyl (BOC) group.

[0110] Preferably, R1 is a C1-C6 alkyl group.

[0111] Preferably, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0112] Preferably, n is 1, 2 or 3.

[0113] Preferably, n is 2 or 3.

[0114] Preferably, n is 3.

[0115] Preferably, step C comprises: reacting the compound of formula (V) to form the 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.

[0116] Suitable electrophilic reagents for use in step C may be selected from the group consisting of acyl halides, anhydrides, sulfonyl halide reagents and mixtures thereof.

[0117] Preferably, the electrophilic reagent used in step C is an acyl halide selected from the group consisting of acyl chloride, acyl bromide, acyl iodide and mixtures thereof.

[0118] Preferably, the electrophilic reagent used in step C is an 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.

[0119] 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, mesyl chloride (MsCl), mesyl bromide, mesyl iodide, tosyl chloride (TsCl), p-Toluenesulfonyl bromide, p-toluenesulfonyl iodide and mixtures thereof.

[0120] Suitable solvents for step C may be selected from the group consisting of water, amides, ethers, ketones, halogenated alkanes, nitriles and mixtures thereof.

[0121] The solvent used in step C may be an amide selected from the group consisting of DMF, DMA, 2-pyrrolidone and a mixture thereof.

[0122] The solvent used in step C may be an ether selected from the group consisting of diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane and a mixture thereof.

[0123] The solvent used in step C may be a ketone selected from the group consisting of acetone, methyl ethyl ketone, cyclohexanone and a mixture thereof.

[0124] The solvent used in step C may be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane and a mixture thereof.

[0125] The solvent used in step C may be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile and mixtures thereof.

[0126] The solvent used in step C may be a mixture of water and one or more organic solvents selected from the group consisting of ethers, ketones, halogenated alkanes and nitriles.

[0127] Suitable bases for use in Step C may be selected from the group consisting of organic bases, inorganic bases and mixtures thereof.

[0128] The base used in step C may be an organic base selected from the group consisting of an amine base, an alkoxide, and a mixture thereof.

[0129] 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.

[0130] The base used in step C may be an alkoxide 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.

[0131] The base used in step C may be an inorganic base selected from the group consisting of hydroxide salts, carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates and mixtures thereof.

[0132] The base used in step C may be a hydroxide salt selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof.

[0133] The base used in step C may be a carbonate selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof.

[0134] The base used in step C may be a bicarbonate selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof.

[0135] The base used in step C may be a phosphate selected from the group consisting of lithium phosphate, sodium phosphate, potassium phosphate and mixtures thereof.

[0136] The base used in step C may be a hydrogen phosphate selected from the group consisting of dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and mixtures thereof.

[0137] The base used in step C may be a dihydrogen phosphate selected from the group consisting of lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and mixtures thereof.

[0138] A suitable buffer for step C is a buffer that maintains the pH of the reaction mixture of step C in a pH range between pH 4 and pH 10. Without wishing to be bound by theory, it is believed that in the pH range below pH 4, impurities may form in step C. Furthermore, without wishing to be bound by theory, it is believed that in the pH range above pH 10, the hydrolysis rate of the electrophile is greater than the rate of step C. Examples of suitable buffers include acetate buffers, such as sodium acetate-acetic acid buffer (pH about 5.2). Other examples of suitable buffers include H3PO4-Na2HPO4 buffer (pH about 4), Na2HPO4-NaH2PO4 buffer (between about pH 5.8 and about pH 10.0), imidazole-HCl buffer (between about pH 6.2 and about pH 7.8), H3PO4-triethylamine (TEA) buffer (pH about 7), citric acid-triethylamine (TEA) buffer (pH about 7), citric acid-tris(hydroxymethyl)aminomethane (TRIS) buffer (pH about 8), and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer (pH about 7).

[0139] Preferably, step C is carried out in the presence of an electrophilic agent and a solvent. Preferably, the electrophilic agent is selected from the group consisting of: mesyl chloride (MsCl), 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, ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN and mixtures thereof. Preferably, the electrophilic agent is selected from the group consisting of: mesyl chloride (MsCl), 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 agent is selected from the group consisting of: mesyl chloride (MsCl), 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 agent is selected from the group consisting of: mesyl chloride (MsCl), 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 agent is selected from the group consisting of: mesyl chloride (MsCl), tosyl chloride (TsCl), acyl chloride and mixtures thereof; 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 electrophile is 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 electrophile is mesyl chloride (MsCl); and the solvent is a mixture of water and THF. Preferably, the electrophile is mesyl chloride (MsCl); and the solvent is a mixture of water and 2-MeTHF. Preferably, the electrophile is mesyl chloride (MsCl); and the solvent is a mixture of water and acetone.Preferably, the electrophile is mesylchloride (MsCl); and the solvent is a mixture of water and DCM. Preferably, the electrophile is mesylchloride (MsCl); and the solvent is a mixture of water and MeCN.

[0140] 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: mesyl chloride (MsCl), tosyl 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, 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: mesyl chloride (MsCl), tosylchloride (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, dilithium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and mixtures thereof. Preferably, the electrophilic reagent is selected from the group consisting of: mesyl chloride (MsCl), 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: mesyl chloride (MsCl), tosylchloride (TsCl), acyl chlorides 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 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 agent is selected from the group consisting of: mesyl chloride (MsCl), 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 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 agent is 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 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 agent is 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 electrophilic agent is 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 agent is 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 agent is 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 agent is 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.

[0141] Preferably, step C is carried out in the presence of an electrophilic agent, a solvent and a buffer. Preferably, the electrophilic agent is selected from the group consisting of: mesyl chloride (MsCl), 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, 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 of step C in a pH range between pH 4 and pH 10. Preferably, the electrophilic agent is selected from the group consisting of: mesylchloride (MsCl), 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, ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN and mixtures thereof; 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 agent is selected from the group consisting of: mesyl chloride (MsCl), 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 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 agent is selected from the group consisting of: mesyl chloride (MsCl), 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 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 agent is selected from the group consisting of: mesyl chloride (MsCl), tosyl chloride (TsCl), acyl chlorides 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 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 agent is selected from the group consisting of: mesyl chloride (MsCl), tosylchloride (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 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 mesylchloride (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 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 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 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 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 electrophile is mesyl chloride (MsCl); the solvent is a mixture of water and DCM; 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 mesyl chloride (MsCl); the solvent is a mixture of water and MeCN; 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.

[0142] Preferably, the ratio of the amount of electrophilic agent to the compound of formula (V) is in the range of 0.05 molar equivalents to 10 molar equivalents. Preferably, the range is 0.1 molar equivalents to 7 molar equivalents. Preferably, the range is 0.2 molar equivalents to 6 molar equivalents. Preferably, the range is 0.25 molar equivalents to 5 molar equivalents. Preferably, the range is 0.3 molar equivalents to 4 molar equivalents. Preferably, the range is 0.4 molar equivalents to 3 molar equivalents. Preferably, the range is 0.5 molar equivalents to 2.5 molar equivalents. Preferably, the range is 0.6 molar equivalents to 2.25 molar equivalents. Preferably, the range is 0.7 molar equivalents to 2 molar equivalents. Preferably, the range is 0.75 molar equivalents to 1.75 molar equivalents. Preferably, the ratio of the amount of electrophilic agent to the compound of formula (V) is about 1.5 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 1.6 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 1.7 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 1.8 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 1.9 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 2 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 2.1 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 2.2 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 2.3 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 2.4 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 2.5 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 3 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 3.5 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 4 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 4.5 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 5 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 0.25 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 0.5 molar equivalents. Preferably, the amount ratio of the electrophilic agent to the compound of formula (V) is about 0.75 molar equivalents. Preferably, the ratio of the amount of electrophile to the amount of the compound of formula (V) is about 1 molar equivalent.

