CN115677718B - Methyl methylamine derivative preparation, pharmaceutical composition and application thereof - Google Patents

Abstract

The invention provides a methyl methylamine derivative preparation, a pharmaceutical composition and application thereof. The methyl methylamine derivative preparation is a derivative of (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine, or pharmaceutically acceptable salt or prodrug thereof, and can be used for preparing medicines for preventing or treating neurological diseases, wherein the neurological diseases are selected from schizophrenia, depression, dysmnesia and dysfunctional diseases related to intelligence and study. The compound has longer half-life period in the microsome metabolism process, relatively lower clearance rate and good microsome metabolism stability, and can maintain the effective blood concentration in the body for a longer time. The compound can maintain a certain concentration in the human plasma metabolism process, has good plasma metabolism stability, and can maintain the effective blood concentration in the human body for a long time.

Description

Methyl methylamine derivative preparation, pharmaceutical composition and application thereof

Technical Field

The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a methylmethylamine derivative preparation, a pharmaceutical composition and applications thereof, and more specifically to a prodrug derivative of (S)-1-(4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)-N-methylmethylamine, a pharmaceutical composition and applications thereof.

Background Art

Schizophrenia is a chronic, protracted disease with recurrent episodes. According to incomplete statistics, approximately 1% of the world's population suffers from this disease, and the number of patients in China may reach 10 million. Schizophrenia is mainly manifested by positive symptoms (mania, hallucinations, delusions, thought disorders, etc.), negative symptoms (anhedonia, aphasia, loss of will, etc.), and cognitive disorders (memory impairment, lack of attention, lack of executive function, etc.). The treatment of schizophrenia is mainly drug therapy. In the past fifty years, research on schizophrenia treatment drugs has made great progress in the control of positive symptoms. However, current schizophrenia treatment drugs have no significant improvement on negative symptoms and cognitive disorders, and there are problems such as drug side effects, making schizophrenia still one of the most difficult diseases to control and cure.

In clinical treatment, it is quite common for patients to not comply with oral antipsychotics. Relapse caused by patients interrupting treatment or reducing medication on their own has become a major difficulty in the entire treatment of schizophrenia. Therefore, the development of long-acting preparations of antipsychotics will not only help improve treatment compliance, prevent relapse, and reduce the care burden on patients, their families and society, but also have great market value.

Since the discovery of chlorpromazine in the 1950s, drug treatment for schizophrenia has really begun. Typical schizophrenia drugs represented by haloperidol are potent inhibitors of dopamine and have good efficacy on the positive symptoms of schizophrenia, but their serious side effects of EPS and strong mental suppression have gradually withdrawn from the market; in the 1980s, atypical antipsychotic drugs represented by risperidone appeared, which not only have good efficacy on positive symptoms, but also can improve EPS side effects [Neuropsychopharmacol., 1999, 21: 106-115], but the adverse reactions of weight gain, increased blood sugar, increased lactation and prolonged QT interval are becoming increasingly prominent [Curr. Opin. Invest. Drugs, 2007, 8: 531-538]. Although in recent years, multi-target antipsychotic drugs based on _D2 /5- _HT2A have had a good effect on improving drug effectiveness and dependence, providing new options for patients with mental illness, they cannot fundamentally eliminate the side effects caused by inhibiting _D2 /5- _HT2A , and their efficacy on negative symptoms and cognitive disorders is also limited.

Recent studies have found that TAAR1 agonists have good effects on positive symptoms, negative symptoms and cognitive impairment in animal models of schizophrenia, and do not have the adverse reactions of existing drugs such as EPS, weight gain, and increased prolactin caused by the _D2 /5- _HT2A mechanism, showing good antipsychotic drugability. Although the exact mechanism is still unclear, it has pointed out a new direction for the research of new non-dopamine antipsychotic drugs.

SEP-363856 [(S)-1-(4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)-N-methylmethanamine] was developed by Sunovion and PsychoGenics. SEP-363856 can activate trace amine-associated receptors (TAAR1) [J Pharmacol Exp Ther. 2019, 371(1):1-14, CNS Spectr. 2019, 24(S1):38-69] and has been granted breakthrough therapy designation by the US FDA for the treatment of schizophrenia. The FDA granted breakthrough therapy designation to SEP-363856 based on the results of a key Phase 2 clinical study (SEP 361-201) and a 6-month open-label extension study (SEP 361-202) to explore safety and tolerability. In the clinical trial results, SEP-363856 was significantly better than placebo for positive and negative symptoms; in terms of side effects, SEP-363856 did not increase the risk of extrapyramidal reactions (EPS), akathisia, and hyperprolactinemia, which is consistent with its mechanism of action that is independent of _D2 receptors [N Engl J Med. 2020, 382(16): 1497-1506]. It is expected to become the first new antipsychotic drug that does not bind to dopamine _D2 receptors to treat schizophrenia.

In view of this, it is necessary to design an improved methyl methylamine derivative preparation, pharmaceutical composition and application thereof to solve the above problems.

Summary of the invention

In order to overcome the above-mentioned deficiencies of the prior art, the object of the present invention is to provide a (S)-1-(4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)-N-methylmethanamine derivative to improve the absorbability of such drugs, prolong the release or reduce their side effects.

To achieve the above-mentioned object of the invention, the present invention provides a methylmethylamine derivative preparation, wherein the methylmethylamine derivative preparation is one of the compounds represented by formula (I)-(V), or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

Wherein, R in formula (I) and (II) and R ₁ , R ₂ , and R ₃ in formula (III) to (V) are independently a substituent group formed by one or more combinations of hydrogen, deuterium, hydroxyl, carboxyl, C _1-15 alkoxy, substituted or unsubstituted C _1-16 alkyl, heteroalkyl, cycloalkyl or alicyclic, aromatic or aromatic heterocyclic.

The compounds of the present invention may be stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compounds represented by the above formulae (I)-(V).

The term "pharmaceutically acceptable salt" as used herein refers to relatively non-toxic, inorganic or organic acid addition salts of compounds of the present invention. For example, see S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

In another aspect, the present invention relates to acceptable optical isomers of the compounds of formula I-V.

As a further improvement of the present invention, R in the formula (I) and (II) is independently a substituent group formed by one or more combinations of hydrogen, hydroxyl, C _1-5 alkoxy, substituted or unsubstituted C _5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic, aromatic or aromatic heterocyclic;

R ₁ and R ₂ in the formula (III) and (V) are independently hydrogen, deuterium, hydroxyl, C _1-5 alkoxy, substituted or unsubstituted C _1-5 alkyl, heteroalkyl;

_R1 and _R2 in the formula (IV) and _R3 in the formulas (III) to (V) are independently hydrogen, hydroxyl, _C1-5 alkoxy, substituted or unsubstituted _C5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic, aromatic or aromatic heterocyclic groups.

As a further improvement of the present invention, R ₁ and R ₂ in the formula (III) and (V) are independently hydrogen, deuterium or methyl.

As a further improvement of the present invention, at least one of R ₁ and R ₂ in the formula (III) and (V) is hydrogen.

As a further improvement of the present invention, the compound represented by formula (I) is selected from the compounds having the following structures:

The compound represented by the formula (II) is selected from the compounds with the following structures:

The formula (III) or its pharmaceutically acceptable salt includes but is not limited to compounds with the following structure:

The compound represented by formula (IV) is selected from the following compounds:

The formula (IV) or its pharmaceutically acceptable salt includes but is not limited to compounds with the following structure:

As a further improvement of the present invention, the compound is selected from:

1-((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)amine)methylacetylglycinate;

Isopropyl ((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)amine)(methoxymethyl)phosphonyl)-L-aminopropanoate;

1-(((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetylglycinate;

1-(((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl palmitate;

1-(((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetyl-L-alaninate;

1-(((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)-2-methylpropylacetylglycinate.

As a further improvement of the present invention, the pharmaceutically acceptable salt of the compound is a salt formed by the compound and an acid: pamoate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.

The present invention also provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable excipient; the active ingredient is one or more of the compounds described above or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable excipient optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

The present invention also provides a use of any one of the above compounds or pharmaceutically acceptable salts thereof, or the above pharmaceutical composition in the preparation of a drug for preventing or treating neurological diseases.

As a further improvement of the present invention, the neurological disease is selected from schizophrenia, depression, memory disorder and functional disorders related to intelligence and learning.

In another aspect, the pharmaceutical composition of the present invention is used in the preparation of a drug for preventing or treating a neurological disease, and optionally the neurological disease is neuralgia. The pharmaceutical composition of the present invention is also used to prepare other drugs for central nervous system diseases, such as drugs for schizophrenia, depression, memory disorders, and functional disorders related to intelligence and learning.

The effective dose of the compound of the present invention can be taken orally together with an inert diluent or a carrier. It can be encapsulated in a gelatin capsule or compressed into tablets. Alternatively, the effective dose of the compound of the present invention can be prepared into an injection solution with a liquid pharmaceutical adjuvant such as sodium chloride and taken in the form of an injection.

