Patent Description:
Tears provide long-lasting moisturization and lubrication to the eyes, which is the key to maintaining vision and eye comfort. Tears are composed of water, lipids, mucus, antibodies, and specific proteins with anti-infective properties. These components are secreted by specific glands located around the eyes. When there is an imbalance in the tear system, people will feel dry eyes.

Dry eye syndrome is a common ocular surface inflammatory disease. People with dry eye may experience eye pain, photosensitivity, itching, redness and blurred vision. Dry eye syndrome is caused by multiple inducing factors, including age, gender, environment, medicine, surgery, and systemic diseases such as autoimmune diseases, diabetes, thyroid disease, and lymphoma. If dry eye disease is not diagnosed and treated properly, it may lead to further complications such as infection, keratinization of the ocular surface, corneal ulceration and conjunctiva squamatization.

Therefore, dry eye syndrome is a very serious disease that affects <NUM>-<NUM>% of the population, especially those who work long hours in front of computer and those after the middle age. More than <NUM>% patients in today's ophthalmologist clinics are dry eye patients. Despite the large number of patients with dry eye syndrome in China, there is no drug approved for the treatment of dry eye syndrome. The patient can only have temporary relief from artificial tears. Therefore, there is an urgent need for drugs for treating dry eye syndrome.

The incidence of dry eye syndrome is directly proportional to the age, about <NUM>% of people over <NUM> years old have different degrees of dry eye syndrome; gender also affects dry eye syndrome, and women, especially older women, have a much higher percentage of dry eye syndrome than men, which may be related to the secretion of sex hormones; white-collar workers stay for a long time in the air-conditioned environment, and the long-term use of the screen also causes a high incidence of dry eye syndrome in this population. Dry eye syndrome is a continuous pathological process in which the condition progresses from light to severe, and there is no obvious boundary between light, medium and severe. Despite the complex etiology of dry eye syndrome, studies find that the pathology of dry eye caused by various causes is similar: immune cells invade the surface tissue of the eyes and trigger chronic inflammation, causing ocular surface damage. Currently, two drugs are approved in the European and American markets: (<NUM>) cyclosporin A suspension. This medicine is a very powerful immune system inhibitor, so it may cause damage to the immune system. At the same time, because it is a suspension, there are problems concerning long-term storage stability, and the eye irritation in the patients using the drug; (<NUM>) Lifitigrast, the drug was approved by the US FDA in December <NUM>, which is an immune cell migration inhibitor, and achieves the therapeutic effect by blocking the immune cells from entering into the site of inflammation; however, the drug is highly lipophilic and has no clinical effect on ><NUM>% of patients.

<CIT> discloses the compound ethyl hydrogen ({[(<NUM>)-<NUM>-methyl-<NUM>-({[<NUM>-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)p hosphonate used for the treatment of dry eyes. The compound, among others, is considered in the application as FPR2 agonist to exhibit ocular anti-inflammatory activity with chemical stability and suitable for ocular delivery. It is said that FPR2 represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in ocular diseases with excessive inflammatory responses.

The invention is related to a new immune cell migration inhibitor. It has good hydrophilicity and can be developed into eye drops. It has a strong inhibitory effect on immune cell migration and can alleviate the symptoms of most dry eye patients.

The invention provides a series of phosphorus-containing compounds, the particular features are represented by the following structure:
<CHM>.

In the preferred embodiments, the invention provides a phosphorus-containing compound which is further characterized in that the above aryl group is selected from phenyl group and derivatives thereof, naphthyl group and derivatives thereof, N or O containing heteroaryl group and derivatives thereof, N or O containing heterocyclic naphthyl group and derivatives thereof;
wherein, the above derivatives refer to the aromatic ring having one or more independently substituted hydrogen, alkyl, alkoxy, halogen, amino, cyano, hydroxyl, nitro, aryl, alkylsulfonyl or phenylsulfonyl thereon.

Further, the invention provides a phosphorus-containing compound which is further characterized in that X is selected from imino (-NH-) and amine (-N(R3)-);
the above Y is selected from (-NH-), amine (-N(RN)-), and ammonium (-N+(R4R5)-, wherein RN may be any substituent group, such as: alkyl such as methyl, ethyl and the like, aromatic group such as phenyl, benzyl and the like, R4 and R5 can be the same or different arbitrary substituent groups, e.g. alkyl group such as methyl, ethyl and the like, aromatic group such as phenyl, benzyl and the like, the anion coordinated to N+ may be selected from halogen. Further, the invention provides a phosphorus-containing compound characterized in that:.

The above heteroaryl group may further have a structure of -N-R<NUM> on it;.

