Process for preparation of tert-butyl (2-azabicyclo [2.2. 1] heptane-4-yl) carbamate and related compounds

Abstract

Provided herein are methods for the preparation of the key structural motif 2-azabicyclo [2.2. 1] heptane-4-amines found in a number of synthetic compounds, which are rho-associated protein kinase inhibitors, and their primary amine protected forms of (2-azabicyclo [2.2. 1] heptane-4-yl) tert-butyl carbamates and enantiomers thereof. Also provided herein are novel intermediate compounds and enantiomers thereof useful in the preparation of the aforementioned target 2-azabicyclo [2.2. 1] heptyl compounds.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 408,695, filed on September 21, 2022, the entirety of which is incorporated herein by reference for any purpose. Technical Field

[0002] The present disclosure generally relates to methods for preparing tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and novel intermediate compounds. Background Art

[0003] The compound 2-azabicyclo[2.2.1]heptane-4-amine (herein designated as the compound of formula T-1) is a key structural motif found in many synthetic compounds that are inhibitors of rho-associated protein kinases. These inhibitors can potentially be used to treat or prevent a variety of diseases or conditions. See, for example, U.S. Publication No. 2011 / 0144150. The chemical structure of the compound of formula T-1 is shown below:

[0004] The selectively protected forms of the compound of formula T-1 and its enantiomers are of great significance as building blocks for various compounds. Accordingly, in one aspect, provided herein is a method for preparing tert-butyl (2-azabicyclo[2.2.1]heptane-4-yl)carbamate, its enantiomers and salts. The compound of formula T-2 is a primary amine protected form of the compound of formula T-1, and its chemical structure is shown below:

[0005] Also provided herein are intermediate compounds useful in preparing T-1 and / or T-2. Summary of the invention

[0006] In certain embodiments, described herein are methods for preparing tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and salts thereof as building blocks for various inhibitor compounds. Also described herein are intermediate compounds used to prepare the compounds.

[0007] Embodiments of the present invention may be more fully understood by reference to the detailed description and examples which are intended to illustrate non-limiting embodiments.

[0008] In one aspect, provided herein is a method for preparing a compound of formula T-2 or a salt thereof.

[0009] In another aspect, provided herein are methods of preparing compounds of formula T-3 and T-4, which are enantiomers of compounds of formula T-2, or salts thereof.

[0010] In certain aspects, provided herein are methods for preparing compounds of formula T-2: or a salt thereof, comprising the following steps: (a) the compound of formula 1: or its salt and a compound of formula 2: or a salt thereof to form a compound of formula 3: or its salts; (b) reacting the compound of formula 3 or its salt with phthalimide to form a compound of formula 4: or its salts; (c) deprotecting the compound of formula 4 or its salt to obtain a compound of formula 5: or its salts; (d) reacting the compound of formula 5 or a salt thereof with a base to form a compound of formula 6: or its salts; (e) reacting a compound of formula 6 or a salt thereof with R3OH in the presence of diphenylphosphoryl azide and an amine base acid to form a compound of formula 7: or its salts; and (f) reacting a compound of formula 7 or a salt thereof with Pg2X to form a compound of formula 8: or its salts; and (g) reducing the compound of formula 8 or a salt thereof to form a compound of formula 9: or its salts; and (h) reducing the compound of formula 9 or a salt thereof to form a compound of formula 10: or its salts; and (i) protecting the primary amine group of the compound of formula 10 or a salt thereof to form a compound of formula 11: or its salts; and (j) reducing the compound of formula 11 or a salt thereof to form a compound of formula T-2.

[0011] In certain aspects, the present invention also provides the preparation of compounds of formula T-2: or a salt thereof, comprising the following steps: (a) deprotecting and subsequently protecting the primary amine group of a compound of formula 7 or a salt thereof: To form a compound of formula 7.5: (b) hydrolyzing the compound of formula 7.5 or a salt thereof to form a compound of formula 8.5: or its salts; and (c) reducing the compound of formula 8.5 or a salt thereof to form a compound of formula 9.5: or its salts; and (d) sequentially protecting the substituent amine and heterocyclic amine of the compound of formula 9.5 or a salt thereof, and selectively deprotecting the substituent amine to form a compound of formula 10: or a salt thereof. DETAILED DESCRIPTION definition

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present disclosure belongs. In the following description, certain specific details are listed to provide a comprehensive understanding of the various embodiments of the present disclosure. It should be understood that the above general description and the following specific embodiments are only exemplary and explanatory and do not limit any claimed subject matter. In the event that any material incorporated herein by reference is inconsistent with the expression of the present disclosure, the expression shall prevail. In the present application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly indicates otherwise. In the present application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms, such as "include", "includes" and "included" is non-restrictive.

[0013] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, that is, as "including, but not limited to."

[0014] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and where appropriate, include its fractions (such as one tenth and one hundredth of an integer). In addition, unless otherwise indicated, any numerical range related to any physical feature (such as polymer subunits, size or thickness) described herein should be understood to include any integer within the range. As used herein, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the indicated range, value or structure.

[0015] Reference in this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearance of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification does not necessarily refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0016] As used herein, the term "salt" refers to an acid or base salt of a compound disclosed herein. It is understood that "pharmaceutically acceptable salts" are non-toxic. Non-limiting examples of pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0017] Pharmaceutically acceptable acid addition salts are salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylaminosulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, quinonic acid, glucose Heptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, benzoylglycine, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyrroleglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, succinic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0018] Pharmaceutically acceptable base addition salts are prepared by adding an inorganic base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Non-limiting examples of inorganic salts include ammonium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, non-limiting examples of which include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylethanolamine, 2-diethylethanolamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

[0019] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance does not occur. For example, "optionally converting compound X to a salt thereof" means that compound X may or may not be converted to a salt. In some embodiments, compound X is converted to a salt, while in other embodiments, compound X is not converted to a salt.

[0020] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described in the context of separate inventions for clarity, the invention may also be implemented in a single embodiment. Synthetic route 1

[0021] In one aspect, provided herein is a method for preparing a compound of formula T-2 or a salt thereof according to the synthetic route outlined in Scheme 1 ("Synthetic Scheme 1"). Scheme 1. Synthesis of Compound T-2

[0022] Thus, in certain embodiments, disclosed herein are the preparation of compounds of formula T-2: or a salt thereof, comprising the following steps: (a) the compound of formula 1: or its salt and a compound of formula 2: or a salt thereof to form a compound of formula 3: or its salts; (b) reacting a compound of formula 3 or a salt thereof with phthalimide to form a compound of formula 4: or its salts; (c) deprotecting the compound of formula 4 or a salt thereof to form a compound of formula 5: or its salts; (d) reacting the compound of formula 5 or a salt thereof with a base to form a compound of formula 6: or its salts; (e) reacting a compound of formula 6 or a salt thereof with R3OH to form a compound of formula 7: or its salts; and (f) reacting a compound of formula 7 or a salt thereof with Pg2X to form a compound of formula 8: or its salts; and (g) reducing the compound of formula 8 or a salt thereof to form a compound of formula 9: or its salts; and (h) reducing the compound of formula 9 or a salt thereof to form a compound of formula 10: or its salts; and (i) protecting the primary amine group of the compound of formula 10 or a salt thereof to form a compound of formula 11: or its salts; and (j) reducing the compound of formula 11 or a salt thereof to form a compound of formula T-2.

[0023] In certain embodiments, step (a) is carried out in the presence of a base. In some embodiments, the base is sodium hydride, sodium tert-butoxide or sodium ethoxide. In other embodiments, the base is sodium ethoxide.

[0024] In certain embodiments, step (a) is performed using an alcohol as a solvent. In certain embodiments, the alcohol is methanol, ethanol or isopropanol. In certain embodiments, the alcohol is ethanol.

[0025] In certain embodiments, step (a) is performed at a temperature between about 0-30°C. In some embodiments, step (a) is performed at a starting temperature of about 0-10°C and then at 20-30°C.

[0026] In certain embodiments, step (a) is performed with a compound of formula 1 or a salt thereof, which is separated into enantiomers, formula 1a and formula 1b or a salt thereof, using kinetic resolution. In certain embodiments, the kinetic resolution is Jacobsen's kinetic resolution. In certain embodiments, the kinetic resolution is a hydrolytic kinetic resolution catalyzed by a chiral cobalt-salen complex.

[0027] In certain embodiments, step (b) further comprises triphenylphosphine and diisopropyl azodicarboxylate.

[0028] In certain embodiments, step (b) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform or a mixture thereof. In certain embodiments, the aprotic solvent is tetrahydrofuran.

[0029] In certain embodiments, step (b) is performed at a temperature between about 0-30°C. In some embodiments, step (b) is performed at a starting temperature of about 0-10°C and then at 20-30°C.

[0030] In certain embodiments, step (c) is performed in the presence of a base. In some embodiments, the base is sodium borohydride, methylamine, methylhydrazine or hydrazine. In other embodiments, the base is hydrazine.

[0031] In certain embodiments, step (c) is carried out using a mixture of an alcohol and an organic solvent. In some embodiments, the alcohol is methanol, ethanol or isopropanol. In some embodiments, the organic solvent is dimethyl sulfoxide, methylene chloride, tetrahydrofuran or 2-methyltetrahydrofuran. In certain embodiments, the alcohol is methanol and the organic solvent is methylene chloride.

[0032] In certain embodiments, step (d) is performed using an inorganic base. In some embodiments, the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate or cesium carbonate. In other embodiments, the inorganic base is cesium carbonate.

[0033] In certain embodiments, step (d) is performed using an alcohol as a solvent. In certain embodiments, the alcohol is methanol, ethanol or isopropanol. In certain embodiments, the alcohol is methanol.

[0034] In certain embodiments, step (d) is performed at a temperature between about 25-80°C. In certain embodiments, step (d) is performed at a temperature between about 50-70°C.

[0035] In certain embodiments, step (e) is performed using an amine base. In certain embodiments, the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisopropylethylamine. In other embodiments, the amine base is N,N-diisopropylethylamine.

[0036] In certain embodiments, step (e) is carried out using an organic solvent. In some embodiments, the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof. In certain embodiments, the organic solvent is 2-methyltetrahydrofuran.

[0037] In certain embodiments, step (e) is performed at a starting temperature between about 40-70°C, followed by a reflux temperature above 50-120°C. In certain embodiments, step (e) is performed at a starting temperature between about 50-60°C, followed by a reflux temperature above 70-100°C.