[0143] Preferably, the amount ratio of the base to the compound of formula (V) is in the range of 0.1 molar equivalents to 10 molar equivalents. Preferably, the range is 0.5 molar equivalents to 9 molar equivalents. Preferably, the range is 0.75 molar equivalents to 8 molar equivalents. Preferably, the range is 1 molar equivalent to 7 molar equivalents. Preferably, the range is 1.5 molar equivalents to 6 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 0.25 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 0.5 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 0.75 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 1 molar equivalent. Preferably, the amount ratio of the base to the compound of formula (V) is about 1.5 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 2 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 2.5 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 3 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 4 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 5 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 6 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 7 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 7.5 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 8 molar equivalents. Preferably, the amount ratio of the base to the compound of formula (V) is about 9 molar equivalents.

[0144] Preferably, the amount of buffer used in step C is sufficient to maintain the pH within a pH range between pH 4 and pH 10 for the duration of step C.

[0145] Preferably, the amount ratio of the buffer to the compound of formula (V) is in the range of 1 molar equivalent to 10 molar equivalents. Preferably, the range is 1.5 molar equivalents to 9 molar equivalents. Preferably, the range is 2 molar equivalents to 8 molar equivalents. Preferably, the range is 2.5 molar equivalents to 7 molar equivalents. Preferably, the amount ratio of the buffer to the compound of formula (V) is about 2 molar equivalents. Preferably, the amount ratio of the buffer to the compound of formula (V) is about 3 molar equivalents. Preferably, the amount ratio of the buffer to the compound of formula (V) is about 4 molar equivalents. Preferably, the amount ratio of the buffer to the compound of formula (V) is about 5 molar equivalents. Preferably, the amount ratio of the buffer to the compound of formula (V) is about 6 molar equivalents. Preferably, the amount ratio of the buffer to the compound of formula (V) is about 7 molar equivalents. Preferably, the amount ratio of the buffer to the compound of formula (V) is about 7.5 molar equivalents. Preferably, the ratio of the amount of buffer to the amount of the compound of formula (V) is about 8 molar equivalents.

[0146] 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.

[0147] Step C can be carried out using formula (V) or a pharmaceutically acceptable salt thereof.

[0148] 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 performed at about -5°C to about 5°C. Preferably, step C is performed at about 0°C. Preferably, step C is performed at about 0°C to about 15°C. Preferably, step C is performed at about 5°C to about 10°C.

[0149] An example of Step C is shown in Scheme 4 and Table III below. Scheme 4 provides an example of the Step C reaction, and Table III provides the reaction conditions used in the reaction shown in Scheme 4. Although the reactant of Scheme 4, the compound of formula (V), is in the form of a zwitterionic N-oxide (i.e., wherein R4 is -O - ), but it may also be a form in which the nitrogen atom of the N-oxide is bonded to -OH (i.e., wherein R4 is -OH) or to a sulfonate such as methanesulfonate (-MsO) (i.e., wherein R4 is -MsO). These forms are shown below: Furthermore, although the product of Scheme 4, the compound of formula (I), is shown as a lactam, it may also be a lactim or an equilibrium of the two forms, as shown below: Table III

[0150] Preferably, step C is followed by an optional deprotection step D, which comprises removing the protecting group in the compound of formula (I) (wherein R1 is a protecting group as described above) by reacting the compound of formula (I) with at least one deprotecting agent to produce a compound of formula (I) (wherein R1 is H).

[0151] Preferably, step D comprises reacting a compound of formula (I) wherein R1 is a protecting group as described above in the presence of a deprotecting agent and a solvent to form a compound of formula (I) wherein R1 is H.

[0152] Suitable deprotecting agents for step D may be selected from the group consisting of acyl halides, anhydrides, organic acids, inorganic acids and mixtures thereof.

[0153] The deprotecting agent used in step D may be an acyl halide selected from the group consisting of acyl chloride, acyl bromide, acyl iodide and a mixture thereof.

[0154] The deprotecting agent used in step D may be an anhydride selected from the group consisting of acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride and a mixture thereof.

[0155] The deprotecting agent used in step D may be an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid and a mixture thereof.

[0156] The deprotecting agent used in step D may be an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid and a mixture thereof.

[0157] Suitable solvents for Step D may be selected from the group consisting of alcohols, ethers, nitriles, halogenated alkanes and mixtures thereof.

[0158] The solvent used in step D may be an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and mixtures thereof.

[0159] The solvent used in step D may be an ether selected from the group consisting of diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof.

[0160] The solvent used in Step D may be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile and mixtures thereof.

[0161] The solvent used in step D may be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0162] Preferably, the deprotecting agent 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.

[0163] Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, diethyl ether, THF, 2-MeTHF, MeCN, DCM, chloroform and mixtures thereof.

[0164] Preferably, the deprotecting agent is an acyl chloride, and the solvent is isopropanol. Preferably, the deprotecting agent is hydrochloric acid, and the solvent is THF. Preferably, the deprotecting agent is trifluoroacetic acid, and the solvent is DCM.

[0165] Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is in the range of 1 molar equivalent to 20 molar equivalents. Preferably, the range is 2 molar equivalents to 17.5 molar equivalents. Preferably, the range is 3 molar equivalents to 15 molar equivalents. Preferably, the range is 4 molar equivalents to 12.5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 7.5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 8 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 9 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 10 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 12.5 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is in the range of 1 molar equivalent to 10 molar equivalents. Preferably, the range is 1.5 molar equivalents to 7.5 molar equivalents. Preferably, the range is 2 molar equivalents to 5 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 2 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 2.5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 3 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (I) (wherein R1 is a protecting group as described above) is about 4 molar equivalents.

[0166] Step D can be carried out using a compound of formula (I) or a pharmaceutically acceptable salt thereof. Step D can produce a compound of formula (I) (wherein R1 is H) or a pharmaceutically acceptable salt thereof.

[0167] 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.

[0168] An example of Step D is shown in Scheme 5 and Table IV below. Scheme 5 provides an example of the Step D reaction, and Table IV provides the reaction conditions used in the reaction shown in Scheme 5. Although the reactant of Scheme 5, the compound of formula (I) wherein R1 is a tert-butoxycarbonyl (BOC) group, is shown in the lactam form, it may also be in the lactim form or an equilibrium of the two forms, as shown below: Furthermore, although the product of Scheme 5, i.e., the compound of formula (I) wherein R1 is H, is shown as a lactam, it may also be a lactim or an equilibrium of the two forms, as shown below: In addition, although the product of Scheme 5, i.e., the compound of formula (I) (wherein R1 is H) is shown as a monohydrochloride, it can also be a dihydrochloride. In addition, the dihydrochloride can be in the lactam form, the lactim form, or a balance of the two forms, as shown below: Table IV

[0169] Preferably, step A is followed by an optional deprotection step E, which comprises removing the protecting group in the compound of formula (IV) (wherein R1 is a protecting group as described above) by reacting the compound of formula (IV) with at least one deprotecting agent to produce a compound of formula (IV) (wherein R1 is H).

[0170] Preferably, step E comprises reacting a compound of formula (IV) wherein R1 is a protecting group as described above in the presence of a deprotecting agent and a solvent to form a compound of formula (IV) wherein R1 is H.

[0171] Suitable deprotecting agents for use in Step E may be selected from the group consisting of acyl halides, anhydrides, organic acids, inorganic acids and mixtures thereof.

[0172] The deprotecting agent used in step E may be an acyl halide selected from the group consisting of acyl chloride, acyl bromide, acyl iodide and a mixture thereof.

[0173] The deprotecting agent used in step E may be an anhydride selected from the group consisting of acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride and a mixture thereof.

[0174] The deprotecting agent used in step E may be an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid and a mixture thereof.

[0175] The deprotecting agent used in step E may be an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid and a mixture thereof.

[0176] Suitable solvents for Step E may be selected from the group consisting of alcohols, ethers, nitriles, halogenated alkanes and mixtures thereof.

[0177] The solvent used in step E may be an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol and mixtures thereof.

[0178] The solvent used in Step E may be an ether selected from the group consisting of diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof.