In the preferred embodiments, the invention provides a phosphorus-containing compound characterized in that the compound represented by the following structure:
<CHM>
wherein, the above C<NUM> and C<NUM> are both carbon atoms, and the bond in-between is single bond, double bond or triple bond.

In the more preferred embodiments, the invention provides a phosphorus-containing compound characterized in that the compound represented by the following structure:
<CHM>.

In the even more preferred embodiments" the invention provides a phosphorus-containing compound characterized in that the compound represented by the following structure:
<CHM>
wherein X<NUM>, X<NUM>, X<NUM>, and X<NUM> are selected from hydrogen, alkyl, halogen, and hydroxyl.

Further, the invention provides a phosphorus-containing compound characterized in that the phosphorus-containing compound selected from the following:.

In addition, the present invention also provides a method for preparing the above phosphorus-containing compound, which is characterized in that:.

Further, the method for preparing a phosphorus-containing compound provided by the invention has the characteristics that the substitution reaction, the addition reaction, the elimination reaction or the replacement reaction, can be carried out between the above L1 and L1' as well as between L2 and L2', and connection bonds between L1 and L1' as well as between L2 and L2' are formed.

Further, the method for preparing a phosphorus-containing compound provided by the invention further has the characteristic that the above L<NUM> is selected from halogen, amino, cyano, thio, hydroxyl and alkoxyl;.

Further, the method for preparing a phosphorus-containing compound provided by the invention is characterized in that the molar ratio of the above compound A to the compound C is <NUM>:<NUM>-<NUM>;
the molar ratio of the above compound C to the compound B is <NUM>:<NUM>-<NUM>.

Further, the method for preparing a phosphorus-containing compound provided by the invention is further characterized in that, the specific process steps are as follows:.

In the present invention, the phosphodiester derivative is a compound represented by the following structure:
<CHM>.

In the reaction, the amount of the added halogenating agent is <NUM> to <NUM> per <NUM> of the phosphodiester derivative.

Step <NUM>: Sequentially adding Grignard reagent and substrate <NUM> to the derivative of methyl ethynylbenzoate at a temperature below <NUM>, reacting for <NUM>-<NUM> hours, quenching the reaction with an acidic solution, extracting the organic phase and evaparoate to obtain the intermediate product <NUM>;.

Step <NUM>, the intermediate product <NUM> and the de-esterification reagent, react at a temperature of <NUM>-<NUM> for <NUM>-<NUM> hours, quenched with the acidic solution, the organic phase from extraction evaporated to dryness, to give the intermediate product <NUM>;.

Step <NUM>, in the intermediate product <NUM>, sequentially adding compound C in which L<NUM> is amino, and the basic catalyst, reacting at a temperature of <NUM>-<NUM> for <NUM>-<NUM> hours, quenching the reaction with an acid solution, and the extracted organic phase was evaporated to dryness to give a phosphorus-containing compound containing alkynyl group.

The molar ratio of the intermediate product <NUM>, the compound C and the basic catalyst is <NUM>:<NUM>-<NUM>:<NUM>-<NUM>;.

The above reaction procedures are all applicable to the scheme in which the next step is carried out without purification, and the yield in each step is about <NUM> to <NUM>%, and the total yield is about <NUM> to <NUM>%.

The specific equations for the above process are as follows:
<CHM>.

Further, the method for preparing a phosphorus-containing compound provided by the invention is further characterized in that, the above alkynyl-containing phosphorus-containing compound undergoes a reduction reaction, and the corresponding phosphorus-containing product can be obtained. Further, the invention provides the application of the above phosphorus-containing compound, in particular, that it can be used as an immune cell migration inhibitor.

Further, the invention provides the application of the above phosphorus-containing compound, in particular, that the eye drops containing the above phosphorus-containing compound can be used for alleviating and treating dry eye syndrome.

The method for preparing the eye drop preparation can be any conventional preparation method.

For example, the above compound is added to <NUM>-<NUM> times by weight of the sterile physiological saline, <NUM>-<NUM> times of alkali solution is added, stirringto a transparent solution; and the buffer solution is added to the above obtained solution until the pH of the solution is between <NUM>-<NUM>; and then the sterile physiological saline is added into the obtained aqueous solution until the total volume reaches <NUM>-<NUM> times of the original volume. The above solution is then purged with nitrogen, bubbling for <NUM>-<NUM> hours, and the resulting solution is sealed and stored at <NUM> under exclusion of light. The solution is dispensed into a disposable eye drop vessel for use. Among them, the above saturated aqueous solution of sodium hydroxide and NaH<NUM>PO<NUM> can be replaced by other buffer solutions.

In the invention, a new class of phosphorus-containing compounds is synthesized, which is a novel immune cell migration inhibitor. It has good hydrophilicity, is easy to develop into eye drops, has a strong inhibitory effect on immune cell migration, and it may alleviate the symptoms of most dry eye patients.

