WO2019034147A1 - 1-methyl-tryptophan compound and preparation method and use thereof - Google Patents

Abstract

The present invention provides a 1-methyl-tryptophan compound and a preparation method and use thereof. The 1-methyl-tryptophan compound of the present invention has a structure shown in formula I. Compared to a corresponding non-deuterated compound, the deuterated 1-methyl-tryptophan compound of the present invention has more excellent pharmacokinetic properties. (I)

Description

1-methyl-tryptophan compound, preparation method and use thereof

The present application claims priority on Chinese Patent Application No. CN201710709533.0, filed on August 17, 2017. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The present invention relates to a 1-methyl-tryptophan compound and a preparation method and use thereof.

Background technique

T cells are the main components of lymphocytes, and they have a variety of biological functions, the most important of which is immune function, which becomes an important tool for attacking tumor cells and fighting disease infections in the body. Tryptophan is one of the important amino acids that maintain T cell growth and proliferation. In mammals, tryptophan is normally metabolized by a kynurenine-based pathway under the action of indoleamine 2,3-dioxygenase (IDO). However, many tumor cells overexpress the indoleamine 2,3-dioxygenase, causing the tryptophan to be rapidly and massively consumed, thus failing to provide nutrients to the T cells, leading to the stop growth and proliferation of T cells, and even the withering. It was cleared and died. On the other hand, toxic products such as 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid produced by the metabolism of tryptophan by the kynurenine pathway in turn inhibit the activation of T cells. These factors lead to the lack of sufficient T cells in the human body to recognize and inhibit tumor cell specific antigens or tumor-associated antigens, resulting in the continued growth, expansion and migration of tumor cells, resulting in immune escape of tumors. Therefore, by developing a suitable drug to inhibit the overexpression of indoleamine 2,3-dioxygenase, T cells can be activated to achieve tumor suppressing effects.

Indoleamine 2,3-dioxygenase 1 (IDO1) was first discovered in the small intestine of rabbits in 1967. In 2006, the crystal structure of IDO1 in human body was determined, and the biochemical function was clear. In addition, experiments have shown that mice that have been knocked out of IDO1 can still live healthy. Therefore, the degree of safety against IDO1 is high, and the risk of toxic side effects of IDO1 inhibitors on the human body is also greatly reduced. The development of IDO inhibitors is divided into two categories: small molecule drugs that directly act on IDO1 and small molecule drugs that achieve IDO inhibition and activate T cells through multiple synergistic pathways.

The two compounds that have progressed rapidly in clinical studies of IDO inhibitors are from Incyte and NewLink. Incyte's Epacadostat has now progressed to clinical phase III, and in combination with Merck's PD-1 antibody Keytruda, early data show that it can significantly improve overall disease control in advanced patients (73%), response to advanced melanoma The rate has also increased to 57%, and when using Keytruda alone, the response rate is only about 28%. In addition, the data also showed that the combination was well tolerated, and the incidence of adverse events of grade 3 or higher was low. In another phase II clinical trial, when Keytruda was combined with Newlink's IDO inhibitor Indoximod, 52% of patients had a significant reduction or complete disappearance of the tumor, and 73% of patients were under control. This combination also showed good tolerance and a low incidence of adverse reactions.

The available data indicate that the development of IDO inhibitors has a very broad prospect, but there have been no approved IDO inhibitor drugs. There is still an urgent need to develop IDO inhibitors with better pharmacokinetic properties.

Summary of the invention

The technical problem to be solved by the present invention is to provide a class of 1-methyl-tryptophan compounds, and a preparation method and use thereof. The present inventors have unexpectedly discovered that the deuterated 1-methyl-tryptophan compounds provided by the present invention have superior pharmacokinetic properties compared to corresponding non-deuterated compounds, specifically embodied in drugs in animals. The amount of exposure in the body has been significantly improved, so it is more suitable as a guanamine 2,3-dioxygenase inhibitor, which is more suitable for the treatment of guanamine 2,3-dioxygenase inhibitor-related diseases. medicine.

According to a first aspect of the present invention, there is provided a 1-methyl-tryptophan compound, an isomer, a prodrug, a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. ,

Wherein R ^a is hydrogen or a carboxylic acid protecting group;

R ^b and R ^c are each independently a hydrogen or an amine protecting group;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or deuterium, and at least one is deuterium.

In one embodiment of the invention, in the 1-methyl-tryptophan compound of formula I, R ^a is hydrogen or a carboxylic acid protecting group;

R ^b and R ^c are each independently a hydrogen or an amine protecting group;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or deuterium, and at least one is deuterium.

In one embodiment of the invention, in the 1-methyl-tryptophan compound of formula I, R ^a , R ^b and R ^c are hydrogen;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or deuterium, and at least one is deuterium.

In one embodiment of the invention, the absolute configuration of the 1-methyl-tryptophan compound as shown in Formula I is in the R configuration or the S configuration.

In one embodiment of the invention, the absolute configuration of the 1-methyl-tryptophan compound of formula I is in the R configuration.

In one embodiment of the invention, the 1-methyl-tryptophan compound of formula I is a compound of formula III:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or deuterium, and at least one of them is deuterium.

