WO2018130140A1 - Novel deuterated urea compound - Google Patents

Abstract

A novel deuterated urea compound, specifically relating to a compound represent by the formula (I), pharmacologically acceptable salts thereof, preparation method therefor, and a pharmaceutical composition containing the compounds. Also disclosed are the use of the compounds and pharmaceutical composition containing the compounds in preparation of drugs for treating pain.

Description

Novel deuterated urea compounds

Cross-reference to related applications

This application claims the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit.

Technical field

The present application is in the field of medicine, and in particular, the present application relates to novel deuterated urea compounds, a process for the preparation thereof, and pharmaceutical compositions containing these compounds. The present application also relates to the use of these compounds and pharmaceutical compositions comprising these compounds in the manufacture of a medicament for the treatment of pain.

Background technique

Opioids are alkaloids extracted from opioids (poppy) and derivatives in vitro and in vivo that interact with centrally-specific receptors to relieve pain and produce well-being. These drugs often have many serious side effects, such as addiction and respiratory depression. Since the 19th century, humans have been searching for safer and more effective analgesics. Although the natural products of morphine, codeine and semi-synthetic heroin, which were later discovered, have improved somewhat compared with raw opium, there are still many shortcomings.

Opioid receptors can be divided into μ, δ, κ, and nociceptive subtypes, and subtype-selective agonists may avoid the side effects of morphine analogs. Although the fully synthetic opioid receptor agonists methadone, fentanyl, and endogenous opioid peptides have been discovered, it is important to look for analgesics with fewer side effects.

Recent studies have shown that opioids bind to the μOR receptor, which activates the Gi protein to produce analgesic effects, but at the same time, the downstream pathway of the μOR receptor, β-arrestin, is also activated, leading to side effects such as respiratory depression and constipation. Therefore, the development of a μOR receptor agonist selective for Gi protein is an effective research idea.

Researchers at Stanford University have discovered a new class of opioid receptor agonists through a structure-based drug design approach. The representative compound is PZM-21. This compound is effective in activating the Gi protein, has a good selectivity for the μOR receptor, and shows only a weak recruitment effect on β-arrestin. Unlike morphine and other drugs, PZM-21 showed significant analgesic effects in animals, but no side effects such as addiction and respiratory depression were found. Therefore, this compound is a very promising drug candidate in the field of analgesia, and the compound is currently in preclinical studies.

Many current drugs suffer from poor absorption, distribution, metabolism, and/or excretion (ADME) characteristics, which hampers their wider use. Poor ADME properties are also a major cause of failure of drug candidates in clinical trials. One potentially attractive strategy for improving the metabolic properties of drugs is to modify the sputum. In this method, an attempt is made to slow CYP-mediated drug metabolism by replacing one or more hydrogen atoms with deuterium atoms. Helium is a safe, stable, non-radiative hydrogen isotope. Tantalum and carbon form stronger bonds than hydrogen. In selected examples, an increase in bond strength given by sputum can have a positive impact on the ADME properties of the drug, creating the potential for improved drug efficacy, safety, and/or tolerance. At the same time, because the size and shape of the crucible is substantially the same as that of hydrogen, the replacement of hydrogen with deuterium does not affect the biochemical efficacy and selectivity of the drug compared to the original chemical containing only hydrogen.

The effect of hydrazine substitution on metabolic rate has been reported in some drugs (see, for example, Blake, MI et al, J Pharm Sci, 1975, 64: 367-91; Foster, AB, Adv Drug Res, 1985, 14: 1- 40; Kushner, DJ et al, Can J Physiol Pharmacol, 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09), the results are variable and unpredictable. For some compounds, deuteration causes a reduction in metabolic clearance in the body. For other compounds, no changes were made to metabolism. For some compounds, increased metabolic clearance has been demonstrated. The variability of sputum effects has also led experts to question or abandon the idea that 氘 modification is a viable drug design strategy to inhibit harmful metabolism (see Foster page 35 and Fisher page 101).

Even when a ruthenium atom is bound to a known site of a metabolite, the effect of oxime modification on the metabolic properties of the drug is unpredictable. Only if the deuterated drugs are actually prepared and tested can the metabolic rate be determined and how it differs from the non-deuterated counterparts. See, for example, Fukuto et al. (J. Med. Chem., 1991, 34, 2871-76). Many drugs have multiple sites where metabolic reactions may occur. The degree of deuteration that is required for hydrazine substitution and the extent to which the effects of metabolism are visible, if any, is different for each drug.

Although PZM-21 has obvious analgesic effect and less side effects from the current research results, it is necessary to further discover new compounds suitable for drug formation with good curative effect, small side effects and better pharmacokinetic properties. .

Summary of the invention

In one aspect, the application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,

among them:

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ and R ₁₉ are each independently Selected from H (hydrogen) or D (氘);

R ₈ , R ₉ and R ₁₃ are each independently selected from CH ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

The condition is that the compound of formula (I) contains at least one ruthenium atom.

In some embodiments of the present application, the carbon atom substituted by R ₁₃ may be in the R configuration or the S configuration.

In some embodiments of the present application, R _{1 is} selected from H.

In some embodiments of the present application, the compound of formula (I) contains from one to twenty 氘 atoms, or the compound of formula (I) contains one to twenty ruthenium atoms, or the compound of formula (I) contains one to fifteen ruthenium atoms. Or the compound of formula (I) contains one to fourteen germanium atoms, or the compound of formula (I) contains one to ten germanium atoms, or the compound of formula (I) contains one to nine germanium atoms, or the compound of formula (I) contains one to eight a ruthenium atom, or a compound of formula (I) containing two to eight ruthenium atoms, or a compound of formula (I) containing two to four ruthenium atoms, or a compound of formula (I) containing six to ten ruthenium atoms, or formula (I) The compound contains three to four germanium atoms, or the compound of formula (I) contains one to two germanium atoms, or the compound of formula (I) contains six to eight germanium atoms. Specifically, the compound of formula (I) contains at least one and two 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 14 Seventeen, eighteen, nineteen or twenty helium atoms.

In some embodiments of the present application, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R _{17 At} least one, two, three, four, five, six or seven of R ₁₈ and R ₁₉ are deuterium atoms.

In some embodiments of the present application, R ₂ and R _{3 are the} same, R ₄ and R _{5 are the} same, R ₆ and R _{7 are the} same, R ₈ and R _{9 are the} same, R ₁₀ and R _{11 are the} same, and R ₁₅ and R _{16 are the} same. R ₁₈ and R _{19 are the} same, and R ₈ , R ₉ and R ₁₃ are each independently selected from CH ₃ or CD ₃ .

In some embodiments of the present application, R ₁ , R ₄ and R ₅ are H.

In some embodiments of the present application, R ₁ , R ₄ , R ₅ and R ₁₇ are H.