[0179] The solvent used in Step E may be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile and mixtures thereof.

[0180] The solvent used in Step E may be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0181] Preferably, the deprotecting agent 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.

[0182] Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, diethyl ether, THF, 2-MeTHF, MeCN, DCM, chloroform and mixtures thereof.

[0183] Preferably, the deprotecting agent is an acyl chloride, and the solvent is isopropanol. Preferably, the deprotecting agent is hydrochloric acid, and the solvent is THF. Preferably, the deprotecting agent is trifluoroacetic acid, and the solvent is DCM.

[0184] According to a preferred embodiment of the present invention, the ratio of the amount of the deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is in the range of 1 molar equivalent to 20 molar equivalents. Preferably, the range is 2 molar equivalents to 17.5 molar equivalents. Preferably, the range is 3 molar equivalents to 15 molar equivalents. Preferably, the range is 4 molar equivalents to 12.5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 7.5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 8 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 9 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 10 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 12.5 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is in the range of 1 molar equivalent to 10 molar equivalents. Preferably, the range is 1.5 molar equivalents to 7.5 molar equivalents. Preferably, the range is 2 molar equivalents to 5 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 2 molar equivalents. Preferably, the ratio of the amount of deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 2.5 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 3 molar equivalents. Preferably, the ratio of the amount of the deprotecting agent to the compound of formula (IV) (wherein R1 is a protecting group as described above) is about 4 molar equivalents.

[0185] Step E can be carried out using a compound of formula (IV) or a pharmaceutically acceptable salt thereof. Step E can produce a compound of formula (IV) (wherein R1 is H) or a pharmaceutically acceptable salt thereof.

[0186] 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.

[0187] Preferably, step B is followed by an optional deprotection step F, which comprises removing the protecting group in the compound of formula (V) (wherein R1 is a protecting group as described above) by reacting the compound of formula (V) with at least one deprotecting agent to produce a compound of formula (V) (wherein R1 is H).

[0188] Preferably, step F comprises reacting a compound of formula (V) wherein R1 is a protecting group as described above in the presence of a deprotecting agent and a solvent to form a compound of formula (V) wherein R1 is H.

[0189] Suitable deprotecting agents for use in Step F may be selected from the group consisting of acyl halides, anhydrides, organic acids, inorganic acids and mixtures thereof.

[0190] The deprotecting agent used in step F may be an acyl halide selected from the group consisting of acyl chloride, acyl bromide, acyl iodide and a mixture thereof.

[0191] The deprotecting agent used in step F may be an anhydride selected from the group consisting of acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride and a mixture thereof.

[0192] The deprotecting agent used in step F may be an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid and a mixture thereof.

[0193] The deprotecting agent used in step F may be an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid and a mixture thereof.

[0194] Suitable solvents for Step F may be selected from the group consisting of alcohols, ethers, nitriles, halogenated alkanes and mixtures thereof.

[0195] The solvent used in step F may be an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol and mixtures thereof.

[0196] The solvent used in step F may be an ether selected from the group consisting of diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof.

[0197] The solvent used in Step F may be a nitrile selected from the group consisting of MeCN, propionitrile, benzonitrile and mixtures thereof.

[0198] The solvent used in step F may be a halogenated alkane selected from the group consisting of DCM, chloroform, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof.

[0199] Preferably, the deprotecting agent 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.

[0200] The solvent is selected from the group consisting of methanol, ethanol, isopropanol, diethyl ether, THF, 2-MeTHF, MeCN, DCM, chloroform and mixtures thereof.

[0201] Preferably, the deprotecting agent is an acyl chloride, and the solvent is isopropanol. Preferably, the deprotecting agent is hydrochloric acid, and the solvent is THF. Preferably, the deprotecting agent is trifluoroacetic acid, and the solvent is DCM.

[0202] According to a preferred embodiment of the present invention, the ratio of the amount of the deprotecting agent to the compound of formula (V) (wherein R1 is a protecting group as described above) is in the range of 1 molar equivalent to 20 molar equivalents, preferably 2 molar equivalents to 17.5 molar equivalents, more preferably 3 molar equivalents to 15 molar equivalents, and further preferably 4 molar equivalents to 12.5 molar equivalents, such as about 5 molar equivalents, about 7.5 molar equivalents, about 8 molar equivalents, about 9 molar equivalents, about 10 molar equivalents or about 12.5 molar equivalents. Further preferably, the ratio of the amount of the deprotecting agent to the compound of formula (V) (wherein R1 is a protecting group as described above) is in the range of 1 molar equivalent to 10 molar equivalents, 1.5 molar equivalents to 7.5 molar equivalents or 2 molar equivalents to 5 molar equivalents. The ratio of the amount of the deprotecting agent to the compound of formula (V) (wherein R1 is a protecting group as described above) can be about 2 molar equivalents, about 2.5 molar equivalents, about 3 molar equivalents or about 4 molar equivalents.

[0203] Step F can be carried out using a compound of formula (V) or a pharmaceutically acceptable salt thereof. Step F can produce a compound of formula (V) (wherein R1 is H) or a pharmaceutically acceptable salt thereof.

[0204] Preferably, step F is performed at about -10°C to about 70°C. Preferably, step F is performed at about -5°C to about 60°C. Preferably, step F is performed at about 0°C to about 50°C. Preferably, step F is performed at about 5°C to about 40°C. Preferably, step F is performed at about 10°C to about 35°C. Preferably, step F is performed at about 15°C to about 30°C. Preferably, step F is performed at room temperature.

[0205] The compounds of Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V) may exist as pharmaceutically acceptable salts.

[0206] Pharmaceutically acceptable salts of 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 and organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acids such as 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 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 between 1 molar equivalent and 5 molar equivalents of the inorganic acid or organic acid to 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), (II), (III), (IV) or (V) is 1 molar equivalent of the inorganic acid or organic acid to 1 molar equivalent of the compound of formula (I), (II), (III), (IV) or (V). Preferably, the ratio of the inorganic acid or organic acid to the compound of formula (I), (II), (III), (IV) or (V) is 2 molar equivalents of the inorganic acid or organic acid to 1 molar equivalent of the compound of formula (I), (II), (III), (IV) or (V).

[0207] The pharmaceutically acceptable salts of the compounds of formula (I), (II), (III), (IV) and (V) may exist as hydrates. The stoichiometry of water molecules to the molecules of the pharmaceutically acceptable salts of the compounds of formula (I), (II), (III), (IV) and (V) depends on the tightness of the binding of water to the corresponding salt and the moisture content.

[0208] Preferably, the hydrate of the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof can be formed by dissolving or suspending the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof in water or a mixture of water and an organic solvent in optional step G.

[0209] Preferably, the hydrate of the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof is formed in step G by dissolving or suspending the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof in water.

[0210] Preferably, the hydrate of the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof is formed in step G by dissolving or suspending the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof in a mixture of water and an organic solvent.

[0211] Suitable organic solvents for Step G are nitriles, such as MeCN or propionitrile; ketones, such as acetone; ethers, for example THF; and alcohols, such as methanol, ethanol, n-propanol and isopropanol.

[0212] Preferably, the hydrate of the compound of Formula (I), (II), (III), (IV), (V), or (V) or a pharmaceutically acceptable salt thereof is formed in step G by dissolving or suspending the compound of Formula (I), (II), (III), (IV), or (V) or a pharmaceutically acceptable salt thereof in a mixture of water and MeCN, acetone, THF, methanol, ethanol, n-propanol or isopropanol.

[0213] 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.

[0214] 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 performed at about 25°C. Preferably, step G is performed at about 20°C.