In one embodiment of the invention, in the compound of formula III, R ¹ is hydrazine;

And/or, R ² and R ³ are 氘;

And/or, R ⁹ , R ¹⁰ and R ¹¹ are deuterium.

In one embodiment of the invention, in the compound of formula III, R ¹ , R ² and R ³ are deuterium.

In one embodiment of the invention, in the compound of Formula III, R ¹ is hydrazine.

In one embodiment of the invention, in the compound of formula III, there is one of R ² and R ³ .

In one embodiment of the invention, in the compound of formula III, R ² and R ³ are deuterium.

In one embodiment of the invention, in the compound of formula III, R ⁴ is deuterium.

In one embodiment of the invention, in the compound of formula III, R ⁵ is deuterium.

In one embodiment of the invention, in the compound of Formula III, R ⁶ is hydrazine.

In one embodiment of the invention, in the compound of formula III, R ⁷ is hydrazine.

In one embodiment of the invention, in the compound of formula III, R ⁸ is deuterium.

In one embodiment of the invention, in the compound of formula III, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are deuterium.

In one embodiment of the invention, in the compound of formula III, R ⁹ , R ¹⁰ and R ¹¹ are deuterium.

In another preferred embodiment, the 1-methyl-tryptophan compound of the formula I is selected from any of the following structures:

In a preferred embodiment of the present invention, the 1-methyl-tryptophan compound represented by Formula I may be Compound 102, and the compound 102 may be obtained by subjecting Compound 101 to hydrolysis reaction in hydrochloric acid;

The retention time of the compound 101 under chiral detection conditions is 8.8 min or 9.6 min;

The chiral detection conditions include:

The chiral column is CHIRALPAK AD-H, 4.6mm x 250mm;

The column temperature is 40 ° C;

Mobile phase A is 0.1% TFA in Hexane, and the percent is volume percent;

Mobile phase B is ethanol;

The gradient is mobile phase A / mobile phase B = 70 / 30, the ratio is the volume ratio;

The flow rate is 0.5 mL/min;

The detection wavelength was UV 210 nm.

In the hydrolysis reaction, the hydrochloric acid may be 2-3N hydrochloric acid. The hydrolysis reaction may have a reaction temperature of 80 to 120 ° C (for example, 100 ° C).

Even if other chiral resolution, purification methods or detection methods are employed, it is within the scope of the present invention to obtain a chiral compound at a corresponding retention time under the chiral separation or detection method described in the present invention.

A second aspect of the invention provides a pharmaceutical composition comprising:

(1) The 1-methyl-tryptophan compound of the formula I, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof;

(2) A pharmaceutically acceptable carrier.

A third aspect of the present invention provides a process for the preparation of the pharmaceutical composition, which comprises the steps of: a 1-methyl-tryptophan compound as shown in Formula I, an isomer thereof, a prodrug, The crystalline form, pharmaceutically acceptable salt, hydrate or solvate and a pharmaceutically acceptable carrier are mixed to obtain the pharmaceutical composition.

According to a fourth aspect of the present invention, there is provided a 1-methyl-tryptophan compound of the formula I, an isomer thereof, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvent. Or the use of said pharmaceutical composition, which is used as a guanamine 2,3-dioxygenase inhibitor, or for the preparation of a medicament for the treatment and prevention of indoleamine 2,3-dioxygenase inhibition The drug of the disease.

In the application, the disease may be selected from an immune disease, particularly a cancer, wherein the cancer includes breast cancer, ovarian cancer, prostate cancer, melanoma, brain cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer. , liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testis Tumor, uterine tumor, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor.

In the above application, the 1-methyl-tryptophan compound, an isomer, a prodrug, a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, of the formula I Or the pharmaceutical composition may be used in combination with another one or more anticancer agents selected from the group consisting of alkylating agents, platinum complexes, metabolic antagonists, alkaloids, antibody drugs, hormones Anticancer, proteasome inhibitor, CDK kinase inhibitor, VEGFR or EGFR inhibitor, m-TOR inhibitor, PI3K kinase inhibitor, B-Raf inhibitor, PARP inhibitor, c-Met kinase inhibitor, ALK kinase Inhibitor, AKT inhibitor, ABL inhibitor, FLT3 inhibitor, PD-1 inhibitor or PD-L1 inhibitor, and the like.

In another preferred embodiment, the pharmaceutical composition may be an injection, a sachet, a tablet, a pill, a powder or a granule.

A fifth aspect of the invention provides a method of treatment comprising administering to a subject in need of treatment a 1-methyl-tryptophan compound, an isomer, a prodrug, a crystal thereof, of the formula I a pharmaceutically acceptable salt, hydrate or solvate, or a pharmaceutical composition as described.

The method of treatment can achieve cancer treatment by inhibiting indoleamine 2,3-dioxygenase.

In another preferred embodiment, the subject is a human having a disease associated with immunosuppression.

According to a sixth aspect of the present invention, there is provided a process 1 for producing a 1-methyl-tryptophan compound of the formula I, which comprises the step of subjecting a compound of the formula II to methylation or sub- Methylation reaction;

Wherein R ^a , R ^b , R ^c , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined above.

In the preparation method 1 of the 1-methyl-tryptophan compound of the formula I, in the methylation reaction or the methyleneation reaction, the reaction solvent is conventional in the field. A reaction solvent such as an ether solvent such as one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether.