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ and R ₁₇ are H.

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H.

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ and R ₉ are CH ₃ .

In some embodiments of the present application, R ₈ and R _{9 are the} same and R ₁₃ is CH ₃ or CD ₃ .

In some embodiments of the present application, R ₈ and R _{9 are the} same, and R _{13 is} different from R ₈ and R ₉ . In some specific embodiments, R ₈ and R ₉ are CD ₃ and R ₁₃ is CH ₃ . In some specific embodiments, R ₈ and R ₉ are CH ₃ and R ₁₃ is CD ₃ .

In some embodiments of the present application, R ₈ , R ₉ , R _{13 are the} same. In some specific embodiments, R ₈ , R ₉ , R ₁₃ are both CH ₃ or CD ₃ .

In some embodiments of the present application, R ₂ and R _{3 are the} same, R ₈ and R _{9 are the} same, R ₁₀ and R _{11 are the} same, R ₁₅ and R _{16 are the} same, R ₁₈ and R _{19 are the} same, and R ₁ , R _{4 are the} same. And R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ , R ₉ and R ₁₃ are each independently selected from CH ₃ or CD ₃ .

In some embodiments of the present application, R ₂ and R _{3 are the} same, R ₈ and R _{9 are the} same, R ₁₅ and R _{16 are the} same, and R ₁₈ and R _{19 are the} same, while R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₇ are H, and R ₈ , R ₉ and R ₁₃ are each independently selected from CH ₃ or CD ₃ .

In some embodiments of the present application, R ₂ and R _{3 are the} same, R ₈ and R _{9 are the} same, R ₁₀ and R _{11 are the} same, R ₁₈ and R _{19 are the} same, and R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ , R ₁₅ , R ₁₆ and R ₁₇ are H, and R ₈ , R ₉ and R ₁₃ are each independently selected from CH ₃ or CD ₃ .

In some embodiments of the present application, R ₈ and R _{9 are the} same, R ₁₀ and R _{11 are the} same, R ₁₅ and R _{16 are the} same, and R ₁₈ and R _{19 are the} same, while R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ , R ₉ and R ₁₃ are each independently selected from CH ₃ or CD ₃ .

In some embodiments of the present application, R ₈ and R ₉ are CD ₃ .

In some embodiments of the present application, R ₁₀ and R ₁₁ are D.

In some embodiments of the present application, R ₂ and R ₃ are D.

In some embodiments of the present application, R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₁₄ is D.

In some embodiments of the present application, R ₁₅ and R ₁₆ are D.

In some embodiments of the present application, R ₁₃ is CD ₃ , and R ₁₄ , R ₁₅ , R ₁₆ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₂ , R ₃ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₈ and R ₉ are CD ₃ and R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₈ and R ₉ are CD ₃ and R ₁₄ is D.

In some embodiments of the present application, R ₈ and R ₉ are CD ₃ , and R ₂ , R ₃ , R ₁₀ and R ₁₁ are D.

In some embodiments of the present application, R ₈ , R ₁₃ and R ₉ are CD ₃ , and R ₁₄ , R ₁₅ , R ₁₆ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₁₀ , R ₁₁ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₁₀ , R ₁₁ and R ₁₄ are D.

In some embodiments of the present application, R ₁₃ is CD ₃ , R ₁₀ , R ₁₁ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₂ , R ₃ and R ₁₄ are D.

In some embodiments of the present application, R ₁₃ is CD ₃ , and R ₂ , R ₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₂ , R ₃ , R ₄ and R ₅ are D.

In some embodiments of the present application, R ₆ and R ₇ are D.

In some embodiments of the present application, R ₁₂ is D.

In some embodiments of the present application, R ₂ and R ₃ are D, R ₈ and R ₉ are CD ₃ , and R ₁₀ and R ₁₁ are D.

In some embodiments of the present application, R ₁₇ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₁₃ is CD ₃ , and R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₁₄ , R ₁₅ , R ₁₆ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₈ , R ₁₃ and R ₉ are CD ₃ .

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ and R ₉ are CH ₃ ; at the same time, R ₂ and R ₃ are D.

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ and R ₉ are CH ₃ ; at the same time, R ₁₀ and R ₁₁ are D.

In some embodiments of the present _{application, R 1, R 4, R} 5, R 6, R 7, R 12 and R ₁₇ is H, and R ₈ and R ₉ is CH _3; the same time, R ₁₄ is D.

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ and R ₉ are CH ₃ ; at the same time, R ₁₈ and R ₁₉ are D.

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ and R ₉ are CH ₃ ; at the same time, R ₁₄ , R ₁₅ , R ₁₆ , R ₁₈ and R ₁₉ are D and R ₁₃ is CD ₃ .

In some embodiments of the present application, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H, and R ₈ and R ₉ are CH ₃ ; at the same time, R ₂ and R ₃ are D, R ₁₈ and R ₁₉ are D.

In some preferred embodiments of the present application, examples of compounds of formula (I) are as follows:

In another aspect, the present application is directed to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present application. In some embodiments, the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.

In another aspect, the present application relates to a method of treating pain in a mammal comprising administering to a mammal in need thereof, preferably a human, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .

In another aspect, the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of pain.

In another aspect, the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of pain.

In another aspect, the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of pain.

The compounds of formula (I) of the present application include specific compounds in one or more assays (eg, μOR agonistic activity (including selectivity), Gi/o agonistic activity, beta-arrestin recruitment assay, pharmacokinetic assay, liver Excellent properties are exhibited in the measurement of microbial metabolic stability and the like. For a specific assay, see Aashish Manglik et al., Structure-based discovery of opioid analgesics with reduced side effects, Nature 537, 185-190 (2016).

definition

Unless otherwise stated, the following terms as used in this application have the following meanings. A particular term should not be considered as undefined or unclear without a particular definition, and should be understood in the ordinary meaning of the art. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.

The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing a disease or disease state from occurring in a mammal, particularly when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state;

(ii) inhibiting the disease or disease state, ie, curbing its development;

(iii) alleviating the disease or condition, even if the disease or condition resolves.

The term "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application in which one or more symptoms of a particular disease, condition, or disorder are described herein. The amount of a compound of the present application which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and the present disclosure.

The term "pharmaceutically acceptable" is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned. .

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

The term "pharmaceutically acceptable excipient" refers to those excipients which have no significant irritating effect on the organism and which 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, and the like.

The word "comprise" or "comprise" and its English variants such as "comprises" or "comprising" shall be understood to mean an open, non-exclusive meaning, ie "including but not limited to".

The intermediates and compounds of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include recombination through some recombination of bonding electrons.

The deuterated atom of each of the specified deuterium atoms of the compound labeled in the present application may be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times. (75%), at least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), At least 6600 times (99%), at least 6633.3 times (99.5%).