The specific reaction equation is as follows:
<CHM>.

<NUM> of dimethyl phenyl phosphate was weighed, <NUM> of thionyl chloride was added, protected with nitrogen, they react at <NUM> for <NUM> hours, and were directly spun-dried.

<NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-ethynylbenzoate was dissolved in <NUM> of tetrahydrofuran, protected with nitrogen, and <NUM> of isopropylmagnesium chloride (<NUM> mol/L) was added at <NUM>, and stirred for <NUM> minutes; Compound <NUM> was dissolved in <NUM> of tetrahydrofuran and added, reacted for <NUM> minutes. The reaction was quenched by <NUM> mol/L dilute HCl solution, and was extracted three times with <NUM> ethyl acetate, the organic phases were combined, spun-dried, and purified to obtain the product (<NUM>, <NUM>%).

Compound <NUM> (<NUM>) and lithium iodide (<NUM>) were dissolved in <NUM> of pyridine, protected with nitrogen, stirred at <NUM> for <NUM> hours, cooled and spun-dried, and <NUM> of <NUM> mol/L dilute HCl solution was added. Extraction was carried out three times with <NUM> of ethyl acetate, and the organic phases were combined and spun-dried without further purification.

Compound <NUM> was dissolved in DMF, benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride (<NUM> eq) was added, then followed by DIPEA (<NUM> eq), HATU (<NUM> eq). After stirring at normal temperature for <NUM>, <NUM> of dilute HCl solution was added, extracted three times with EA, the organic phases were combined and spun-dried. Purification was prepared with the reverse phase, spun-dried at <NUM> under reduced pressure to obtain <NUM> of the target product.

Compound <NUM> was dissolved in <NUM> of methanol, Pd/C (<NUM>%, <NUM> eq) was added, and then hydrogenated under normal pressure for <NUM>, filtered, spun-dried, prepared by reverse phase, and <NUM> of lyophilized product was obtained. LCMS ESI(+)m/z:<NUM>(M+<NUM>); <NUM>H-NMR (<NUM>,DMSO) δ <NUM> (d,J=<NUM>,<NUM>), <NUM> (s,<NUM>), <NUM> (m,<NUM>), <NUM> (m,<NUM>), <NUM> (m,<NUM>), <NUM> (m,<NUM>), <NUM> (s,<NUM>), <NUM> (m, <NUM>), <NUM> (dd, J=<NUM>, J=<NUM>, <NUM>), <NUM> (s,<NUM>), <NUM> (dd, J=<NUM>, J=<NUM>, <NUM>), <NUM> (m,<NUM>), <NUM> (m,<NUM>).

<NUM> of diethyl m-methoxyphenyl phosphate was weighed, and <NUM> of thionyl chloride was added, protected with nitrogen, and reacted at <NUM> for <NUM> hours, and then directly spun-dried.

<NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-ethynylbenzoate was dissolved in <NUM> of tetrahydrofuran, protected with nitrogen, and <NUM> of <NUM> mol/L of isopropyl magnesium chloride was added at <NUM>, and stirred for <NUM> minutes; Compound <NUM> was dissolved in <NUM> of tetrahydrofuran and reacted for <NUM> minutes. The reaction was quenched with <NUM> mol/L dilute HCl solution, and extracted three times with <NUM> ethyl acetate, the organic phases are combined, spun-dried, and purified to obtain the product (<NUM>, <NUM>%).

Compound <NUM> (<NUM>) and lithium iodide (<NUM>) were dissolved in <NUM> of pyridine, protected with nitrogen, stirred at <NUM> for <NUM> hours, cooled and spun-dried, and <NUM> of <NUM> mol/L dilute HCl solution was added. Extraction was carried out three times with <NUM> of ethyl acetate, the organic phases were combined and spun-dried without further purification.

Compound <NUM> was dissolved in DMF, and benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride (<NUM> eq) was added, then followed by DIPEA (<NUM> eq), and HATU ( <NUM>. After stirring at normal temperature for <NUM>, <NUM> of dilute HCl solution was added. Extraction was carried out three times with EA, and the organic phases were combined and spun-dried. Purification was prepared by reverse phase, spun-dried at <NUM> under reduced pressure to give the target product, <NUM>.

Compound <NUM> (<NUM>) was dissolved in <NUM> of DCM, protected with nitrogen, and <NUM> of boron tribromide (<NUM> mol/L) was added at -<NUM>, and then stirred at <NUM> for <NUM> minutes. The reaction was quenched by adding water at -<NUM>°, extracted with <NUM> of EA, dried over anhydrous sodium sulfate, spun-dried and purified to obtain <NUM> of product.