The compounds provided by the present invention and their pharmaceutically acceptable salts, solvates and hydrates can be used in combination with pharmaceutically acceptable carriers or diluents to form pharmaceutical preparations. Pharmaceutically acceptable suitable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.

The dosage of the compounds of this invention depends on the type and severity of the disease or condition, and also on the characteristics of the subject, such as general health, age, sex, body weight and drug tolerance. The technician can determine the appropriate dosage based on these or other factors. The effective dose of the central nervous system drugs commonly used is well known to the technician. The total daily dose is usually between about 0.05mg and 2000mg.

The present invention relates to a pharmaceutical composition which can provide about 0.01 to 1000 mg of active ingredient per unit dose. The composition can be administered by any appropriate route, such as oral administration in the form of capsules, parenteral administration in the form of injections, topical administration in the form of creams or lotions, rectal administration in the form of suppositories, and transdermal administration in the form of delivery systems such as patches.

The beneficial effects of the present invention are:

The methylmethylamine derivative preparation provided by the present invention is a derivative of (S)-1-(4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)-N-methylmethylamine, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and can be used to prepare a drug for preventing or treating neurological diseases; and has a long half-life in the microsomal metabolism process, a relatively low clearance rate, and can maintain an effective blood drug concentration in the body for a long time, and can also maintain a certain concentration in the human plasma metabolism process, indicating that the preparation provided by the present invention has good microsomal metabolic stability and good plasma metabolic stability, and can maintain an effective blood drug concentration in the body for a long time.

DETAILED DESCRIPTION

In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is described in detail below in conjunction with specific embodiments.

It should also be noted that, in order to avoid obscuring the present invention due to unnecessary details, only structures and/or processing steps closely related to the scheme of the present invention are shown in the specific embodiments, while other details that are not closely related to the present invention are omitted.

In addition, it should be noted that the terms "comprises", "includes" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or apparatus.

Example 1. (S)-N-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N-methylacetamide (1)

Dissolve (S)-1-(4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)-N-methylmethanamine in dichloromethane, add triethylamine, and add acetyl chloride dropwise under ice bath. After the addition is complete, react at room temperature for 1 hour and monitor by TLC (petroleum ether:ethyl acetate=4:1). After the reaction is complete, add water to quench, then separate the layers, wash the dichloromethane layer with water, dry over anhydrous sodium sulfate, and pass through a silica gel column with eluent (petroleum ether:ethyl acetate=10:1) to obtain a colorless oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.19 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.03-4.98 (m, 1H), 4.12-4.08 (m, 1H), 3.83-3.78 (m, 1H), 3.33-3.29 (m, 2H), 3.07 (s, 3H), 2.94 (s, 3H), 2.83-2.81 (m, 1H), 2.66-2.63 (m, 1H). MS (ESI) m/z 226.1 ([M+H] ⁺ ).

Example 2. (S)-N-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N-methyl-n-tetradecanoic acid amide (2)

The target compound was prepared according to the method of Example 1, using tetradecyl chloride instead of acetyl chloride as the raw material.

The results of the H NMR spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.20 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.03-4.99 (m, 1H), 4.11-4.08 (m, 1H), 3.83-3.79 (m, 1H), 3.32-3.29 (m, 2H), 3.06 (s, 3H), 2.92 (t, J=10.0HZ, 2H), 2.83-2.81 (m, 1H), 2.65-2.63 (m, 1H), 1.72-1.66 (m, 2H), 1.21-1.28 (m, 20H), 0.89 (t, J=10.0HZ, 3H). MS (ESI) m/z 394.3 ([M+H] ⁺ ).

Example 3. (S)-N-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N-methylisopropylamide (3)

The target compound was prepared according to the method of Example 1 using isopropionyl chloride instead of acetyl chloride as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.20 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.04-4.99 (m, 1H), 4.12-4.09 (m, 1H), 3.84-3.78 (m, 1H), 3.33-3.29 (m, 2H), 3.08 (s, 3H), 2.83-2.81 (m, 1H), 2.65-2.62 (m, 1H), 1.85-1.79 (m, 1H), 1.12 (d, J=5.0 HZ, 6H). MS (ESI) m/z 354.2 ([M+H] ⁺ ).

Example 4. (S)-N-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N-methylcyclopropylamide (4)

The target compound was prepared according to the method of Example 1, using cyclopropaneyl chloride instead of acetyl chloride as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.18 (d, J=5.0HZ, 1H), 6.83 (d, J=5.0HZ, 1H), 5.04-5.02 (m, 1H), 4.17-4.12 (m, 1H), 3.77-3.72 (m, 1H), 3.27-3.23 (m, 2H), 3.07 (s, 3H), 2.84-2.80 (m, 1H), 2.65-2.62 (m, 1H), 1.83-1.78 (m, 1H), 0.89-0.75 (m, 4H). MS (ESI) m/z 252.2 ([M+H] ⁺ ).

Example 5. (S)-N-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N-methylcyclohexylamide (5)

The target compound was prepared according to the method of Example 1 using cyclohexanoyl chloride instead of acetyl chloride as raw material.

The results of the hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.19 (d, J=5.0HZ, 1H), 6.83 (d, J=5.0HZ, 1H), 5.04-4.99 (m, 1H), 4.17-4.11 (m, 1H), 3.77-3.68 (m, 1H), 3.27-3.24 (m, 2H), 3.04 (s, 3H), 2.86-2.79 (m, 1H), 2.65-2.58 (m, 1H), 1.86-1.81 (m, 1H), 1.27-1.18 (m, 10H). MS (ESI) m/z 294.2 ([M+H] ⁺ )

Example 6. (S)-N-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N-methylbenzamide (6)

The target compound was prepared according to the method of Example 1 using benzoyl chloride instead of acetyl chloride as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.59-7.51 (m, 2H), 7.42-7.35 (m, 3H), 7.21 (d, J＝5.0HZ, 1H), 6.84 (d, J＝5.0HZ, 1H), 5.02-4.99 (m, 1H), 4.16-4.11 (m, 1H), 3.75-3.68 (m, 1H), 3.27-3.24 (m, 2H), 3.07 (s, 3H), 2.86-2.77 (m, 1H), 2.65-2.62 (m, 1H). MS (ESI) m/z 288.1 ([M+H] ⁺ ).

Example 7. (S)-N-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N-methylfuran-2-amide (7)

The target compound was prepared according to the method of Example 1 using furan-2-yl chloride instead of acetyl chloride as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.56 (d, J＝5.0HZ, 1H), 7.41 (d, J＝5.0HZ, 1H), 7.21 (d, J＝5.0HZ, 1H), 6.89-6.84 (m, 2H), 5.03-4.99 (m, 1H), 4.16-4.12 (m, 1H), 3.75-3.69 (m, 1H), 3.27-3.22 (m, 2H), 3.06 (s, 3H), 2.86-2.78 (m, 1H), 2.65-2.61 (m, 1H). MS (ESI) m/z 278.1 ([M+H] ⁺ ).

Example 8. N ¹ ,N ⁵ -bis(((S)4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)-N ¹ ,N ⁵ -dimethylglutaramide (8)

The target compound was prepared according to the method of Example 1, using glutaryl chloride instead of acetyl chloride as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J＝5.0HZ, 2H), 6.85 (d, J＝5.0HZ, 2H), 5.03-4.99 (m, 2H), 4.16-4.12 (m, 2H), 3.75-3.69 (m, 2H), 3.27-3.22 (m, 4H), 3.07 (s, 6H), 2.96-2.93 (m, 4H), 2.86-2.79 (m, 2H), 2.65-2.63 (m, 2H), 2.34-2.29 (m, 2H). MS (ESI) m/z 463.2 ([M+H] ⁺ ).

Example 9. Dodecyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (9)

Dissolve (S)-1-(4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)-N-methylmethanamine in dichloromethane, add triethylamine, and add dodecyl chloroformate dropwise under ice bath. After the addition is complete, react at room temperature for 1 hour and monitor by TLC (petroleum ether:ethyl acetate=4:1). After the reaction is complete, add water to quench, then separate the layers, wash the dichloromethane layer with water, dry over anhydrous sodium sulfate, and pass through a silica gel column with eluent (petroleum ether:ethyl acetate=10:1) to obtain an oily substance.

The results of the H NMR spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.04-5.01 (m, 1H), 4.15-4.11 (m, 1H), 4.03 (t, J=10.0HZ, 2H), 3.84-3.79 (m, 1H), 3.32-3.29 (m, 2H), 3.07 (s, 3H), 2.83-2.80 (m, 1H), 2.65-2.62 (m, 1H), 1.72-1.67 (m, 2H), 1.26-1.21 (m, 20H), 0.87 (t, J=10.0HZ, 3H). MS (ESI) m/z 396.2 ([M+H] ⁺ ).

Example 10. Hexadecyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (10)

The target compound was prepared according to the method of Example 9, using hexadecyl chloroformate instead of dodecyl chloroformate as raw material.

