Deuterated quinoline derivatives

Abstract

The present application relates to deuterated quinoline derivatives, in particular, the present application relates to compounds of formula (I), pharmaceutical compositions thereof, and methods of use and preparation. The deuterated quinoline derivatives of the present application can be used as an internal standard for the analytical detection of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine, and can also be used to treat diseases mediated by tyrosine kinases in mammals.

Description

Technical Field

[0001] This invention relates to deuterated quinoline derivatives, their preparation methods, and uses, belonging to the field of pharmaceutical chemistry. Background Technology

[0002] Receptor tyrosine kinases are a class of enzymes that span the cell membrane, possessing an extracellular binding region for binding growth factors, a transmembrane structural region, and an intracellular portion. The intracellular portion functions as a kinase to phosphorylate specific tyrosine residues in proteins, thereby influencing cell proliferation. Tyrosine kinases can be classified into growth factor receptor kinases (e.g., EGFR, PDGFR, FGFR, and erbB2) or non-receptor kinases (e.g., c-src and bcr-abl). These kinases are aberrantly expressed in common human cancers and are associated with various cancers.

[0003] WO2008112407 has disclosed that 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine, represented by formula A, can act as a tyrosine kinase inhibitor. Given the important role of tyrosine kinase in physiological processes, further research on its derivatives or analogues is essential.

[0004] Summary of the Invention

[0005] In a first aspect, this application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0006]

[0007] Where X and Y are independent, C(R) 8 )3; Z, U, V are independent and C(R) 9 )2;R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Independently selected from hydrogen or deuterium; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 At least one of them is deuterium.

[0008] In some implementation schemes, R 5 R6 R 7 R 8 Among them, at least one is deuterium.

[0009] In some typical implementation schemes, R 5 R 6 R 7 In the given information, at least one of the elements is deuterium, and X is CD3.

[0010] In some more typical implementation schemes, R 5 R 6 R 7 All are deuterium, and X is CD3.

[0011] In some typical implementations, Y is CD3.

[0012] In some implementation schemes, R 1 R 2 R 3 R 4 Among them, at least one is deuterium.

[0013] In some typical implementation schemes, R 3 It is deuterium.

[0014] In some more typical implementation schemes, R 3 It is deuterium, and R 1 R 2 R 4 It is hydrogen.

[0015] In some implementation schemes, R 8 R 9 Among them, at least one is deuterium.

[0016] In some typical implementations, at least one of Z, U, and V is CD2.

[0017] In some more typical implementations, Z is CD2.

[0018] In some more typical implementations, Z stands for CD2, and U and V stand for CH2.

[0019] In some more typical implementations, Z represents CH2, and U and V represent CD2.

[0020] In some more typical implementations, Z, U, and V are all CD2.

[0021] When a compound of this application is designated as deuterium at a certain position, those skilled in the art will understand that the abundance of deuterium at that position is greater than the natural abundance, i.e., greater than 0.015%.

[0022] In some embodiments, the abundance of deuterium in the compound of this application at each designated deuterated position is at least 1%, 5%, 10%, 20%, 50%, 70%, 80%, 90%, 95%, 97%, 98%, or 99%.

[0023] In some implementation schemes, R 3 R 5 -R 7 The abundance of deuterium in X is at least 10%; in some implementations, R 3 R 5 -R 7 The abundance of deuterium in X is at least 20%; in some implementations, R 3 R 5 -R 7 The abundance of deuterium in X is at least 30%.

[0024] In some embodiments of this application, R 3 The abundance of deuterium is at least 50%; in some implementations, R 3 The abundance of medium deuterium exceeds 70%.

[0025] In some embodiments of this application, R 5 The abundance of deuterium is at least 20%; in some implementations, R 5 The abundance of deuterium exceeds 40%; in some implementations, R 5 The abundance of deuterium was 50%.

[0026] In some embodiments of this application, R 6 The abundance of deuterium is at least 10%; in some implementations, R 6 The abundance of deuterium exceeds 20%; in some implementations, R 6 The abundance of deuterium was 30%.

[0027] In some embodiments of this application, R 7 The abundance of deuterium is at least 60%; in some implementations, R 7 The abundance of deuterium exceeds 80%; in some implementations, R 7 The abundance of deuterium was 95%.

[0028] In some embodiments of this application, the abundance of deuterium in X is at least 60%; in some embodiments, the abundance of deuterium in X exceeds 80%; and in some embodiments, the abundance of deuterium in X is 95%.