[0038] In certain embodiments, step (e) is performed at a temperature of about 40-70°C, then about 50-120°C. In certain embodiments, step (e) is performed at a temperature of about 50-60°C or about 50-70°C, then about 70-100°C.

[0039] In certain embodiments, after step (e), the compound of Formula 7 or a salt thereof is separated into enantiomers, Formula 7a and Formula 7b or a salt thereof, using superfluid chromatography.

[0040] In certain embodiments, step (f) is carried out in the presence of a non-nucleophilic base. In some embodiments, the non-nucleophilic base is N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide. In other embodiments, the non-nucleophilic base is lithium bis(trimethylsilyl)amide.

[0041] In certain embodiments, step (f) is performed using an ether solvent. In certain embodiments, the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether or a mixture thereof. In certain embodiments, the ether solvent is tetrahydrofuran.

[0042] In certain embodiments, step (g) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium barium sulfate, or palladium on carbon (Pd / C). In other embodiments, the transition metal is palladium on carbon (Pd / C).

[0043] In certain embodiments, step (g) is performed using an alcohol as a solvent. In certain embodiments, the alcohol is methanol, ethanol or isopropanol. In certain embodiments, the alcohol is methanol.

[0044] In certain embodiments, step (h) is performed using a reducing agent. In some embodiments, the reducing agent is a metal hydride, aluminum hydride, borohydride or a borane reagent. In some embodiments, the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran or borane dimethyl sulfoxide. In other embodiments, the reducing agent is borane dimethyl sulfoxide.

[0045] In certain embodiments, step (h) is performed using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is tetrahydrofuran.

[0046] In certain embodiments, step (h) is performed at a temperature between about 25-80°C. In certain embodiments, step (h) is performed at a temperature between about 60-70°C.

[0047] In certain embodiments, step (i) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, ethylene dichloride, toluene, methanol, ethanol, isopropanol or 2-methyl-THF, dioxane, ethyl acetate or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene or tetrahydrofuran.

[0048] In certain embodiments, step (j) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium barium sulfate, or palladium on carbon (Pd / C). In other embodiments, the transition metal is palladium on carbon (Pd / C).

[0049] In certain embodiments, step (j) is performed using an alcohol as a solvent. In certain embodiments, the alcohol is methanol, ethanol or isopropanol. In certain embodiments, the alcohol is methanol. Synthetic route 2

[0050] In another aspect, provided herein is a method for preparing compound Formula T-2 or a salt thereof according to the synthetic route outlined in Scheme 2 ("Synthetic Route 2"). Scheme 2. Synthesis route 2 of compound of formula T-2

[0051] Thus, in certain embodiments, disclosed herein are the preparation of compounds of formula T-2: or a salt thereof, comprising the following steps: (a) deprotecting and subsequently protecting the primary amine group of a compound of formula 7 or a salt thereof: To form a compound of formula 7.5: (b) hydrolyzing the compound of formula 7.5 or a salt thereof to form a compound of formula 8.5: or its salts; and (c) reducing the compound of formula 8.5 or a salt thereof to form a compound of formula 9.5: or its salts; and (d) sequentially protecting the substituent amine and heterocyclic amine of the compound of formula 9.5 or a salt thereof, and selectively deprotecting the substituent amine to form a compound of formula 10: or a salt thereof.

[0052] In certain embodiments, step (a) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium barium sulfate, or palladium on carbon (Pd / C). In other embodiments, the transition metal is palladium on carbon (Pd / C).

[0053] In certain embodiments, step (a) is performed using an alcohol as a solvent. In certain embodiments, the alcohol is methanol, ethanol or isopropanol. In certain embodiments, the alcohol is methanol.

[0054] In certain embodiments, step (a) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene or tetrahydrofuran.

[0055] In certain embodiments, step (b) is performed with an acid. In certain embodiments, the acid is trifluoroacetic acid, hydrochloric acid, or phosphoric acid. In certain embodiments, the acid is trifluoroacetic acid.

[0056] In certain embodiments, step (b) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene or tetrahydrofuran.

[0057] In certain embodiments, step (b) is performed at a temperature of about 20-30°C.

[0058] In certain embodiments, step (c) is performed using a reducing agent. In some embodiments, the reducing agent is a metal hydride, aluminum hydride, borohydride or a borane reagent. In some embodiments, the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran or borane dimethyl sulfoxide. In other embodiments, the reducing agent is lithium aluminum hydride.

[0059] In certain embodiments, step (c) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, or a mixture thereof.

[0060] In certain embodiments, step (d) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene or tetrahydrofuran.

[0061] In certain embodiments, the selective deprotection of the substituent amine in step (d) is carried out using an acid. In some embodiments, the acid is hydrochloric acid. Compound

[0062] In one aspect, provided herein is a compound of formula T-2: or a salt thereof, wherein Pg1 is a first protecting group.

[0063] In certain embodiments, Pg1 is tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene or fluorenylmethoxycarbonyl. In certain embodiments, Pg1 is tert-butyloxycarbonyl.

[0064] In certain embodiments, the compound of formula T-2 is separated into enantiomers, compounds of formula T-3 and formula T-4: or a salt thereof.

[0065] In one aspect, provided herein is a novel intermediate compound for synthesizing a compound of formula T-2 or a salt thereof. In certain embodiments, the novel intermediate compound is: or a salt thereof.

[0066] In certain embodiments, Pg2 is a second protecting group. In certain embodiments, Pg2 is tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene or fluorenylmethoxycarbonyl. In certain embodiments, Pg2 is a benzyl group optionally substituted by C1-C6 alkoxy, C1-C6 alkyl or halide.

[0067] In certain embodiments, R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide.

[0068] In certain embodiments, the novel intermediate compound is separated into enantiomers, and the novel intermediate compound is: or a salt thereof. Certain non-limiting embodiments