The results of the H NMR spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0HZ, 1H), 6.85 (d, J=5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.03 (t, J=10.0HZ, 2H), 3.84-3.79 (m, 1H), 3.32-3.29 (m, 2H), 3.07 (s, 3H), 2.83-2.80 (m, 1H), 2.66-2.63 (m, 1H), 1.72-1.69 (m, 2H), 1.26-1.22 (m, 28H), 0.87 (t, J=10.0HZ, 3H). MS (ESI) m/z 452.3 ([M+H] ⁺ ).

Example 11. Heptyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (11)

The target compound was prepared according to the method of Example 9, using heptyl chloroformate instead of dodecyl chloroformate as raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.20(d,J＝5.0HZ,1H),6.85(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.11(m,1H),4.04(t,J＝10.0HZ,2H),3.84-3.78(m,1H),3.32-3.29(m,2H) ),3.08(s,3H),2.84-2.81(m,1H),2.66-2.62(m,1H),1.71-1.69(m,2H),1.26-1.22(m,10H),0.86(t,J＝10.0HZ,3H).MS(ESI)m/z326.2([M+H] ⁺ ).

Example 12. Decyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (12)

The target compound was prepared according to the method of Example 9, using decyl chloroformate instead of dodecyl chloroformate as raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H) ),3.07(s,3H),2.84-2.81(m,1H),2.66-2.64(m,1H),1.72-1.68(m,2H),1.26-1.22(m,16H),0.85(t,J＝10.0HZ,3H).MS(ESI)m/z368.2([M+H] ⁺ ).

Example 13. Octyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (13)

The target compound was prepared according to the method of Example 9, using octyl chloroformate instead of dodecyl chloroformate as raw material.

The results of the H NMR spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.03 (t, J=10.0HZ, 2H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.72-1.68 (m, 2H), 1.26-1.22 (m, 12H), 0.86 (t, J=10.0HZ, 3H). MS (ESI) m/z 340.2([M+H] ⁺ ).

Example 14. Nonyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (14)

The target compound was prepared according to the method of Example 9 using nonyl chloroformate instead of dodecyl chloroformate as raw material.

The results of the hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.03 (t, J=10.0HZ, 2H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.72-1.68 (m, 2H), 1.26-1.22 (m, 14H), 0.86 (t, J=10.0HZ, 3H). MS (ESI) m/z 354.2([M+H] ⁺ ).

Example 15. Cyclopentyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (15)

The target compound was prepared according to the method of Example 9, using cyclopentyl chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0HZ, 1H), 6.87 (d, J=5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.10 (m, 2H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.72-1.68 (m, 2H), 1.29-1.25 (m, 8H). MS (ESI) m/z 296.2 ([M+H] ⁺ ).

Example 16. Hexyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (16)

The target compound was prepared according to the method of Example 9, using hexyl chloroformate instead of dodecyl chloroformate as raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H) ),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,2H),1.26-1.22(m,8H),0.88(t,J＝10.0HZ,3H).MS(ESI)m/z312.2([M+H] ⁺ ).

Example 17. Pentyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (17)

The target compound was prepared according to the method of Example 9, using pentyl chloroformate instead of dodecyl chloroformate as raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.04(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H ),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,2H),1.29-1.24(m,6H),0.89(t,J＝10.0HZ,3H).MS(ESI)m/z298.2([M+H] ⁺ ).

Example 18. Methoxyethyl (S)-((4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (18)

The target compound was prepared according to the method of Example 9, using methoxy chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 4H), 4.06-4.03 (m, 4H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H). MS (ESI) m/z 286.2 ([M+H] ⁺ ).

Example 19. 2-(Benzyloxy)ethyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (19)

The target compound was prepared according to the method of Example 9, using 2-(benzyloxy)ethyl chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.38-7.34 (m, 5H), 7.22 (d, J＝5.0HZ, 1H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.08-4.04 (m, 6H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H). MS (ESI) m/z 362.2 ([M+H] ⁺ ).

Example 20. 2-(Methylsulfonyl)ethyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (20)

The target compound was prepared according to the method of Example 9, using 2-(methylsulfonyl)ethyl chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 HZ, 1H), 6.87 (d, J=5.0 HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.08-4.04 (m, 4H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 4H), 2.67-2.63 (m, 1H). MS (ESI) m/z 334.1 ([M+H] ⁺ ).

Example 21. 2-Ethylbutyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (21)

The target compound was prepared according to the method of Example 9, using 2-ethylbutyl chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.03 (d, J=5.0 HZ, 2H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.72-1.68 (m, 3H), 1.26-1.01 (m, 10H). MS (ESI) m/z 312.2 ([M+H] ⁺ ).

Example 22. Hexane-2-yl (S)-((4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (22)

The target compound was prepared according to the method of Example 9, using hexane-2-yl chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.05-4.03 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.25-1.22 (m, 6H), 0.95-0.89 (m, 6H). MS (ESI) m/z 312.2 ([M+H] ⁺ ).

Example 23. p-Tolyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (23)

The target compound was prepared according to the method of Example 9, using p-tolyl chloroformate instead of dodecyl chloroformate as raw material.

The results of H NMR spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22-7.18 (m, 5H), 6.86 (d, J=5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 4.05-4.03 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 2.26 (s, 3H). MS (ESI) m/z 318.2 ([M+H] ⁺ ).

Example 24. Naphthalene-2-yl (S)-((4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (24)

The target compound was prepared according to the method of Example 9, using naphthyl 2-chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.82-7.77 (m, 5H) 7.51-7.45 (m, 2H) 7.22-7.18 (m, 3H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.11 (m, 1H), 4.05-4.03 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.29 (m, 2H), 3.08 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H). MS (ESI) m/z 354.2 ([M+H] ⁺ ).

Example 25. tert-Butyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (25)

The target compound was prepared according to the method of Example 9, using tert-butyl chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J＝5.0HZ, 1H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.16-4.11 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.29 (m, 2H), 3.08 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.47 (s, 9H). MS (ESI) m/z 284.2 ([M+H] ⁺ ).

Example 26. Ethane-1,2-diylbis(S)-((4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (26)

The target compound was prepared according to the method of Example 9, using 1,2-diyl chloroformate as raw material instead of dodecyl chloroformate.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 HZ, 2H), 6.86 (d, J=5.0 HZ, 2H), 5.04-5.01 (m, 2H), 4.15-4.11 (m, 2H), 4.03 (t, J=10.0 HZ, 4H), 3.84-3.79 (m, 2H), 3.32-3.29 (m, 4H), 3.07 (s, 6H), 2.83-2.80 (m, 2H), 2.65-2.62 (m, 2H). MS (ESI) m/z 481.2 ([M+H] ⁺ ).

Example 27. Butane-1,4-diylbis(S)-((4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbonate (27)

The target compound was prepared according to the method of Example 9, using butane-1,4-diyl chloroformate instead of dodecyl chloroformate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 HZ, 2H), 6.86 (d, J=5.0 HZ, 2H), 5.04-5.01 (m, 2H), 4.15-4.11 (m, 2H), 4.03 (t, J=10.0 HZ, 4H), 3.84-3.79 (m, 2H), 3.32-3.29 (m, 4H), 3.07 (s, 6H), 2.83-2.80 (m, 2H), 2.65-2.62 (m, 2H), 1.29-1.24 (m, 4H). MS (ESI) m/z 509.2 ([M+H] ⁺ ).

Example 28. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyl acetate (28)

Dissolve (S)-1-(4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)-N-methylmethanamine in DMF, add potassium carbonate, and add chloromethyl acetate dropwise. After the addition is complete, react at 80 degrees for 8 hours and monitor by TLC (PE:EA=4:1). After the reaction is complete, add water to quench, then separate the layers, extract with dichloromethane for 3 times, combine the extracts, dry over anhydrous sodium sulfate, and pass through a silica gel column with an eluent (PE:EA=10:1) to obtain an oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J＝5.0HZ, 1H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.45 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 2.38 (s, 3H). MS (ESI) m/z 256.1 ([M+H] ⁺ ).

Example 29. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methylbutyrate (29)

The target compound was prepared according to the method of Example 28, using chloromethyl butyrate instead of chloromethyl acetate as raw material.

The results of the hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.45 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.92 (t, J=5.0HZ, 2H), 2.84-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.65-1.61 (m, 2H), 0.92 (t, J=10.0HZ, 3H). MS (ESI) m/z 284.2 ([M+H] ⁺ ).

Example 30. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyldecanoate (30)

The target compound was prepared according to the method of Example 28, using chloromethyl decanoate instead of chloromethyl acetate as raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.48(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s, 3H),2.96(t,J＝5.0HZ,2H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.67-1.64(m,2H),1.27-1.22(m,12H),0.89(t,J＝10.0HZ,3H).MS(ESI)m/z 368.2( M+H] ⁺ )

Example 31. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyl palmitate (31)

The target compound was prepared according to the method of Example 28, using chloromethyl palmitate instead of chloromethyl acetate as raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.48(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s, 3H),2.96(t,J＝5.0HZ,2H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.67-1.64(m,2H),1.27-1.22(m,24H),0.89(t,J＝10.0HZ,3H).MS(ESI)m/z 452.2([ M+H] ⁺ ).