In the preparation method 1 of the 1-methyl-tryptophan compound of the formula I, in the methylation reaction or the methyleneation reaction, the reaction temperature is conventional in the field. The reaction temperature is, for example, -78 ° C to -30 ° C.

In the preparation method 1 of the 1-methyl-tryptophan compound of the formula I, in the methylation reaction or the methyleneation reaction, the methylation reagent is a reaction of the type in the art. Conventional methylating agents such as methyl iodide, methyl bromide, deuterated methyl iodide or dimethyl sulfate.

In the production method 1 of the 1-methyl-tryptophan compound represented by the formula I, the methylation reaction or the methyleneation reaction is preferably carried out under basic conditions. The basic conditions may be provided by conventional alkaline agents of this type in the art, for example, the alkaline agent may be one or more of lithium amide, sodium amide and potassium amide.

Among them, the compound II can be according to the literature (Chem. Eur. J. 2009, 15, 10397-10404; J. Am. Chem. Soc. 2000, 122, 1008-1014; J. Label Compd. Radiopharm 2010, 53, 486-487; Org. Lett. 2007, 9, 1513-1516; J. Am. Chem. Soc. 1984, 106, 4286-4287; Angew. Chem. Int. Ed. 2015, 54, 9381-9385; Biochimica et Biophysica Acta, 1976 , 446, 479-485; Tetrahedron Lett. 2002, 43, 2389-2392; Tetrahedron Lett. 1985, 26, 5891-5894).

In a preferred embodiment of the present invention, the preparation method 1 of the 1-methyl-tryptophan compound represented by Formula I includes the following steps:

At -78 ° C, add alkali metal to the liquid ammonia solution of ferric nitrate, then add the organic solution of compound II, continue stirring at this temperature for 30 min, add methylation reagent, and stir the reaction at -78 ° C ~ 30 ° C for 15 min. ~6h, TLC showed the reaction was complete, quenched, adjusted to pH 4-6, filtered and beaten to give compound I.

In a preferred embodiment of the above Process 1 for producing a 1-methyl-tryptophan compound of the formula I, the alkali metal is preferably one or more of lithium, sodium and potassium.

In a preferred embodiment of the above Process 1 for producing a 1-methyl-tryptophan compound of the formula I, the organic solvent is preferably diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and methyl t-butyl. One or more of the ethers.

In a preferred embodiment of the above Process 1 for preparing a 1-methyl-tryptophan compound of the formula I, the methylating agent is preferably methyl iodide, methyl bromide, deuterated methyl iodide or dimethyl sulfate. ester.

The present invention also provides a second preparation method of the 1-methyl-tryptophan compound of the formula I, which comprises the steps of: subjecting the compound of the formula IA to a hydrogen/hydrazine exchange reaction;

Wherein R ^a , R ^b , R ^c , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined above.

In one embodiment of the present invention, in the production method 2 of the 1-methyl-tryptophan compound of the formula I, R ^a , R ^b , R ^c , R ⁹ , R ¹⁰ and R ¹¹ Is hydrogen and R ⁵ is hydrazine.

In one embodiment of the present invention, in the production method 2 of the 1-methyl-tryptophan compound of the formula I, R ^a , R ^b , R ^c , R ⁹ , R ¹⁰ and R ¹¹ Is hydrogen, and R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are deuterium.

In the preparation method 2 of the 1-methyl-tryptophan compound represented by the formula I, the conditions of the hydrogen/deuterium exchange reaction may be conventional conditions for such a reaction in the art. The present invention preferably has the following conditions: the reaction solvent of the hydrogen/deuterium exchange reaction may be D ₂ O. The amount of the reaction solvent to be used is not particularly limited as long as it does not affect the progress of the reaction. The hydrogen/deuterium exchange reaction can be carried out in the presence of a deuteration reagent, preferably deuterated hydrochloric acid. The hydrogen/deuterium exchange reaction may also be fed with other reagents such as sodium, acetic anhydride or thioglycolic acid. The reaction temperature of the hydrogen/deuterium exchange reaction is preferably from 20 ° C to 110 ° C.

In a preferred embodiment of the present invention, the preparation method 2 of the 1-methyl-tryptophan compound represented by Formula I may comprise the following steps:

Dissolve compound IA in D ₂ O, add deuteration reagent (such as deuterated hydrochloric acid) and reaction reagent (such as sodium, acetic anhydride or thioglycolic acid) to the reaction equipment at 20 ° C ~ 110 ° C, continue stirring at this temperature for 30 min. ~24h, filtered and dried to give compound I.

The reaction apparatus described in this scheme is preferably a conventional organic reaction flask, an oil bath, a 400 W high pressure mercury lamp or a heat resistant quartz glass apparatus.

The invention also provides a preparation method of a 1-methyl-tryptophan compound represented by the formula ID, which comprises the following steps:

(1) subjecting a compound represented by the formula IB to a hydrogen/hydrazine exchange reaction in a deuterated solvent to obtain a compound represented by the formula IC;

(2) subjecting a compound represented by the formula IC to a deprotection reaction to obtain a compound represented by the formula ID;

Wherein R ^a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or deuterium;

R ¹² is an amino protecting group, preferably a C _1-10 alkylcarbonyl group (e.g., acetyl).