[0069] Certain aspects of the invention are provided in the following numbered embodiments. 1. A method for preparing a compound of formula (T-2): or a salt thereof, comprising: Reduction of the compound of formula (11): or a salt thereof, wherein Pg1 is a first protecting group; and Pg2 is the second protecting group; To form the compound of formula (T-2). 2. The method according to embodiment 1, wherein: a) The compound of formula (T-2) is a compound of formula (T-3): And the compound of formula (11) is a compound of formula (11a): or b) The compound of formula (T-2) is a compound of formula (T-4): And the compound of formula (11) is a compound of formula (11b): 3. The method according to embodiment 1 or embodiment 2, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl. 4. The method according to embodiment 1 or embodiment 2, wherein Pg1 is tert-butyloxycarbonyl. 5. The method according to embodiment 1 or embodiment 2, wherein Pg2 is a benzyl group optionally substituted with a C1-C6 alkoxy group, a C1-C6 alkyl group or a halide. 6. The method according to any one of embodiments 1-5, wherein the reduction of formula (11) or a salt thereof is catalyzed by a transition metal to form a compound of formula (T-2) or a salt thereof. 7. The method according to embodiment 6, wherein the transition metal is palladium chloride, palladium barium sulfate or palladium carbon (Pd / C). 8. A method according to embodiment 6, wherein the transition metal is palladium on carbon (Pd / C). 9. The method according to any one of embodiments 1-8, wherein the reaction is carried out using an alcohol as solvent. 10. The method according to embodiment 9, wherein the alcohol is methanol, ethanol or isopropanol. 11. The method of embodiment 9, wherein the alcohol is methanol. 12. The method according to any one of embodiments 1-11, wherein the compound of formula (11) or a salt thereof is prepared by protecting the primary amine group of the compound of formula (10) or a salt thereof: 13. A method for preparing a compound of formula (11), or a salt thereof, comprising: Protecting the primary amine group of the compound of formula (10) or its salt: in: wherein Pg1 is a first protecting group; and Pg2 is the second protecting group; To form the compound of formula (11). 14. The method according to embodiment 13, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl. 15. The method according to embodiment 13, wherein Pg1 is tert-butyloxycarbonyl. 16. The method according to embodiment 13, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide. 17. The method according to any one of embodiments 12-16, wherein: a) The compound of formula (11) is a compound of formula (11a): And the compound of formula (10) is a compound of formula (10a): or b) The compound of formula (11) is a compound of formula (11b): And the compound of formula (10) is a compound of formula (10b): 18. The method according to any one of embodiments 12-17, wherein the reaction is carried out using an organic solvent. 19. The method according to embodiment 18, wherein the organic solvent is chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol or 2-methyl-THF, dioxane, ethyl acetate or tetrahydrofuran. 20. The method according to embodiment 18, wherein the organic solvent is chloroform, methanol, toluene or tetrahydrofuran. 21. The method according to any one of embodiments 1-20, wherein the compound of formula (10) or its salt is prepared by sequentially protecting the substituent amine and heterocyclic amine of the compound of formula (9.5) or its salt with Pg2 and Pg1, respectively: This is then prepared by selective deprotection of the substituent amine to form a compound of formula (10). 22. The method according to any one of embodiments 1-20, wherein the compound of formula (10) or a salt thereof is prepared by reducing the compound of formula (9) or a salt thereof: Prepared to form a compound of formula (10). 23. A method for preparing a compound of formula (10), or a salt thereof, comprising: Reduction formula (9) compound: or a salt thereof, Wherein Pg2 is a second protecting group to form a compound of formula (10). 24. The method of embodiment 23, wherein Pg2 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl. 25. The method according to embodiment 23, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide. 26. The method according to any one of embodiments 22-25, wherein: a) The compound of formula (10) is a compound of formula (10a): And the compound of formula (9) is a compound of formula (9a): or b) The compound of formula (10) is a compound of formula (10b): And the compound of formula (9) is a compound of formula (9b): 27. A method according to any one of embodiments 22-26, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride or a borane reagent. 28. The method of embodiment 27, wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran or borane dimethyl sulfoxide. 29. The method of embodiment 27, wherein the reducing agent is borane dimethyl sulfoxide. 30. The method of any one of embodiments 22-29, wherein the reaction is carried out using an aprotic solvent. 31. The method according to embodiment 30, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform or a mixture thereof. 32. The method of embodiment 30, wherein the aprotic solvent is tetrahydrofuran. 33. The method of any one of embodiments 22-32, wherein the reaction is carried out at a temperature of about 25-80°C. 34. The method according to embodiment 33, wherein the reaction is carried out at a temperature of about 60-70°C. 35. The method according to any one of embodiments 22-34, wherein the compound of formula (9) or a salt thereof is prepared by reducing a compound of formula (8) or a salt thereof to form a compound of formula (9): in: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; and Pg2 is the second protecting group. 36. A method for preparing a compound of formula (9), or a salt thereof, comprising: Reduction formula (8) compound: or a salt thereof, wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; and Pg2 is the second protecting group, To form the compound of formula (9). 37. The method of embodiment 36, wherein Pg2 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl. 38. The method according to embodiment 36, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide. 39. The method according to any one of embodiments 35-38, wherein: a) The compound of formula (9) is a compound of formula (9a): And the compound of formula (8) is a compound of formula (8a): or b) The compound of formula (9) is a compound of formula (9b): And the compound of formula (8) is a compound of formula (8b): 40. The method of any one of embodiments 35-39, wherein the reduction is catalyzed by a transition metal. 41. The method of embodiment 40, wherein the transition metal is palladium chloride, palladium barium sulfate, or palladium on carbon (Pd / C). 42. The method of embodiment 40, wherein the transition metal is palladium on carbon (Pd / C). 43. A method according to any one of embodiments 35-42, wherein the reaction is carried out using an alcohol as solvent. 44. The method of embodiment 43, wherein the alcohol is methanol, ethanol or isopropanol. 45. The method of embodiment 43, wherein the alcohol is methanol. 46. ​​The method according to any one of embodiments 35-45, wherein the compound of formula (8) or a salt thereof is obtained by reacting the compound of formula (7) with or a salt thereof is reacted with Pg2X to form a compound of formula (8), wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; Pg2 is a second protecting group; and X is a leaving group. 47. A method for preparing a compound of formula (8), or a salt thereof, comprising: The compound of formula (7): or a salt thereof is reacted with Pg2X, wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; Pg2 is a second protecting group; and X is a leaving group; To form the compound of formula (8). 48. The method of embodiment 46 or embodiment 47, wherein: a) The compound of formula (8) is a compound of formula (8a): And the compound of formula (7) is a compound of formula (7a): or b) The compound of formula (8) is a compound of formula (8b): And the compound of formula (7) is a compound of formula (7b): 49. The method of any one of embodiments 46-48, wherein Pg2 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl. 50. The method of any one of embodiments 46-48, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide. 51. The method of any one of embodiments 46-50, wherein the reaction is carried out in the presence of a non-nucleophilic base. 52. The method of embodiment 51, wherein the non-nucleophilic base is N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide. 53. The method according to embodiment 51, wherein the non-nucleophilic base used in the reaction with the compound of formula (7) is lithium bis(trimethylsilyl)amide. 54. The method of any one of embodiments 46-53, wherein the reaction is carried out using an ether solvent. 55. The method according to embodiment 54, wherein the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether or a mixture thereof. 56. The method of embodiment 54, wherein the ether solvent is tetrahydrofuran. 57. A method for preparing a compound of formula (10), or a salt thereof, wherein Pg2 is a second protecting group, the method comprising: The substituent amine and heterocyclic amine of the compound of formula (9.5) or its salt are protected in sequence with Pg2 and Pg1 respectively: The substituent amine is then selectively deprotected to form compounds of formula (10). 58. The method of embodiment 57, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl. 59. The method of embodiment 57, wherein Pg1 is optionally substituted benzyl. 60. The method of embodiment 57, wherein Pg2 is an optionally substituted benzyloxycarbonyl group. 61. The method according to any one of embodiments 21 or 57-60, wherein: a) The compound of formula (10) is a compound of formula (10a): And the compound of formula (9.5) is a compound of formula (9.5a): or b) The compound of formula (10) is a compound of formula (10b): And the compound of formula (9.5) is a compound of formula (9.5b): 62. The method according to any one of embodiments 21 or 57-61, wherein the protection reaction is carried out using an organic solvent. 63. The method according to embodiment 62, wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran. 64. The method according to embodiment 62, wherein the organic solvent is dichloromethane, methanol, toluene or tetrahydrofuran. 65. The method according to any one of embodiments 21 or 57-64, wherein the selective deprotection of the substituent amine is carried out with an acid. 66. The method of embodiment 65, wherein the acid is hydrochloric acid. 67. The method according to any one of embodiments 21 or 57-66, wherein the compound of formula (9.5) or a salt thereof is prepared by reducing the compound of formula (8.5) or a salt thereof. Prepared to form a compound of formula (9.5). 68. A method for preparing a compound of formula (9.5), or a salt thereof, comprising: Reduced compound (8.5): or a salt thereof to form a compound of formula (9.5). 69. The method of embodiment 67 or embodiment 68, wherein: a) The compound of formula (9.5) is a compound of formula (9.5a): And the compound of formula (8.5) is a compound of formula (8.5a): or c) The compound of formula (9.5) is a compound of formula (9.5b): And the compound of formula (8.5) is a compound of formula (8.5b): 70. The method of any one of embodiments 67-69, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or a borane reagent. 71. The method of embodiment 70, wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethyl sulfoxide. 72. The method of embodiment 70, wherein the reducing agent is lithium aluminum hydride. 73. The method of any one of embodiments 67-72, wherein the reaction is carried out using an aprotic solvent. 74. The method of embodiment 73, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. 75. The method of embodiment 73, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, or a mixture thereof. 76. The method of any one of embodiments 67-75, wherein the compound of formula (8.5) or a salt thereof is prepared by hydrolyzing the compound of formula (7.5) or a salt thereof to form a compound of formula (8.5): Wherein Pg1 is the first protecting group. 77. A method for preparing a compound of formula (8.5), or a salt thereof, comprising: Hydrolysis of the compound of formula (7.5): or a salt thereof, wherein Pg1 is a first protecting group to form a compound of formula (8.5). 78. The method of embodiment 76 or embodiment 77, wherein Pg1 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl. 79. The method of embodiment 76 or embodiment 77, wherein Pg1 is tert-butyloxycarbonyl. 80. The method of any one of embodiments 76-79, wherein: a) The compound of formula (8.5) is a compound of formula (8.5a): And the compound of formula (7) is a compound of formula (7a): or d) The compound of formula (8.5) is a compound of formula (8.5b): And the compound of formula (7.5) is a compound of formula (7.5b): 81. The method of any one of embodiments 76-80, wherein the hydrolysis is performed with an acid. 82. The method of embodiment 81, wherein the acid is trifluoroacetic acid, hydrochloric acid, or phosphoric acid. 83. The method of embodiment 81, wherein the acid is trifluoroacetic acid. 84. A method according to any one of embodiments 76-83, wherein the protection reaction is carried out using an organic solvent. 85. The method according to embodiment 84, wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran. 86. The method of embodiment 84, wherein the organic solvent is dichloromethane, methanol or toluene. 87. The method of any one of embodiments 76-86, wherein the reaction is carried out at a temperature of about 20-30°C. 88. A method according to any one of embodiments 76-87, wherein the compound of formula (7.5) or a salt thereof is prepared by deprotecting and subsequently protecting the primary amine group of the compound of formula (7) or a salt thereof, 89. A method for preparing a compound of formula (7.5), or a salt thereof, wherein Pg1 is a first protecting group, wherein the method comprises: Deprotecting and then protecting the primary amine group of the compound of formula (7) or a salt thereof, Wherein R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide to form a compound of formula (7.5). 90. The method of embodiment 88 or embodiment 89, wherein Pg1 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl. 91. The method of embodiment 88 or embodiment 89, wherein Pg1 is tert-butyloxycarbonyl. 92. The method of any one of embodiments 88-91, wherein: a) The compound of formula (7.5) is a compound of formula (7.5a): And the compound of formula (7) is a compound of formula (7a): or b) The compound of formula (7.5) is a compound of formula (7.5b): And the compound of formula (7) is a compound of formula (7b): 93. The method of any one of embodiments 88-92, wherein the deprotection is catalyzed by a transition metal. 