In the present application, any atom not designated as hydrazine is present in its natural isotopic abundance.

The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.

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

Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.

In all methods of administration of the compounds of formula (I) described herein, the daily dose is from 0.01 to 200 mg/kg body weight.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.

The chemical reactions of the specific embodiments of the present application are accomplished in a suitable solvent which is suitable for the chemical changes of the present application and the reagents and materials required thereof. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the prior embodiments.

The compound of the formula (I) of the present application can be prepared by a person skilled in the art of organic synthesis (Nature 537 (2016): 185-190), which is prepared by the standard method in the art by the route 1, except that it is in the route. The intermediate fragments involved are selected for the particular purpose of the synthesis, the definition of which is as defined above:

Route 1

The deuterated or non-deuterated intermediate compound of formula II is subjected to a condensation reaction with a deuterated or non-deuterated intermediate compound of formula V under basic conditions to provide a compound of formula (I).

The synthesis method of the non-deuterated compound II is as follows: (s)-2-amino-3-phenyl-propionamide (commercially available) is obtained by a reductive amination reaction and a reduction reaction in this order. The synthesis method of the compound of the formula II of the deuterated is: according to the deuteration site, the flexible selection of the first generation and then the reductive amination reaction, the reduction reaction, or the reductive amination reaction, the reduction reaction, or the deuteration, or directly through the deuterium The reagent is prepared by a reductive amination reaction and/or a reduction reaction.

The deuterated or non-deuterated V compound is prepared by reacting a deuterated or non-deuterated compound of formula IV with p-nitrophenyl chloroformate. The deuterated or non-deuterated compound IV can be prepared by methods conventional in the art, and those skilled in the art can flexibly select the deuterated reaction step according to the deuterated site.

In the compound of formula (I), when the carbon atom substituted by R ₁₃ is in the R configuration or the S configuration, a chiral R configuration or an S configuration V compound can be directly prepared from the compound of formula II, or The racemic compound of formula V is condensed with a compound of formula II and separated by a chiral preparative column.

detailed description

The following specific embodiments are intended to enable those skilled in the art to understand and practice the invention. They should not be considered as limiting the scope of the application, but are merely exemplary and typical representations of the application. Those skilled in the art will appreciate that there are other synthetic routes to form the compounds of the present application, and non-limiting examples are provided below.

Unless otherwise indicated, the materials used in this application were purchased directly from the market and used without further purification.

DCM is dichloromethane; MeOH is methanol; THF is tetrahydrofuran; LAH is lithium aluminum hydride; MW is microwave

Synthesis of Intermediate II-1

step 1)

(s)-2-Amino-3-(4-hydroxyphenyl)propanamide (10.00 g, 55.50 mmol), acetonitrile (100 ml) was added to the reaction mixture, and then 37% aqueous formaldehyde (50 ml) was added to the reaction mixture. 66.60 mmol); After stirring at room temperature for 30 min, sodium triacetoxyborohydride (58.80 g, 277. After the reaction was completed by TLC, the reaction mixture was evaporated, evaporated, evaporated, evaporated, Filter and spin off to remove the solvent. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:

^{1 H-NMR (500M, DMSO} -d 6): δ = 9.01 (s, 1H), 7.13 (s, 1H), 6.97 ~ 6.98 (d, J = 7.5Hz, 2H), 6.81 (s, 1H), 6.62 to 6.64 (d, J = 7.5 Hz, 2H), 3.07 to 3.10 (dd, J = 8.0 Hz, 5.5 Hz, 1H), 2.79 to 2.84 (m, 1H), 2.60 to 2.63 (dd, J = 13 Hz, 4 Hz, 1H), 2.24 (s, 6H).

HR-ESIMS: 209.1294 [M+H] ⁺ .

Step (2)

To the reaction flask was added the compound I-1 (0.50 g, 2.40 mmol), anhydrous tetrahydrofuran (5 ml), and the mixture was stirred under nitrogen for 30 minutes at 0 ° C; 1.0 M BH3-THF (13.28 ml, 13.28 mmol), heated to reflux overnight after completion of the dropwise addition. After the TLC was monitored for completion, the reaction was quenched by the slow addition of methanol at low temperature. The reaction mixture was evaporated to dryness then EtOAc EtOAc (EtOAc) Acetone (10 ml) was added to the reaction flask, and a solid precipitated. Filtration and drying under reduced pressure at 45 ° C gave Compound II-1 (0.50 g).

¹ H-NMR (500M, DMSO-d ₆ ): δ = 11.12 (br, 1H), 9.51 (br, 1H), 8.64 (br, 2H), 7.14 to 7.16 (d, J = 8.5 Hz, 2H), 6.77 to 6.79 (d, J = 8.5 Hz, 2H), 3.84 to 3.87 (m, 1H), 3.38 to 3.44 (m, 1H), 3.15 to 3.19 (dd, J = 14 Hz, 4 Hz, 1H), 2.79 to 2.87 (m, 6H), 2.71 to 2.76 (m, 2H)

HR-ESIMS: 195.1496 [M+H] ⁺ .

Synthesis of intermediate (S)-V-1

step 1)

Formic acid (38.5 ml, 1 mol) was placed in a 500 ml three-necked flask, and ethanolamine (43.5 ml, 0.72 mol) was added dropwise under ice-cooling, and the addition was completed over 20 minutes. Nitroethane (65.3 ml, 0.91 mol) and 3-thiophenecarboxaldehyde (20 ml, 0.23 mol) were successively added to the reaction mixture, and the mixture was heated to 98 ° C for 6 hours, and the reaction of the starting material was confirmed by TLC. The reaction solution was poured into 500 ml of ice water, a large amount of yellow solid was precipitated, filtered, and the filter cake was washed with water (100 ml*3). The filter cake was recrystallized from ethanol / water (4:1) to give compound III-1 as 28 g.

¹ H NMR (500 MHz, Chloroform-d): δ = 8.07 (s, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.44 (dd, J = 5.1, 2.8 Hz, 1H), 7.28 (dd, J=5.1, 1.3 Hz, 1H), 2.50 (s, 3H).

Step (2)

III-1 (14.5 g, 0.0857 mol) was dissolved in anhydrous tetrahydrofuran (420 ml) and added dropwise to a 1M solution of lithium tetrahydrogenhydride in tetrahydrofuran (420 ml, 0.42 mol) to maintain the micro-reflow state. After the dropwise addition, the temperature was raised to reflux for 30 minutes. The reaction was quenched by slowly adding NaSO ₄ ·10H ₂ O while cooling to 0 °C. Filter and rinse the filter cake twice with ethyl acetate (500 mL). The filtrate was desolvated under reduced pressure to give a tan oil. Ethyl acetate (300 ml) was added to the oil, which was diluted and then extracted twice with 1M HCl solution (300 ml). The combined aqueous layers were adjusted to pH 13 to 14 with aqueous ammonia and extracted three times with ethyl acetate (500 mL). The organic layer was desolvated under reduced pressure to give a yellow oily compound (IV-1) 11.1 g.