[0029] In some implementations, this application further relates to the following exemplary implementations:

[0030]

[0031]

[0032] In some typical embodiments, this application relates to the following compounds or pharmaceutically acceptable salts thereof:

[0033]

[0034] On the other hand, this application relates to pharmaceutical compositions comprising a compound of formula (I) of this application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.

[0035] On the other hand, this application provides a method for determining the content of quinoline analogs, including using at least one deuterated quinoline derivative of this application or a pharmaceutically acceptable salt thereof as an internal standard. In some embodiments, this application provides a method for determining the content of anlotinib or a salt thereof, including using at least one deuterated quinoline derivative of this application or a salt thereof as an internal standard.

[0036] On the other hand, this application relates to the use of compound of formula (I) as an internal standard in the analytical detection of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine or its pharmaceutically acceptable salt.

[0037] In some embodiments, this application provides a method for detecting the content of anlotinib or its salt in the extracellular fluid (e.g., plasma, cerebrospinal fluid) of mammals, comprising (1) adding a certain weight of the compound of formula (I) of this application or its pharmaceutically acceptable salt as an internal standard to the sample to be tested, (2) performing chromatographic analysis on the sample containing the internal standard, and (3) determining the content of anlotinib in the sample.

[0038] On the other hand, this application relates to a method of treating diseases mediated by tyrosine kinases in mammals, comprising administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0039] On the other hand, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of tyrosine kinase-mediated diseases.

[0040] Compound (I) can be administered as its free base, or as its salt, hydrate, solvate, or prodrug, which is converted in vivo to the free base form of compound (I). For example, compound (I) can be administered in a pharmaceutically acceptable salt form. Within the scope of this invention, the salt can be prepared from various organic and inorganic acids according to methods known in the art.

[0041] In some embodiments, the compound is administered as a hydrochloride salt of formula (I). In some embodiments, the compound is administered as a monohydrochloride salt of formula (I). In some embodiments, the compound is administered as a dihydrochloride salt of formula (I). In some embodiments, the compound is administered as a crystalline form of the hydrochloride salt of formula (I). In a particular embodiment, the compound is administered as a crystalline form of the dihydrochloride salt of formula (I).

[0042] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered via a variety of routes, including but not limited to those selected from: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intrafacial, intra-articular, intraperitoneal, and intrathecal. In one particular embodiment, administration is by oral administration.

[0043] Compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or more daily. Preferably, a therapeutically effective amount of compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. It may be administered in a single or multiple doses, preferably a single dose once daily. Administering the above-mentioned dose level of compound of formula (I) or a pharmaceutically acceptable salt thereof once daily improves patient compliance. In one embodiment, it is administered once daily, and optionally in a single dose once daily. In one embodiment, it is administered once daily in a single-dose oral capsule. In all methods of administration of the general formula (I) compound described herein, the daily dose is from 0.01 to 200 mg / kg body weight, in single or separate doses.

[0044] The inventors unexpectedly discovered that the compound of formula (I) or a pharmaceutically acceptable salt thereof could maintain its therapeutic effect without requiring daily administration; that is, intermittent administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient could provide a therapeutically effective amount of the compound of formula (I) in the plasma.

[0045] The interval dosing includes a dosing period and a withdrawal period. During the dosing period, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or more daily. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered daily during the dosing period, followed by a withdrawal period during which dosing is stopped for a period of time, then the dosing period continues, followed by the withdrawal period, and so on. The ratio of the dosing period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, and more preferably 2:0.5 to 1.

[0046] In some implementations, the drug is administered continuously for 2 weeks and then stopped for 2 weeks. In some implementations, the drug is administered once daily for 14 days, then stopped for 14 days; then once daily for 14 days, then stopped for 14 days, and this dosing pattern of continuous administration for 2 weeks and then stop for 2 weeks can be repeated multiple times.

[0047] In some implementations, the drug is administered continuously for 2 weeks and then stopped for 1 week. In some implementations, the drug is administered once daily for 14 days, then stopped for 7 days; then once daily for 14 days, then stopped for 7 days, and this dosing pattern of continuous administration for 2 weeks and stopping for 1 week can be repeated multiple times.

[0048] In some implementations, the drug is administered for 5 consecutive days and then stopped for 2 days. In some implementations, the drug is administered once daily for 5 consecutive days, then stopped for 2 days; then administered once daily for 5 consecutive days, then stopped for 2 days, and this dosing pattern of 5 consecutive days followed by 2 days can be repeated multiple times.