[0215] An example of Step G is shown below in Scheme 6 and Table V. Scheme 6 provides an example of the Step G reaction, and Table V provides the reaction conditions used in the reaction shown in Scheme 6. Although the reactants of Scheme 6 are shown in lactam form, they may also be in lactim form or an equilibrium of the two forms as shown below: Furthermore, although the product of Scheme 6 is shown as a lactam, it may also be in the lactim form or an equilibrium of the two forms as shown below: Table V

[0216] All reaction steps continue until they are completed, as determined by standard laboratory techniques. For example, when at least one reagent is no longer detected in the reaction mixture, it can be determined that the step has been completed. Alternatively, when no concentration change of reagent, reaction product or both is detected in the reaction mixture, it can be determined that the step has been completed. The detection of reagent, product or both can be carried out using standard laboratory techniques and instruments. For example, thin layer chromatography, gas chromatography or liquid chromatography are used to monitor reagent, product or both.

[0217] The product obtained from each reaction step can be separated and further purified by standard synthesis techniques. For example, separation can be carried out by evaporating the reaction mixture, followed by conventional aqueous phase post-treatment and subsequent product chromatography purification or crystallization. Alternatively, the product contained in the reaction mixture can also be precipitated directly from the reaction mixture by adding a suitable anti-solvent such as water and / or alcohol.

[0218] The amount of solvent used in any step is determined by standard laboratory techniques. For example, the amount of solvent can be such that all reagents in a step are dissolved in the solvent. Alternatively, the amount of solvent is set to be sufficient to control the reaction rate of the step. definition

[0219] The term "alcohol" refers to a compound of the formula R'-OH. R' can be a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 Alkyl group; substituted or unsubstituted cyclic alkyl group, such as substituted or unsubstituted C3-C 10 a cyclic alkyl group; 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.

[0220] The term "alkane" refers to a straight or branched chain alkane having 1 to 20 carbon atoms, and "substituted alkane" refers to a straight or branched chain alkane having 1 to 20 carbon atoms and further bearing one or more substituents.

[0221] The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms, and "substituted alkyl" refers to an alkyl group further carrying one or more substituents.

[0222] The term "amide" refers to an amide of the formula R'-C(O)-NR"R α R' may be H; a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 alkyl group; or a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. R" may be H; a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 an alkyl group; or a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. α It may be H; a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 an alkyl group; or a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. R', R" and R α Two or more of may be the same, or R', R" and R αR', R" and R α The two together may be substituted or unsubstituted cyclic alkyl groups, such as substituted or unsubstituted C3-C 10 Cyclic alkyl group. Examples of amides include dimethylformamide, dimethylacetamide and 2-pyrrolidone.

[0223] The term "aryl" refers to an aromatic group having 6 to 24 carbon atoms, and "substituted aryl" refers to an aryl group further bearing one or more substituents.

[0224] The term "buffer" refers to a solution that resists changes in pH when acid or base is added.

[0225] The term "aqueous solution" refers to a solution comprising water and a solute selected from the group consisting of a salt, an acid, a base, a buffer, a water-soluble or water-miscible organic solvent, and mixtures thereof.

[0226] The term "catalyst" refers to an agent that is capable of increasing the rate of a chemical reaction and is selected from the group consisting of an organic compound, an inorganic compound or an organometallic compound. 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.

[0227] The term "cycloalkyl" refers to cyclic ring-containing moieties containing from 3 to 20 carbon atoms, and "substituted cycloalkyl" refers to cycloalkyl moieties further bearing one or more substituents.

[0228] The terms "electrophile" and "electrophile" refer to Lewis acids. Examples of electrophiles include alkyl halides, acyl halides, anhydrides, and sulfonyl halide reagents.

[0229] The term "ester" refers to a compound of the formula R'-C(O)-OR". R' can be a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 or a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. R" may be a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 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 substituted or unsubstituted C3-C 10 Cyclic alkyl group. Examples of esters include methyl acetate, ethyl acetate, and mixtures thereof.

[0230] The term "ether" refers to a compound of the formula R'-OR". R' can be a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 or a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. R" may be a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 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 substituted or unsubstituted C3-C 10 Cyclic alkyl groups. Examples of ethers include THF, 2-MeTHF, MTBE, 1,4-dioxane, DME, and mixtures thereof.

[0231] Halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0232] The term "haloalkane" refers to an alkane containing one or more carbon atoms and one or more halogen atoms. The halogenated alkane may contain between 1 and 10 carbon atoms and between 1 and 10 halogen atoms. Examples of halogenated alkanes include DCM, chloroform, carbon tetrachloride, and 1,2-dichloroethane.

[0233] 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 substituted or unsubstituted C1-C 10 or a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. R" may be a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 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 substituted or unsubstituted C3-C 10 Cyclic alkyl group. Examples of ketones include acetone, methyl ethyl ketone, cyclohexanone, and mixtures thereof.

[0234] The term "nitrile" refers to a compound of the formula R'-CN. R' can be a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted C1-C 10 Alkyl group; substituted or unsubstituted cyclic alkyl group, such as substituted or unsubstituted C3-C 10 a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. Examples of nitriles include MeCN, propionitrile, benzonitrile, and mixtures thereof.

[0235] The terms "nucleophile" and "nucleophile" refer to a Lewis base. Examples of nucleophiles include ammonia, azides, amines, enols, organolithium reagents, alkylmagnesium halides, allylmagnesium halides, vinylmagnesium halides, arylmagnesium halides, and mixtures thereof.

[0236] The term "oxidant" refers to a compound that gains electrons and is reduced in a chemical reaction. Examples of oxidants include peroxides such as hydrogen peroxide, urea hydrogen peroxide, acetylbenzoyl peroxide, benzoyl peroxide, tert-butyl hydroperoxide, diacetyl peroxide, ethyl hydroperoxide, methyl ethyl ketone peroxide, sodium percarbonate, and peroxyacids; oxygen; ozone; halogens; metal oxides; permanganate compounds such as potassium permanganate; and perborates such as lithium perborate, sodium perborate, and potassium perborate. Examples of peroxyacids include peracetic acid, performic acid, peroxybenzoic acid, mCPBA, peroxysulfuric acid, peroxynitric acid, and peroxyphosphoric acid. Perborate may be in the form of a hydrate such as sodium perborate tetrahydrate.

[0237] The term "pharmaceutically acceptable" refers to non-toxic materials that do not interfere with the effectiveness of the active ingredients.

[0238] The term "reducing agent" refers to a compound that loses electrons and is oxidized in a chemical reaction. Examples of reducing agents include hydrogen gas, lithium aluminum hydride, sodium borohydride, thiosulfate, hydrazine, and diisobutylaluminum hydride.

[0239] The term "room temperature" refers to the temperature range between 19°C and 26°C.

[0240] 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、-COOR e and -CO(NR f R g );where R a , R b , R c , R d , R e , R f and R g Each of is independently selected from H or C1-C6 alkyl.

[0241] As used herein, "water" refers to both tap water, distilled water, or deionized water.

[0242] As used herein, the terms Formula (I), (II), (III), (IV) and (V) may hereinafter be referred to as "compounds of the invention", "the present invention", and "compounds of Formula (I)", "compounds of Formula (II)", "compounds of Formula (III)", "compounds of Formula (IV)" and "compounds of Formula (V)", respectively. Such terms are also defined to include all forms of compounds of Formula (I), compounds of Formula (II), compounds of Formula (III), compounds of Formula (IV) and compounds of Formula (V), including pharmaceutically acceptable salts, hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs and metabolites thereof. For example, a compound of the invention or a pharmaceutically acceptable salt thereof may exist in both unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0243] Example Example 1 - Synthesis of compounds of formula (IV)