A yellow oil (9.0 g, 0.0637 mol) was dissolved in ethanol (90 mL). D-(-)-di-p-methoxybenzoyltartaric acid (26.65 g, 0.0637 mol) was dissolved in acetonitrile (180 ml) and warmed to reflux, until the solid was completely dissolved, and a pre-formed ethanol (90 ml) solution was added thereto. A large amount of solid precipitated. 46 ml of water was added thereto and heated to reflux to obtain a clear transparent solution, and the heating was turned off to cool down naturally. Filtration and washing of the filter cake with cold acetonitrile (10 mL) gave a white fluffy solid. The solid was dissolved in 1M aqueous sodium hydroxide (100 mL) and extracted with chloroform (100 mL). The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated.

^{1 H NMR (500MHz, DMSO-} d6): δ = 7.429-7.413 (m, 1H), 7.139-7.134 (m, 1H), 6.987-6.975 (m, 1H), 3.046-3.008 (m, 1H), 2.564 -2.551 (m, 2H), 1.37 (br, s, 2H), 0.968 (d, 3H).

¹³ C NMR (500 MHz, DMSO-d6) δ 140.87, 129.32, 125.93, 121.79, 48.04, 41.10, 23.88

HR-ESIMS: 142.0943 [M+H] ⁺ .

Step (3)

Compound (S)-IV-1 (2.23 g, 15.8 mmol) was placed in a 250 mL three-necked flask and dissolved in 30 mL of anhydrous THF. Triethylamine (4.4 mL, 31.6 mmol) and p-nitrophenyl chloroformate (3.18 g, 15.8 mmol) were added in vacuo, and stirred at room temperature for four hours. TLC detects the end of the reaction and spins the solvent. 20 mL of DCM, 50 mL of saturated sodium bicarbonate solution was added, the organic phase was separated and the aqueous phase was extracted with DCM 20mL*2. The organic phases were combined, dried and dried to give a crude yellow product. The crude product was beaten with petroleum ether: diethyl ether = 43 mL: 40 mL. After filtration, the compound (S)-V-1 was found to be 4.12 g, yield 78%, ee = 97.5%.

¹ H NMR (500 MHz, DMSO): δ = 8.25 (d, J = 9.0 Hz, 2H), 8.04 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 4.7, 2.9 Hz, 1H), 7.34 (d, J = 9.1 Hz, 2H), 7.23 (s, 1H), 7.03 (d, J = 4.8 Hz, 1H), 3.84 - 3.78 (m, 1H), 2.80 (dd, J = 24.2, 6.8 Hz, 2H), 1.15 (d, J = 6.6 Hz, 3H).

Example 1. Preparation of 1-((S)-2-(bis(methyl-d ₃ )amino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophene) -3-yl)propan-2-yl)urea (compound (S)-1)

step 1)

Was added (s) added to the reaction flask -2-amino-3- (4-hydroxyphenyl) propionamide (3.00g, 16.65mmol), acetonitrile (35ml), was then added to the reaction mixture 20% d ₂ - weight of formaldehyde Aqueous solution (27 ml, 166.50 mmol) was stirred at room temperature. At the same time, sodium borohydride (4.06 g, 96.99 mmol), acetonitrile (5 ml) was added to another reaction flask, and deuterated acetic acid was added dropwise to the reaction at 0 °C. 20ml, 290.97mmol); the resulting d ₁ - the reaction mixture prior to the deuterated sodium triacetoxyborohydride was added in the suspension. After the reaction was completed by TLC, the reaction mixture was evaporated, evaporated, evaporated, evaporated. The desiccant was removed by suction filtration, and the solvent was removed by rotary evaporation. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:

^{1 H-NMR (500M, DMSO} -d 6): δ = 9.08 (s, 1H), 7.12 (s, 1H), 6.97 ~ 6.99 (d, J = 8.5Hz, 2H), 6.81 (s, 1H), 6.62~6.64 (dd, J=6.5Hz, 2Hz, 2H), 3.07~3.10 (dd, J=9.0Hz, 5.0Hz, 1H), 2.79~2.84 (dd, J=13.5Hz, 9Hz, 1H), 2.59 ~ 2.63 (dd, J = 13.5 Hz, 9 Hz, 1H).

HR-ESIMS: 215.1679 [M+H] ⁺ .

Step (2)

To the reaction flask was added the compound I-2 (1.00 g, 4.67 mmol), anhydrous tetrahydrofuran (10 ml), and the mixture was stirred under nitrogen for 30 minutes at 0 ° C; 1.0 M BH3-THF (28.00 ml, 28.00 mmol), heated to reflux overnight after completion of the dropwise addition. After the TLC was monitored for completion, the reaction was quenched by the slow addition of methanol at low temperature. The reaction mixture was evaporated to dryness and then evaporated and then evaporated. Acetone (10 ml) was added to the reaction flask, and a solid precipitated. The compound II-2 (0.96 g) was obtained by suction filtration under reduced pressure at 45 °C.

¹ H-NMR (500M, DMSO-d ₆ ): δ = 11.04 (br, 1H), 9.53 (br, 1H), 8.62 (br, 2H), 7.14 to 7.16 (d, J = 8.5 Hz, 2H), 6.77 to 6.79 (d, J = 8.5 Hz, 2H), 3.84 to 3.87 (m, 1H), 3.40 (m, 1H), 3.14 to 3.18 (dd, J = 14 Hz, 4 Hz, 1H), 2.84 to 2.86 (m) , 1H), 2.71 to 2.76 (m, 1H)

HR-ESIMS: 201.1878 [M+H] ⁺ .

Step (3)

Compound II-2 (0.60 g, 2.20 mmol), Compound (S)-V-1 (0.60 g, 1.96 mmol) anhydrous DMF (8 ml), triethylamine (0.49 g, 4.84 mmol), Stir at room temperature overnight under nitrogen. After the reaction was completed by TLC, the reaction was quenched with saturated aqueous sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic phase was combined and dried over anhydrous magnesium sulfate. The solvent was removed by suction filtration and the solvent was removed by evaporation. ISCO was purified by preparative chromatography (2% MeOH / DCM - 10% MeOH / DCM).