94. The method of embodiment 93, wherein the transition metal is palladium chloride, palladium barium sulfate, or palladium on carbon (Pd / C). 95. The method of embodiment 93, wherein the transition metal is palladium on carbon (Pd / C). 96. A method according to any one of embodiments 88-95, wherein the reaction is carried out using an alcohol as a solvent. 97. The method of embodiment 96, wherein the alcohol is methanol, ethanol or isopropanol. 98. The method of embodiment 96, wherein the alcohol is methanol. 99. A method according to any one of embodiments 88-98, wherein the protection reaction is carried out using an organic solvent. 100. The method according to embodiment 99, wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran. 101. The method according to embodiment 99, wherein the organic solvent is dichloromethane, methanol, toluene or tetrahydrofuran. 102. The method according to any one of embodiments 46-56 or 88-101, wherein the compound of formula (7) or a salt thereof is obtained by converting a compound of formula (6): or a salt thereof, It is prepared by reacting with R3OH in the presence of diphenylphosphoryl azide and an amine base to form a compound of formula (7), wherein R3 is benzyl optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide. 103. A method for preparing a compound of formula (7), or its salt, wherein R1 is an amino protecting group or a benzyl carbamate optionally substituted with a C1-C6 alkoxy group, a C1-C6 alkyl group, or a halide, comprising: The compound of formula (6): or a salt thereof is reacted with R3OH in the presence of diphenylphosphoryl azide and an amine base to form a compound of formula (7), wherein R3 is benzyl optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide. 104. The method of embodiment 102 or embodiment 103, wherein: a) The compound of formula (7) is a compound of formula (7a): And the compound of formula (6) is a compound of formula (6a): or b) The compound of formula (7) is a compound of formula (7b): And the compound of formula (6) is a compound of formula (6b): 105. The method of any one of embodiments 102-104, wherein the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisopropylethylamine. 106. The method of embodiment 105, wherein the amine base is N,N-diisopropylethylamine. 107. The method of any one of embodiments 102-106, wherein the reaction is carried out using an organic solvent. 108. The method according to embodiment 107, wherein the organic solvent used in the reaction is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof. 109. The method according to embodiment 107, wherein the organic solvent used in the reaction is 2-methyltetrahydrofuran. 110. The method according to any one of embodiments 102-109, wherein the reaction is carried out at a starting temperature of about 40-70°C and then at a reflux temperature above 50-120°C. 111. The method according to embodiment 110, wherein the reaction is carried out at a starting temperature of about 50-60°C or about 60-70°C and then at a reflux temperature of about 70-100°C. 112. The method according to any one of embodiments 102-111, wherein the compound of formula (7) or its salt is separated into enantiomers, the compound of formula (7a) and the compound of formula (7b) or its salt using superfluid chromatography. 113. The method according to any one of embodiments 102-112, wherein the compound of formula (6) or a salt thereof is obtained by converting a compound of formula (5): or a salt thereof is reacted with a base to form a compound of formula (6). 114. A method for preparing a compound of formula (6), or a salt thereof, comprising: The compound of formula (5): or a salt thereof is reacted with a base to form a compound of formula (6). 115. The method of embodiment 113 or 114, wherein: a) The compound of formula (6) is a compound of formula (6a): And the compound of formula (5) is a compound of formula (5a), or b) The compound of formula (6) is a compound of formula (6b): And the compound of formula (5) is a compound of formula (5b), 116. The method of any one of embodiments 113-115, wherein the base is an inorganic base. 117. The method according to embodiment 116, wherein the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate or cesium carbonate. 118. The method of embodiment 116, wherein the inorganic base is cesium carbonate. 119. The method according to any one of embodiments 113-118, wherein the reaction is carried out using an alcohol as solvent. 120. The method of embodiment 119, wherein the alcohol is methanol, ethanol or isopropanol. 121. The method of embodiment 119, wherein the alcohol is methanol. 122. The method of any one of embodiments 113-121, wherein the reaction is carried out at a temperature of about 25-80°C. 123. The method of embodiment 122, wherein the reaction is carried out at a temperature of about 50-70°C. 124. The method according to any one of embodiments 113-123, wherein the compound of formula (5) or its salt is prepared by deprotecting the amine of the compound of formula (4) or its salt: To form the compound of formula (5). 125. A method for preparing a compound of formula (5) or a salt thereof, It includes: Deprotecting the compound of formula (4) or its salt: To form the compound of formula (5). 126. The method of embodiment 124 or embodiment 125, wherein: a) The compound of formula (5) is a compound of formula (5a): And the compound of formula (4) is a compound of formula (4a), or b) The compound of formula (5) is a compound of formula (5b): And the compound of formula (4) is a compound of formula (4b), 127. The method of any one of embodiments 124-126, wherein the deprotection is performed using a base. 128. The method of embodiment 127, wherein the base is sodium borohydride, methylamine, methylhydrazine, or hydrazine. 129. The method of embodiment 127, wherein the base is hydrazine. 130. The method of any one of embodiments 124-129, wherein the reaction is carried out using a mixture of an alcohol and an organic solvent. 131. The method of embodiment 130, wherein the alcohol is methanol, ethanol, or isopropanol. 132. The method of embodiment 130, wherein the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran. 133. The method of embodiment 130, wherein the alcohol is methanol and the organic solvent is dichloromethane. 134. The method according to any one of embodiments 124-133, wherein the compound of formula (4) or a salt thereof is obtained by converting a compound of formula (3): or a salt thereof is reacted with phthalimide to form a compound of formula (4). 135. A method for preparing a compound of formula (4), or a salt thereof, comprising, The compound of formula (3): or a salt thereof is reacted with phthalimide to form a compound of formula (4). 136. The method of embodiment 134 or embodiment 135, wherein: a) The compound of formula (4) is a compound of formula (4a): And the compound of formula (3) is a compound of formula (3a), or b) The compound of formula (4) is a compound of formula (4b): And the compound of formula (3) is a compound of formula (3b), 137. The method of any one of embodiments 134-136, wherein the reaction further comprises triphenylphosphine and diisopropyl azodicarboxylate. 138. The method according to any one of embodiments 134-137, wherein the reaction is carried out using an aprotic solvent. 139. The method according to embodiment 138, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. 140. The method of embodiment 138, wherein the aprotic solvent is tetrahydrofuran. 141. The method of any one of embodiments 134-140, wherein the reaction is carried out at a temperature of about 0-30°C. 142. A method according to embodiment 141, wherein the reaction is carried out at a starting temperature of about 0-10°C and then at 20-30°C. 143. The method according to any one of embodiments 134-142, wherein the compound of formula (3) or a salt thereof is obtained by converting a compound of formula (1): or its salts And the compound of formula (2): or a salt thereof to form a compound of formula (3). 144. A method for preparing a compound of formula (3) or a salt thereof, It includes: The compound of formula (1): or a salt thereof, And the compound of formula (2): or a salt thereof to form a compound of formula (3). 145. The method of embodiment 143 or embodiment 144, wherein: a) The compound of formula (3) is a compound of formula (3a): And the compound of formula (1) is a compound of formula (1a), or b) The compound of formula (3) is a compound of formula (3b): And the compound of formula (1) is a compound of formula (1b), 146. The method of any one of embodiments 143-145, wherein the reaction is carried out in the presence of a base. 147. The method of embodiment 146, wherein the base is sodium hydride, potassium tert-butoxide, or sodium ethoxide. 148. The method of embodiment 146, wherein the base is sodium ethoxide. 149. The method according to any one of embodiments 143-148, wherein the reaction is carried out using an alcohol as solvent. 150. The method of embodiment 149, wherein the alcohol is methanol, ethanol, or isopropanol. 151. The method of embodiment 149, wherein the alcohol is ethanol. 152. The method of any one of embodiments 143-151, wherein the reaction is carried out at a temperature of about 0-30°C. 153. A method according to embodiment 152, wherein the reaction is carried out at a starting temperature of about 0-10°C and then at 20-30°C. 154. The method according to any one of embodiments 143-153, wherein the compound of formula (1) or its salt is separated into isomers, formula (1a) and formula (1b) or their salts using kinetic resolution. 155. The method according to embodiment 154, wherein the kinetic resolution is Jacobsen's kinetic resolution or hydrolytic kinetic resolution catalyzed by a chiral cobalt-salen complex. 156. A method for preparing a compound of formula (T-2) or a salt thereof, comprising the following steps: in: R3 is benzyl optionally substituted by C1-C6 alkoxy, C1-C6 alkyl or halide; R1 is benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide; Pg1 is the first protecting group; Pg2 is a second protecting group; and X is a leaving group. 157. A method for preparing a compound of formula (T-2) or a salt thereof, comprising the following steps: in: R1 is benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide; Pg1 is the first protecting group; Pg2 is a second protecting group; and X is a leaving group. 158. The method of embodiment 156 or embodiment 157, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl. 159. Compound of formula (T-3): or a salt thereof, wherein Pg1 is a first protecting group. 160. Compound of formula (T-4): or a salt thereof, wherein Pg1 is a first protecting group. 161. A compound according to embodiment 159 or embodiment 160, wherein Pg1 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl. 162. A compound according to embodiment 159 or embodiment 160, wherein Pg1 is tert-butyloxycarbonyl. 163. Compound of formula (3): or a salt thereof. 164. The compound according to embodiment 163, wherein the compound of formula (3) or a salt thereof is a compound of formula (3a): or a salt thereof; or a compound of formula (3b): or a salt thereof. 165. Compound of formula (4): or a salt thereof. 166. The compound according to embodiment 165, wherein the compound of formula (4) or a salt thereof is a compound of formula (4a): or a salt thereof; or a compound of formula (4b): or a salt thereof. 167. Compound of formula (5): or a salt thereof. 168. The compound according to embodiment 167, wherein the compound of formula (5) or a salt thereof is a compound of formula (5a): or a salt thereof; or a compound of formula (5b): or a salt thereof. 169. Compound of formula (6): or a salt thereof. 170. The compound according to embodiment 169, wherein the compound of formula (6) or a salt thereof is a compound of formula (6a): or a salt thereof; or a compound of formula (6b): or a salt thereof. 171. Compound of formula (7): or a salt thereof, wherein R1 is an amino protecting group or a benzyl carbamate optionally substituted with a C1-C6 alkoxy group, a C1-C6 alkyl group or a halide. 172. The compound according to embodiment 171, wherein the compound of formula (7) or a salt thereof is a compound of formula (7a): or a salt thereof; or a compound of formula (7b): or a salt thereof. 173. Compound of formula (8): or a salt thereof, wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; and Pg2 is the second protecting group. 174. The compound according to embodiment 173, wherein the compound of formula (8) or a salt thereof is a compound of formula (8a): or a salt thereof; or a compound of formula (8b): or a salt thereof. 175. Compound of formula (9): or a salt thereof, wherein Pg2 is a second protecting group. 176. The compound according to embodiment 175, wherein the compound of formula (9) or a salt thereof is a compound of formula (9a): or a salt thereof; or a compound of formula (9b): or a salt thereof. 177. Compound of formula (7.5): or a salt thereof, wherein Pg1 is a first protecting group. 178. The compound according to embodiment 177, wherein the compound of formula (7.5) is a compound of formula (7.5a): or a salt thereof; or a compound of formula (7.5b): or a salt thereof. 179. Compound of formula (8.5): or a salt thereof. 180. The compound according to embodiment 179, wherein the compound of formula (8.5) or a salt thereof is a compound of formula (8.5a): or a salt thereof; or a compound of formula (8.5b): or a salt thereof. 181. Compound of formula (9.5): or a salt thereof. 182. The compound according to embodiment 181, wherein the compound of formula (9.5) or a salt thereof is a compound of formula (9.5a): or a salt thereof; or a compound of formula (9.5b): or a salt thereof. 183. Compound of formula (10): or a salt thereof, wherein Pg2 is a second protecting group. 184. The compound according to embodiment 183, wherein the compound of formula (10) or a salt thereof is a compound of formula (10a): or a salt thereof; or a compound of formula (10b): or a salt thereof. 185. Compound of formula (11): or a salt thereof, wherein: Pg1 is a first protecting group; and Pg2 is the second protecting group. 186. The compound according to embodiment 185, wherein the compound of formula (11) or a salt thereof is a compound of formula (11a): or a salt thereof; or a compound of formula (11b): or a salt thereof. 187. A compound according to embodiment 185 or embodiment 186, wherein Pg1 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl. 188. A compound according to embodiment 185 or embodiment 186, wherein Pg1 is tert-butyloxycarbonyl. 189. A compound according to any one of embodiments 233-242, wherein Pg2 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl. 190. A compound according to any one of embodiments 173-176 or 183-189, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide. Example