[0049] In some implementations, administering the compound of formula (I) or its pharmaceutically acceptable salt at intervals using the method described above not only keeps the patient's blood drug concentration below 100 ng / ml and controls drug accumulation, but also achieves therapeutic effects, benefiting a variety of tumors.

[0050] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided as the sole active ingredient for treating tyrosine kinase-mediated diseases. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided in combination with other antitumor drugs as an active ingredient for treating tyrosine kinase-mediated diseases. In some embodiments, the other antitumor drugs include, but are not limited to, one or more of platinum complexes, fluoropyrimidine derivatives, camptothecin and its derivatives, anthraquinone antitumor antibiotics, taxane compounds, mitomycin, and trastuzumab. In some embodiments, platinum complexes include, but are not limited to, one or more of cisplatin, carboplatin, nedaplatin, and oxaliplatin; in some embodiments, fluoropyrimidine derivatives include, but are not limited to, one or more of capecitabine, fluorouracil, difuryl fluorouracil, deoxyfluorouracil, tegafur, and carmofluuron; in some embodiments, camptothecin and its derivatives include, but are not limited to, one or more of camptothecin, hydroxycamptothecin, irinotecan, and topotecan; in some embodiments, anthraquinone antitumor antibiotics include, but are not limited to, one or more of doxorubicin, epirubicin, daunorubicin, and mitoxantrone; in some embodiments, taxane compounds include, but are not limited to, paclitaxel and / or docetaxel.

[0051] On the other hand, this application relates to a method for preparing the compound of formula (Ⅰ), the specific steps and route of which are shown below:

[0052] (1) Compound C and compound B react in a base and a solvent to give compound D;

[0053] (2) Compound D is deprotected to obtain compound E;

[0054] (3) Compound E and compound F react in a solvent in the presence of a base to obtain compound G;

[0055] (4) Compound G is transformed into compound H;

[0056]

[0057] Where X and Y are C(R) 8 )3; Z, U, V are C(R) 9 )2;R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Independently selected from hydrogen or deuterium; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 At least one of them is deuterium; PG1 and PG2 are protecting groups, which may be independently selected from the fifth edition of Greene's protective groups in organic synthesis; in some embodiments, PG1 and PG2 are independently selected from benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl and 4-(dimethylamino)carbonylbenzyl; in a particular embodiment, PG1 and PG2 are independently selected from benzyl; L is a leaving group, which in some embodiments is selected from OMs, OTf, OTs and Cl.

[0058] In some embodiments, the base in step (1) is selected from triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate, DMAP, sodium tert-butoxide, potassium tert-butoxide or sodium hydride, preferably potassium carbonate or DMAP, and more preferably DMAP.

[0059] In some embodiments, the solvent in step (1) is selected from 2,6-dimethylpyridine, pyridine, 1,4-dioxane, chloroform, dichloromethane or mixtures thereof, preferably 2,6-dimethylpyridine.

[0060] In some embodiments, the molar ratio of compound B, compound C and base in step (1) is 1 to 1.5:1:1 to 6, preferably 1 to 1.2:1:1.5 to 3, and more preferably 1:1:2.

[0061] In some embodiments, the reaction temperature range of the compound of formula B and the compound of formula C in step (1) is 100°C to 180°C, preferably 140°C to 160°C, and more preferably 140°C.

[0062] In some embodiments, compound D is reduced in a solvent under the action of a catalyst to remove the protecting group, yielding compound E.

[0063] In some embodiments, the catalyst in step (2) is selected from 5% Pd / C, 10% Pd / C, 20% Pd / C or 50% Pd / C, preferably 10% Pd / C or 20% Pd / C, and more preferably 10% Pd / C.

[0064] In some embodiments, the solvent in step (2) is selected from a mixed solvent of MeOD or MeOH and THF, a mixed solvent of MeOD or MeOH and ethyl acetate, or a mixed solvent of EtOD or EtOH and THF, preferably a mixed solvent of MeOD and THF, or a mixed solvent of MeOH and THF.

[0065] In some embodiments, the mass ratio of the compound of formula D and the catalyst in step (2) is 1 to 10:1, preferably 4 to 6:1, and more preferably 4.5:1.

[0066] In some embodiments, the alkali in step (3) is selected from potassium iodide / potassium carbonate, sodium iodide / sodium carbonate, potassium iodide / sodium carbonate, or potassium iodide / cesium carbonate, preferably potassium iodide / potassium carbonate or potassium iodide / cesium carbonate, and more preferably potassium iodide / potassium carbonate.