Example 32. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyloctanoate (32)

The target compound was prepared according to the method of Example 28, using chloromethyl octanoate instead of chloromethyl acetate as raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.47(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3 H),2.97(t,J＝5.0HZ,2H),2.85-2.81(m,1H),2.67-2.64(m,1H),1.67-1.63(m,2H),1.27-1.23(m,8H),0.90(t,J＝10.0HZ,3H).MS(ESI)m/z 340.2([M+ H] ⁺ ).

Example 33. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyl tert-butyrate (33)

The target compound was prepared according to the method of Example 28 using chloromethyl tert-butyrate instead of chloromethyl acetate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J＝5.0HZ, 1H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.47 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.85-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.26 (s, 9H). MS (ESI) m/z 298.2 ([M+H] ⁺ ).

Example 34. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyl-3-methylbutyrate (34)

The target compound was prepared according to the method of Example 28, using 3-methylbutyric acid chloromethyl ester instead of chloromethyl acetate as raw material.

The results of the hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J = 5.0HZ, 1H), 6.86 (d, J = 5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.47 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.97 (t, J = 5.0HZ, 2H), 2.85-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.69-1.65 (m, 1H), 0.92 (d, J = 5.0HZ, 6H). MS (ESI) m/z 298.2 ([M+H] ⁺ ).

Example 35. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methylbenzoate (35)

The target compound was prepared according to the method of Example 28 using chloromethyl benzoate instead of chloromethyl acetate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.59-7.51 (m, 2H), 7.42-7.35 (m, 3H), 7.21 (d, J＝5.0HZ, 1H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.47 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.85-2.81 (m, 1H), 2.67-2.64 (m, 1H). MS (ESI) m/z 318.2 ([M+H] ⁺ ).

Example 36. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)-methylcyclopentyl ester (36)

The target compound was prepared according to the method of Example 28, using chloromethyl cyclopentanoate instead of chloromethyl acetate as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.05-5.01 (m, 1H), 4.47 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.89-2.83 (m, 2H), 2.67-2.64 (m, 1H), 1.93-1.65 (m, 8H). MS (ESI) m/z 310.2 ([M+H] ⁺ ).

Example 37. 1-((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)ethyl-decanoic acid methyl ester (37)

The H NMR spectrum results of this example show that the target compound was prepared according to the method of Example 28 using 1-chloroethyldecanoate instead of chloromethyl acetate as the raw material.

The results of the nuclear magnetic hydrogen spectrum of this example are: ¹ H NMR (500MHz, CDCl ₃ )δ7.22(d,J＝5.0HZ,1H),6.88(d,J＝5.0HZ,1H),5.06-5.02(m,1H),4.46-4.44(m,1H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3. 09(s,3H),2.96(t,J＝5.0HZ,2H),2.86-2.81(m,1H),2.67-2.63(m,1H),1.67-1.62(m,2H),1.27-1.21(m,12H),0.92-0.89(m,6H).MS(ESI)m/z382. 2([M+H] ⁺ ).

Example 38. 1-((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methylacetylglycinate (38)

Preparation of (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methanol

(1) 0.8 g of compound 18 [methoxyethyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate] was dissolved in 50 ml of dry THF and cooled in an ice bath. 0.4 g of sodium borohydride was added in batches over a period of about 15 minutes. After the addition was complete, the mixture was heated to room temperature and reacted for 2 h. TLC monitoring (petroleum ether:ethyl acetate=6:1) was performed. After the reaction was completed, the mixture was quenched with ice water, and the solvent was then dried by rotary evaporation. The mixture was extracted with dichloromethane three times. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and passed through a silica gel column with an eluent (petroleum ether:ethyl acetate=12:1) to obtain a colorless oil.

Preparation of 1-((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methylacetylglycine ester (38)

(2) (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methanol was dissolved in dichloromethane, DMAP was added, EDC was added in batches, and then acetylglycine was added. After the addition, the mixture was reacted at room temperature for 6 h and monitored by TLC (petroleum ether:ethyl acetate=4:1). After the reaction was completed, the dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and passed through a silica gel column with an eluent (petroleum ether:ethyl acetate=10:1) to obtain a colorless oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.05-5.02 (m, 1H), 4.46 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.67-2.62 (m, 3H), 2.38 (s, 3H). MS (ESI) m/z 313.1 ([M+H] ⁺ ).

Example 39. 1-((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyl 4-aminobutyrate trifluoroacetate (39)

(1) (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methanol was dissolved in dichloromethane, DMAP was added, EDC was added in batches, and then BOC aminobutyric acid was added. After the addition, the reaction was carried out at room temperature for 6 hours and monitored by TLC (petroleum ether:ethyl acetate=4:1). After the reaction was completed, the dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and passed through a silica gel column with an eluent (petroleum ether:ethyl acetate=10:1) to obtain a colorless oil.

(2) In a reaction flask, add 200 mg of the product of step 1, 3 mL of trifluoroacetic acid and 1.5 mL of dichloromethane, and stir at room temperature for 0.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 170 mg of a colorless oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J＝5.0HZ, 1H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.02 (m, 1H), 4.46 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 2H), 2.67-2.61 (m, 3H), 1.45-1.38 (m, 2H). MS (ESI) m/z 299.2 ([M+H] ⁺ ).

Example 40. (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyl(2-(1-(aminomethyl)cyclohexyl)ethyl ester trifluoroacetate (40)

(1) (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methanol was dissolved in dichloromethane, DMAP was added, EDC was added in batches, and then 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid was added. After the addition, the mixture was reacted at room temperature for 8 hours and monitored by TLC (petroleum ether:ethyl acetate=4:1). After the reaction was completed, the dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and passed through a silica gel column with an eluent (petroleum ether:ethyl acetate=10:1) to obtain a colorless oil.

(2) In a reaction flask, add 200 mg of the product of step 1, 3 mL of trifluoroacetic acid and 1.5 mL of dichloromethane, and stir at room temperature for 0.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 180 mg of a colorless oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.05-5.02 (m, 1H), 4.46 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 2H), 2.67-2.61 (m, 3H), 1.61-1.38 (m, 10H). MS (ESI) m/z 367.2 ([M+H] ⁺ ).

Example 41. ((((S)-4,7-Dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methyl-3-(aminomethyl)-5-methylhexyl ester trifluoroacetate (41)

(1) (S)-(((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)methanol was dissolved in dichloromethane, DMAP was added, EDC was added in batches, and then 3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoic acid was added. After the addition, the mixture was reacted at room temperature for 8 hours and monitored by TLC (petroleum ether:ethyl acetate=4:1). After the reaction was completed, the dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and passed through a silica gel column with an eluent (petroleum ether:ethyl acetate=10:1) to obtain a colorless oil.

(2) In a reaction flask, add 200 mg of the product of step 1, 3 mL of trifluoroacetic acid and 1.5 mL of dichloromethane, and stir at room temperature for 0.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 160 mg of a colorless oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J＝5.0HZ, 1H), 6.86 (d, J＝5.0HZ, 1H), 5.05-5.02 (m, 1H), 4.46 (s, 2H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 2H), 2.67-2.61 (m, 3H), 1.69-1.61 (m, 2H), 1.24-1.04 (m, 3H), 0.92-0.88 (m, 6H). MS (ESI) m/z 355.2 ([M+H] ⁺ ).

Example 42. Methyl ((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)(methoxymethyl)phosphonyl)-L-aminopropanoate (42)

Compound (methoxymethyl)phosphonic acid dichloride (1.2 g) was dissolved in dry dichloromethane (10 mL), cooled to -30 ° C under nitrogen protection, and a mixture of dichloromethane solution (5 mL) of L-alanine methyl ester (1.0 g) and triethylamine (3.0 g) was slowly added dropwise. After the addition was complete, the reaction was continued at -30 ° C for 30 min, and compound 114A (1.150 g, 3.491 mmol) was added, and the temperature was naturally raised to room temperature and then heated to reflux for 1 h. Saturated sodium dihydrogen phosphate aqueous solution (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and the liquid was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:1 to 1:4) to obtain compound 41 as an oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.05-4.98 (m, 3H), 4.48 (s, 6H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.67-2.61 (m, 2H), 1.52 (d, J=5.0 HZ, 3H). MS (ESI) m/z 378.2 ([M+H] ⁺ ).