In the method for producing a 1-methyl-tryptophan compound represented by the formula ID, the reaction conditions of the hydrogen/deuterium exchange reaction may be as described above.

The conditions of the deprotection reaction can be conventional conditions for such reactions in the art. The present invention preferably performs a deprotection reaction in the presence of hydrochloric acid (e.g., 2-3N hydrochloric acid). The reaction temperature of the deprotection reaction may be from 80 to 120 °C.

The invention also provides a process for the preparation of a compound of formula Ia or Ib comprising the steps of:

(1) reacting a compound of the formula IAa in D ₂ O in the presence of sodium metal and acetic anhydride to obtain a compound of the formula In;

(2) subjecting a compound as shown in Formula In to chiral HPLC to give a compound as shown in Formula Io or Ip;

(3) respectively, the compound represented by the formula Io or Ip is subjected to hydrolysis reaction in hydrochloric acid to obtain a compound represented by the formula Ia or Ib;

Wherein, the compound represented by formula IAa may be in the R configuration and/or the S configuration (ie, the compound of formula IAa including the R configuration, the compound of formula IAa in the S configuration, and the compound of formula IAa in the R configuration and the S configuration. a mixture of compounds of the formula IAa).

The chiral HPLC resolution conditions can include:

The chiral column is CHIRALPAK AD 30mmx250mm, 5μm;

The column temperature is 38 ° C;

Mobile phase A is CO ₂ ;

Mobile phase B is methanol;

The gradient is mobile phase A / mobile phase B = 85 / 15, the ratio is the volume ratio;

The flow rate is 80 mL/min;

The detection wavelength is UV 220 nm.

The invention also provides the following compounds:

The invention also provides the following compounds:

The retention time of the compound 101 under chiral detection conditions is 8.8 min or 9.6 min;

The chiral detection conditions include:

The chiral column is CHIRALPAK AD-H, 4.6mm x 250mm;

The column temperature is 40 ° C;

Mobile phase A is 0.1% TFA in Hexane, and the percent is volume percent;

Mobile phase B is ethanol;

The gradient is mobile phase A / mobile phase B = 70 / 30, the ratio is the volume ratio;

The flow rate is 0.5 mL/min;

The detection wavelength was UV 210 nm.

If commercially available, the compound of formula I can also be prepared by the above-described route using commercially available deuterated compounds of formula II; for example, by purchasing the intermediates of formula II above, and then in accordance with the methods provided above. The procedure provides a compound of formula I.

The terminology used in the present invention has the following meanings, unless stated to the contrary:

The carboxylic acid protecting group of the present invention is a suitable group for carboxylic acid protection known in the art, see the carboxylic acid protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GMWuts). . As an example, preferably, the carboxylic acid protecting group may be a C _1-10 alkyl group such as a methyl group, an ethyl group, a t-butyl group or the like;

The amine protecting group of the present invention is a suitable group for amine group protection known in the art, see the amine protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GMWuts). . As an example, preferably, the amine protecting group may be an amide protecting group, a carbamate protecting group or the like. For example: formyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.;

"Alkyl" means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-B 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy , heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo.

In the present invention, "deuterated" means that one or more hydrogens in the compound or group are replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted.

In another preferred embodiment, the cerium isotope content of cerium at the cerium substitution site is greater than the natural strontium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95%, more preferably The ground is greater than 97%, more preferably greater than 99%, and even more preferably greater than 99.5%.

In the present invention, the term "pharmaceutically acceptable salt" means a salt of the compound of the present invention which is formed with an acid or a base and which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. Another preferred class of salts are the salts of the compounds of the invention with bases. Bases suitable for salt formation include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, S-phenylethylamine, R-phenylethylamine, L-benzene. Glycinamide and the like.

The "enantiomer 1" and "enantiomer 2" as used in the present invention refer to two compounds having the same structural formula but different chiral configurations (i.e., R configuration or S configuration). The compounds are a pair of enantiomers to each other.

Abbreviation table:

abbreviation	Full name
D 2 O	heavy water

The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention.

The reagents and starting materials used in the present invention are commercially available.

A positive progressive effect of the present invention is that the deuterated 1-methyl-tryptophan compound of the present invention has superior pharmacokinetic properties compared to the corresponding non-deuterated compound.

Detailed ways

The invention will be explained in detail below with reference to specific examples, which are to be understood by those of ordinary skill in the art.

The following table shows the structural formula of the compounds involved in the examples.

Example 1: Preparation of Compound In

The compound IAa (1.0 g, 4.6 mmol) was dissolved in D ₂ O (10 mL) at 20 ° C, and then sodium metal (0.6 g) and acetic anhydride (3 mL) were added successively, and the mixture was stirred for 18 hours, and the solid was collected by filtration and washed with water. Drying in vacuo gave Compound In (0.67 g).

MS (ESI) m/z: 262 (M+H ⁺ ).

^{1 H-NMR (400MHz, DMSO} ) δ8.15 (s, 1H), 7.54 (d, 1H), 7.38 (d, 1H), 7.14 (dd, 1H), 7.11 (s, 1H), 7.02 (dd, 1H), 3.73 (s, 3H), 3.13 (d, 1H), 2.98 (d, 1H), 1.81 (s, 3H).