[0067] In some embodiments, the solvent in step (3) is selected from 2-butanone, acetone, DMF or a mixture thereof, preferably 2-butanone.

[0068] In some embodiments, the molar ratio of compound E and compound F in step (3) is 0.5 to 3:1, preferably 0.5 to 1:1, and more preferably 1:1.

[0069] In some embodiments, the reaction temperature range of the compound of formula E and the compound of formula F in step (3) is 40°C to 100°C, preferably 50°C to 70°C, and more preferably 60°C.

[0070] In some embodiments, the compound of formula G is reduced in the presence of a solvent, a catalyst and a hydrogen source to remove the protecting group, thereby yielding the compound of formula H.

[0071] In some embodiments, the catalyst in step (4) is selected from 10% Pd / C, 20% Pd / C, 50% Pd / C or 5% Pt / C, preferably 10% Pd / C or 20% Pd / C, and more preferably 10% Pd / C.

[0072] In some implementations, the hydrogen source in step (4) is selected from hydrogen, hydrazine hydrate or ammonium formate, preferably hydrazine hydrate or ammonium formate, and more preferably ammonium formate.

[0073] In some embodiments, the solvent in step (4) is selected from MeOD, EtOD or a mixture thereof, preferably MeOD.

[0074] In some embodiments, the mass ratio of compound G and catalyst in step (4) is selected from 1 to 10:1, preferably 1 to 5:1, and more preferably 2 to 2.5:1;

[0075] The molar ratio of compound G and hydrogen source in step (4) is selected from 1:1 to 10, preferably 1:5 to 8, and more preferably 1:5.5.

[0076] In some embodiments, the reaction temperature of the reduction reaction in step (4) is 25°C to 60°C, preferably 40°C to 60°C, and more preferably 50°C.

[0077] In some embodiments, the deuterated compound of formula B can be prepared by reacting in the presence of a catalyst, D2O, and H2 or NaBH4; in some embodiments, examples of the catalyst include, but are not limited to, platinum oxide, platinum, and Pd (e.g., palladium on carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride); in some embodiments, the catalyst is 10% Pd / C, PtO2, or 5% Pt / C.

[0078]

[0079] In some specific embodiments, the compounds of formula I-1 or formula I-4 of this application can be prepared by the following method, wherein in the final reaction step, if deuterated methanol is used, the compound of formula I-1 is generated; if undeuterated methanol is used, the compound of formula I-4 is generated.

[0080]

[0081] In some embodiments, examples of preparing deuterated C compounds are disclosed, wherein in some embodiments, step 1) is a reaction in the presence of CD3I and NaH; and in some embodiments, step 2) is a reaction in the presence of POCl3.

[0082]

[0083] In some specific embodiments, compound I-2 of this application can be prepared according to the following method.

[0084]

[0085] In some embodiments, exemplary methods for preparing deuterated compounds of formula F are disclosed, as follows.

[0086]

[0087] In some embodiments, methods for preparing compounds of formula I-3 are disclosed.

[0088]

[0089] definition

[0090] Unless otherwise stated, the following terms as used in this application have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0091] The term "H" refers to a hydrogen atom.

[0092] The term "D" refers to the deuterium atom.

[0093] The term "10% Pd / C" refers to 10% palladium / carbon.

[0094] The term "PtO2" refers to platinum dioxide.

[0095] The term "D2O" refers to deuterium water.

[0096] The term "DCM" refers to dichloromethane.

[0097] The term "DMAP" refers to 4-dimethylaminopyridine.

[0098] The term "TLC" refers to thin-layer chromatography.

[0099] The term "PE" refers to petroleum ether.

[0100] The term "EA" refers to ethyl acetate.

[0101] The term "1N HCl" refers to an aqueous solution of hydrochloric acid with a concentration of 1 mol / L.

[0102] The term "K2CO3" refers to potassium carbonate.

[0103] The term "KI" refers to potassium iodide.

[0104] The term "THF" refers to tetrahydrofuran.

[0105] The term "DMF" stands for N,N-dimethylformamide.

[0106] The term "MeOD" refers to deuterated methanol.

[0107] The term "MeOH" refers to methanol.

[0108] The term "Ms" refers to methylsulfonyl group.

[0109] The term "OMs" refers to methylsulfonyl oxygen.

[0110] The term "OTf" refers to trifluoromethylsulfonyloxy.

[0111] The term "OTs" refers to p-toluenesulfonyloxy.