Example 43. Isopropyl ((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)(methoxymethyl)phosphonyl)-L-aminopropanoate (43)

The target compound was prepared according to the method of Example 42 using L-alanine isopropyl ester instead of L-alanine methyl ester as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0HZ, 1H), 6.86 (d, J=5.0HZ, 1H), 5.05-4.98 (m, 3H), 4.48-4.42 (m, 4H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.67-2.61 (m, 2H), 1.52-1.39 (m, 9H). MS (ESI) m/z 405.2 ([M+H] ⁺ ).

Example 44. Isopropyl (((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)(phenoxymethyl)phosphonyl)-L-aminopropanoate (44)

The target compound was prepared according to the method of Example 43 using (phenoxymethyl)phosphonic dichloride instead of (methoxymethyl)phosphonic dichloride as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.36-7.31 (m, 2H), 7.24-7.19 (m, 4H), 6.86 (d, J＝5.0HZ, 1H), 5.05-4.98 (m, 3H), 4.48-4.42 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.67-2.61 (m, 2H), 1.52-1.39 (m, 9H). MS (ESI) m/z 467.2 ([M+H] ⁺ ).

Example 45. tert-Butyl ((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)amine)(methoxymethyl)phosphonyl)-L-aminopropanoate (45)

The target compound was prepared according to the method of Example 42 using L-alanine tert-butyl ester instead of L-alanine methyl ester as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 HZ, 1H), 6.86 (d, J=5.0 HZ, 1H), 5.05-4.98 (m, 3H), 4.48-4.42 (m, 3H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.67-2.61 (m, 2H), 1.54-1.39 (m, 12H). MS (ESI) m/z 419.2 ([M+H] ⁺ ).

Example 46. Phenyl (((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)amine)(methoxymethyl)phosphonyl)-L-aminopropanoate (46)

The target compound was prepared according to the method of Example 42 using L-alanine phenyl ester instead of L-alanine methyl ester as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.39-7.31 (m, 2H), 7.25-7.19 (m, 4H), 6.86 (d, J＝5.0HZ, 1H), 5.05-4.98 (m, 3H), 4.17-4.12 (m, 4H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.67-2.61 (m, 2H), 1.52-1.39 (m, 3H). MS (ESI) m/z 439.2 ([M+H] ⁺ ).

Example 47. (S)-((((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)methyl-2-ethylbutyrate (47)

Dissolve (S)-1-(4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)-N-methylmethanamine in dichloromethane, add triethylamine, and add chloromethyl chloroformate dropwise under ice bath. After the addition is complete, react at room temperature for 1 hour and monitor by TLC (petroleum ether:ethyl acetate=4:1). After the reaction is complete, add water to quench, then separate the layers, wash the dichloromethane layer with water, dry over anhydrous sodium sulfate, and pass through a silica gel column with eluent (petroleum ether:ethyl acetate=10:1) to obtain an oily substance.

Dissolve 1.5 g of the first step product and 0.44 g of TBAI in 8 mL of DMF, add 2 g of valproic acid, and heat at 60°C overnight under argon protection. Stop the reaction, add 30 mL of saturated NaCl and 40 mL of ethyl acetate and stir, separate the organic phase, wash with saturated NaC (30 mL), wash with water (stirring with 30 mL), wash with saturated NaHCO ₃ (30 mL), wash with saturated NaCl (30 mL), dry with anhydrous Na ₂ SO ₄ , filter, spin dry, and chromatograph on a silica gel column (petroleum ether/ethyl acetate = 3:1) to obtain an oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.92-6.87 (m, 3H), 5.12-5.01 (m, 1H), 4.16-4.11 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.29 (m, 2H), 3.08 (s, 3H), 2.86-2.81 (m, 1H), 2.67-2.59 (m, 2H), 1.47-1.32 (m, 4H), 0.90 (t, J=5.0 Hz, 6H). MS (ESI) m/z 356.2 ([M+H] ⁺ ).

Example 48. (S)-((((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)methylnicotinate (48)

The target compound was prepared according to the method of Example 47 using niacin instead of valproic acid as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.59-7.45 (m, 2H), 7.39-7.35 (m, 1H), 7.21 (d, J＝5.0HZ, 1H), 6.92-6.87 (m, 3H), 5.05-5.01 (m, 3H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.85-2.81 (m, 1H), 2.67-2.64 (m, 1H). MS (ESI) m/z 363.2 ([M+H] ⁺ ).

Example 49. (S)-((((4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)methyldecanoate (49)

The target compound was prepared according to the method of Example 47 using decanoic acid instead of valproic acid as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0HZ, 1H), 6.92-6.87 (m, 3H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), , 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 2.45 (t, J=5.0HZ, 2H), 1.27-1.22 (m, 14H), 0.92 (t, J=10.0HZ, 3H). MS (ESI) m/z 412.2 ([M+H] ⁺ ).

Example 50. (S)-((((4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)methyl dodecanoate (50)

The target compound was prepared according to the method of Example 47 using dodecanoic acid instead of valproic acid as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0HZ, 1H), 6.92-6.87 (m, 3H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), , 2.86-2.81 (m, 1H), 2.67-2.64 (m, 1H), 2.43 (t, J=5.0HZ, 2H), 1.27-1.21 (m, 18H), 0.91 (t, J=10.0HZ, 3H). MS (ESI) m/z 440.2 ([M+H] ⁺ ).

Example 51. ((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)methyl-3-(aminomethyl)-5-methylhexyl ester trifluoroacetate (51)

Dissolve 1.5 g of chloromethyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate and 0.44 g of TBAI in 8 mL of DMF, add 2 g of 3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoic acid, and heat at 60°C overnight under argon protection. Stop the reaction, add 30 mL of saturated NaCl and 40 mL of ethyl acetate to stir, separate the organic phase, wash with saturated NaC (30 mL), wash with water (stirring 30 mL), wash with saturated NaHCO ₃ (30 mL), wash with saturated NaCl (30 mL), dry with anhydrous Na ₂ SO ₄ , filter, spin dry, and chromatograph on a silica gel column (petroleum ether/ethyl acetate = 5:1) to obtain an oil.

(2) In a reaction flask, add 220 mg of the product of step 1, 3 mL of trifluoroacetic acid and 1.5 mL of dichloromethane, and stir at room temperature for 0.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 160 mg of a colorless oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.23 (d, J=5.0 Hz, 1H), 6.92-6.87 (m, 3H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 2H), 2.67-2.60 (m, 3H), 1.69-1.61 (m, 2H), 1.21-1.02 (m, 3H), 0.93-0.88 (m, 6H). MS (ESI) m/z 399.2 ([M+H] ⁺ ).

Example 52. ((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)methyl(2-(1-(aminomethyl)cyclohexyl)ethyl ester trifluoroacetate (52)

(1) Dissolve 1.5 g of chloromethyl (S)-((4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbonate and 0.44 g of TBAI in 8 mL of DMF, add 2 g of 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid, and heat at 60°C overnight under argon protection. Stop the reaction, add 30 mL of saturated NaCl and 40 mL of ethyl acetate and stir, separate the organic phase, wash with saturated NaC (30 mL), wash with water (stirring 30 mL), wash with saturated NaHCO ₃ (30 mL), wash with saturated NaCl (30 mL), dry over anhydrous Na ₂ SO ₄ , filter, spin dry, and chromatograph on a silica gel column (petroleum ether/ethyl acetate = 5:1) to obtain an oil.

(2) In a reaction flask, add 220 mg of the product of step 1, 3 mL of trifluoroacetic acid and 1.5 mL of dichloromethane, and stir at room temperature for 0.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 180 mg of a colorless oil.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.92-6.87 (m, 3H), 5.05-5.01 (m, 1H), 4.16-4.11 (m, 1H), 3.84-3.80 (m, 1H), 3.32-3.26 (m, 2H), 3.09 (s, 3H), 2.86-2.81 (m, 2H), 2.67-2.60 (m, 3H), 1.59-1.39 (m, 10H). MS (ESI) m/z 411.2 ([M+H] ⁺ ).

Example 53. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetylglycinate (53)

The target compound was prepared according to the method of Example 47 using acetylglycine instead of valproic acid and 1-chloroethyl chloroformate instead of chloromethyl chloroformate as raw materials.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.20 (d, J=5.0 Hz, 1H), 6.92-6.87 (m, 2H), 5.05-4.96 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 2H), 3.36-3.28 (m, 1H), 3.09 (s, 3H), , 2.86-2.82 (m, 1H), 2.69-2.64 (m, 1H), 2.07 (s, 3H), 1.86-1.85 (m, 2H) 1.67-1.61 (m, 3H). MS (ESI) m/z 371.2 ([M+H] ⁺ ).

Example 54. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetyl-L-proline ester (54)

The target compound was prepared according to the method of Example 53 using N-acetyl-L-proline instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.20 (d, J=5.0 Hz, 1H), 6.86-6.82 (m, 2H), 5.04-4.97 (m, 1H), 4.48-4.36 (m, 1H), 4.16-4.12 (m, 1H), 3.79-3.62 (m, 4H), 3.36-3.28 (m, 1H), 3.06 (s, 3H), 2.84-2.82 (m, 1H), 2.68-2.64 (m, 1H), 2.07-1.95 (m, 6H), 1.52-1.48 (m, 3H). MS (ESI) m/z 411.2 ([M+H] ⁺ ).