[0244] At room temperature and nitrogen, in a round bottom flask, DMF (15 volumes) was charged with isoquinolin-6-ol (40.0 g, 1.0 equiv.), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.6 equiv.), and potassium carbonate (4.0 equiv.). The reaction mixture was heated to 100° C. over 1 hour, and the reaction mixture was kept at 100° C. for 16 hours. The reaction system was then cooled to room temperature over 1 hour, and water (30 volumes) was added. The reaction mixture was extracted with methyl tert-butyl ether MTBE (3×10 volumes), and the combined MTBE layers were washed with 10% aqueous NaOH (2×5 volumes) and then with water (10 volumes). The MTBE layer was distilled to up to 1 volume at below 45° C. under vacuum, n-hexane (5 volumes) was added and evaporated to 1 volume. The same procedure was repeated once more with n-hexane (5 volumes) and distilled completely to dryness to constant weight at below 45°C under vacuum to give 85.0 g of crude product. n-Hexane (5 volumes) was added to the crude product at room temperature, cooled to 0°C-5°C within 30 minutes and stirred at 0°C-5°C for 1 hour. The solid was filtered, washed with cold n-hexane (2 volumes) and sucked dry. The wet cake was dried to constant weight at below 45°C under vacuum to give 69.5 g of tert-butyl 4-(isoquinolin-6-yloxy)piperidine-1-carboxylate, a compound of formula (IV), in a yield of 77%. Example 2—Synthesis of compounds of formula (V)

[0245] Compound 4-(isoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (90.0 g, 1.0 eq.) of formula (IV) was added to DCM (15 vol.) in a round bottom flask and cooled to 5-10°C over a period of 30 minutes. mCPBA (1.8 eq.) was added in batches (4 equal portions) at 5-10°C. The reaction mixture was allowed to reach room temperature over a period of 2 hours and maintained at room temperature for 1 hour. The reaction system was monitored by HPLC. The reaction mixture was diluted with DCM (10 vol.) and quenched with 40% aqueous sodium metabisulfite solution (10 vol.) at room temperature. The resulting aqueous and DCM layers were separated and the DCM layer was washed with 10% aqueous NaOH solution (10 vol.) and then with water (10 vol.). The DCM layer was distilled to up to 1 vol. and MTBE (5 vol.) was added. The solvent was distilled off to up to 1 vol. and the same procedure was repeated once more with MTBE (5 vol.). MTBE (5 volumes) was added to the reaction mixture and stirred at room temperature for 1 hour. The resulting solid was filtered and washed with MTBE (2 volumes). The wet cake was dried to constant weight under vacuum at less than 45°C to give 75.0 g of compound 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isoquinoline 2-oxide of formula (V) in 80% yield. Example 3 - Synthesis of compounds of formula (I)

[0246] Compound 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isoquinoline 2-oxide (70.0 g, 1.0 eq.) of formula (V) and water:THF (10 vol:10 vol) were added to a round bottom flask at room temperature to form a homogeneous reaction mixture. MsCl (2.0 eq.) was added to the reaction mixture at room temperature for 30 minutes. The reaction mixture was kept at room temperature for 2 hours. MTBE (10 vol) was added to the reaction mixture, and the aqueous layer was extracted with MTBE (2×10 vol). The combined MTBE layers were washed with 10% KHSO4 aqueous solution (2×10 vol). The solvent was distilled to constant weight at below 45° C. under vacuum to give 52.0 g of crude product with a purity of 95.35% (measured by HPLC). Acetone (4 vol) was added to the crude product (52.0 g) and stirred at room temperature for 3 hours. The solid was filtered and washed with cold acetone (1 vol). The resulting solid was dried to constant weight under vacuum at less than 45° C. to afford 33.0 g of tert-butyl 4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)piperidine-1-carboxylate, a compound of formula (I), as an off-white solid in a 47% yield. Example 4 - Deprotection of compounds of formula (I)

[0247] To a solution of the acid chloride (7.5 eq) in isopropanol (10 vol) was added tert-butyl 4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)piperidine-1-carboxylate (5.5 g, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solids in the reaction mixture were filtered and washed with isopropanol (2 vol) to give 4.2 g of 6-(piperidin-4-yloxy)isoquinolin-1(2H)-one hydrochloride (yield 93%, purity 98.4% by HPLC). Example 5 - Synthesis of compounds of formula (IV)

[0248] Under nitrogen, isoquinolin-6-ol (1.0 equiv), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.6 equiv) and cesium carbonate (2.0 equiv) were added to a 500-mL three-necked flask equipped with an overhead stirrer, a thermometer and a condenser. Dimethylformamide (DMF, 5 vol) was added to form a slurry, and then water (1 vol) was slowly added. The reaction mixture was heated to 90°C for 16 hours. The reaction mixture was then cooled to room temperature, and water (5 vol) and MTBE (5 vol) were added. The resulting mixture was stirred, and the organic and aqueous layers were separated. The aqueous layer was extracted with MTBE (3 vol), and the combined MTBE layers were washed sequentially with 10% aqueous NaOH (2×5 vol), water (5 vol), and brine (5 vol). The resulting MTBE layer was distilled to 5 vol at 40°C-50°C under vacuum, and then heptane (5 vol) was added, and the organic layer was concentrated to 5 vol. The process of vacuum distillation, addition of heptane and concentration was repeated twice until the amount of residual MTBE was ≤2% mass ratio concentration (w / w). The resulting slurry was cooled to 5°C and stirred overnight. The slurry was then filtered and washed with heptane cooled to 5°C. The resulting solid was suction dried on the filter overnight and balanced with nitrogen to obtain tert-butyl 4-(isoquinolin-6-yloxy)piperidine-1-carboxylate as an off-white solid with a yield of 85% and a purity of ≥98% determined by HPLC. Example 6 - Synthesis of Compounds of Formula (V)

[0249] In a 500-mL three-necked flask purged with nitrogen, equipped with a thermometer, condenser and overhead stirrer, tert-butyl 4-(isoquinolin-6-yloxy)piperidine-1-carboxylate, urea-hydrogen peroxide (2.2 eq.) and PMA (0.2 mol%) were added to MeCN (10 vol.). The reaction mixture was heated to 50°C for 16 hours. The reaction mixture was then cooled to room temperature, and dimethyl sulfoxide (DMSO, 1.5 eq.) was added to the reaction mixture to quench excess peroxide. Subsequently, DCM (10 vol.) and water (5 vol.) were added. The resulting mixture was stirred, and the organic and aqueous layers were separated. The organic layer was washed sequentially with 5% aqueous NaOH solution (5% aq. NaOH) (5 vol.), 10% aqueous citric acid solution (5 vol.), water (5 vol.) and brine (2 vol.). The organic layer was concentrated to 5 volumes in vacuo at 40°C, and then MTBE (5 volumes) was added to the organic layer at 50°C, and then the organic layer was concentrated again to 5 volumes by vacuum distillation. The process of vacuum concentration, addition of MTBE and re-concentration was repeated three times until the amount of residual DCM was ≤0.5% w / w, the amount of residual MeCN was ≤10% w / w, and the amount of residual water was ≤0.5% w / w. The resulting slurry was cooled to room temperature and stirred overnight. The slurry was then filtered and washed with MTBE (2 volumes). The resulting solid was suction dried on the filter overnight and balanced with nitrogen to give 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isoquinoline 2-oxide as an off-white solid in 85% yield with a purity of ≥98% by HPLC. Example 7 - Synthesis of compounds of formula (I)

[0250] In a 500-mL three-necked flask purged with nitrogen, equipped with an overhead stirrer, thermometer, addition funnel, and batch cooling, 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isoquinoline 2-oxide (1 eq) and NaHCO3 (4.0 eq) were added to THF (10 vol) and water (10 vol). The resulting solution was then cooled to 5°C, and methanesulfonyl chloride (MsCl, 2.0 eq) was added dropwise over 15 min. The reaction mixture was stirred at 5°C for 2-3 h. The pH of the reaction mixture was monitored and maintained above pH 4 by adding additional NaHCO3 to the reaction mixture as needed. The reaction mixture was then warmed to room temperature. The organic and aqueous layers were separated, and the aqueous layer was back-extracted with 2×2.5 volumes of THF. The combined organic layers were then washed with 25% w / w aqueous K3PO4 (3.5 vol) for 1 h while monitoring for a stable pH reading above pH 4. The organic layer was then concentrated to 4 volumes by vacuum distillation at 40°C, MeCN (4 volumes) was added to the organic layer, and then the organic layer was concentrated again to 4 volumes by vacuum distillation at 40°C. The process of vacuum concentration, addition of MeCN and re-concentration was repeated twice until the amount of residual THF was ≤1% w / w. The resulting slurry was then warmed to 45°C and water (8.3 volumes) was added over 1 hour. The slurry was then cooled to room temperature and stirred for 3 hours, after which the slurry was filtered and washed with water (2 volumes). The resulting solid was suction dried on the filter overnight and balanced with nitrogen to give tert-butyl 4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)piperidine-1-carboxylate as an off-white solid in 70% yield and ≥98% purity by HPLC. Example 8 - Deprotection of compounds of formula (I)