<NUM>H-NMR(<NUM>,DMSO), δ9. <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>),<NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>),<NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>).

Compound <NUM> (<NUM>) was dissolved in <NUM> of methanol, and <NUM> of Pd/C (<NUM>%) was added, and hydrogenated at normal pressure for <NUM>, then filtered. The product was spun-dried and purified to give <NUM> of product.

LCMS ESI(+)m/z:<NUM>(M+<NUM>). <NUM>H-NMR(<NUM>,DMSO), δ9. <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>),.

Compound <NUM> (<NUM>) was dissolved in <NUM> of methanol, trimethylsilyldiazomethane (<NUM> eq) was added, and stirred at room temperature for <NUM> minutes. The reaction was quenched with an appropriate amount of acetic acid, spun-dried, and <NUM> of dilute HCl solution was added. The extraction was carried out three times with EA, and the organic phases were combined, and spun-dried. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

Compound <NUM> was dissolved in methanol (<NUM>), and <NUM> of Pd/C (<NUM>%) was added thereto, and the mixture was hydrogenated at normal pressure for <NUM> hour, filtered, spun-dried and purified to obtain the target product.

<NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(m,<NUM>),<NUM>(m,<NUM>),<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>(m,<NUM> ),<NUM>(d,J=<NUM>,<NUM>),<NUM>(dd,J=<NUM>,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(dd,J=<NUM>,J=<NUM>. <NUM>,<NUM>),<NUM>(m,<NUM>),<NUM>(m,<NUM>).

Compound <NUM> was dissolved in DCM, and <NUM> mol/L of boron tribromide (<NUM> eq) was added at -<NUM>, stirred at <NUM> for <NUM> minutes and then the reaction was quenched with water at -<NUM>. The reaction was extracted <NUM> times with EA, and the organic phases were combined, spun-dried and purified to give the target product. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

<NUM>-NMR(<NUM>,DMSO)δ9. <NUM>(d,J=<NUM>,<NUM>),<NUM>(m,<NUM>),<NUM>(m,<NUM>),
<NUM>(m,<NUM>),<NUM>(m,<NUM>),<NUM>(m,<NUM>),<NUM>(m,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>(dd,J=<NUM>,J=<NUM>,<NUM>).

Compound <NUM> was dissolved in DCM, and <NUM> mol/L of boron tribromide (<NUM> eq) was added at low temperature, and stirred at <NUM> for <NUM> minutes, then the reaction was quenched at -<NUM>, extracted with EA three times, and the organic phases were combined, and spun-dried.

Compound <NUM> was dissolved in DMF, and benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride (<NUM> eq) was added, followed by DIPEA (<NUM> eq), and HATU ( <NUM>. After stirring at normal temperature for <NUM>, and <NUM> of dilute HCl solution was added, extracted with EA three times, and the organic phases were combined and spun-dried. Purification was prepared by reverse phase, spun-dried at <NUM> under reduced pressure to give the target product.

Compound <NUM> was dissolved in <NUM> of methanol, and Pd/C (<NUM>%, <NUM> eq) was added, and the mixture was hydrogenated under normal pressure for <NUM>, filtered, spun-dried and purified to give the product.

<NUM>H-NMR(<NUM>,DMSO)δ9. <NUM>(s,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),.

Compound <NUM> (<NUM>) was dissolved in <NUM> of methanol, and trimethylsilyldiazomethane (<NUM> eq) was added, and the mixture was stirred at room temperature for <NUM> minutes. The reaction was quenched with an appropriate amount of acetic acid, spun-dried, and <NUM> of dilute HCl solution was added. It was extracted <NUM> times with EA, and the organic phases were combined and spun-dried.

Compound <NUM> (<NUM>) was dissolved in DCM, and <NUM> mol/L of boron tribromide (<NUM> eq) was added at -<NUM>, stirred at <NUM> for <NUM> minutes and then the reaction was quenched with water at -<NUM>. It was extracted <NUM> times with EA, and the organic phases were combined, dried and spun-dried to give <NUM> of the target product.

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>).

Compound <NUM> (<NUM>) was dissolved in methanol (<NUM>), <NUM> of Pd/C (<NUM>%) was added, the mixture was hydrogenated under normal pressure for <NUM> hour, filtered and spun-dried, purified to give <NUM> of target product.

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>).

<NUM> of methyl methylphenyl phosphate was weighed, and <NUM> of thionyl chloride was added, protected with nitrogen. The reaction was performed at <NUM> for <NUM> hours, and then spun-dried directly.

<NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-ethynylbenzoate was dissolved in <NUM> of tetrahydrofuran, protected with nitrogen, and <NUM> of <NUM> mol/L isopropyl magnesium chloride was added at <NUM>, and stirred for <NUM> minutes; Compound <NUM> was dissolved in <NUM> of tetrahydrofuran and added, the reaction was performed for <NUM> minutes. The reaction was quenched with <NUM> mol/L dilute HCl solution, extracted three times with <NUM> ethyl acetate, the organic phases were combined, spun-dried and purified to obtain the product (<NUM>, <NUM>%).

Compound <NUM> (<NUM>) and lithium iodide (<NUM>) were dissolved in <NUM> of pyridine, protected with nitrogen, stirred at <NUM> for <NUM> hours, cooled and spun-dried, and <NUM> of <NUM> mol/L dilute HCl solution was added. It was extracted three times with <NUM> of ethyl acetate, and the organic phases were combined, spun-dried without purification (<NUM>). LCMS ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> was dissolved in DMF, and benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propanoic acid hydrochloride (<NUM> eq) was added, followed by DIPEA (<NUM> eq), and HATU (<NUM> eq). After stirring at normal temperature for <NUM>, <NUM> of dilute hydrochloric acid solution was added. It was extracted three times with EA, and the organic phases were combined, spun-dried, and purified to give <NUM> of the target product. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) was dissolved in DCM and <NUM> mol/L boron tribromide (<NUM> eq) was added at low temperature, stirred at <NUM> for <NUM> minutes, then the reaction was quenched at -<NUM>, extracted three times with EA, and the organic phases were combined, spun-dried, and purified to give <NUM> of the target product. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>),<NUM>(s,<NUM>), <NUM>(s,<NUM>),.

Compound <NUM> (<NUM>) was dissolved in methanol (<NUM>), and <NUM> of Pd/C (<NUM>%) was added, the mixture was hydrogenated under normal pressure for <NUM> hour, filtered and spun-dried, purified to give <NUM> of the target product. LCMS ESI(+) m/z: <NUM> (M+<NUM>). <NUM>H-NMR(<NUM>,DMSO) δ <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>, <NUM>, <NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>.

Thionyl chloride (<NUM>) was added to the compound diethyl m-methoxy phosphate (<NUM>), and the mixture was stirred at <NUM> overnight. After spinning dry, <NUM> mol/L methyl magnesium chloride (<NUM>) was added at <NUM>, stirred for <NUM> minutes, then the reaction was quenched with dilute HCl solution, extracted with EA, dried and spun-dried, purified to give the target product (<NUM>, <NUM>%). LCMS ESI(+) m/z: <NUM> (M+<NUM>).

To Compound <NUM> (<NUM>), thionyl chloride was added, the mixture was stirred at <NUM> for <NUM> hours, and spun-dried to give the target product.

<NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-ethynylbenzoate was dissolved in <NUM> of tetrahydrofuran, protected with nitrogen, <NUM> of <NUM> mol/L of isopropyl magnesium chloride was added at <NUM>, and stirred for <NUM> minutes; Compound <NUM> was dissolved in <NUM> of tetrahydrofuran and added, the reaction lasted for <NUM> minutes. The reaction was quenched with <NUM> mol/L dilute HCl solution and extracted three times with <NUM> of ethyl acetate. The organic phases were combined, spun-dried, and purified to give the target product (<NUM>, <NUM>%). LCMS ESI (+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) was dissolved in <NUM> of DCM, protected with nitrogen, and <NUM> of boron tribromide (<NUM> mol/L) was added at -<NUM>, and then stirred at <NUM> for <NUM> minutes. The reaction was quenched at -<NUM>, extracted three times with <NUM> of ethyl acetate, dried over anhydrous sodium sulfate and spun-dried. <NUM> of the target product was obtained. ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> was dissolved in DMF and benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propanoic acid hydrochloride (<NUM> eq) was added, then followed by DIPEA (<NUM> eq) and HATU (<NUM> Eq). After stirring at normal temperature for <NUM>, <NUM> of dilute HCl solution was added, extracted three times with EA, and the organic phases were combined, spun-dried. Purification was prepared with the reverse phase, and spun-dried at under reduced pressure at <NUM> to give <NUM> of the target product. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) was dissolved in <NUM> of DCM, protected with nitrogen, and <NUM> of boron tribromide (<NUM> mol/L) was added at -<NUM>, and then stirred at <NUM> for <NUM> minutes. The reaction was quenched by adding water at -<NUM>, extracted with <NUM> EA, dried over anhydrous sodium sulfate, spun-dried, and purified to give <NUM> of product.

<NUM>H-NMR(<NUM>,DMSO), δ <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>),.

Compound <NUM> (<NUM>) was dissolved in <NUM> of DCM, protected with nitrogen, and <NUM> of boron tribromide (<NUM> mol/L) was added at -<NUM>, stirred for <NUM> minutes, then quenched with water, extracted with <NUM> of EA, dried over anhydrous sodium sulfate, spun-dried and purified to give <NUM> of the product.