Example 55. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl(3-methylbutanoyl)glycinate (55)

The target compound was prepared according to the method of Example 53 using N-isovalerylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.86-6.81 (m, 2H), 5.05-4.97 (m, 1H), 4.48-4.36 (m, 2H), 4.16-4.12 (m, 1H), 3.79-3.62 (m, 4H), 3.36-3.28 (m, 1H), 3.06 (s, 3H), , 2.84-2.82 (m, 1H), 2.68-2.64 (m, 1H), 2.07-1.95 (m, 1H), 1.52-1.48 (m, 3H), 0.99-0.92 (m, 6H). MS (ESI) m/z 413.2 ([M+H] ⁺ ).

Example 56. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethylphenylacetylglycinate (56)

The target compound was prepared according to the method of Example 53 using phenylacetylglycine instead of acetylglycine as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.23-7.12 (m, 6H), 6.87-6.81 (m, 2H), 5.06-4.97 (m, 1H), 4.48-4.36 (m, 2H), 4.16-4.12 (m, 1H), 3.79-3.62 (m, 4H), 3.36-3.28 (m, 1H), 3.06 (s, 3H), 2.84-2.82 (m, 1H), 2.68-2.64 (m, 1H), 2.27-2.21 (m, 2H), 1.52-1.48 (m, 3H). MS (ESI) m/z 413.2 ([M+H] ⁺ ).

Example 57. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetyl-aminopropanoate (57)

The target compound was prepared according to the method of Example 53 using N-acetyl-D-alanine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.89-6.82 (m, 2H), 5.06-4.97 (m, 1H), 4.48-4.36 (m, 2H), 4.16-4.12 (m, 1H), 3.79-3.62 (m, 4H), 3.36-3.28 (m, 1H), 3.06 (s, 3H), 2.84-2.82 (m, 1H), 2.68-2.64 (m, 1H), 2.27-2.18 (m, 1H), 2.07 (s, 3H), 1.52-1.48 (m, 3H). MS (ESI) m/z 385.2 ([M+H] ⁺ ).

Example 58. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethylbenzoylglycinate (58)

The target compound was prepared according to the method of Example 53 using benzoylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.56-7.49 (m, 2H) 7.21-7.12 (m, 4H), 6.87-6.81 (m, 2H), 5.06-4.99 (m, 1H), 4.48-4.39 (m, 2H), 4.16-4.12 (m, 1H), 3.79-3.63 (m, 4H), 3.36-3.29 (m, 1H), 3.07 (s, 3H), 2.84-2.81 (m, 1H), 2.68-2.62 (m, 1H), 1.52-1.49 (m, 3H). MS (ESI) m/z 435.2 ([M+H] ⁺ ).

Example 59. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl palmitate (59)

The target compound was prepared according to the method of Example 53 using palmitic acid instead of acetylglycine as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.89-2.82 (m, 3H), 2.67-2.64 (m, 1H), 1.67-1.62 (m, 2H), 1.27-1.21 (m, 24H), 0.93-0.89 (m, 6H). MS (ESI) m/z 510.3 ([M+H] ⁺ ).

Example 60. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl dodecanoate (60)

The target compound was prepared according to the method of Example 53 using dodecanoic acid instead of acetylglycine as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.06-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.83-3.72 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.87-2.81 (m, 1H), 2.67-2.64 (m, 1H), 1.67-1.62 (m, 2H), 1.27-1.21 (m, 14H), 0.93-0.89 (m, 6H). MS (ESI) m/z 454.3 ([M+H] ⁺ ).

Example 61. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyldecanoate (61)

The target compound was prepared according to the method of Example 53, using decanoic acid instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.69 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.89-2.81 (m, 1H), 2.67-2.62 (m, 1H), 1.67-1.61 (m, 2H), 1.27-1.20 (m, 12H), 0.94-0.88 (m, 6H). MS (ESI) m/z 426.2 ([M+H] ⁺ ).

Example 62. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethylcarbamoylglycinate (62)

The target compound was prepared according to the method of Example 53 using formylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.80 (m, 2H), 5.07-5.01 (m, 1H), 4.16-4.11 (m, 1H), 3.84-3.72 (m, 3H), 3.32-3.29 (m, 2H), 3.08 (s, 3H), 2.89-2.80 (m, 1H), 2.67-2.62 (m, 1H), 0.95-0.92 (m, 3H). MS (ESI) m/z 457.1 ([M+H] ⁺ ).

Exact Mass:356.10.

Example 63. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethylhexanoyl glycinate (63)

The target compound was prepared according to the method of Example 53, using hexanoylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.73 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.87-2.81 (m, 1H), 2.67-2.58 (m, 3H), 1.67-1.61 (m, 2H), 1.29-1.22 (m, 4H), 0.97-0.92 (m, 6H). MS (ESI) m/z 427.2 ([M+H] ⁺ ).

Example 64. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl 2-((N-phthalimido)acetate (64)

The target compound was prepared according to the method of Example 53, using phthalylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.26-7.18 (m, 5H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.94-3.73 (m, 3H), 3.32-3.26 (m, 2H), 3.08 (s, 3H), 2.87-2.81 (m, 1H), 2.67-2.58 (m, 1H), 0.96-0.91 (m, 3H). MS (ESI) m/z 459.2 ([M+H] ⁺ ).

Example 65. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl((E)-2-methylbut-2-enoyl)glycinate (65)

The target compound was prepared according to the method of Example 53 using crotonylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 6.46-6.35 (m, 1H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.94-3.73 (m, 3H), 3.32-3.26 (m, 2H), 3.08 (s, 3H), 2.87-2.81 (m, 1H), 2.67-2.38 (m, 7H), 0.96-0.91 (m, 3H). MS (ESI) m/z 411.1 ([M+H] ⁺ ).

Example 66. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyldodecanoylglycine (66)

The target compound was prepared according to the method of Example 53, using dodecylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 3H), 3.84-3.69 (m, 3H), 3.32-3.28 (m, 1H), 3.09 (s, 3H), 2.89-2.81 (m, 1H), 2.67-2.62 (m, 3H), 1.67-1.62 (m, 2H), 1.27-1.20 (m, 16H), 0.94-0.88 (m, 6H). MS (ESI) m/z 511.3 ([M+H] ⁺ ).

Example 67. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl-acetamidopropanoate (67)

The target compound was prepared according to the method of Example 53 using N-acetyl-β-alanine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.94-3.73 (m, 3H), 3.32-3.26 (m, 3H), 3.08 (s, 3H), 2.87-2.81 (m, 1H), 2.67-2.38 (m, 3H), 1.96-1.71 (m, 6H). MS (ESI) m/z 385.1 ([M+H] ⁺ ).

Example 68. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetyl-L-alaninate (68)

The target compound was prepared according to the method of Example 53 using N-acetyl-L-alanine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.34-4.12 (m, 2H), 3.94-3.73 (m, 3H), 3.32-3.26 (m, 1H), 3.08 (s, 3H), 2.87-2.81 (m, 1H), 2.67-2.38 (m, 1H), 1.96-1.51 (m, 9H). MS (ESI) m/z 385.1 ([M+H] ⁺ ).

Example 69. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl isobutyryl-L-alaninate (69)

The target compound was prepared according to the method of Example 53 using N-isobutyryl-L-alanine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.36-4.12 (m, 2H), 3.94-3.76 (m, 3H), 3.32-3.27 (m, 1H), 3.08 (s, 3H), 2.87-2.82 (m, 1H), 2.67-2.39 (m, 2H), 1.96-1.51 (m, 12H). MS (ESI) m/z 413.2 ([M+H] ⁺ ).

Example 70. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetylphenylalaninate (70)

The target compound was prepared according to the method of Example 53 using N-acetylphenylalanine instead of acetylglycine as raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22-7.11 (m, 6H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.45-4.12 (m, 2H), 3.94-3.76 (m, 2H), 3.32-3.27 (m, 3H), 3.08 (s, 3H), 2.87-2.82 (m, 1H), 2.67-2.39 (m, 2H), 1.96-1.51 (m, 6H). MS (ESI) m/z 461.2 ([M+H] ⁺ ).

Example 71. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetyltryptophanate (71)

The target compound was prepared according to the method of Example 53 using acetyltryptophan instead of acetylglycine as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.65-7.45 (m, 2H), 7.26-7.15 (m, 3H), 6.87-6.81 (m, 2H), 5.07-5.02 (m, 1H), 4.45-4.15 (m, 1H), 3.94-3.79 (m, 2H), 3.32-3.28 (m, 3H), 3.09 (s, 3H), 2.89-2.82 (m, 1H), 2.67-2.42 (m, 2H), 1.96-1.59 (m, 6H). MS (ESI) m/z 500.2 ([M+H] ⁺ ).