[0112] The term "HCOONH4" refers to ammonium methyl methacrylate.

[0113] The term "HRMS" refers to high-resolution mass spectrometry.

[0114] The term "hydrogen source" refers to a substance that produces hydrogen gas through a reaction during the preparation process.

[0115] The term "substitution" refers to the substitution of one or more hydrogen atoms on a specified atom or ring by a specified group, such as deuterium, provided that the substitution does not exceed the normal chemical valence of the specified atom.

[0116] In this application, any atom not designated as deuterium exists at its natural isotopic abundance. When a specific position is deuterium, it can be understood that the abundance of deuterium at that position is greater than the natural abundance of deuterium, which is approximately 0.015%.

[0117] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0118] The term "treatment" means administering the compound or preparation described in this application to prevent, improve, or eliminate a disease or one or more symptoms related to said disease, and includes:

[0119] (i) To prevent the occurrence of disease or disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state;

[0120] (ii) Suppress the disease or disease state, that is, curb its development;

[0121] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides.

[0122] The term "therapeutic effective amount" means the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0123] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0124] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0125] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0126] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0127] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0128] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0129] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0130] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0131] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0132] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0133] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. Detailed Implementation Plan

[0134] Example 1

[0135]

[0136] Compound A-1 (2.0 g), 10% Pd / C (0.20 g), PtO2 (0.02 g), and D2O (20 ml) were added to a 35 ml microwave reaction flask and stirred until homogeneous at room temperature. Then, NaBH4 (0.01 g) was added to the reaction mixture and stirred at room temperature for 5 minutes. The mixture was then microwaved (150 W, 160 °C) for 6 hours. After the reaction was complete, the mixture was extracted with DCM (30 ml x 3 times), the organic phases were combined, and dried with anhydrous sodium sulfate. The desiccant was removed by vacuum filtration, the solvent was removed by rotary evaporation, and finally, compound B-1 (1.36 g) was obtained by drying under reduced pressure at room temperature.

[0137] HRMS(ESI,[M+H]+)m / z: 172.1046.

[0138] Example 2

[0139]

[0140] Compound C-1 (2.38 g), compound B-1 (1.36 g), DMAP (1.94 g), and 2,6-dimethylpyridine (12 ml) were added to a 250 ml round-bottom single-necked flask. The reaction mixture was heated to 140 °C. After 4 hours, the reaction was monitored by TLC (PE:EA = 1:1 as the developing solvent), indicating completion. The reaction mixture was cooled to room temperature, and 100 ml of DCM was added to dilute the reaction solution. Then, 50 ml of 1 N HCl was slowly added dropwise. The mixture was separated, and the organic phase was washed with an aqueous solution of K₂CO₃ and dried over anhydrous sodium sulfate. The drying agent was removed by suction filtration, and the solvent was removed by rotary evaporation. Finally, compound D-1 (2.25 g) was obtained by drying under reduced pressure.

[0141] HRMS(ESI,[M+H]+)m / z: 435.1828.

[0142] Example 3

[0143]

[0144] Compound D-1 (2.25 g), 10% Pd / C (0.50 g), MeOD (20 ml), and THF (10 ml) were added to a 250 ml round-bottom single-necked flask. The system was rinsed three times with nitrogen, and then three times with hydrogen. The reaction was stirred for 5 hours at room temperature under hydrogen at 1 atm. TLC monitoring showed that the reaction was complete (developing solvent DCM:MeOH = 10:1). The drying agent was removed by vacuum filtration, and the solvent was removed by rotary evaporation. Finally, the mixture was dried under reduced pressure to obtain compound E-1 (1.49 g).

[0145] HRMS(ESI,[M+H]+)m / z: 345.1543.

[0146] Example 4

[0147]

[0148] Compound E-1 (1.49 g), KI (2.52 g), K₂CO₃ (2.10 g), and 2-butanone (40 ml) were added to a 250 ml round-bottom flask, and the reaction mixture was heated to 60 °C. Compound F-1 (1.30 g, added in four portions, every 2 hours) was added in multiple portions. After reacting overnight, the reaction was monitored by TLC (developing solvent DCM:MeOH = 10:1). The reaction was complete. Water and DCM were added to dilute the reaction mixture. The aqueous phase was extracted with DCM (30 ml * 3 times) by separation. The organic phases were combined and dried with anhydrous sodium sulfate. The drying agent was removed by vacuum filtration, and the solvent was removed by rotary evaporation. The residue was then separated by silica gel column chromatography (gradient elution: 100% DCM ~ 10% DCM:MeOH), and finally dried under reduced pressure to obtain compound G-1 (2.36 g).