<NUM>-NMR(<NUM>,DMSO) δ <NUM>(d,J=<NUM>,<NUM>) ,<NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>).

Compound <NUM> (<NUM>) was dissolved in <NUM> of THF, and lithium hydroxide (<NUM>) was taken and dissolved in <NUM> of water, stirred at room temperature for <NUM> minutes. PH = <NUM> was adjusted with concentrated hydrochloric acid, spun-dried, and purified to give <NUM> of product.

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(m,<NUM>),<NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>).

Compound <NUM> (<NUM>) was dissolved in methanol (<NUM>), and <NUM> of Pd/C (<NUM>%) was added, the mixture was hydrogenated at normal pressure for <NUM> hour, filtered and spun-dried, purified to give <NUM> of the target product. LCMS ESI (+) m/z: <NUM>(M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>).

the same procedure as in Example <NUM> was carried out except that "diethyl m-methoxy phosphate" was replaced with "diethyl p-methoxy phosphate". LCMS ESI (+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>).

the same procedure as in Example <NUM> was carried out except that "Compound <NUM>" was replaced with "Compound <NUM>".

<NUM>H-NMR(<NUM>,DMSO)δ9. <NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM> (m, <NUM>),<NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>).

Methyl ((S)-<NUM>-amino-<NUM>-((<NUM>,<NUM>-dimethylethoxy)amide)propanoate, HCl salt (<NUM>, <NUM> mmol) were dissolved in water (<NUM>), placed on the ice bath and stirred. THF (<NUM>), NaOH (<NUM> aqueous solution, <NUM>) and <NUM>-Thiophenecarbonyl chloride (<NUM> mmol) were added to the resulting solution. After the reaction was stirred for <NUM>. , EtOAc (<NUM>) was added therein, and the aqueous layer was separated and discarded. The organic layer was rinsed with water (<NUM>) and saturated NaCl solution, and then dried over anhydrous MgSO<NUM>, filtered, spun-dried to give the pure Compound <NUM> (<NUM>, <NUM>%). LCMS ESI(+) m/z: <NUM>(M+<NUM>).

Compound <NUM> (<NUM>) was dissolved in DCM (<NUM>), HCl-dioxane solution (<NUM>, <NUM>) was added, stirred for <NUM>, spun-dried, and the obtained product (hydrochloride) was directly used for the next reaction. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) was dissolved in methanol (<NUM>), and <NUM> of Pd/C (<NUM>%) was added, hydrogenated under normal pressure for <NUM> hours, filtered and spun-dried to give <NUM> of the target product.

Compound <NUM> (<NUM>) was dissolved in <NUM> of DCM, protected with nitrogen, and <NUM> of boron tribromide (<NUM> mol/L) was added at -<NUM>, and then stirred at <NUM> for <NUM> minutes. The reaction was quenched by adding water at -<NUM>, extracted three times with <NUM> of EA, dried over anhydrous sodium sulfate, and spun-dried, to give <NUM> of the target product. ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) was dissolved in DMF (<NUM>). Compound <NUM> (<NUM> eq) was then added, followed by DIPEA (<NUM> eq) and HATU (<NUM> eq). After stirring at normal temperature for <NUM>, <NUM> of dilute HCl solution was added, extracted three times with EA, and the organic phases were combined, spun-dried. Purification was prepared with the reverse phase, and spun-dried under reduced pressure at <NUM> to yield <NUM> of the target product.

Compound <NUM> (<NUM>) was dissolved in <NUM> of THF, and lithium hydroxide (<NUM>) was dissolved in <NUM> of water, mixed, and stirred at room temperature for <NUM> minutes. PH = <NUM> was adjusted with concentrated hydrochloric acid, spun-dried, and purified by high pressure liquid phases to give <NUM> of product.

<NUM> NMR (<NUM>, CD3OD): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, J=<NUM>, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM>(m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, J=<NUM>, <NUM>).

Compound: methyl Boc-<NUM>-(<NUM>-pyridyl)-L-alaninate (<NUM>, <NUM> mmol) was dissolved in ethanol (<NUM>), and methyl iodide (<NUM>) was added to the solution, and the reaction was stirred at <NUM> until the reaction was completed. The reaction temperature was lowered to <NUM>, and sodium borohydride (<NUM>) was added to the solution in portions. After the reaction was stirred for <NUM> hour, <NUM> of acetone was added to the reaction, and EtOAc (<NUM>) was added. The resulting organic solution was washed with saturated NH4Cl solution (<NUM>), water (<NUM>) and saturated salt solution, dried over anhydrous MgSO<NUM>, filtered and spun-dried. The crude product obtained was purified by silica gel column (<NUM>-<NUM>% MeOH/DCM) to yield Compound <NUM>.