[0251] In a 250-mL three-necked flask purged with nitrogen and equipped with an overhead stirrer, thermometer, and addition funnel was added isopropanol (5 vol). The isopropanol was cooled to 0°C-5°C and acetyl chloride (7.5 eq) was added to isopropanol over 30 minutes while maintaining the temperature at no more than 25°C. A slurry of tert-butyl 4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)piperidine-1-carboxylate (1 eq) in isopropanol (5 vol) was added to the mixture of acetyl chloride in isopropanol over 10 minutes. The reaction mixture was then stirred at room temperature for 24 hours. The resulting slurry was filtered and washed with isopropanol (2 x 2 vol). The resulting solid was suction dried on the filter overnight and equilibrated with nitrogen to give 6-(piperidinyl-4-yloxy)isoquinolin-1(2H)-one hydrochloride as an off-white solid in 88% yield with a purity of ≥98% by HPLC. Example 9 - Hydrate Formation of Salts of Compounds of Formula (I)

[0252] In a 100-mL reactor purged with nitrogen, 6-(piperidin-4-yloxy)isoquinolin-1(2H)-one hydrochloride was added. Acetone (2 volumes) was then added to 6-(piperidin-4-yloxy)isoquinolin-1(2H)-one hydrochloride in the reactor, followed by water (2 volumes). The resulting slurry was heated to 65°C to obtain a solution. The resulting solution was polish filtered into a preheated container and rinsed with a 2:1 mixture of acetone:water (1 volume). The resulting slurry was then reheated to 65°C to obtain a solution, which was then cooled to 50°C over 30 minutes. Acetone (2 volumes) was added to the solution over 1 hour, and then the solution was cooled to 5°C over 7.5 hours and stirred overnight. The resulting slurry was filtered and washed with a 2:1 mixture of acetone:water (1 volume) that had been cooled to 5°C. The resulting solid was dried and then further dried in a vacuum oven at 30°C containing brine solution to afford 6-(piperidin-4-yloxy)isoquinolin-1(2H)-one hydrochloride dihydrate as an off-white solid in 83% yield with a purity of 99.9% as determined by HPLC.

[0253] Although the preferred embodiments of the present invention have been described in detail herein, those skilled in the art will appreciate that various changes may be made without departing from the spirit of the invention or the scope of the appended claims.

[0254] The subject matter of the present disclosure may also relate to, among other things, the following aspects:

[0255] The first aspect relates to a method for preparing a compound of formula (V) or a pharmaceutically acceptable salt thereof The method comprises: i) step A: making a compound of formula (II) or a pharmaceutically acceptable salt thereof Reaction with a compound of formula (III) or a pharmaceutically acceptable salt thereof To produce a compound of formula (IV) or a pharmaceutically acceptable salt thereof ii) Step B: reacting a compound of formula (IV) or a pharmaceutically acceptable salt thereof To produce a compound of formula (V) or a pharmaceutically acceptable salt thereof wherein R1 is H, a C1-C6 alkyl group or a protecting group which prevents the nitrogen atom to which the protecting group is attached from reacting with other molecules during a chemical reaction, and the protecting group is selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a toluenesulfonyl (tosyl, Ts) group; n is 1, 2, 3 or 4; R2 is -OH or L1, L1 is an ion which can be substituted by a nucleophile and is selected from the group consisting of Leaving group: fluoride (-F), chloride (-Cl), bromide (-Br), iodide (-I), p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3); R3 is -OH or L2, L2 is a leaving group that can be replaced 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 selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

[0256] The second aspect relates to a method according to 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).

[0257] The third aspect relates to a method according to aspect 1 or 2, wherein R1 is a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a toluenesulfonyl (tosyl, Ts) group; n is 2 or 3; R2 is L1 and R3 is -OH, or R2 is -OH and R3 is L2; ​​wherein L1 is selected from the group consisting of a chloride ion (-Cl), a bromide ion (-Br), an iodide ion (-I), a toluenesulfonate (-TsO), a methanesulfonate (-MsO) and a trifluoromethanesulfonate (-CF3SO3); and L2 is selected from the group consisting of a chloride ion (-Cl), a bromide ion (-Br), an iodide ion (-I), a toluenesulfonate (-TsO), a methanesulfonate (-MsO) and a trifluoromethanesulfonate (-CF3SO3).

[0258] The fourth aspect relates to a method according to aspects 1 to 3, wherein R1 is a tert-butoxycarbonyl (BOC) group; n is 3; R2 is L1, and wherein L1 is methanesulfonate (-MsO); or R2 is -OH, and L2 is chloride (-Cl), bromide (-Br) or iodide (-I).

[0259] The fifth aspect relates to a method according to any one of the preceding aspects, 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.

[0260] A sixth aspect relates to a method according to any one of the preceding aspects, wherein 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.

[0261] The seventh aspect relates to a method according to any one of the preceding aspects, wherein in step A, a compound of formula (II) or a pharmaceutically acceptable salt thereof is used in an amount of 1 to 5 molar equivalents relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0262] The eighth aspect relates to the method according to any one of the preceding aspects, 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 oxidant and a solvent.

[0263] The ninth aspect relates to the method according to aspect 8, wherein, in step A, 1 to 5 molar equivalents of a 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 1 to 7 molar equivalents of a base are used relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0264] The tenth aspect relates to the method according to aspect 8 or 9, wherein, in step B, an oxidant is used in an amount of 1 to 10 molar equivalents relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0265] The eleventh aspect relates to the method according to any one 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 ( The oxidant 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-chloroperbenzoic acid (mCPBA), dimethyldioxirane, potassium hydrogen persulfate (potassium permonosulfate), 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, acetonitrile (MeCN), propionitrile, benzonitrile, acetic acid, formic acid, trifluoroacetic acid and mixtures thereof.

[0266] The twelfth aspect relates to a method according to any one of aspects 8 to 11, 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, ether, MTBE and mixtures thereof; the oxidant in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, perbenzoic acid, mCPBA, peroxysulfuric acid, peroxynitric acid, peroxyphosphoric 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.

[0267] A thirteenth aspect relates to a method according to any one of the preceding aspects, 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 oxidant, a catalyst and a solvent.

[0268] A fourteenth aspect relates to a method according to aspect 13, wherein, in step B, an oxidant having 1 to 10 molar equivalents relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof is used, and a catalyst having 0.001 to 1 molar equivalents relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof is used.

[0269] A fifteenth aspect relates to a method according to 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 oxidant in step B is selected from 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, methyltrioxide rhenium (VII) (MeReO3, MTO), phosphomolybdic acid (PMA) and mixtures thereof.

[0270] A sixteenth aspect relates to a method according to any one 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, ether, MTBE and mixtures thereof; the oxidant in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, perbenzoic 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.

[0271] A seventeenth aspect relates to a method according to any one of the preceding aspects, 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 oxidant, a catalyst, a base and a solvent.

[0272] Aspect 18 relates to a method according to aspect 17, wherein, in step B, an oxidant is used in an amount of 1 to 10 molar equivalents relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, a catalyst is used in an amount of 0.001 to 1 molar equivalent relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, and a base is used in an amount of 1 to 10 molar equivalents relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0273] A nineteenth aspect relates to a method according to aspect 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, ether, MTBE and mixtures thereof; the oxidant in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic 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.