[0070] These examples are provided for illustrative purposes only, and do not limit the scope of the claims provided herein.

[0071] Abbreviations used: 2-MeTHF 2-Methyltetrahydrofuran BMS Borane dimethyl sulfide Cbz N-(Benzyloxycarbonyl)succinimide DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEPA N,N-Diisopropylethylamine DMSO Dimethyl sulfoxide DPPA Diphenylphosphoryl azide EtOAc Ethyl acetate EtOH Ethanol h Hour LC-MS,LC / MS,LCMS Liquid chromatography–mass spectrometry LHMDS Lithium Hexamethyldisilazide MeOH Methanol min minute MTBE Methyl tert-butyl ether NaOEt Sodium ethoxide NMR Nuclear Magnetic Resonance SFC Supercritical Fluid Chromatography TFA Trifluoroacetic acid THF Tetrahydrofuran Example 1. Synthesis of T-2 from 2-(2-bromoethyl)oxirane Example S1.1 Synthesis of Compound 3

[0072] Diethyl malonate (156g, 964mmol) and EtOH (740mL) were added to a 3L 3-neck round-bottom flask. The solution was cooled to 0-5°C. A brown solution of sodium ethoxide (396mL, 21wt% in EtOH, 1060mmol) was added via an additional funnel over 20min. The temperature was then slightly raised to 9°C. After the reaction mixture was stirred at 0-5°C for 15min, 2-(2-bromoethyl)oxirane (150g, 964mmol) was added, and the reaction mixture was stirred at room temperature to provide a brown suspension. After stirring at room temperature for 18h, the reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (1L) and brine (500mL). The aqueous layer was extracted again with EtOAc (300mL). The combined organic layers were separated, dried over Na2SO4, filtered and concentrated in vacuo to afford the product diethyl 3-hydroxycyclopentane-1,1-dicarboxylate (200 g, 782 mmol, 81% yield) as a brown oil with a purity of -90%, which was used directly in the next step without further purification. LC-MS[M+1]231. 1 H NMR (400MHz, chloroform-d) δ4.44–4.36(m,1H),4.26–4.15(m,4H),2.47–2.26(m,3H),2.07(br d,J=4.5Hz,1H),1.94(dtd,J=13.5,8.5,5.2Hz,1H),1.84–1.67(m,1H),1.33–1.20(m,6H). Example S1.2 Synthesis of Compound 4 Triphenylphosphine (PPh3, 117 g, 443 mmol) and THF (1400 mL) were added to a 5L 3-neck round bottom flask. The colorless solution was cooled to 5°C with an ice-water bath, and diisopropyl azodicarboxylate (DIAD, 86 mL, 443 mmol) was added dropwise through an addition funnel over 35 min while keeping the internal temperature below 15°C. Before each addition, the yellow color of DIAD was almost eliminated. During the addition of DIAD, the clear reaction mixture became a white suspension. The white thick suspension was stirred in an ice-water bath for 30 min. The formation of a pure white thick slurry indicated the successful preparation of the PPh3-DIAD complex. A solution of diethyl 3-hydroxycycloheptane-1,1-dicarboxylate (108 g, 422 mmol) was poured into the reaction mixture and the temperature was raised to 15°C. Isoindoline-1,3-dione (59.9 g, 407 mmol) was then added in small portions while keeping the reaction temperature below 15°C. After addition, the reaction mixture was warmed to room temperature. The reaction mixture became a light orange solution and was stirred at room temperature overnight. The reaction mixture was quenched with brine (400mL) and the aqueous layer was extracted with EtOAc (300mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to 1L in a vacuum. Colorless crystals (triphenylphosphine oxide (Ph3P=O)) were observed to precipitate from the concentrated EtOAc solution. The suspension was left at room temperature overnight. The filtrate brown oil was added to the stirred 500mL Et2O in a 2L beaker to form a suspension. After 30min, the obtained peach-colored solid was removed by filtration. The Et2O filtrate was filtered once more and then concentrated to obtain a crude brown oil. It was added to MeOH (200mL) to form a white suspension. The precipitated pure product was collected by filtration and washed with methanol to obtain a white solid. The mother liquor was concentrated and purified on an ISCO column chromatography with a gradient of 0–10% acetone / hexane. A total of 93 g (yield 61%) of diethyl 3-(1,3-dioxoisoindolin-2-yl)cyclopentane-1,1-dicarboxylate was obtained as a white solid. LC-MS [M+1] 360.0. 1 H NMR (400MHz, chloroform-d) δ7.83(dd,J=5.5,3.0Hz,2H),7.73–7.69(m,2H),4.81(quin,J=8.8Hz,1H),4.29–4.20(m,4H),2 .78–2.66(m,3H),2.36–2.28(m,1H),2.19(dt,J=13.3,7.5Hz,1H),2.11–2.04(m,1H),1.29(td,J=7.1,2.6Hz,6H). Example S1.3 Synthesis of Compound 5

[0073] To a 5L 3-neck flask equipped with a mechanical stirrer, 3-(1,3-dioxoisoindolin-2-yl)cyclopentane-1,1-dicarboxylic acid diethyl ester (120g, 334mmol), MeOH (1580mL), DCM (1050mL) and hydrazine (121mL, 1336mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 18h. The reaction formed a thick suspension, which was filtered. The filter cake was rinsed with DCM (500mL), and the combined filtrate was concentrated in vacuo. DCM (900mL) and 1N NaOH (440mL) were then added to the residue. The organic phase was collected, washed with water (200mL) and brine (200mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the product 3-aminocyclopentane-1,1-dicarboxylic acid diethyl ester, which was a light yellow oil (68g). The combined organic phase was stripped with DCM to obtain another 3g product. The combined desired product was 71 g (93% yield) and was used in the next step without further purification. LC-MS[M+1]:230. 1 H NMR (400MHz, chloroform-d) δ4.19(quin,J=7.1Hz,4H),3.45(t,J=6.7Hz,1H),2.55–2.39(m,2H),2.1 7(dt,J=13.8,7.9Hz,1H),2.01–1.90(m,2H),1.64–1.37(m,3H),1.25(td,J=7.1,3.7Hz,6H). Example S1.4 Synthesis of Compound 6

[0074] 3-aminocyclopentane-1,1-dicarboxylic acid diethyl ester (71 g, 310 mmol), cesium carbonate (202 g, 619 mmol) and MeOH (670 mL) were added to a 2L 3-neck flask with a condenser under N2. The reaction mixture was stirred at 65 ° C for 4 h. The reaction was completed after 4 h and cooled to room temperature and then concentrated below 35 ° C in vacuum to remove MeOH to obtain a yellow oil. H2O (30 ml) and 2-MeTHF (120 mL) were added to the yellow residue, and the mixture was acidified to pH ~ 3 with aqueous NaHSO4 (149 g in 170 mL H2O). The resulting solution was then extracted with 2-MeTHF (200 mL x4). The combined extracts were concentrated by removing the solvent in vacuum to obtain a yellow solid. The solid was then suspended in benzene (500 mL) and heated with a Dean-Stark apparatus (Azeotropy) to remove water to obtain 43.5 g of a yellow powder. The powder was co-rotavaporated with toluene (200 mL x 3) to remove any residual moisture to afford the desired product (42.8 g, 89% yield) as a yellow powder, which was directly used in the next step reaction without further purification. LC-MS[M+1]:156.0. 1 H NMR (400 MHz, methanol-d4) δ 3.91–3.87 (m, 1H), 2.23–2.10 (m, 2H), 2.08–1.91 (m, 1H), 1.84–1.66 (m, 3H). Example S1.5 Synthesis of Compound 7

[0075] To a suspension of 3-oxo-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (37.0 g, 238 mmol) in 2-Me-THF (610 mL) was added N,N-diisopropylethylamine (104 mL, 596 mmol) and diphenylphosphoryl azide (DPPA, 58.1 mL, 262 mmol). The reaction mixture was heated to 70 ° C until it became a clear solution (within 5 min). LC / MS confirmed that the starting material was completely consumed within 20 min. After stirring at 70 ° C for 50 min, benzyl alcohol (64.5 mL, 620 mmol) was added at 70 ° C in one go, and the reaction mixture was stirred at 80 ° C for a total of 9 h until the reaction was complete. After cooling to room temperature, most of the 2-MeTHF (~650 mL) was removed in vacuo. The residue was diluted with (650mL), washed with water (250mL) and brine (200mL), dried over Na2SO4 and filtered and concentrated in vacuo to obtain the extract as a yellow oil. Water and brine washings were combined and stripped with EtOAc (350mL x 8). The organic extracts were dried, concentrated and combined to obtain the crude product (177g) as a yellow oil. The crude product was first purified on ISCO column chromatography with 0-50% acetone / hexane gradient and then purified by SFC to obtain two enantiomers: peak 1: 23.7g (yield 38.2%); and peak 2: 23.5g (yield 37.9%). LC / MS[M+1]:260.7. 1 H NMR (400MHz, chloroform-d) δ7.39–7.31(m,5H),5.69(br s,2H),5.12(br s,2H),3.87(br s,1H),2.53–2.44(m,1H),2.41(br d,J=9.1Hz,1H),2.06(br s,1H),1.92(dq,J=9.2,2.3Hz,1H),1.78–1.67(m,1H),1.52–1.41(m,1H). Example S1.6 Synthesis of Compound 8

[0076] To a solution of benzyl (3-oxo-2-azabicyclo[2.2.1]heptane-4-yl)carbamate (1.66 g, 6.38 mmol) in THF (36 mL) was added LHMDS (1 M in THF, 6.70 mL, 6.70 mmol) dropwise at 0-5 °C. After stirring for 10 min, benzyl bromide (0.834 mL, 7.02 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred for 20 h. Saturated NH4Cl solution (20 mL) was added to quench the reaction. EtOAc (20 mL) was then added, and the organic layer was collected. The aqueous layer was washed with EtOAc (15 mL). The organic layer and washings were combined and washed with brine (30 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by ISCO column chromatography with a 50-100% EtOAc / heptane gradient to afford benzyl (2-benzyl-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (2.0 g, 5.71 mmol, 89% yield) as a white solid. LC / MS[M+1]:351.3. 1 H NMR (400MHz, chloroform-d) δppm 1.25–1.51(m,1H)1.52–1.61(m,1H)1.76–1.94(m,2H)2.37(br d,J=9.05Hz,1H)2.47(td,J=11.43,4.28Hz,1H)3.67(br s,1H)4.10(d,J=15.16Hz,1H)4.73(d,J=14.92Hz,1H)5.13(s,2H)5.79(s,1H)7.23–7.41(m,10H) Example S1.7 Synthesis of Compound 9