Compound <NUM> (<NUM>, <NUM> mmol) was dissolved in DCE (<NUM>). <NUM>-chloroethyl chloroformate (<NUM> mmol) was added, and the reaction was heated to <NUM>, kept for <NUM> hours and spun-dried. Dry methanol (<NUM>) was added, and the mixture was refluxed for <NUM> hour and then spun-dried. DCM (<NUM>) and TEA (<NUM> mmol) were added to the obtained intermediate product, and the mixture was cooled to <NUM>, and methanesulfonyl chloride (<NUM> mmol) was added to the reaction. After stirring for <NUM> hour, the reaction was diluted with EtOA (<NUM>), washed twice with water, dried, filtered and spun-dried to yield Compound <NUM>.

Compound <NUM> (<NUM>) was dissolved in DCM (<NUM>). HCl-dioxane solution (<NUM>, <NUM>) was added, the reaction was stirred for <NUM> hours and spun-dried, the obtained product (hydrochloride) is ready for direct use in the further reaction. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

The same procedure for preparing Compound <NUM> from Compound <NUM> was used to prepare Compound <NUM> from <NUM>, wherein Compound <NUM> was replaced by Compound <NUM>.

methyl <NUM>-amino-N-tert-butoxycarbonyl-L-alaninate, HCl salt (<NUM>, <NUM> mmol) were dissolved in ethanol (<NUM>), and dimethyl N-cyanoimido-S,S-dithiocarbonate (<NUM> mmol) and DIPEA (<NUM>) were added. The reaction was stirred for <NUM> hours, and EtOAc (<NUM>) was added thereto. The mixture was washed with water (<NUM>) and saturated NaCl solution, then dried over anhydrous MgSO<NUM>, filtered, and spun-dried to yield the pure Compound <NUM>, which is ready for direct use in the further reaction.

The obtained Compound <NUM> was dissolved in acetonitrile (<NUM>), and (R)-pyrrolidin-<NUM>-ol (<NUM> mmol) and silver nitrate (<NUM> mmol) were added. The reaction was refluxed for <NUM> hours, filtered over silica gel and spun-dried. The crude product was separated on a silica gel column, and separated with <NUM>/<NUM>/<NUM> DCM/MeOH/EtOAc to yield the product.

Compound <NUM> (<NUM>) was dissolved in DCM (<NUM>), HCl-dioxane solution (<NUM>, <NUM>) was added, and the reaction was stirred for <NUM> hours, and spun-dried. The obtained product (hydrochloride) is ready for direct use in the further reaction.

The same procedure for preparing Compound <NUM> from Compound <NUM> was used to prepare Compound <NUM> from <NUM>, wherein Compound <NUM> was replaced by Compound <NUM>. LC-MS: m/z <NUM> (M+H)+.

<NUM>H NMR (<NUM>, CD3OD): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

dimethyl (<NUM>-methoxyphenyl)phosphate (<NUM>, <NUM> mmol) was dissolved in anhydrous THF (<NUM>). The solution was cooled to -<NUM>, and EtMgBr (<NUM>, <NUM>) was added. The reaction was gradually warmed to room temperature (temperature rising process lasted for about <NUM> hours), the reaction was quenched with saturated aqueous NH4Cl solution, and EtOAc (<NUM>) was added. The reaction was washed with water, dried over anhydrous MgSO4, filtered and spun-dried. The crude product was isolated on a silica gel column to give the target product.

Compound <NUM> was dissolved in DCE (<NUM>), oxalyl chloride (<NUM>) was added, and the resulting solution was refluxed for <NUM> hours, and the reaction solution was spun-dried to give the target product ready for direct use in the further step.

The exact same procedure for preparing Compound <NUM> was carried out for preparing Compound <NUM>, wherein Compound <NUM> was used to replace Compound <NUM>.

The exact same procedure for preparing Example <NUM> was carried out for preparing Example <NUM>, wherein Compound <NUM> was replaced by Compound <NUM>. LCMS ESI(+) m/z: <NUM>. <NUM>H-NMR(<NUM>,DMSO)δ9. <NUM>(s,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM> (d,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>), <NUM>(m,<NUM>),<NUM>(s,<NUM>), <NUM>-<NUM>(m,<NUM>),.

The exact same procedure for preparing Example <NUM> was used for preparing Example <NUM>, wherein the ethyl Grignard reagent was replaced by the cyclopropyl Grignard reagent. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM> (s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>),.

The exact same procedure for preparing Example <NUM> was used to prepare Example <NUM>, wherein the ethyl Grignard reagent was replaced by the butyl Grignard reagent. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM> (s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM> (m,<NUM>), <NUM> (m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>(t,J= <NUM>,<NUM>).