Example 72. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetyl valine ester (72)

The target compound was prepared according to the method of Example 53, using acetylvaline instead of acetylglycine as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.23 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.07-5.02 (m, 1H), 4.45-4.15 (m, 1H), 3.94-3.79 (m, 2H), 3.32-3.28 (m, 3H), 3.09 (s, 3H), 2.89-2.82 (m, 1H), 2.67-2.42 (m, 1H), 1.96-1.59 (m, 6H), 0.99-0.92 (m, 6H). MS (ESI) m/z 413.2 ([M+H] ⁺ ).

Example 73. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl N-acetyl-N-methylglycinate (73)

The target compound was prepared according to the method of Example 53, using N-acetyl-N-methylglycine instead of acetylglycine.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.92-6.86 (m, 2H), 5.05-4.99 (m, 1H), 4.16-4.11 (m, 1H), 3.84-3.79 (m, 2H), 3.36-3.29 (m, 3H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.69-2.62 (m, 1H), 2.07 (s, 3H), 1.86-1.85 (m, 2H) 1.67-1.61 (m, 3H). MS (ESI) m/z 385.1 ([M+H] ⁺ ).

Example 74. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl(2,2,2-trifluoroacetyl)glycinate (74)

The target compound was prepared according to the method of Example 53 using trifluoroacetylglycine instead of acetylglycine.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.23 (d, J=5.0 Hz, 1H), 6.95-6.86 (m, 2H), 5.06-4.99 (m, 1H), 4.18-4.14 (m, 1H), 3.84-3.79 (m, 2H), 3.36-3.29 (m, 3H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.72-2.62 (m, 1H), 1.96-1.89 (m, 3H). MS (ESI) m/z 425.1 ([M+H] ⁺ ).

Example 75. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl dimethylglycinate (75)

The target compound was prepared according to the method of Example 53, using dimethylglycine instead of acetylglycine.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.95-6.86 (m, 2H), 5.06-5.01 (m, 1H), 4.18-4.12 (m, 1H), 3.84-3.65 (m, 8H), 3.36-3.29 (m, 3H), 3.09 (s, 3H), 2.87-2.81 (m, 1H), 2.72-2.62 (m, 1H), 1.92-1.86 (m, 3H). MS (ESI) m/z 357.1 ([M+H] ⁺ ).

Example 76. 1-((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl-3-(aminomethyl)-5-methylhexyl trifluoroacetate (76)

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.92-6.86 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.86-2.82 (m, 2H), 2.67-2.60 (m, 3H), 1.89-1.61 (m, 5H), 1.21-1.02 (m, 3H), 0.93-0.88 (m, 6H). MS (ESI) m/z 413.2 ([M+H] ⁺ ).

Example 77. 1-((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl(2-(1-(aminomethyl)cyclohexyl)ethyl ester trifluoroacetate (77)

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.94-6.87 (m, 2H), 5.06-5.01 (m, 1H), 4.16-4.10 (m, 1H), 3.84-3.81 (m, 1H), 3.32-3.26 (m, 2H), 3.08 (s, 3H), 2.86-2.80 (m, 2H), 2.67-2.60 (m, 3H), 1.89-1.76 (m, 3H), 1.59-1.39 (m, 10H). MS (ESI) m/z 425.2 ([M+H] ⁺ ).

Example 78. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)propylacetyl glycinate (78)

The target compound was prepared according to the method of Example 47 using acetylglycine instead of valproic acid and 1-chloropropyl chloroformate instead of chloromethyl chloroformate as raw materials.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.92-6.87 (m, 2H), 5.05-4.96 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 2H), 3.36-3.28 (m, 1H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.69-2.64 (m, 1H), 2.07 (s, 3H), 1.86-1.62 (m, 8H). MS (ESI) m/z 385.2 ([M+H] ⁺ ).

Example 79. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)propylacetyl-L-aminopropionate (79)

The target compound was prepared according to the method of Example 78 using N-acetyl-L-alanine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.89-6.82 (m, 2H), 5.06-4.97 (m, 1H), 4.48-4.36 (m, 2H), 4.16-4.12 (m, 1H), 3.79-3.62 (m, 2H), 3.36-3.28 (m, 1H), 3.06 (s, 3H), 2.84-2.82 (m, 1H), 2.68-2.64 (m, 1H), 2.27-2.18 (m, 1H), 2.07 (s, 3H), 1.79-1.52 (m, 6H). MS (ESI) m/z 399.2 ([M+H] ⁺ ).

Example 80. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)propylbenzoylglycinate (80)

The target compound was prepared according to the method of Example 78 using benzoylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.56-7.48 (m, 2H) 7.21-7.11 (m, 4H), 6.87-6.81 (m, 2H), 5.06-5.01 (m, 1H), 4.48-4.39 (m, 1H), 4.16-4.12 (m, 1H), 3.79-3.63 (m, 4H), 3.36-3.29 (m, 1H), 3.07 (s, 3H), 2.84-2.81 (m, 1H), 2.68-2.62 (m, 1H), 1.79-1.52 (m, 6H). MS (ESI) m/z 447.2 ([M+H] ⁺ ).

Example 81. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)propyldecanoate (81)

The target compound was prepared according to the method of Example 78 using decanoic acid instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.69 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.89-2.81 (m, 1H), 2.67-2.62 (m, 1H), 1.88-1.61 (m, 4H), 1.27-1.20 (m, 12H), 0.99-0.88 (m, 6H). MS (ESI) m/z 440.2 ([M+H] ⁺ ).

Example 82. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)propyl palmitate (82)

The target compound was prepared according to the method of Example 78 using palmitic acid instead of acetylglycine as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.89-2.82 (m, 3H), 2.67-2.64 (m, 1H), 1.89-1.62 (m, 4H), 1.27-1.20 (m, 24H), 0.93-0.88 (m, 6H). MS (ESI) m/z 510.3 ([M+H] ⁺ ).

Example 83. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)-2-methylpropylacetylglycinate (83)

The target compound was prepared according to the method of Example 47 using acetylglycine instead of valproic acid and 1-chloro-2-methylpropyl chloroformate instead of chloromethyl chloroformate as raw materials.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.95-6.87 (m, 2H), 5.06-4.96 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 2H), 3.36-3.28 (m, 1H), 3.09 (s, 3H), 2.86-2.82 (m, 1H), 2.69-2.64 (m, 1H), 2.07 (s, 3H), 1.86-1.62 (m, 10H). MS (ESI) m/z 399.2 ([M+H] ⁺ ).

Example 84. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)-2-methylpropylacetyl-L-aminopropanoate (84)

The target compound was prepared according to the method of Example 83 using N-acetyl-L-alanine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.89-6.82 (m, 2H), 5.06-4.97 (m, 1H), 4.48-4.36 (m, 2H), 4.16-4.12 (m, 1H), 3.79-3.62 (m, 2H), 3.36-3.28 (m, 1H), 3.06 (s, 3H), 2.84-2.82 (m, 1H), 2.68-2.64 (m, 1H), 2.07 (s, 3H), 1.89-1.57 (m, 6H). MS (ESI) m/z 413.2 ([M+H] ⁺ ).

Example 85. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)-2-propylbenzoylglycinate (85)

The target compound was prepared according to the method of Example 83 using benzoylglycine instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.56-7.48 (m, 2H) 7.21-7.11 (m, 4H), 6.87-6.81 (m, 2H), 5.06-5.01 (m, 1H), 4.48-4.39 (m, 1H), 4.16-4.12 (m, 1H), 3.79-3.63 (m, 3H), 3.36-3.29 (m, 1H), 3.07 (s, 3H), 2.84-2.81 (m, 1H), 2.68-2.62 (m, 1H), 1.79-1.52 (m, 6H). MS (ESI) m/z 461.2 ([M+H] ⁺ ).

Example 86. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)-2-propyldecanoate (86)

The target compound was prepared according to the method of Example 83 using decanoic acid instead of acetylglycine as the starting material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.22 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.69 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.89-2.81 (m, 1H), 2.67-2.62 (m, 1H), 1.88-1.61 (m, 3H), 1.27-1.20 (m, 12H), 0.99-0.90 (m, 9H). MS (ESI) m/z 454.2 ([M+H] ⁺ ).

Example 87. 1-(((((S)-4,7-dihydro-5H-thiophene[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)-2-propyl palmitate (87)

The target compound was prepared according to the method of Example 83 using palmitic acid instead of acetylglycine as the raw material.

The results of hydrogen nuclear magnetic spectrum of this example are: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.21 (d, J=5.0 Hz, 1H), 6.87-6.81 (m, 2H), 5.05-5.01 (m, 1H), 4.16-4.12 (m, 1H), 3.84-3.79 (m, 3H), 3.32-3.28 (m, 2H), 3.09 (s, 3H), 2.89-2.82 (m, 3H), 2.67-2.64 (m, 1H), 1.89-1.62 (m, 3H), 1.27-1.20 (m, 24H), 0.96-0.88 (m, 9H). MS (ESI) m/z 524.3 ([M+H] ⁺ ).