¹ H-NMR (500 M, CDCl ₃ ): δ = 7.23 to 7.25 (dd, J = 5.0 Hz, 3.0 Hz, 1H), 6.99 to 7.00 (d, J = 2.0 Hz, 1H), 6.95 to 6.97 (dd, J=6.0 Hz, 5.0 Hz, 2H), 6.77 to 6.79 (d, J=8.0 Hz, 2H), 5.36 (br, 1H), 4.83 (br, 1H), 3.97 to 3.99 (m, 1H), 3.31 3.32 (m, 1H), 2.89 to 2.96 (ddd, 1H), 2.86 to 2.87 (d, J = 3.5 Hz, 1H), 2.83 to 2.84 (d, J = 5.5 Hz, 1H), 2.80 to 2.81 (d, J=5.5 Hz, 1H), 2.71 to 2.76 (m, 1H), 2.27 to 2.32 (dd, J = 13.5 Hz, 10.5 Hz, 1H), 1.10 to 1.11 (d, J = 7.0 Hz, 3H)

HR-ESIMS: 368.2275 [M+H] ⁺ .

Example 2. Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl-1,1-d ₂ )-3-((S)-1-( Thiophen-3-yl)propan-2-yl)urea (compound (S)-2)

step 1)

To the reaction flask was added the compound I-1 (1.00 g, 4.80 mmol), anhydrous tetrahydrofuran (10 ml), and the mixture was stirred under nitrogen for 30 minutes at 0 ° C; 1.0 M BD3-THF (28.90 ml, 28.90 mmol), heated to reflux overnight after completion of the dropwise addition. After the TLC was monitored for completion, the reaction was quenched by the slow addition of methanol at low temperature. The reaction mixture was evaporated to dryness then EtOAc (EtOAc) (EtOAc) Acetone (10 ml) was added to the reaction flask, and a solid precipitated. The compound II-3 (0.674 g) was obtained by suction filtration under reduced pressure at 45 °C.

^{1 H-NMR (500M, DMSO} -d 6): δ = 11.09 (br, 1H), 9.52 (br, 1H), 8.59 (br, 2H), 7.14 ~ 7.16 (d, J = 8.5Hz, 2H), 6.77 to 6.78 (d, J = 8.5 Hz, 2H), 3.82 to 3.84 (m, 1H), 3.48 (m, 1H), 3.14 to 3.18 (dd, J = 14 Hz, 4 Hz, 1H), 2.71 to 2.79 (m) , 6H)

HR-ESIMS: 197.1622 [M+H] ⁺ .

Step (2)

To the reaction flask was added compound II-3 (0.60 g, 2.23 mmol), Compound V-1 (0.60 g, 1.96 mmol), dry DMF (8 ml), triethylamine (0.49 g, 4. Stir at room temperature overnight. After the reaction was completed by TLC, the reaction was quenched with saturated aqueous sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic phase was combined and dried over anhydrous magnesium sulfate. The solvent was removed by suction filtration and the solvent was removed by evaporation. ISCO was purified by preparative chromatography (2% MeOH / DCM - 10% MeOH / DCM).

¹ H-NMR (500 M, CDCl ₃ ): δ = 7.23 to 7.25 (dd, J = 5.0 Hz, 3.0 Hz, 1H), 6.99 to 7.00 (d, J = 2.0 Hz, 1H), 6.95 to 6.97 (m, 2H), 6.77 to 6.79 (d, J = 8.0 Hz, 2H), 5.35 (br, 1H), 4.84 (br, 1H), 3.95 to 4.01 (m, 1H), 2.83 to 2.90 (ddd, 1H), 2.80 ～2.81 (d, J=5.5 Hz, 1H), 2.76 to 2.77 (d, J=3.0 Hz, 1H), 2.71 to 2.75 (m, 1H), 2.38 (s, 6H), 2.32 to 2.36 (dd, J) =13.5 Hz, 10.5 Hz, 1H), 1.10 to 1.11 (d, J=7.0 Hz, 3H)

HR-ESIMS: 364.2039 [M+H] ⁺ .

Example 3. Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl-3,5-d ₂ )propyl)-3-((S)-1-( Thiophen-3-yl)propan-2-yl)urea (compound (S)-3)

step 1)

Trifluoroacetic anhydride (1.5 g, 7.41 mmol) was added to a microwave reaction flask, and heavy water (15 ml) was slowly added dropwise thereto in an ice water bath; Compound II-1 (0.8, 2.99 mmol) was added to the above reaction mixture. Under microwave conditions, 160 ° C, 150 Power, reaction for two hours. After completion of the reaction, the heavy aqueous solution was removed by rotary evaporation, and the same amount of trifluoroacetic anhydride and heavy water were added thereto, and exchanged again under the same reaction conditions. After completion of the reaction, the solvent was evaporated to dryness, and then acetone was added to be pulverized, and finally dried under reduced pressure to give Compound II-4 (0.654 g).

¹ H-NMR (500 M, DMSO-d ₆ ): δ=11.10 (br, 1H), 9.45 (br, 1H), 8.51 (br, 2H), 7.13 (s, 2H), 3.77 (m, 1H), 3.46 (m, 1H), 3.12 to 3.16 (dd, J = 14 Hz, 4 Hz, 1H), 2.83 to 2.85 (m, 6H), 2.67 to 2.72 (m, 2H)

HR-ESIMS: 197.1563 [M+H] ⁺ .

Step (2)

Compound II-4 (0.60 g, 2.23 mmol), Compound (S)-V-1 (0.60 g, 1.96 mmol) anhydrous DMF (8 ml), triethylamine (0.49 g, 4.84 mmol), Stir at room temperature overnight under nitrogen. After the reaction was completed by TLC, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Purification by medium and low pressure preparative chromatography (2% MeOH / DCM - 10%MeOH / DCM)

¹ H-NMR (500 M, CDCl ₃ ): δ = 7.23 to 7.25 (dd, J = 5.0 Hz, 3.0 Hz, 1H), 6.99 to 7.00 (d, J = 2.0 Hz, 1H), 6.95 to 6.96 (dd, J=6.0 Hz, 5.0 Hz, 2H), 5.37 (br, 1H), 4.84 (br, 1H), 3.97 to 3.99 (m, 1H), 3.31 to 3.32 (m, 1H), 2.89 to 2.96 (ddd, 1H) ), 2.86 to 2.87 (d, J = 3.5 Hz, 1H), 2.83 to 2.84 (d, J = 5.5 Hz, 1H), 2.80 to 2.81 (d, J = 5.5 Hz, 1H), 2.70 to 2.79 (m, 1H), 2.38 (s, 6H), 2.32 to 2.36 (dd, J = 13.5 Hz, 10.5 Hz, 1H), 1.10 to 1.11 (d, J = 6.5 Hz, 3H)

HR-ESIMS: 364.2016 [M+H] ⁺ .