[0077] A solution of (2-benzyl-3-oxo-2-azabicyclo [2.2.1] heptane-4-yl) benzyl carbamate (3.15 g, 8.99 mmol) in MeOH (30 mL) was added to a 250 mL three-necked round-bottom flask. The solution was bubbled with N2 for 10 min. 10% wet Pd / C (300 mg, 10% w / w) was added under N2. The reaction mixture was then degassed until no bubbles were visible. A H2 balloon was inserted, and the reaction mixture was stirred for 20 h. LC / MS indicated that the reaction was complete. The H2 balloon was removed, and the reaction mixture was degassed until no bubbles were visible. The flask was then filled with N2. The mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated in vacuo to obtain the product 4-amino-2-benzyl-2-azabicyclo [2.2.1] heptane-3-one (1.9 g, 8.78 mmol, 98% yield) as a colorless oil. LC / MS[M+1]:217.4. 1 H NMR (400 MHz, chloroform-d) δ ppm 1.55–1.63 (m, 2H) 1.66–1.92 (m, 6H) 3.58–3.61 (m, 1H) 4.03 (d, J = 15.16 Hz, 1H) 4.73 (d, J = 15.16 Hz, 1H) 7.25–7.37 (m, 5H) Example S1.8 Synthesis of Compound 10 Borane dimethyl sulfide complex (2.22 mL, 4.44 mmol) was added dropwise to a solution of 4-amino-2-benzyl-2-azabicyclo [2.2.1] heptane-3-one (320 mg, 1.480 mmol) in THF (15 mL) at room temperature. The reaction mixture was heated to 65 ° C and stirred for 20 h. After cooling to room temperature, 6N HCl solution (4.0 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was then heated to 50 ° C and stirred for 20 h. After cooling to room temperature, brine (20 mL) and EtOAc (20 mL) were added, and then 1N NaOH was added to adjust the pH of the aqueous layer to ~ 14. The amine product was then extracted using DCM (20 mL x3). The yield of 2-benzyl-2-azabicyclo [2.2.1] heptane-4-amine was estimated to be 100%. LC / MS[M+1]:203.4 Example S1.9 Synthesis of Compound 11

[0078] To a DCM solution (10 mL) containing ~300 mg of 2-benzyl-2-azabicyclo[2.2.1]heptan-4-amine was added di-tert-butyl dicarbonate (355 mg, 1.627 mmol) and stirred for 1 h. After removal of DCM, the residue was purified by ISCO column chromatography with a 20-100% EtOAc / heptane gradient to afford tert-butyl (2-benzyl-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (330 mg, 1.091 mmol, 73.8% yield). LC / MS[M+1]:303.3. 1H NMR (400 MHz, chloroform-d) δ ppm 1.37-1.53 ​​(m, 9H) 1.59-1.72 (m, 2H) 1.75-1.88 (m, 2H) 1.92-2.14 (m, 2H) 2.45-2.68 (m, 1H) 2.87-3.09 (m, 1H) 3.11-3.30 (m, 1H) 3.59-3.85 (m, 2H) 4.63-5.00 (m, 1H) 7.16-7.46 (m, 5H) Example S1.10 Synthesis of Compound T-2

[0079] By (2-benzyl-2-azabicyclo [2.2.1] heptane-4-yl) tert-butyl carbamate (2.0g, 6.61mmol) is dissolved in ethanol (6mL), 10% Pd (OH) 2 / C (200mg, 10% w / w) is added thereto. The reaction vessel is degassed, filled with N 2, degassed, and filled with H 2 balloon. The reaction mixture is then stirred for 18h. The reaction vessel is then degassed and filled with N 2 many times. The reaction mixture is then filtered with a diatomaceous earth pad and concentrated in vacuo to obtain tert-butyl (2-azabicyclo [2.2.1] heptane-4-yl) carbamate (1.3g, 6.12mmol, 93% yield) as a white solid. LC / MS[M+1]:213.3. 1 H NMR (400 MHz, chloroform-d) δ ppm 1.45 (s, 9H) 1.57-1.67 (m, 1H) 1.69-1.78 (m, 1H) 1.81-1.97 (m, 5H) 3.01 (s, 2H) 3.40 (s, 1H) 4.92 (s, 1H) Example 2. Synthesis of T-2 via Selective Deprotection of Diamine Example S2.1 Synthesis of Compound 7.5

[0080] To a solution of (3-oxo-2-azabicyclo [2.2.1] heptane-4-yl) benzyl carbamate (5.2g, 19.98mmol) in MeOH (100mL), di-tert-butyl dicarbonate (4.80g, 21.98mmol) and 10% Pd / C (0.52g, 0.489mmol, 10% W / W) were added. The reaction vessel was degassed, filled with N2, degassed, and filled with H2 balloons. The reaction mixture was stirred for 18h, and then the reaction vessel was degassed and filled with N2 several times. The reaction mixture was then filtered through a diatomaceous earth pad and concentrated in vacuo to obtain a crude product, which was then wet-ground with 2-MeTHF at room temperature to -20°C to obtain the product (3-oxo-2-azabicyclo [2.2.1] heptane-4-yl) tert-butyl carbamate (4.3g, 19.00mmol, 95% yield). LC / MS[M+1]:227.3 Example S2.2 Synthesis of Compound 8.5

[0081] In 100mL flask, add (3-oxo-2-azabicyclo [2.2.1] heptane-4-yl) tert-butyl carbamate (872mg, 3.85mmol) and DCM (10mL).The mixture is stirred at room temperature until all solids dissolve and then trifluoroacetic acid (2.97mL, 38.5mmol) is added.The mixture is stirred at room temperature overnight and concentrated in vacuo.In vacuo, the mixture is co-evaporated twice with toluene (10mL) to obtain 4-amino-2-azabicyclo [2.2.1] heptane-3-one 2,2,2-trifluoroacetate (918mg, 3.82mmol, 99% yield). 1 H NMR (400MHz, DMSO-d6) δppm 8.81 (br s, 3H) 8.36 (s, 1H) 3.86 (s, 1H) 1.98-2.09 (m, 1H) 1.84-1.96 (m, 2H) 1.76 (d, J=8.8Hz, 1H) 1.52-1.68 (m, 2H) Example S2.3 Synthesis of Compound 9.5

[0082] 4-amino-2-azabicyclo [2.2.1] heptane-3-one 2,2,2-trifluoroacetate (711 mg, 2.96 mmol) and THF (15 mL) were added to a 100 mL flask. The mixture was cooled in an ice-water bath, and lithium aluminum hydride (1M in THF) (14.80 mL, 14.80 mmol) was added dropwise. The mixture was stirred for 10 min and brought to room temperature by removing the ice-water bath. The mixture was heated at 55 ° C (heating block temperature) for 5 h and stirred at room temperature overnight. The mixture was cooled to 0 ° C and water (0.5 mL) was added dropwise. After stirring for 10 min, 15% NaOH solution (0.5 mL) was added and water (1.5 mL) was subsequently added. The mixture was diluted with ether (15 mL) and stirred for 1 h. The suspension was filtered through a diatomaceous earth pad and washed with ether (15 mL). The filtrate was dried over Na2SO4, filtered and concentrated to afford crude 2-azabicyclo[2.2.1]heptane-4-amine which was used in the next step without purification (estimated 100% yield). 1 H NMR(400MHz,DMSO-d6)δppm 9.90(br s,1H)9.36(s,1H)9.16(s,2H)8.96(s,1H)3.96(s,1H)3.09–3.28(m,2H)1.83–2.11(m,6H)1.71-1.83(m,1H) Example S2.4 Synthesis of Compound 10

[0083] Crude 2-azabicyclo [2.2.1] heptane-4-amine (330 mg, 2.94 mmol) was dissolved in DCM (10 mL) and MeOH (10 mL), to which benzaldehyde (0.313 mL, 3.09 mmol) and magnesium sulfate (2.08 g, 17.28 mmol) were added. The mixture was stirred at room temperature overnight and then cooled to 0 ° C. A solution (5 mL) of Cbz-OSu (0.770 g, 3.09 mmol) in 1: 1 MeOH / DCM was added dropwise. The mixture was stirred at 0 ° C for 30 min, filtered through a diatomaceous earth pad and concentrated in vacuo. The residue was redissolved in 15 mL MeOH and 1N hydrochloric acid (15 mL, 15.00 mmol). The mixture was stirred at room temperature for 30 min to hydrolyze the imine. Most of the methanol was removed in vacuo and the water layer was extracted with DCM (10 mL x 2). The first extraction was discarded and the aqueous layer was basified to pH 12 with 1 N NaOH solution and then extracted with DCM (10 mL x 3). The combined organic extracts were concentrated in vacuo to afford benzyl 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (367 mg, 1.490 mmol, 50.6% yield) as a yellow oil. 1 H NMR(400MHz, DMSO-d6)7.27–7.52(m,5H)5.04–5.25(m,2H)4.09–4.35(m,1H)3.09–3.28(m,2H)1.35–1.98(m,8H) Example S2.5 Synthesis of Compound 11

[0084] To a solution of 4-amino-2-azabicyclo [2.2.1] heptane-2-carboxylic acid benzyl ester (362 mg, 1.470 mmol) in DCM (10 mL) was added Boc-anhydride (385 mg, 1.764 mmol). The mixture was stirred at room temperature for 20 h. LCMS showed that SM was almost completely consumed. The solvent was evaporated and the residue was purified by ISCO column chromatography with 20-100% EtOAc / heptane gradient to obtain 4-((tert-butyloxycarbonyl)amino)-2-azabicyclo [2.2.1] heptane-2-carboxylic acid benzyl ester (478 mg, 1.380 mmol, 94% yield). 1H NMR (400 MHz, DMSO-d6) 7.30–7.43 (m, 5H) 5.08–5.21 (m, 2H) 4.78–4.92 (m, 1H) 4.09–4.32 (m, 1H) 3.46–3.59 (m, 1H) 3.36–3.45 (m, 1H) 1.65–2.05 (m, 6H) 1.45 (s, 9H) Example S2.6 Synthesis of Compound T-2