[0149] HRMS(ESI,[M+H]+)m / z: 548.2205.

[0150] Example 5

[0151]

[0152] Compound G-1 (2.35 g), 10% Pd / C (1.0 g), HCOONH4 (1.50 g), and MeOD (35 ml) were added to a 250 ml round-bottom flask. The reaction mixture was heated to 50 °C. After 1 hour, the reaction was monitored by TLC (developing solvent DCM:MeOD = 10:1), indicating that the reaction was complete. The catalyst was removed by vacuum filtration, and the solvent was removed by rotary evaporation of the filtrate. The residue was then separated by silica gel column chromatography (gradient elution: 100% DCM to 5% DCM:MeOH). The products were combined, the solvent was removed by rotary evaporation, and finally, the target compound H-1 (0.864 g) was obtained by drying under reduced pressure.

[0153] 1 H NMR (500MHz, DMSO-d6): δ11.45(s,1H),7.616(s,1H),7.39(s,1H),6.33(s,1H),4.11(s,2H),3.99(s,3H),0.73(dd,4H).

[0154] HRMS(ESI,[M+H]+)m / z: 415.2136.

Claims

1. A method for preparing a compound of formula H-1, characterized in that, (1) Compound C-1 and compound B-1 react in a base and a solvent to give compound D-1; (2) The protecting group of compound D-1 is removed to obtain compound E-1; (3) Compound E-1 and compound F-1 react in a solvent in the presence of a base to obtain compound G-1; (4) Compound G-1 is converted into compound H-1 in the presence of MeOD, EtOD or a mixture thereof as solvent, catalyst and hydrogen source.

2. The method of claim 1, characterized in that, The alkali mentioned in step (1) is selected from triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate, DMAP, sodium tert-butoxide, potassium tert-butoxide, or sodium hydride.

3. The method of claim 1 characterized in that, The solvent used in step (1) is selected from 2,6-dimethylpyridine, pyridine, 1,4-dioxane, chloroform, dichloromethane, or mixtures thereof.

4. The method of claim 1 characterized in that, The molar ratio of compound B-1, compound C-1 and base in step (1) is 1 to 1.5:1:1 to 6.

5. The method of claim 1 characterized in that, The reaction temperature range of the compounds of formula B-1 and formula C-1 described in step (1) is 100℃~180℃.

6. The method of claim 1, characterized in that, The deprotection of compound D-1 in step (2) is carried out under catalytic conditions, with the catalyst selected from 5% Pd / C, 10% Pd / C, 20% Pd / C or 50% Pd / C.

7. The method of claim 6, characterized in that, The mass ratio of the D-1 compound and the catalyst described in step (2) is 1 to 10:

1.

8. The method of claim 1, characterized in that, The solvent used in step (2) is selected from a mixed solvent of MeOD or MeOH and THF, a mixed solvent of MeOD or MeOH and ethyl acetate, or a mixed solvent of EtOD or EtOH and THF.

9. The method of claim 1, characterized in that, The alkali mentioned in step (3) is selected from potassium iodide / potassium carbonate, sodium iodide / sodium carbonate, potassium iodide / sodium carbonate, or potassium iodide / cesium carbonate.

10. The method of claim 1, characterized in that, The solvent used in step (3) is selected from 2-butanone, acetone, DMF or a mixture thereof.

11. The method of claim 1, characterized in that, The molar ratio of compound E-1 and compound F-1 in step (3) is 0.5 to 3:

1.

12. The method of claim 1, characterized in that, The reaction temperature range of the compounds of formula E-1 and formula F-1 described in step (3) is 40℃~100℃.

13. The method of claim 1, characterized in that, The catalyst mentioned in step (4) is selected from 10% Pd / C, 20% Pd / C, 50% Pd / C or 5% Pt / C.

14. The method of claim 1, characterized in that, The hydrogen source mentioned in step (4) is selected from hydrogen, hydrazine hydrate or ammonium formate.

15. The method of claim 1, characterized in that, The mass ratio of the G-1 compound and the catalyst in step (4) is selected from 1 to 10:

1.

16. The method of claim 1, characterized in that, The molar ratio of the compound of formula G-1 and the hydrogen source in step (4) is selected from 1:1 to 10.

17. The method of claim 1, characterized in that, The reaction temperature in step (4) is 25℃~60℃.

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