Referring to the preparation methods of the intermediates II2/3/4 in Examples 1 to 3, the following intermediate compounds were prepared according to the existing raw materials:

Example 4. Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl-2) , 5-d ₂ )propan-2-yl)urea (compound (S)-4) and 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)- 3-((R)-1-(thiophen-3-yl-2,5-d ₂ )propan-2-yl)urea (compound (R)-4)

step 1)

Heavy water (19.2 ml, 1.06 mol) was placed in a microwave tube, and trifluoroacetic anhydride (2 ml, 14 mmol) was slowly added, and the ice bath was removed and allowed to react at room temperature for 15 minutes. Intermediate IV-1 was added to the above solution, and microwaved at 100 ° C for 2 hours. The reaction solution was diluted with 50 ml of ethyl acetate, and then basified to pH 8 with a saturated sodium hydrogen carbonate solution. The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated 1.6 g of this oil was subjected to a second deuteration, and the first operation was repeated to obtain 1.5 g of an intermediate IV-2 oil.

HR-ESIMS: 144.0812 [M+H] ⁺ .

Step (2)

Intermediate IV-2 (1.00 g, 6.98 mol) was placed in a 100 ml single-necked flask and dissolved in 15 ml of THF. Triethylamine (1.93 ml, 13.96 mol) and p-nitrophenyl chloroformate (1.41 g, 6.98 mol) were added in that order. After reacting at room temperature for 0.5 hour, TLC confirmed that the starting material was completely reacted. The mixture was extracted with EtOAc. EtOAc (EtOAc) Ether: 15 ml of petroleum ether = 1:1 solution was beaten and filtered to give 1.00 g of a gray solid. The filter cake was purified by column chromatography to give Compound V-2 850 mg.

¹ H NMR (500 MHz, Chloroform-d): δ = 8.26 - 8.20 (m, 2H), 7.29-7.24 (m, 2H), 6.98 (s, 1H), 4.96 (d, J = 8.3 Hz, 1H), 4.12–4.00 (m, 1H), 2.90 (d, J = 6.3 Hz, 2H), 1.26 (d, J = 6.3 Hz, 3H).

Step (3)

Intermediate V-2 (800 mg, 2.59 mol) and compound II-1 (693 mg, 2.59 mol) were placed in a 50 ml single-necked flask, and 5 ml of DMF and triethylamine (394 mg, 3.89 mol) were added. After reacting for 2 hours at room temperature, TLC confirmed that the starting material was completely reacted. The reaction mixture was evaporated to dryness and purified by column chromatography to yield 460 g of Compound 4.

Resolution by high pressure preparative chromatography gave (S)-4 as 170 mg and (R)-4 as 170 mg.

Compound (S)-4:

¹ H NMR (500 MHz, DMSO-d6): δ = 9.18 (s, 1H), 6.97-6.99 (d, J = 8 Hz, 2H), 6.94 (s, 1H), 6.67-6.69 (d, J = 8.5 Hz , 2H), 6.04-6.06 (d, J=8Hz, 1H), 5.65 (br, 1H), 3.72-3.77 (m, 1H), 3.06-3.11 (m, 1H), 2.82 (s, 1H), 2.73 -2.76(d, J=13.5Hz, 1H), 2.66-2.70(m,1H), 2.55-2.59(m,1H), 2.30(s,6H),2.22-2.25(m,1H),1.16-1.19 (t, 1H), 0.94-0.95 (d, J = 6.5 Hz, 3H)

HR-ESIMS: 364.2066 [M+H] ⁺ .

Compound (R)-4:

¹ H NMR (500 MHz, DMSO-d6): δ=9.16 (s, 1H), 6.95-6.98 (m, 3H), 6.67-6.68 (d, J = 8.5 Hz, 2H), 6.02-6.03 (d, J = 7.5 Hz, 1H), 5.59 (br, 1H), 3.72-3.76 (m, 1H), 3.04-3.09 (m, 1H), 2.77-2.81 (m, 1H), 2.71-2.74 (m, 1H), 2.66-2.70(m,1H), 2.56-2.60(m,1H), 2.26(s,6H), 2.17-2.21(m,1H), 1.24(s,1H),0.92-0.94(d,J=6.5 Hz, 3H)

HR-ESIMS: 364.2046 [M+H]+.

Example 5. Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propane -2-yl-2-d)urea (compound (S)-5) and 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-( (R)-1-(thiophen-3-yl)propan-2-yl-2-d)urea (compound (R)-5)

step 1)

1-Thien-3-yl-propan-2-one (3.0 g, 23.4 mmol) was placed in a 250 ml single-necked flask, and 45 ml of THF was added and replaced with nitrogen three times. Under ice cooling, sodium borohydride (1.8 g, 42.7 mmol) was slowly added, and the mixture was stirred for 10 minutes under ice bath. The ice bath was removed, and the mixture was allowed to stand at room temperature for 30 minutes, and TLC showed that the starting material remained. The oil bath was heated to 60 ° C and reacted for 1 hour, and TLC showed the starting material was completely reacted. The reaction solution was diluted with ethyl acetate, and the reaction was quenched with saturated sodium hydrogen carbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ = 7.40 (dd, J = 4.9, 2.9 Hz, 1H), 7.15 - 7.13 (m, 1H), 6.99 (dd, J = 4.9, 1.3 Hz, 1H) , 4.51 (s, 1H), 2.71-2.66 (m, 1H), 2.62-2.55 (m, 1H), 1.02 (s, 3H).

Step (2)

Intermediate VI-1 (2.9 g, 20.21 mmol) was placed in a 100 ml three-necked flask, and 50 ml of THF and triethylamine (4.1 g, 40.41 mol) were added and replaced with nitrogen three times. Under ice-cooling, methanesulfonyl chloride (2.78 g, 24.24 mol) was added dropwise, and the mixture was stirred for 5 minutes and stirred for 10 minutes under ice bath. The ice bath was removed, and the mixture was reacted at room temperature for 2 hours, and it was confirmed by TLC that the starting material was completely reacted. The reaction mixture was diluted with ethyl acetate. EtOAc was evaporated, evaporated, evaporated, evaporated. g.

^{1 H NMR (500MHz, DMSO-} d 6): δ = 7.48 (dd, J = 4.9,2.9Hz, 1H), 7.30 (dd, J = 3.0,1.2Hz, 1H), 7.07 (dd, J = 4.9, 1.3 Hz, 1H), 2.95 (s, 2H), 2.89 (s, 3H), 1.31 (s, 3H).

Step (3)

Intermediate VII-1 (3.70 g, 16.72 mol) was placed in a 100 ml single-necked flask, and 15 ml of solvent DMSO, sodium azide (1.20 g, 18.39 mol) was sequentially added, and the mixture was stirred at room temperature for 10 minutes. The oil bath was heated to 60 ° C for 3 hours, and TLC showed the starting material was completely reacted. The reaction mixture was diluted with ethyl acetate. EtOAc was evaporated.