[0085] Benzyl 4-((tert-butyloxycarbonyl)amino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (478 mg, 1.380 mmol) was hydrogenated overnight in MeOH (10 mL) with a balloon filled with H2 in the presence of 10% Pd / C (50 mg, 0.047 mmol). The resulting mixture was filtered through a pad of celite, washed with methanol, and concentrated to afford tert-butyl (2-azabicyclo[2.2.1]heptane-4-yl)carbamate (284 mg, 1.338 mmol, 97% yield). LC / MS[M+1]:213.3. Example 3. Synthesis of T-3 Example S3.1 Synthesis of T-3 from chiral separated compound 7a

[0086] Compound T-3 is the enantiomer of compound T-2, prepared from enantiomer 7a obtained by chiral separation of compound 7. Each reaction process from compound 7a to 8a, 8a to 9a, 9a to 10a, 10a to 11a, and 11a to T-3 is the same as the reaction process described in Examples 1.6, 1.7, 1.8, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method for chiral separation is Jacobsen's kinetic resolution. In some embodiments, the kinetic resolution method for chiral separation is hydrolytic kinetic resolution catalyzed by a chiral cobalt-salen complex. Example S3.2 Synthesis of T-3 from chirally isolated compound 7a via selective protection of diamine

[0087] Compound T-3 is the enantiomer of compound T-2, prepared from enantiomer 7a obtained by chiral separation of compound 7. Each reaction process from compound 7a to 7.5a, 7.5a to 8.5a, 8.5a to 9.5a, 9.5a to 10a and 11a to T-3 is the same as the reaction process described in Examples 2.1, 2.2, 2.3, 2.4, 1.9 and 1.10, respectively. In some embodiments, the kinetic resolution method for chiral separation is Jacobsen's kinetic resolution. In some embodiments, the kinetic resolution method for chiral separation is hydrolytic kinetic resolution catalyzed by a chiral cobalt-salen complex. Example S3.3 Synthesis of T-3 from chiral separated compound 1a

[0088] Compound T-3 is the enantiomer of compound T-2, prepared from enantiomer 1a obtained by chiral separation of compound 1 using Jacobsen's kinetic resolution. The reaction process is the same as described in Example 1. The Jacobsen's kinetic resolution method used to prepare 1a is described as follows.

[0089] S,S-Co-Salen (6.12 g, 10.13 mmol) and DCM (60 mL) were added to a 500 mL flask. After stirring at room temperature for 10 min, perfluorotert-butyl alcohol (7.08 mL, 50.7 mmol) was added dropwise, and the mixture was vigorously stirred in air for 1 h. The color of the mixture changed from dark red to black. The mixture was concentrated to dryness using a rotary evaporator. The solid was scraped off the wall with a spatula and dried in a vacuum for 2 h to obtain an active catalyst. Racemic 2-(2-bromoethyl)oxirane (102 g, 675 mmol), phenol (35.0 g, 372 mmol) and MTBE (50 mL) were added to another 250 mL flask. The mixture was cooled to 3-5 ° C in an ice-water bath and then added to a flask containing the dried catalyst and placed in an ice-water bath. The mixture was stirred in an ice-water bath for 30 min and then kept at 0-5 ° C for 20 h. The flask was then warmed to room temperature and MTBE was distilled out using a rotary evaporator (40°C / 70mmHg). The short-path distillation adapter was then connected to the flask and the mixture was distilled under reduced pressure to obtain 47g of product (bp 66-68°C / 25mmHg, then 43-45°C / 8mmHg). At the end of the distillation, the bath was heated to 100°C and the vacuum was reduced to 5-6mmHg to maximize the recovery of epoxide. NMR showed 89% purity. The crude product was redistilled from a 100mL flask using the same short-path distillation adapter to obtain (S)-2-(2-bromoethyl)oxirane (36.0g, 212mmol, 31.4% yield). Purity was shown to be ~95% by NMR. 1 H NMR (400MHz, chloroform-d) δ = 3.53 (dd, J = 6.0, 7.4Hz, 2H), 3.11 (dtd, J = 2.7, 4.2, 6.8Hz, 1H), 2.86 (dd, J = 3.8, 4 .9Hz,1H),2.60(dd,J=2.7,4.9Hz,1H),2.18(dtd,J=4.6,7.5,15.0Hz,1H),2.07(qd,J=6.0,15.0Hz,1H) Example 4. Synthesis of T-4 Example S4.1 Synthesis of T-4 from chiral separated compound 7b

[0090] Compound T-4 is the enantiomer of compound T-2, prepared from enantiomer 7b obtained by chiral separation of compound 7. Each reaction process from compound 7b to 8b, 8b to 9b, 9b to 10b, 10b to 11b, and 11b to T-4 is the same as the reaction process described in Examples 1.6, 1.7, 1.8, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method for chiral separation is Jacobsen's kinetic resolution. In some embodiments, the kinetic resolution method for chiral separation is hydrolytic kinetic resolution catalyzed by a chiral cobalt-salen complex. Example S4.2 Synthesis of T-4 from chirally isolated compound 7b via selective protection of diamine

[0091] Compound T-4 is the enantiomer of compound T-2, prepared from enantiomer 7b obtained by chiral separation of compound 7. Each reaction process from compound 7b to 7.5b, 7.5b to 8.5b, 8.5b to 9.5b, 9.5b to 10b and 11b to T-4 is the same as the reaction process described in Examples 2.1, 2.2, 2.3, 2.4, 1.9 and 1.10, respectively. In some embodiments, the kinetic resolution method for chiral separation is Jacobsen's kinetic resolution. In some embodiments, the kinetic resolution method for chiral separation is hydrolytic kinetic resolution catalyzed by a chiral cobalt-salen complex. Example S4.3 Synthesis of T-3 from chiral separated compound 1b

[0092] Compound T-4 is the enantiomer of compound T-2, prepared from enantiomer 1b obtained by chiral separation of compound 1 using Jacobsen's kinetic resolution. The reaction process was the same as described in Example 1. Jacobsen's kinetic resolution method was the same as described in Example S3.3.

Claims

1. A method for preparing a compound of formula (T-2): or a salt thereof, comprising: Reduction of the compound of formula (11): or a salt thereof, wherein Pg1 is a first protecting group; and Pg2 is the second protecting group; To form the compound of formula (T-2).

2. The method according to claim 1, wherein: a) The compound of formula (T-2) is a compound of formula (T-3): And the compound of formula (11) is a compound of formula (11a): or c) The compound of formula (T-2) is a compound of formula (T-4): And the compound of formula (11) is a compound of formula (11b):

3. A method according to claim 1 or claim 2, wherein the reduction of the compound of formula (11) or a salt thereof is catalyzed by a transition metal to form a compound of formula (T-2) or a salt thereof.

4. The method according to claim 3, wherein the transition metal is palladium chloride, palladium barium sulfate or palladium carbon (Pd / C).

5. The process according to any one of claims 1 to 4, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol or isopropanol.

6. The method according to any one of claims 1 to 5, wherein the compound of formula (11) or its salt is prepared by protecting the primary amine group of the compound of formula (10) or its salt:

7. A method for preparing a compound of formula (11), or a salt thereof, comprising: Protecting the primary amine group of the compound of formula (10) or its salt: in: wherein Pg1 is a first protecting group; and Pg2 is the second protecting group; To form the compound of formula (11).

8. The method according to any one of claims 1 to 7, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl.

9. The method according to any one of claims 6 to 8, wherein the reaction is carried out using an organic solvent, optionally wherein the organic solvent is chloroform, ethylene dichloride, toluene, methanol, ethanol, isopropanol or 2-methyl-THF, dioxane, ethyl acetate or tetrahydrofuran.

10. The method according to any one of claims 1 to 9, wherein the compound of formula (10) or its salt is prepared by sequentially protecting the compound of formula (9.5) with Pg2 and Pg1 respectively: or a substituent amine and a heterocyclic amine of a salt thereof, and then selectively deprotecting the substituent amine to form a compound of formula (10); or The compound of formula (10) or its salt is prepared by reducing the compound of formula (9): or a salt thereof to form a compound of formula (10).

11. A method for preparing a compound of formula (10), or a salt thereof, comprising: Reduction formula (9) compound: or a salt thereof, wherein Pg2 is a second protecting group to form a compound of formula (10), optionally wherein Pg2 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl.

12. The method according to claim 10 or 11, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride or a borane reagent, optionally wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran or borane dimethyl sulfoxide.

13. The method according to any one of claims 10-12, wherein the reaction is carried out using an aprotic solvent, optionally wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform or a mixture thereof.

14. The method according to any one of claims 10 to 13, wherein the compound of formula (9) or a salt thereof is prepared by reducing a compound of formula (8): or a salt thereof to form a compound of formula (9), wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; and Pg2 is the second protecting group.

15. A method for preparing a compound of formula (9) or a salt thereof, comprising: Reduction formula (8) compound: or a salt thereof, wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide; and Pg2 is the second protecting group To form a compound of formula (9), optionally wherein Pg2 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl.

16. The method of claim 14 or 15, wherein the reduction is catalyzed by a transition metal, optionally wherein the transition metal is palladium chloride, palladium barium sulfate or palladium on carbon (Pd / C).

17. The process according to any one of claims 14 to 16, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol or isopropanol.

18. The method according to any one of claims 14 to 17, wherein the compound of formula (8) or a salt thereof is prepared by reacting a compound of formula (7): or a salt thereof is reacted with Pg2X to form a compound of formula (8), wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; Pg2 is a second protecting group; and X is a leaving group.

19. A method for preparing a compound of formula (8) or a salt thereof, comprising: The compound of formula (7): or a salt thereof is reacted with Pg2X, wherein: R1 is an amino protecting group or benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; Pg2 is a second protecting group; and X is a leaving group; To form a compound of formula (8), optionally wherein Pg2 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl.

20. The method according to claim 18 or 19, wherein the reaction is carried out in the presence of a non-nucleophilic base, optionally wherein the non-nucleophilic base is N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide or lithium bis(trimethylsilyl)amide.

21. The method according to any one of claims 18 to 20, wherein the reaction is carried out using an ether solvent, optionally wherein the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether or a mixture thereof.

22. A method for preparing a compound of formula (10), or a salt thereof, wherein Pg2 is a second protecting group, comprising: The substituent amine and heterocyclic amine of the compound of formula (9.5) or its salt are protected in sequence with Pg2 and Pg1 respectively. The substituent amine is then selectively deprotected to form a compound of formula (10), optionally wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl.