Example 2: Preparation of Compound Io

The racemic compound In was separated and separated by chiral column CHIRALPAK AD (30mmx250mm, 5μm), the column temperature was 38 °C, the mobile phase A was CO ₂ , the mobile phase B was methanol, the running time was 5 minutes, and the gradient was mobile phase. A/mobile phase B (85/15, v/v), flow rate 80 mL/min, detection wavelength UV 220 nm, separation and collection at the peak RT of 1.96 minutes to obtain the first single configuration of the compound as a compound Io (enantiomer 1), detected by chiral column CHIRALPAK AD-H (4.6mm x 250mm), column temperature 40 ° C, mobile phase A is 0.1% TFA in Hexane (v / v), mobile phase B is ethanol The running time was 20 minutes, the gradient was mobile phase A/mobile phase B (70/30), the flow rate was 0.5 mL/min, the detection wavelength was UV 210 nm, RT 8.8 min, and the ee value was 97.6%.

MS (ESI) m/z: 262 (M+H ⁺ ).

^{1 H-NMR (400MHz, DMSO} ) δ8.15 (s, 1H), 7.54 (d, 1H), 7.38 (d, 1H), 7.14 (dd, 1H), 7.11 (s, 1H), 7.02 (dd, 1H), 3.73 (s, 3H), 3.13 (d, 1H), 2.98 (d, 1H), 1.81 (s, 3H).

Example 3: Preparation of Compound Ip

The racemic compound In was separated and separated by chiral column CHIRALPAK AD (30mmx250mm, 5μm), the column temperature was 38 °C, the mobile phase A was CO ₂ , the mobile phase B was methanol, the running time was 5 minutes, and the gradient was mobile phase. A/mobile phase B (85/15, v/v), flow rate of 80 mL/min, detection wavelength of UV 220 nm, separation and collection at peak RT of 2.40 minutes to obtain the first single configuration of the compound as a compound Ip (enantiomer 2), detected by chiral column CHIRALPAK AD-H (4.6mm x 250mm), column temperature 40 ° C, mobile phase A is 0.1% TFA in Hexane (v / v), mobile phase B is ethanol, run The time was 20 minutes, the gradient was mobile phase A/mobile phase B (70/30), the flow rate was 0.5 mL/min, the detection wavelength was UV 210 nm, RT was 9.6 min, and the ee value was 99.0%.

MS (ESI) m/z: 262 (M+H ⁺ ).

^{1 H-NMR (400MHz, DMSO} ) δ8.15 (s, 1H), 7.54 (d, 1H), 7.38 (d, 1H), 7.14 (dd, 1H), 7.11 (s, 1H), 7.02 (dd, 1H), 3.73 (s, 3H), 3.13 (d, 1H), 2.98 (d, 1H), 1.81 (s, 3H).

Example 4: Preparation of Compound Ia

The compound Io (0.53 g, 2 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) After the compound Ia was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the test result was the same as the compound Io, and the ee value was 96.6%.

MS (ESI) m/z: 220 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.61 (d, 1H), 7.37 (d, 1H), 7.20 (dd, 1H), 7.13 (s, 1H), 7.09 (dd, 1H), 3.79 (s, 3H), 3.48 (d, 1H), 3.33 (d, 1H).

Example 5: Preparation of Compound Ib

The compound Ip (0.53 g, 2 mmol) was dissolved in 2N hydrochloric acid (20 mL), and the mixture was stirred at 100 °C for 6 hr. After the reaction was completed by TLC, the solid was concentrated to afford compound Ib (400 mg). After the compound Ib was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the result was the same as the compound Ip, and the ee value was 97.6%.

MS (ESI) m/z: 220 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.61 (d, 1H), 7.37 (d, 1H), 7.20 (dd, 1H), 7.13 (s, 1H), 7.09 (dd, 1H), 3.79 (s, 3H), 3.48 (d, 1H), 3.33 (d, 1H).

Example 6: Preparation of Compound Ic

To a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL) was added sodium metal (120 mg) at -78 ° C, then a solution of compound IIc (200 mg, 0.98 mmol) in diethyl ether (5 mL). After 30 min, iodomethane (180 mg) was added, and the reaction was stirred at -78 ° C for 6 h. TLC showed the reaction was completed, quenched with water, pH was adjusted to 4-6, and solid was allowed to stand. After filtration, it was pulverized in tetrahydrofuran to give compound Ic. (181 mg). After the compound Ic was derivatized by acetylation, it was examined according to the chromatographic conditions provided in Example 2, and the ee value was 97.3%.

MS (ESI) m/z: 220 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.61 (d, 1H), 7.37 (d, 1H), 7.20 (dd, 1H), 7.13 (s, 1H), 7.09 (dd, 1H), 4.23 (d, 1H), 3.79 (s, 3H), 3.46 (d, 1H).

Example 7: Preparation of Compound Id

To a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL), lithium metal (100 mg) was added at -78 ° C, then a solution of compound IId (200 mg, 0.98 mmol) in tetrahydrofuran (5 mL) was added and the reaction was stirred at this temperature. After 30 min, dimethyl sulfate (260 mg) was added, and the reaction was stirred at -60 ° C for 4 h. TLC showed the reaction was completed, quenched with water, pH was adjusted to 4-6, and solids were allowed to stand. After filtration, the mixture was filtered in tetrahydrofuran. Compound Id (172 mg). After compound Id was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the ee value was 98.2%.