^{1 H NMR (500MHz, DMSO-} d 6): δ = 7.48-7.44 (m, 1H), 7.28-7.24 (m, 1H), 7.06-7.02 (m, 1H), 2.78 (s, 2H), 1.18 ( s, 3H).

Step (4)

Intermediate VIII-1 (2.20 g, 13.08 mol) was placed in a 100 ml single-necked flask, and 10 ml of THF was added. LAH (993 mg, 26.15 mol) was slowly added under ice bath. After the addition was completed, stirring was continued for 10 minutes in an ice bath. The ice bath was removed and reacted at room temperature for 0.5 hours. TLC monitoring showed complete reaction of the starting material. The reaction solution was diluted with 20 ml of THF, and the reaction was quenched by slowly adding NaSO ₄ ·10H ₂ O in an ice bath until no bubbles were formed. Filter and filter cake with a small amount of THF. The filtrate was evaporated to dryness to give-1.

^{1 H NMR (500MHz, DMSO-} d 6): δ = 7.44-7.41 (m, 1H), 7.15-7.12 (m, 1H), 6.98-6.95 (m, 1H), 2.53 (s, 2H), 0.94 ( s, 3H).

HR-ESIMS: 143.0745 [M+H] ⁺ .

Step (5)

Synthesis of Intermediate V-3 The synthesis method of Intermediate V-2 in Example 4 was referred to.

^{1 H NMR (500MHz, DMSO-} d 6): δ = 8.27-8.21 (m, 2H), 8.03 (brs, 1H), 7.46 (dd, J = 4.9,2.9Hz, 1H), 7.36-7.30 (m, 2H), 7.22 (dd, J = 2.9, 1.2 Hz, 1H), 7.02 (dd, J = 4.9, 1.3 Hz, 1H), 2.85 - 2.72 (m, 2H), 1.13 (s, 3H).

Step (6)

Synthesis of Compound 5 The synthesis method of Compound 4 in Example 4 was referred to. Compound 5 was obtained to be 1.27 g. The (S)-5 resolved by high pressure preparative chromatography was 400 mg, and (R)-5 was 420 mg.

Compound (S)-5:

^{1 H NMR (500MHz, DMSO-} d6): δ = 9.17 (s, 1H), 7.40-7.42 (m, 1H), 7.12 (s, 1H), 6.97-6.99 (d, J = 7.5Hz, 2H), 6.93-6.94 (d, J=5 Hz, 1H), 6.67-6.69 (d, J=17 Hz, 2H), 6.03 (s, 1H), 5.65 (br, 1H), 3.06-3.10 (m, 1H), 2.19 -2.84(m,1H),2.74-2.76(d,1H),2.66-2.69(d,1H),2.55-2.58(d,1H),2.30(s,6H),2.25(s,1H), 1.16 -1.19(t, J=7Hz, 1H), 0.94(s, 3H)

HR-ESIMS: 363.1957 [M+H] ⁺ .

Compound (R)-5:

^{1 H NMR (500MHz, DMSO-} d6): δ = 9.14 (s, 1H), 7.41-7.42 (m, 1H), 7.12-7.13 (d, J = 2Hz, 1H), 6.95-6.97 (m, 3H) , 6.66-6.68 (d, J = 8.5 Hz, 2H), 6.01 (s, 1H), 5.57 (br, 1H), 3.04-3.09 (m, 1H), 2.76-2.81 (m, 1H), 2.66-2.73 (m, 2H), 2.53-2.59 (m, 1H), 2.25 (s, 6H), 2.16-2.20 (m, 1H), 1.14-1.20 (m, 1H), 0.92 (s, 3H)

HR-ESIMS: 363.1957 [M+H] ⁺ .

Example 6. Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl-2) , 5-d ₂ )propan-2-yl-1,1,2,3,3,3-d ₆ )urea (compound (S)-6) and 1-((S)-2-(dimethylamino) --3-(4-hydroxyphenyl)propyl)-3-((R)-1-(thiophen-3-yl-2,5-d ₂ )propan-2-yl-1,1,2, 3,3,3-d ₆ )urea (compound (R)-6)

step 1)

Phosphorus pentoxide (150 mg, 1.07 mmol) was placed in a 35 ml microwave tube, and under ice bath, heavy water (22.0 g, 1.10 mol) was slowly added. The ice bath was removed and stirred at room temperature for 0.5 hours. To the solution was added 1-thiophen-3-yl-propan-2-one (1.50 g, 10.70 mol), MW, 150 ° C, and reacted for 2 hours. The same reaction was carried out in a total of three microwave tubes. The reaction mixture was combined and diluted with ethyl acetate. The mixture was evaporated and evaporated. Subsequent second and third deuteration exchanges were repeated and the first operation was repeated and purified by column chromatography to give intermediate d7-1-thiophen-3-yl-propan-2-one as a brown oil 3.15 g.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=6.97 (s, 1H).

Step (2)

Synthesis of Intermediate VI-2 Refer to the synthesis of Intermediate VI-1 in Example 5.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=6.98 (s, 1H).

Step (3)

Synthesis of Intermediate VII-2 Refer to the synthesis of Intermediate VII-1 in Example 5.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=7.06 (s, 1H), 2.90 (s, 3H).

Step (4)

Synthesis of Intermediate VIII-2 Refer to the synthesis of Intermediate VIII-1 in Example 5.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=7.03 (s, 1H).

Step (5)

Synthesis of Intermediate IV-4 Refer to the synthesis of Intermediate IV-3 in Example 5.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=6.97 (s, 1H).

HR-ESIMS: 150.1189 [M+H] ⁺ .

Step (6)

Synthesis of Intermediate V-4 The synthesis method of Intermediate V-2 in Example 4 was referred to.

¹ H NMR (500 MHz, CDCl 3 ): δ = 8.25 (d, J = 9.1 Hz, 2H), 7.29 (d, J = 10.2 Hz, 2H), 7.00 (s, 1H), 5.00 (s, 1H).

Step (7)

The synthesis of Compound 6 is referred to the synthesis method of Compound 4 in Example 4. After hand-off, 275 mg of Compound (S)-6, 250 mg of Compound (R)-6 were obtained.

Compound (S)-6:

^{1 H NMR (500MHz, CDCl3)} : δ = 6.94 (d, J = 6.7Hz, 3H), 6.78 (d, J = 8.2Hz, 2H), 5.60 (s, 1H), 5.01 (s, 1H), 3.33 – 3.26 (m, 1H), 2.96-2.85 (m, 3H), 2.43 (s, 6H), 2.35-2.30 (m, 1H).

HR-ESIMS: 370.2414 [M+H] ⁺ .