[0274] The twentieth aspect relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising step C: reacting a compound of formula (V) or a pharmaceutically acceptable salt thereof To produce a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is H, a C1-C6 alkyl group or a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a toluenesulfonyl (tosyl, Ts) group; n is 1, 2, 3 or 4; and R4 is selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

[0275] A twenty-first aspect relates to the method according to aspect 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in its lactam form and / or its lactim form.

[0276] The twenty-second aspect relates to a method according to aspect 20 or 21, wherein 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 triphenylmethyl (Tr) group, (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, tert-butoxycarbonyl (BOC) group and p-toluenesulfonyl (tosyl, Ts) group; n is 1, 2 or 3; R4 is selected from the group consisting of -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

[0277] A twenty-third aspect relates to a method according to aspect 22, wherein R1 is a protecting group selected from the group consisting of: a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group; n is 2 or 3; R4 is selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

[0278] A twenty-fourth aspect relates to the method according to any one of aspects 20 to 23, wherein R1 is a tert-butyloxycarbonyl (BOC) group; n is 3; and R4 is selected from the group consisting of: -OH, -O - and methanesulfonate (-MsO).

[0279] A twenty-fifth aspect relates to the method according to any one of aspects 20 to 24, wherein step C is performed at a temperature of about -10°C to about 100°C.

[0280] A twenty-sixth aspect relates to the method according to aspect 25, wherein step C is performed at a temperature of about 5°C to about 50°C.

[0281] The twenty-seventh aspect relates to the method according to any one of aspects 20 to 26, wherein step C is carried out in the presence of an electrophilic reagent, a solvent and a base.

[0282] Aspect 28 relates to a method according to aspect 27, wherein, in step C, an electrophilic reagent having 0.05 molar equivalents to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof is used, and a base having 0.1 molar equivalents to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof is used.

[0283] The twenty-ninth aspect relates to the method according to any one of aspects 20 to 26, wherein step C is carried out in the presence of an electrophilic reagent, a solvent and a buffer.

[0284] The thirtieth aspect relates to the method according to aspect 29, wherein, in step C, an electrophilic reagent having 0.05 molar equivalents to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof is used, and a buffer having 0.1 molar equivalents to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof is used.

[0285] A thirty-first aspect relates to a method according to any one of aspects 27 to 30, wherein the electrophilic reagent in step C is selected from the group consisting of 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, mesyl chloride (MsCl), mesyl bromide, mesyl iodide, tosyl chloride (tosyl chloride), chloride, TsCl), p-toluenesulfonyl bromide, p-toluenesulfonyl iodide and mixtures thereof; the solvent in step C is selected from the group consisting of water, DMF, DMA, 2-pyrrolidone, 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 the base in step C is selected from the group consisting of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, Amines, 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.

[0286] The thirty-second aspect relates to a method according to any one of aspects 27 to 31, wherein the electrophilic reagent is selected from the group consisting of: mesyl chloride (MsCl), 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 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.

[0287] The thirty-third aspect relates to a method according to aspect 32 or 33, wherein the electrophilic reagent in step C is selected from the group consisting of: mesyl chloride (MsCl), 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, ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN and mixtures thereof; and the buffer in step C is a buffer that maintains the pH of the reaction mixture of step C within a pH range between pH 4 and pH 10.

[0288] The thirty-fourth aspect relates to the method according to aspect 33, wherein 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.

[0289] A thirty-fifth aspect relates to a method according to any one of aspects 20 to 34, further comprising a deprotection step D: making a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a p-toluenesulfonyl (tosyl, Ts) group, and n is 1, 2, 3 or 4; reacting with a deprotecting agent to produce a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is H and n is 1, 2, 3 or 4; and wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in its lactam form and / or its lactimide form.

[0290] A thirty-sixth aspect relates to the method according to aspect 35, wherein the protecting group is a tert-butoxycarbonyl (BOC) group.

[0291] Aspect thirty-seven relates to a method according to aspect 35 or 36, wherein the deprotection agent is selected from the group consisting of: acyl chloride, acyl bromide, acyl iodide, 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.

[0292] Aspect 38 relates to a method according to any one of aspects 35 to 37, wherein the protecting group is a tert-butoxycarbonyl (BOC) group, and the deprotecting agent is selected from the group consisting of: acyl chloride, acyl bromide, acetic anhydride, formic acid, acetic acid, trifluoroacetic acid and hydrochloric acid.

[0293] A thirty-ninth aspect relates to a method according to any one of aspects 35 to 38, wherein the protecting group is a tert-butoxycarbonyl (BOC) group, and the deprotecting agent is selected from the group consisting of: acyl chloride, trifluoroacetic acid and hydrochloric acid.

[0294] The fortieth aspect relates to a method according to any one of aspects 35 to 39, wherein step D produces a monohydrochloride or dihydrochloride salt of a compound of formula (I), and wherein the monohydrochloride or dihydrochloride salt of the compound of formula (I) is present in its lactam form and / or its imide form.

[0295] The forty-first aspect relates to a method according to any one of Aspects 20 to 40, wherein step C produces a monohydrochloride or dihydrochloride salt of a compound of formula (I), and wherein the monohydrochloride or dihydrochloride salt of the compound of formula (I) is present in its lactam form and / or its imide form.

[0296] Aspect 42 relates to a method according to any one of aspects 35 to 41, wherein in step D, a deprotection reagent having 1 to 20 molar equivalents relative to the compound of formula (I) or a pharmaceutically acceptable salt thereof is used.

[0297] The forty-third aspect relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof wherein n is 1, 2, 3 or 4; R1 is H, a C1-C6 alkyl group or a protecting group which prevents the nitrogen atom connected to the protecting group from reacting with other molecules during a chemical reaction, and the protecting group is selected from the group consisting of a trityl (triphenymethyl, Tr) group, a (4-methoxyphenyl) diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a p-toluenesulfonyl (tosyl, Ts) group; and R4 is selected from the group consisting of -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

[0298] The forty-fourth aspect relates to a compound according to 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.

[0299] The forty-fifth aspect relates to the compound according to aspect 43 or 44, wherein n is 2 or 3.

[0300] A forty-sixth aspect relates to a compound according to 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).

[0301] A forty-seventh aspect relates to the compound according to aspects 43 to 45, wherein n is 3; R1 is H; and R4 is selected from the group consisting of: -OH, -O - and methanesulfonate (-MsO).

[0302] In addition to the features mentioned in each of the above listed independent aspects, some examples may show, alone or in combination, optional features mentioned in the dependent aspects and / or as disclosed in the above description and shown in the drawings.

Claims

1. A method for preparing a compound of formula (V) or a pharmaceutically acceptable salt thereof The method comprises: i) Step A: preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof Reaction with a compound of formula (III) or a pharmaceutically acceptable salt thereof To produce a compound of formula (IV) or a pharmaceutically acceptable salt thereof ii) Step B: reacting a compound of formula (IV) or a pharmaceutically acceptable salt thereof To produce a compound of formula (V) or a pharmaceutically acceptable salt thereof in, R1 is H, a C1-C6 alkyl group or a protecting group, the protecting group prevents the nitrogen atom to which the protecting group is attached from reacting with other molecules during a chemical reaction, and the protecting group is selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a toluenesulfonyl (tosyl, Ts) group; n is 1, 2, 3, or 4; R2 is -OH or L1, wherein L1 is a leaving group that can be displaced 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, wherein L2 is a leaving group that can be displaced 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 selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

2. The method according to claim 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; n is 1, 2, or 3; L1 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), toluenesulfonate (—TsO), methanesulfonate (—MsO), and trifluoromethanesulfonate (—CF3SO3); and L2 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), toluenesulfonate (—TsO), methanesulfonate (—MsO), and trifluoromethanesulfonate (—CF3SO3).