MS (ESI) m / z: 221 (M+H ⁺ ).

^{1 H-NMR (400MHz, MeOD} ) δ7.60 (d, 1H), 7.38 (d, 1H), 7.20 (dd, 1H), 7.13 (s, 1H), 7.09 (dd, 1H), 4.25 (s, 1H), 3.79 (s, 3H).

Example 8: Preparation of Compound Ie

The compound IAA (100 mg, 0.49 mmol) was dissolved in a heat-resistant quartz reactor containing D ₂ O (50 mL), and irradiated with a 400 W high-pressure mercury lamp at room temperature for 30 minutes, and then the reaction solution was freeze-dried on a lyophilizer to obtain a compound Ie (100 mg). ). After the compound Ie was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the ee value was 97.5%.

MS (ESI) m/z: 220 (M+H ⁺ ).

^{1 H-NMR (400MHz, MeOD} ) δ7.38 (d, 1H), 7.18 (dd, 1H), 7.13 (s, 1H), 7.10 (d, 1H), 4.25 (dd, 1H), 3.79 (s, 3H), 3.49 (dd, 1H), 3.35 (dd, 1H).

Example 9: Preparation of Compound If

Add potassium metal (150 mg) to a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL) at -78 ° C, then add a solution of compound IIf (200 mg, 0.98 mmol) in 2-methyltetrahydrofuran (5 mL). After stirring at this temperature for 30 min, methyl bromide (150 mg) was added, and the reaction was stirred at -50 ° C for 3 h. TLC showed the reaction was completed, quenched with water, adjusted to pH 4-6, and allowed to stand for solids. After filtration, it was beaten in tetrahydrofuran. Compound If (163 mg) was obtained. After the compound If was derivatized by acetylation, it was examined according to the chromatographic conditions provided in Example 2, and the ee value was 98.0%.

MS (ESI) m/z: 220 (M+H ⁺ ).

^{1 H-NMR (400MHz, MeOD} ) δ7.60 (s, 1H), 7.38 (d, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 4.25 (dd, 1H), 3.79 (s, 3H), 3.48 (dd, 1H), 3.35 (dd, 1H).

Example 10: Preparation of Compound Ig

To a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL), sodium metal (150 mg) was added at -78 ° C, then a solution of compound IIg (200 mg, 0.98 mmol) in methyl tert-butyl ether (5 mL) was added and the reaction was continued. After stirring at this temperature for 30 min, iodomethane (180 mg) was added, and the reaction was stirred at -40 ° C for 2 h. TLC showed that the reaction was completed, quenched with water, adjusted to pH 4-6, and allowed to stand to solid, and filtered, in tetrahydrofuran The product was pulverized to give the compound Ig (156 mg). After the compound Ig was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the ee value was 98.5%.

MS (ESI) m/z: 220 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.61 (d, 1H), 7.37 (s, 1H), 7.13 (s, 1H), 7.10 (d, 1H), 4.25 (dd, 1H), 3.79 (s, 3H), 3.48 (dd, 1H), 3.36 (dd, 1H).

Example 11: Preparation of Compound Ih

To a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL) was added sodium metal (150 mg) at -78 ° C, then a solution of compound IIh (200 mg, 0.98 mmol) in diethyl ether (5 mL). After 30 min, iodomethane (180 mg) was added, and the reaction was stirred at -30 ° C for 2 h. TLC showed the reaction was completed, quenched with water, pH was adjusted to 4-6, and solid was allowed to stand. After filtration, it was pulverized in tetrahydrofuran to give compound Ih. (177 mg). After the compound Ih was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the ee value was 98.8%.

MS (ESI) m/z: 220 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.60 (d, 1H), 7.19 (d, 1H), 7.13 (s, 1H), 7.09 (dd, 1H), 4.26 (dd, 1H), 3.79 (s, 3H), 3.48 (dd, 1H), 3.35 (dd, 1H).

Example 12: Preparation of Compound Ii

To a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL) was added sodium metal (150 mg) at -78 ° C, then a solution of compound IIi (200 mg, 0.98 mmol) in diethyl ether (5 mL). After 30 min, iodomethane (180 mg) was added, and the reaction was stirred at -10 ° C for 1 h. TLC showed the reaction was completed, quenched with water, pH was adjusted to 4-6, and solid was allowed to stand. After filtration, it was pulverized in tetrahydrofuran to give compound Ii. (177 mg). After the compound Ii was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the ee value was 98.3%.

MS (ESI) m/z: 220 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.61 (d, 1H), 7.38 (d, 1H), 7.20 (dd, 1H), 7.09 (dd, 1H), 4.25 (dd, 1H), 3.80 (s, 3H), 3.47 (dd, 1H), 3.35 (dd, 1H).

Example 13: Preparation of Compound Ij

Dissolving the compound IAa (300mg, 1.38mmol) in D ₂ O (2mL) and deuterated hydrochloric acid (0.4 mL of) was added mercaptoacetic acid (0.1 mL), the reaction was stirred at 110 ℃ 8h. After the reaction mixture was extracted with ethyl acetate, the aqueous layer was lyophilized on a lyophilizer to give Compound Ij (290 mg). After the compound Ij was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the ee value was 98.5%.