Example 88. Metabolic stability in microsomes

Experimental system

(1) Prepare stock solutions of the test compound and positive control at a concentration of 10 mM using DMSO as a diluent, and then dilute all stock solutions to a working concentration of 0.25 mM using 70% acetonitrile;

(2) The cofactor used in the test was the NADPH regeneration system, which consisted of 6.5 mM NADP, 16.5 mM G-6-P, and 3 U/mL G-6-PD;

(3) The quencher consists of acetonitrile containing toluenesulfonamide and propanol (used as internal standard);

(4) The buffer used in the test was 100 mM phosphate buffer containing 3.3 mM MgCl ₂ ;

(5) The mixture contained 0.2 mg/mL liver microsomal protein and 1 μM test compound/positive control and was incubated in 100 mM potassium phosphate buffer.

Experimental methods

(1) Prepare 0 minute samples by adding 80 μL aliquots of each incubation mixture to 300 μL quenching reagent to precipitate proteins. Vortex the samples and then add 20 μL aliquots of NADPH regeneration system.

(2) The reaction was initiated by adding 130 μL of NADPH regeneration system to 520 μL of each incubation mixture. The final incubation conditions achieved in 650 μL were: 0.2 mg/mL microsomal protein, 1 μM test substance/positive control, 1.3 mM NADP, 3.3 mM 6-phosphate glucose, 0.6 U/mL 6-phosphate glucose dehydrogenase.

(3) The mixture was incubated in a 37°C water bath with gentle shaking. At 5, 10, 30, and 60 minutes, 100 μL aliquots of each mixture were transferred to a clean 96-well plate containing 300 μL of quencher to precipitate proteins, followed by centrifugation (5000×g, 10 minutes).

(4) Place 100 μL of the supernatant into a 96-well assay plate pre-filled with 300 μL of ultrapure water, and then analyze by LC-MS/MS.

Table 1 Metabolism of compounds in microsomes

Table 2 Enzyme kinetic parameters of compounds

The above results show that the compounds of the present invention have a long half-life and a relatively low clearance rate during microsomal metabolism, indicating that the compounds of the present invention have good microsomal metabolic stability and can maintain effective blood drug concentrations in vivo for a long time.

Embodiment 89

Human plasma metabolic stability test

Experimental system

(1) Prepare stock solutions of the test compound and positive control at a concentration of 10 mM using DMSO as a diluent. Then dilute the stock solution of the positive control with 50% acetonitrile to a working concentration of 0.2 mM, and then dilute the stock solution of the test compound with 50% acetonitrile to a working concentration of 1 mM.

(2) The quencher consisted of acetonitrile containing toluenesulfonamide and propranolol (used as an internal standard).

Experimental methods

(1) Positive control and test article working solutions (in duplicate) were added to human plasma and concentrated to 1 μM and 5 μM, respectively.

(2) Prepare 0 minute samples by adding an 80 μL aliquot of each incubation mixture to 320 μL of quenching reagent to precipitate proteins.

(3) The mixture was placed in a 37°C water bath and incubated with gentle shaking. At 0, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, and 8 h, 80 μL aliquots of each mixture were transferred to a clean 96-well plate containing 320 μL of quencher to precipitate proteins, followed by centrifugation (4000×g, 15 min).

(4) 80 μL of the supernatant was placed in a 96-well assay plate pre-added with 160 μL of ultrapure water, and then analyzed by LC-MS/MS.

Table 3 Results of human plasma metabolic stability test of compounds

The results show that the compound of the present invention can maintain a certain concentration during the metabolism process in human plasma, indicating that the compound of the present invention has good plasma metabolic stability and can maintain an effective blood drug concentration in the body for a long time.

Embodiment 90

Tablet preparation

Table 6 Tablet ingredients

The raw and auxiliary materials were sieved through an 80-mesh sieve for later use. According to the ratio in Table 6, the prescribed amount of active ingredients, microcrystalline cellulose, lactose, and povidone K30 were weighed and added to a high-speed mixer. The mixture was stirred at a low speed and mixed evenly. An appropriate amount of purified water was added, the mixture was stirred at a low speed, and the granules were cut at a high speed. The wet granules were dried at 60°C for 3 h, and sieved through a 24-mesh sieve. Then, the prescribed amount of sodium carboxymethyl starch, silicon dioxide, and magnesium stearate were added, the mixture was mixed, and the tablets were pressed on a rotary tablet press.

Embodiment 91

Preparation of capsules (230 mg)

Table 7 Capsule ingredients

The raw and auxiliary materials were sieved through an 80-mesh sieve for later use. According to the ratio in Table 7, the prescribed amount of active ingredients, lactose, starch, and povidone K30 were weighed and added to a high-speed mixer. The mixture was stirred at a low speed and evenly mixed. An appropriate amount of purified water was added, the mixture was stirred at a low speed, and the granules were cut at a high speed. The wet granules were dried at 60°C for 3h, and granulated through a 24-mesh sieve. Then, the prescribed amount of silicon dioxide and magnesium stearate were added, the mixture was mixed, and the capsules were filled with a capsule filling machine.

Embodiment 92

Preparation of injection (5 mL)

Table 7 Injection ingredients

Weigh the active ingredient, lactose and sodium chloride according to the amount, dissolve them with water for injection, prepare sodium citrate into a 0.1 mol/L solution with water for injection, drop it into the above solution, monitor the pH value to 6.8-7.0 and then stop dropping to obtain a drug aqueous solution; filter the above drug aqueous solution through a filter membrane, dry, grind aseptically, and fill to obtain an injection.

In summary, the methyl methylamine derivative preparation provided by the present invention has good microsomal metabolic stability and good plasma metabolic stability, and can maintain an effective blood drug concentration in the body for a long time. Therefore, the drug effect is long-lasting and the side effects are small.

The above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solution of the present invention.

Claims (9)

1. A methylmethylamine derivative preparation, characterized in that the methylmethylamine derivative preparation is one of the compounds represented by formula (I)-(V), or a pharmaceutically acceptable salt thereof: , , , , ; Wherein, R in formula (I) and (II) and R ₁ , R ₂ , and R ₃ in formula (III) to (V) are independently hydrogen, deuterium, hydroxyl, carboxyl, C _1-15 alkoxy, substituted or unsubstituted C _1-16 alkyl, heteroalkyl, cycloalkyl or alicyclic, aromatic or aromatic heterocyclic groups or a combination thereof to form a substituent group; R in the formula (I) and (II) is independently a substituent group formed by one or more combinations of hydrogen, hydroxyl, C _1-5 alkoxy, substituted or unsubstituted C _5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic, aromatic or aromatic heterocyclic; _R1 and _R2 in the formula (III) and (V) are independently hydrogen, deuterium, hydroxyl, _C1-5 alkoxy, substituted or unsubstituted _C1-5 alkyl, heteroalkyl; _R1 and _R2 in the formula (IV) and _R3 in the formulas (III) to (V) are independently hydrogen, hydroxyl, _C1-5 alkoxy, substituted or unsubstituted _C5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic, aromatic or aromatic heterocyclic groups. 2. The methylmethylamine derivative preparation according to claim 1, characterized in that _R1 and _R2 in the formula (III) and (V) are independently hydrogen, deuterium or methyl. 3. The methyl methylamine derivative preparation according to claim 2, characterized in that at least one of _R1 and _R2 in the formula (III) and (V) is hydrogen. 4. The methyl methylamine derivative preparation according to claim 1, characterized in that the formula (I) is selected from the following compounds: The formula (II) is selected from the following compounds: The formula (III) or its pharmaceutically acceptable salt is a compound with the following structure: The formula (IV) is selected from the following compounds: The formula (IV) or its pharmaceutically acceptable salt is a compound with the following structure: . 5. The methyl methylamine derivative preparation according to claim 4, characterized in that the compound is selected from: 1-((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)amine)methylacetylglycinate; Isopropyl ((((S)-4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)amine)(methoxymethyl)phosphonyl)-L-aminopropanoate; 1-(((((S)- 4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetylglycinate; 1-(((((S)- 4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl palmitate; 1-(((((S)- 4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)ethyl acetyl-L-alaninate; 1-(((((S)- 4,7-dihydro-5H-thienyl[2,3-c]pyran-7-yl)methyl)(methyl)carbamoyl)oxy)-2-methylpropylacetylglycinate. 6. The methylmethylamine derivative preparation according to claim 1, characterized in that the pharmaceutically acceptable salt of the compound is a salt formed by the compound and an acid: pamoate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate. 7. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises an active ingredient and a pharmaceutically acceptable excipient; the active ingredient is one or more of the compounds described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. 8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the preparation of a medicament for preventing or treating a neurological disease. 9. The use according to claim 8, characterized in that the neurological disease is selected from schizophrenia, depression, memory disorders, and functional disorders related to intelligence and learning.