3. The method according to claim 1 or 2, wherein: R1 is a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (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; wherein L1 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), toluenesulfonate (—TsO), methanesulfonate (—MsO), and trifluoromethanesulfonate (—CF3SO3); and L2 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), toluenesulfonate (—TsO), methanesulfonate (—MsO), and trifluoromethanesulfonate (—CF3SO3).

4. The method according to any one of claims 1 to 3, wherein: R1 is a tert-butyloxycarbonyl (BOC) group; n is 3; and R2 is L1; and L1 is methanesulfonate (-MsO); or R2 is -OH; and L2 is chloride (-Cl), bromide (-Br), or iodide (-I).

5. A method according to any one of the preceding claims, wherein: Step A is performed at about 0°C to about 150°C; and Step B is performed at about -10°C to about 50°C or about 25°C to about 150°C.

6. A method according to any one of the preceding claims, wherein: Step A is performed at about 50°C to about 110°C; and Step B is performed at about 0°C to about 25°C or about 45°C to about 100°C.

7. A method according to any one of the preceding claims, wherein: In step A, the compound of formula (II) or a pharmaceutically acceptable salt thereof is used in an amount of 1 to 5 molar equivalents relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof.

8. A method according to any one of the preceding claims, 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 method 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 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 method according to claim 8 or 9, wherein: In step B, the oxidizing agent is used in an amount of 1 to 10 molar equivalents relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

11. The method according to any one of claims 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, 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 oxidant 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-chloroperbenzoic acid (mCPBA), dimethyldioxirane, potassium hydrogen persulfate (potassium permonosulfate), peroxysulfuric acid, peroxynitric acid, peroxyphosphoric 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, acetonitrile (MeCN), propionitrile, benzonitrile, acetic acid, formic acid, trifluoroacetic acid and a mixture thereof.

12. The method according to any one of claims 8 to 11, wherein: The base in step A is selected from the group consisting of potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide and a mixture thereof; The solvent in step A is selected from the group consisting of: DMF, MeCN, water, ether, MTBE and mixtures thereof; The oxidant in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, perbenzoic acid, mCPBA, peroxysulfuric acid, peroxynitric acid, peroxyphosphoric 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 a mixture thereof.

13. A method according to any one of the preceding claims, 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. The method according to claim 13, wherein: In step B, 1 to 10 molar equivalents of an oxidant are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, and 0.001 to 1 molar equivalents of a catalyst are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

15. The method according to claim 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, ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, DMF, DMA, 2-pyrrolidone, MeCN, propionitrile, benzonitrile and mixtures thereof; The oxidant 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, peroxysulfuric acid, peroxynitric acid, peroxyphosphoric 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, methyltrioxide rhenium (VII) (MeReO3, MTO), phosphomolybdic acid (PMA) and mixtures thereof.

16. The method according to any one of claims 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 a mixture thereof; The solvent in step A is selected from the group consisting of: DMF, MeCN, water, ether, MTBE and mixtures thereof; The oxidant in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic acid, perbenzoic acid, mCPBA, peroxysulfuric acid, peroxynitric acid, peroxyphosphoric 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 a mixture thereof; and The catalyst in step B is selected from the group consisting of acetic acid, MTO, PMA and a mixture thereof.

17. A method according to any one of the preceding claims, 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. The method according to claim 17, wherein: In step B, 1 to 10 molar equivalents of an oxidant are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, 0.001 to 1 molar equivalents of a catalyst are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof, and 1 to 10 molar equivalents of a base are used relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

19. The method according to claim 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 a mixture thereof; The solvent in step A is selected from the group consisting of: DMF, MeCN, water, ether, MTBE and mixtures thereof; The oxidant in step B is selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, sodium percarbonate, peracetic acid, performic 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.

20. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising step C: reacting a compound of formula (V) or a pharmaceutically acceptable salt thereof To produce a compound of formula (I) or a pharmaceutically acceptable salt thereof in, R1 is H, a C1-C6 alkyl group or a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a p-toluenesulfonyl (tosyl, Ts) group; n is 1, 2, 3, or 4; and R4 is selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

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

22. The method according to claim 20 or 21, wherein: 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 a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a p-toluenesulfonyl (tosyl, Ts) group; n is 1, 2, or 3; and R4 is selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

23. The method according to claim 22, wherein: R1 is a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group and a p-toluenesulfonyl (tosyl, Ts) group; n is 2 or 3; and R4 is selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

24. The method according to any one of claims 20 to 23, wherein: R1 is a tert-butoxycarbonyl (BOC) group; n is 3; and R4 is selected from the group consisting of: -OH, -O - and methanesulfonate (-MsO).

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

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. The method according to claim 27, wherein: In step C, an electrophilic agent is used in an amount of 0.05 to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof, and a base is used in an amount of 0.1 to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof.

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.

30. The method of claim 29, wherein: In step C, an electrophilic agent having 0.05 to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof is used, and a buffer having 0.1 to 10 molar equivalents relative to the compound of formula (V) or a pharmaceutically acceptable salt thereof is used.

31. The method according to any one of claims 27 to 30, wherein: The electrophilic reagent in step C is selected from the group consisting of: 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, mesyl chloride (MsCl), methanesulfonyl bromide, methanesulfonyl iodide, tosyl chloride (TsCl), p-toluenesulfonyl bromide, p-toluenesulfonyl iodide and mixtures thereof; 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 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.

32. The method according to any one of claims 27 to 31, wherein: The electrophilic reagent is selected from the group consisting of: mesyl chloride (MsCl), 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 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.

33. The method according to claim 29 or 30, wherein: The electrophilic reagent in step C is selected from the group consisting of: mesyl chloride (MsCl), 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, ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, acetone, methyl ethyl ketone, cyclohexanone, DCM, chloroform, MeCN and mixtures thereof; and The buffer in step C is a buffer that maintains the pH of the reaction mixture of step C within a pH range between pH 4 and pH 10.

34. The method of claim 33, wherein: 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.

35. The method according to any one of claims 20 to 34, further comprising a deprotection step D: making the compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is a protecting group selected from the group consisting of a triphenylmethyl (Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butoxycarbonyl (BOC) group, and a tosyl (Ts) group; and n is 1, 2, 3 or 4 reacting with a deprotecting agent to produce a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is H and n is 1, 2, 3 or 4; and The compound of formula (I) or a pharmaceutically acceptable salt thereof exists in its lactam form and / or its lactim form.

36. The method of claim 35, wherein: The protecting group is a tert-butoxycarbonyl (BOC) group.

37. The method according to claim 35 or 36, wherein: The deprotecting agent is selected from the group consisting of acyl chloride, acyl bromide, acyl iodide, 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. A method according to any one of claims 35 to 37, wherein: The protecting group is a tert-butoxycarbonyl (BOC) group, and the deprotecting agent is selected from the group consisting of an acyl chloride, an acyl bromide, 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-butoxycarbonyl (BOC) group, and the deprotecting agent is selected from the group consisting of an acyl chloride, trifluoroacetic acid, and hydrochloric acid.

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

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

42. The method according to any one of claims 35 to 41, wherein: In step D, a deprotecting agent is used in an amount of 1 to 20 molar equivalents relative to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

43. A compound of formula (V) or a pharmaceutically acceptable salt thereof in, n is 1, 2, 3, or 4; R1 is H, a C1-C6 alkyl group or a protecting group, which prevents the nitrogen atom connected to the protecting group from reacting with other molecules during a chemical reaction, and the protecting group is selected from the group consisting of a triphenylmethyl group, (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, tert-butoxycarbonyl (BOC) group and p-toluenesulfonyl (Ts) group; and R4 is selected from the group consisting of: -OH, -O - , p-toluenesulfonate (-TsO), methanesulfonate (-MsO) and trifluoromethanesulfonate (-CF3SO3).

44. The compound according to claim 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.

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

46. ​​A compound according to any one of claims 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).

47. A compound according to any one of claims 43 to 45, wherein n is 3; R1 is H; and R4 is selected from the group consisting of: -OH, -O - and methanesulfonate (-MsO).

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