MS (ESI) m / z: 224 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOH) δ 4.23 (dd, 1H), 3.45 (dd, 1H), 3.32 (dd, 1H).

Example 14: Preparation of Compound Ik

To a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL) was added sodium metal (150 mg) at -78 ° C, then a solution of compound IIk (200 mg, 0.98 mmol) in diethyl ether (5 mL). After 30 min, iodomethane (180 mg) was added, and the reaction was stirred at 30 ° C for 15 min. TLC showed the reaction was completed, quenched with water, adjusted to pH 4-6, and allowed to stand for solids. After filtration, it was pulverized in tetrahydrofuran to give compound Ik ( 149 mg). After the compound Ik was derivatized by acetylation, it was examined according to the chromatographic conditions provided in Example 2, and the ee value was 97.9%.

MS (ESI) m / z: 222 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.61 (d, 1H), 7.38 (d, 1H), 7.20 (dd, 1H), 7.13 (s, 1H), 7.10 (dd, 1H), 3.79 (s, 3H).

Example 15: Preparation of Compound Im

To a solution of ferric nitrate (5 mg) in liquid ammonia (10 mL) was added sodium metal (150 mg) at -78 ° C, then a solution of compound IIm (200 mg, 0.98 mmol) in diethyl ether (5 mL). After 30 min, deuterated iodomethane (180 mg) was added, and the reaction was stirred at -78 °C for 3 h. TLC showed the reaction was completed, quenched with water, pH was adjusted to 4-6, and solids were left, filtered, and then pulverized in tetrahydrofuran. Compound Im (178 mg). After the compound Ia was derivatized by acetylation, it was detected according to the chromatographic conditions provided in Example 2, and the ee value was 98.6%.

MS (ESI) m / z: 222 (M+H ⁺ ).

¹ H-NMR (400 MHz, MeOD) δ 7.60 (d, 1H), 7.37 (d, 1H), 7.18 (dd, 1H), 7.13 (s, 1H), 7.09 (dd, 1H), 4.25 (dd, 1H), 3.48 (dd, 1H), 3.35 (dd, 1H).

Example 16: Pharmacokinetic evaluation of rats

Male SDF-grade healthy SD rats with good physical examination and no abnormality were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. Compounds IAa, Ia, Ib, Id, Im were administered by intravenous injection (dose 12.5 mg/kg). Blood was collected by jugular vein puncture, and each sample was collected about 0.2 mL. Heparin sodium was anticoagulated. The time of blood collection was as follows:

Before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h and 48 h after administration.

Blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis.

Blood samples were analyzed by LC-MS/MS from the analytical department of the laboratory.

According to the blood drug concentration data of the drug, the pharmacokinetic parameters ANU _0-t , AUC _0-∞ , MRT _0-∞ , CL were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2. Parameters such as T _1/2 and Vd and their mean and standard deviation.

The pharmacokinetic parameters of the deuterated compound and the non-deuterated compound are shown in the above table. According to the experimental results, the deuterated compounds Ia, Id, Im of the present invention have a markedly improved exposure (AUC) of the drug in animals compared to the corresponding non-deuterated compound IAa. Among them, the amount of exposure of compound Ia in animals (AUC) was increased by more than 70%.

While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims (20)

1. a 1-methyl-tryptophan compound, an isomer, a prodrug, a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, as shown in Formula I,

   

   Wherein R ^a is hydrogen or a carboxylic acid protecting group;

   R ^b and R ^c are each independently a hydrogen or an amine protecting group;

   R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or deuterium, and at least one is deuterium.
2. The 1-methyl-tryptophan compound of the formula I, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, according to claim 1. Characterized by

   R ^a is hydrogen or a carboxylic acid protecting group;

   R ^b and R ^c are each independently a hydrogen or an amine protecting group;

   R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or deuterium, and at least one is deuterium.
3. The 1-methyl-tryptophan compound of the formula I, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, according to claim 1. Characterized by

   R ^a , R ^b and R ^c are hydrogen;

   R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or deuterium, and at least one is deuterium.
4. The 1-methyl-tryptophan compound of the formula I according to claim 1 or 3, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof It is characterized in that the absolute configuration of the 1-methyl-tryptophan compound as shown in Formula I is an R configuration or an S configuration.
5. The 1-methyl-tryptophan compound of the formula I according to claim 1 or 3, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof It is characterized in that the absolute configuration of the 1-methyl-tryptophan compound as shown in Formula I is in the R configuration.
6. The 1-methyl-tryptophan compound of the formula I, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, according to claim 1. The structure of the 1-methyl-tryptophan compound as shown in Formula I is as shown in Formula III:

   

   Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or deuterium, and at least one of them is deuterium.
7. The 1-methyl-tryptophan compound of the formula I, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, according to claim 6. Characterized in that R ¹ is 氘;

   And/or, R ² and R ³ are 氘;

   And/or, R ⁹ , R ¹⁰ and R ¹¹ are deuterium.
8. The 1-methyl-tryptophan compound of the formula I, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, according to claim 1. The 1-methyl-tryptophan compound of the formula I is selected from any of the following structures:

   
9. The 1-methyl-tryptophan compound of the formula I, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, according to claim 1. The invention is characterized in that the 1-methyl-tryptophan compound represented by the formula I is the compound 102, and the compound 102 is obtained by subjecting the compound 101 to hydrolysis reaction in hydrochloric acid;

   

   The retention time of the compound 101 under chiral detection conditions is 8.8 min or 9.6 min;

   The chiral detection conditions include:

   The chiral column is CHIRALPAK AD-H, 4.6mm x 250mm;

   The column temperature is 40 ° C;

   Mobile phase A is 0.1% TFA in Hexane, and the percent is volume percent;

   Mobile phase B is ethanol;

   The gradient is mobile phase A / mobile phase B = 70 / 30, the ratio is the volume ratio;

   The flow rate is 0.5 mL/min;

   The detection wavelength was UV 210 nm.
10. A pharmaceutical composition comprising:

    (1) The 1-methyl-tryptophan compound of the formula I according to any one of claims 1 to 9, an isomer, a prodrug, a crystal form, a pharmaceutically acceptable salt thereof , hydrate or solvate;

    (2) A pharmaceutically acceptable carrier.
11. A process for the preparation of a pharmaceutical composition according to claim 10, which comprises the step of: 1-methyl- as shown in formula I according to any one of claims 1-9. The tryptophan compound, an isomer thereof, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof and a pharmaceutically acceptable carrier are mixed to obtain the pharmaceutical composition.
12. A method for treating cancer by inhibiting a guanamine 2,3-dioxygenase, comprising administering to a patient in need of such treatment a 1 of the formula I according to any one of claims 1-9 a methyl-tryptophan compound, an isomer thereof, a prodrug, a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate, or a pharmaceutical composition according to claim 10.
13. The 1-methyl-tryptophan compound of the formula I according to any one of claims 1 to 9, an isomer thereof, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate Or a solvate, or the use of the pharmaceutical composition according to claim 10 for the preparation of a medicament for treating an immune disease, in particular for the preparation of a medicament for treating cancer, wherein the cancer is breast cancer, ovary Cancer, prostate cancer, melanoma, brain cancer, nasopharyngeal cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, Liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testicular tumor, uterine tumor, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder Tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor.
14. The use according to claim 13 wherein the 1-methyl-tryptophan compound, isomer, prodrug, crystalline form, pharmaceutically acceptable salt thereof, of formula I a hydrate or solvate, or a pharmaceutical composition for use in combination with another one or more anticancer agents selected from the group consisting of alkylating agents, platinum complexes, metabolic antagonists, organisms Alkali, antibody drug, hormone anticancer agent, proteasome inhibitor, CDK kinase inhibitor, VEGFR or EGFR inhibitor, m-TOR inhibitor, PI3K kinase inhibitor, B-Raf inhibitor, PARP inhibitor, c-Met A kinase inhibitor, an ALK kinase inhibitor, an AKT inhibitor, an ABL inhibitor, a FLT3 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.
15. A process for the preparation of a 1-methyl-tryptophan compound of the formula I, which comprises the step of subjecting a compound of the formula II to methylation or hydrazine methylation ;

    

    Wherein R ^a , R ^b , R ^c , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined in claim 1 Said in any one of 9.
16. A process for the preparation of a 1-methyl-tryptophan compound of the formula I, which comprises the steps of subjecting a compound of the formula IA to a hydrogen/hydrazine exchange reaction;

    

    Wherein R ^a , R ^b , R ^c , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined in claim 1 Said in any one of 9.
17. A method for preparing a 1-methyl-tryptophan compound represented by the formula ID, which comprises the following steps:

    (1) subjecting a compound represented by Formula IB to a hydrogen/hydrazine exchange reaction in a deuterated solvent to obtain a compound as shown in Formula IC;

    (2) subjecting a compound represented by the formula IC to a deprotection reaction to obtain a compound represented by the formula ID;

    

    Wherein R ^a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or deuterium;

    R ¹² is an amino protecting group, preferably a C _1-10 alkylcarbonyl group.
18. A process for the preparation of a compound of the formula Ia or Ib, characterized in that it comprises the steps of:

    (1) subjecting a compound represented by the formula IAa to a hydrogen/hydrazine exchange reaction in a deuterated solvent to obtain a compound represented by the formula In;

    (2) subjecting a compound as shown in Formula In to chiral HPLC to give a compound as shown in Formula Io or Ip;

    (3) respectively, the compound represented by the formula Io or Ip is subjected to hydrolysis reaction in hydrochloric acid to obtain a compound represented by the formula Ia or Ib;

    

    Wherein the compound of formula IAa is in the R configuration and/or the S configuration.
19. A compound of any of the following structures:

    
20. A compound of the structure:

    

    The retention time of the compound 101 under chiral detection conditions is 8.8 min or 9.6 min;

    The chiral detection conditions include:

    The chiral column is CHIRALPAK AD-H, 4.6mm x 250mm;

    The column temperature is 40 ° C;

    Mobile phase A is 0.1% TFA in Hexane, and the percent is volume percent;

    Mobile phase B is ethanol;

    The gradient is mobile phase A / mobile phase B = 70 / 30, the ratio is the volume ratio;

    The flow rate is 0.5 mL/min;

    The detection wavelength was UV 210 nm.