Compound (R)-6:

^{1 H NMR (500MHz, CDCl3)} : δ = 6.94 (d, J = 7.3Hz, 3H), 6.77 (d, J = 8.2Hz, 2H), 5.45 (s, 1H), 4.90 (s, 1H), 3.32 –3.25(m,1H), 2.97–2.91(m,1H), 2.87(dd,J=13.4,3.2Hz,1H),2.81–2.75(m,1H), 2.39(s,6H), 2.29(dd , J=13.1, 10.6Hz, 1H).

HR-ESIMS: 370.2406 [M+H] ⁺ .

Example 7

Synthesis of Compound 7 The synthesis method of Compound 4 in Example 4 was referred to. After hand-off, 100 mg of compound (S)-7, 250 mg of compound (R)-7 was obtained.

Compound (S)-7:

^{1 H NMR (500MHz, DMSO-} d6) δ9.14 (s, 1H), 6.94 (d, J = 18.7Hz, 3H), 6.02 (d, J = 7.8Hz, 1H), 5.59 (s, 1H), 3.74 (dt, J = 13.7, 6.7 Hz, 1H), 3.12-3.02 (m, 1H), 2.83 - 2.75 (m, 1H), 2.72 (dd, J = 13.4, 3.1 Hz, 1H), 2.67 (dd, J=13.9, 6.2 Hz, 1H), 2.56 (dd, J=13.9, 6.9 Hz, 2H), 2.26 (s, 6H), 2.22-2.16 (m, 1H), 0.94 (d, J=6.5 Hz, 3H) ¹³ C NMR (126 MHz, DMSO-d6) δ 157.78, 155.78, 139.79, 130.16, 129.21, 65.92, 46.10, 40.52, 40.45, 39.52, 37.50, 30.74, 21.18.HR-ESIMS: 366.2172[M+H]+.

Compound (R)-7:

^{1 H NMR (500MHz, DMSO-} d6) δ9.13 (s, 1H), 6.95 (d, J = 7.5Hz, 3H), 6.01 (d, J = 7.8Hz, 1H), 5.57 (d, J = 4.8 Hz, 1H), 3.73 (dt, J = 13.4, 6.7 Hz, 1H), 3.10-3.02 (m, 1H), 2.78 (t, J = 11.1 Hz, 1H), 2.74 - 2.64 (m, 2H), 2.57 (dd, J = 13.9, 6.8 Hz, 2H), 2.25 (s, 6H), 2.18 (dd, J = 13.0, 9.8 Hz, 1H), 0.92 (d, J = 6.5 Hz, 3H). ¹³ C NMR ( 126 MHz, DMSO-d6) δ 157.73, 155.76, 139.82, 130.15, 129.24, 65.98, 46.11, 40.52, 40.48, 39.52, 37.50, 30.72, 21.24. HR-ESIMS: 366.2173 [M+H]+.

Example 8-15

The compounds of Examples 8-15 were isolated by high pressure preparation according to the synthesis procedures in Example 7 according to the intermediates II-2\3\4 and V-2\3\4.

Example 16-21

Referring to the preparation methods of the intermediates V2/3/4 in Examples 4 to 6, the following intermediate compounds were prepared according to the existing raw materials:

The compounds of Examples 16-21 (Compound (S)-16 and the compound were isolated by high pressure preparation according to the synthesis methods in Example 7 according to the intermediates II-5\6\7\8 and V-5\6. (R)-16, compound (S)-17 and compound (R)-17, compound (S)-18 and compound (R)-18, compound (S)-19 and compound (R)-19, compound ( S)-20 and compound (R)-20, compound (S)-21 and compound (R)-21).

Example 22. Activity Research Section

1. Example compounds Human liver microsome metabolism assay steps and results:

300 μL of the final incubation system: containing 30 μL of human liver microsomes (protein concentration: 5 mg/mL, BD, USA), 30 μL of NADPH (10 mM) + MgCl ₂ (5 mM), 3 μL of the substrate as the example compound (50% aqueous acetonitrile solution) Dissolved, 100 μM), 237 μL of PBS buffer in which the ratio of organic solvent (acetonitrile) was 0.5%.

Each tube was first prepared with a total volume of 270 μL of substrate and enzyme mixture. After pre-incubation at 37 °C for 5 min, add 30 μL of NADPH+MgCl ₂ and remove 50 μL of diazepam with internal standard at 0 and 60 min. The reaction was stopped by ice acetonitrile (20 ng/mL) 300 μL.

After vortexing for 5 min, centrifuge (13,000 rpm, 4 ° C) for 10 min. Pipette 100 μL of the supernatant into the injection vial and perform 1 μL injection for LC-MS/MS analysis to calculate the remaining percentage, as shown in the table below.

2. The activity of the example compounds on the μOR opioid receptor was determined.

3. The inhibitory activity of the compound of the example on Gi/o mediated cAMP signaling was determined.

4. The recruitment of the compound of the example to β-Arrestin was determined.

For experimental procedures, see: Manglik A, Lin H, Aryal D K, et al. Structure-based discovery of opioid analgesics with reduced side effects [J]. Nature, 2016, 537 (7619): 185-190.

The experiments showed that the compound of the example had good binding activity to the μ-opioid receptor (μOR) and strong inhibitory activity against the signaling pathway Gi/o-mediated cAMP. Meanwhile, the recruitment of β-Arrestin was weak.

Claims (14)

1. a compound of formula (I) or a pharmaceutically acceptable salt thereof,

   

   among them:

   R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ and R ₁₉ are each independently Selected from H (hydrogen) or D (氘);

   R ₈ , R ₉ and R ₁₃ are each independently selected from CH ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

   The condition is that the compound of formula (I) contains at least one ruthenium atom.
2. The compound according to claim 1, wherein the carbon atom substituted by R ₁₃ may be in the R configuration or the S configuration.
3. The compound according to claim 2, wherein R ₁ , R ₄ , R ₅ and R ₁₇ are H.
4. The compound according to claim 2, wherein R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₂ and R ₁₇ are H.
5. The compound according to claim 4, wherein R ₈ and R ₉ are CH ₃ .
6. The compound according to any one of claims 1 to 5, wherein R ₁₀ and R ₁₁ are D.
7. The compound according to any one of claims 1 to 5, wherein R ₂ and R ₃ are D.
8. The compound according to any one of claims 1 to 5, wherein R ₁₈ and R ₁₉ are D.
9. The compound according to any one of claims 1 to 5, wherein R ₁₄ is D.
10. The compound according to any one of claims 1 to 5, wherein R ₁₄ , R ₁₅ , R ₁₆ , R ₁₈ and R ₁₉ are D and R ₁₃ is CD ₃ .
11. The compound according to any one of claims 1 to 5, wherein R ₂ and R ₃ are D, and R ₁₈ and R ₁₉ are D.
12. The compound of claim 1 selected from the group consisting of:

    

    

    
13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof.
14. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of pain.