23. The method according to claim 10 or 22, wherein the protection reaction is carried out using an organic solvent, optionally wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran.

24. The process according to any one of claims 10, 22 and 23, wherein the selective deprotection of the substituent amine is carried out with an acid, optionally wherein the acid is hydrochloric acid.

25. The method according to any one of claims 10 or 22-24, wherein the compound of formula (9.5) or a salt thereof is prepared by reducing the compound of formula (8.5), or a salt thereof to form a compound of formula (9.5).

26. A method for preparing a compound of formula (9.5), or a salt thereof, comprising: Reduced compound (8.5): or a salt thereof to form a compound of formula (9.5).

27. The method according to claim 25 or 26, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride or a borane reagent, optionally wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran or borane dimethyl sulfoxide.

28. The method according to any one of claims 25-27, wherein the reaction is carried out using an aprotic solvent, optionally wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform or a mixture thereof.

29. The method according to any one of claims 25 to 28, wherein the compound of formula (8.5) or its salt is prepared by hydrolyzing the compound of formula (7.5): or a salt thereof to form a compound of formula (8.5), wherein Pg1 is a first protecting group.

30. A method for preparing a compound of formula (8.5), or a salt thereof, comprising: Hydrolysis of the compound of formula (7.5): or a salt thereof, wherein Pg1 is a first protecting group to form a compound of formula (8.5), optionally wherein Pg1 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl.

31. The process of claim 29 or 30, wherein the hydrolysis is performed with an acid, optionally wherein the acid is trifluoroacetic acid, hydrochloric acid or phosphoric acid.

32. The method according to any one of claims 29-31, wherein the protection reaction is carried out using an organic solvent, optionally wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran.

33. The method according to any one of claims 29 to 32, wherein the compound of formula (7.5) or a salt thereof is prepared by reacting a compound of formula (7), Or the primary amine group of a salt thereof is deprotected and then protected.

34. A method for preparing a compound of formula (7.5), or a salt thereof, wherein Pg1 is a first protecting group, wherein the method comprises: The primary amine group of the compound of formula (7) or its salt is deprotected and then protected wherein R1 is an amino protecting group or a benzyl carbamate optionally substituted with a C1-C6 alkoxy group, a C1-C6 alkyl group, or a halide to form a compound of formula (7.5), optionally wherein Pg1 is selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl.

35. The method of claim 33 or 34, wherein the deprotection is catalyzed by a transition metal, optionally wherein the transition metal is palladium chloride, palladium barium sulfate or palladium on carbon (Pd / C).

36. The process according to any one of claims 33-35, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol or isopropanol.

37. The method according to any one of claims 33 to 36, wherein the protection reaction is carried out using an organic solvent, optionally wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene or tetrahydrofuran.

38. The method according to any one of claims 18, 19 and 33-37, wherein the compound of formula (7) or a salt thereof is prepared by reacting a compound of formula (6): or a salt thereof, It is prepared by reacting with R3OH in the presence of diphenylphosphoryl azide and an amine base to form a compound of formula (7), wherein R3 is benzyl optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide.

39. A method for preparing a compound of formula (7), or its salt, wherein R1 is an amino protecting group or a benzyl carbamate optionally substituted with a C1-C6 alkoxy group, a C1-C6 alkyl group, or a halide, comprising: The compound of formula (6): or a salt thereof is reacted with R3OH in the presence of diphenylphosphoryl azide and an amine base to form a compound of formula (7), wherein R3 is benzyl optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide.

40. The method of claim 38 or 39, wherein the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine or N,N-diisopropylethylamine.

41. The process according to any one of claims 38 to 40, wherein the reaction is carried out using an organic solvent, optionally wherein the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran or 2-methyltetrahydrofuran or a mixture thereof.

42. The method according to any one of claims 38 to 41, wherein the compound of formula (7) or a salt thereof is separated into enantiomers, a compound of formula (7a) and a compound of formula (7b) or a salt thereof, using superfluid chromatography.

43. The method according to any one of claims 38 to 42, wherein the compound of formula (6) or a salt thereof is prepared by converting a compound of formula (5): or a salt thereof is reacted with a base to form a compound of formula (6).

44. A method for preparing a compound of formula (6), or a salt thereof, comprising: The compound of formula (5): or a salt thereof is reacted with a base to form a compound of formula (6).

45. The process of claim 43 or 44, wherein the base is an inorganic base, optionally wherein the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate or cesium carbonate.

46. ​​The process according to any one of claims 43-45, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol or isopropanol.

47. The method according to any one of claims 43 to 46, wherein the compound of formula (5) or a salt thereof is prepared by reacting a compound of formula (4) with or a salt thereof by deprotecting the amine to form a compound of formula (5).

48. A method for preparing a compound of formula (5), or a salt thereof, comprising: For the compound of formula (4): or a salt thereof for deprotection to form a compound of formula (5).

49. The method of claim 47 or 48, wherein the deprotection is performed using a base, optionally wherein the base is sodium borohydride, methylamine, methylhydrazine or hydrazine.

50. The process according to any one of claims 47-49, wherein the reaction is carried out using a mixture of an alcohol and an organic solvent, optionally wherein the alcohol is methanol, ethanol or isopropanol, and the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran or 2-methyltetrahydrofuran.

51. The method according to any one of claims 47-50, wherein the compound of formula (4) or a salt thereof is prepared by reacting a compound of formula (3): or a salt thereof is reacted with phthalimide to form a compound of formula (4).

52. A method for preparing a compound of formula (4), or a salt thereof, comprising, The compound of formula (3): or a salt thereof is reacted with phthalimide to form a compound of formula (4).

53. The method of claim 51 or 52, wherein the reaction further comprises triphenylphosphine and diisopropyl azodicarboxylate.

54. The method of any one of claims 51-53, wherein the reaction is carried out using an aprotic solvent, optionally wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform or a mixture thereof.

55. The method according to any one of claims 51-54, wherein the compound of formula (3) or a salt thereof is prepared by reacting a compound of formula (1): or a salt thereof, And the compound of formula (2): CH2(COOEt)2 2 or a salt thereof to form a compound of formula (3).

56. A method for preparing a compound of formula (3), or a salt thereof, comprising: The compound of formula (1): or a salt thereof, And the compound of formula (2): CH2(COOEt)2 2 or a salt thereof to form a compound of formula (3).

57. The process of claim 55 or 56, wherein the reaction is carried out in the presence of a base, optionally wherein the base is sodium hydride, potassium tert-butoxide or sodium ethoxide.

58. The process according to any one of claims 55-57, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol or isopropanol.

59. The method of any one of claims 55-58, wherein the compound of formula (1) or a salt thereof is separated into enantiomers, formula (1a) and formula (1b) or a salt thereof, using kinetic resolution, optionally wherein the kinetic resolution is Jacobsen's kinetic resolution or hydrolytic kinetic resolution catalyzed by a chiral cobalt-salen complex.

60. A method for preparing a compound of formula (T-2) or a salt thereof, comprising the following steps: in: R3 is benzyl optionally substituted by C1-C6 alkoxy, C1-C6 alkyl or halide; R1 is benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide; Pg1 is the first protecting group; Pg2 is a second protecting group; and X is a leaving group.

61. A method for preparing a compound of formula (T-2) or a salt thereof, comprising the following steps: in: R1 is benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide; Pg1 is the first protecting group; Pg2 is a second protecting group; and X is a leaving group.

62. The method of claim 156 or claim 157, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene, and fluorenylmethoxycarbonyl.

63. A compound selected from: (a) a compound of formula (T-3) or a compound of formula (T-4): or its salts; (b) Compound of formula (3): or a salt thereof, optionally wherein the compound of formula (3) or a salt thereof is a compound of formula (3a): or its salts; Or a compound of formula (3b): or its salts; (c) Compound of formula (4): or a salt thereof, wherein the compound of formula (4) or a salt thereof is a compound of formula (4a): or its salts; Or a compound of formula (4b): or its salts; (d) Compounds of formula (5): or a salt thereof, optionally wherein the compound of formula (5) or a salt thereof is a compound of formula (5a): or its salts; Or a compound of formula (5b): or its salts; (e) Compound of formula (6): or a salt thereof, wherein the compound of formula (6) or a salt thereof is a compound of formula (6a): or its salts; Or a compound of formula (6b): or its salts; (f) Compound of formula (7): or a salt thereof, wherein the compound of formula (7) or a salt thereof is a compound of formula (7a): or its salts; Or a compound of formula (7b): or its salts; (g) Compound of formula (8): or a salt thereof, wherein the compound of formula (8) or a salt thereof is a compound of formula (8a): or its salts; Or a compound of formula (8b): or its salts; (h) Compound of formula (9): or a salt thereof, wherein the compound of formula (9) or a salt thereof is a compound of formula (9a): or its salts; Or a compound of formula (9b): or its salts; (i) Compound of formula (7.5): or a salt thereof, optionally wherein the compound of formula (7.5) or a salt thereof is a compound of formula (7.5a): or its salts; Or a compound of formula (7.5b): or its salts; (j) Compound of formula (8.5): or a salt thereof, optionally wherein the compound of formula (8.5) or a salt thereof is a compound of formula (8.5a): or its salts; Or a compound of formula (8.5b): or its salts; (k) Compound of formula (9.5): or a salt thereof, optionally wherein the compound of formula (9.5) or a salt thereof is a compound of formula (9.5a): or its salts; Or a compound of formula (9.5b): or its salts; (1) Compound of formula (10): or a salt thereof, wherein Pg2 is a second protecting group, optionally wherein the compound of formula (10) or a salt thereof is a compound of formula (10a): or its salts; Or a compound of formula (10b): or its salts; as well as (m) Compound of formula (11): or a salt thereof, wherein the compound of formula (11) or a salt thereof is a compound of formula (11a): or its salts; Or a compound of formula (11b): or its salts; wherein Pg1 is the first protecting group; Pg2 is the second protecting group; and R1 is an amino protecting group or benzyl carbamate optionally substituted with a C1-C6 alkoxy group, a C1-C6 alkyl group, or a halide.

64. The compound of claim 63, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, tosyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted benzyloxycarbonyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylethylene and fluorenylmethoxycarbonyl.

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