Compound <NUM>-bromobenzofuran (<NUM>, <NUM> mmol) was dissolved in diethyl phosphite (<NUM>). Pd(OAc)<NUM> (<NUM>) and TEA (<NUM>) were added. The reaction was heated to <NUM> on a microwave reactor for <NUM> minutes. EtOAc (<NUM>) was added, washed twice with water, dried, filtered and spun-dried. The crude product was separated on a silica gel column, <NUM>-<NUM>% MeOH/DCM was mobile phase, and the target product <NUM> was obtained.

Compound <NUM> (<NUM>) was dissolved in THF (<NUM>). The solution was cooled to -<NUM>, and MeMgBr (<NUM>, <NUM>) was added. The reaction was gradually warmed to room temperature (the temperature rising process lasted for <NUM> hours), and quenched with saturated aqueous NH4Cl solution. EtOAc (<NUM>) was added, and the reaction was washed once with water, dried over anhydrous MgSO4, filtered and spun-dried. The crude product was isolated on a silica gel column to give the target product.

Compound <NUM> was dissolved in thionyl chloride (<NUM>), and the resulting solution was refluxed for <NUM> hours, and the reaction solution was spun-dried to give the target product for direct use in the further step.

The exact same procedure for preparing Compound <NUM> was used to prepare Compound <NUM>, wherein Compound <NUM> was used to replace Compound <NUM>.

<NUM>H-NMR(<NUM>,DMSO)δ9. <NUM>(d,J=<NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM> (m, <NUM>),<NUM>-<NUM>(m,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(d, J=<NUM> ,<NUM>), <NUM>(m,<NUM>),<NUM>(d, J=<NUM>,<NUM>).

The exact same procedure for preparing Example <NUM> was used to prepare Example <NUM>, wherein Compound <NUM> was used to replace Compound <NUM>.

<NUM>H-NMR(<NUM>,DMSO)δ9. <NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(d,J=<NUM>,<NUM>)<NUM>(s,<NUM>),<NUM><NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(s,<NUM>),<NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM> (m,<NUM>), <NUM>(m,<NUM>), <NUM> (m,<NUM>), <NUM>(d, J=<NUM>,<NUM>).

The exact same procedure for preparing compound <NUM> was used to prepare compound <NUM>, wherein <NUM>-benzofuran was used to replace <NUM>-benzofuran.

<NUM>H-NMR(<NUM>,DMSO)δ9. <NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(d, J=<NUM>,<NUM>), <NUM>(t,<NUM>),.

The exact same procedure for preparing Compound <NUM> was used to prepare Compound <NUM>, wherein <NUM>-Ms-<NUM>-Br-indole was used to replace <NUM>-benzofuran.

Dimethyl <NUM>,<NUM>-dichloroterephthalate (<NUM>, <NUM> mmol) was dissolved in THF (<NUM>), lithium borohydride (<NUM> mmml) was slowly added, and the reaction was stirred for <NUM> hour, then acetone (<NUM>) and EtOAc (<NUM>) were added. The resulting solution was washed twice with water, dried over anhydrous Na2SO4, filtered and spun-dried. The crude product was ready for direct use in the further step.

Compound <NUM> was dissolved in pyridine (<NUM>), lithium iodide (<NUM> mmml) was added, and the reaction was stirred under reflux for <NUM> hours, then spun-dried, and the crude product was purified using silica gel column, and separated with the mobile phase <NUM>/<NUM>/<NUM> (v/v/v) DCM/MeOH/AcOH.

Compound <NUM> was dissolved in DMF, and methyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride (<NUM> eq), followed by DIPEA (<NUM> eq) and HATU (<NUM> Eq). After stirring at normal temperature for <NUM> hours, <NUM> of dilute hydrochloric acid solution was added, and extracted with EA three times, and the organic phases were combined and spun-dried. Purification was made by reverse phase, spun-dried under reduced pressure at <NUM> to obtain the target product.

Compound <NUM> was dissolved in THF and LiOH (<NUM> eq) was added. The reaction was stirred at room temperature for <NUM> hours, and the dilute hydrochloric acid solution was added to adjust pH value to about <NUM>-<NUM>. It was extracted three times with EA, and the organic phases were combined, spun-dried to give the target product. The product was not purified and ready for direct use in the further step.

Compound <NUM> was dissolved in DCM, cooled to <NUM>, TEA (<NUM> eq) was added, followed by methylphenylphosphinic chloride (<NUM> eq). The reaction was stirred at room temperature for <NUM>, quenched with water (<NUM> eq) and spun-dried. The crude product was purified by reverse phase preparative HPLC to give the target product.

Chloromethyl (methyl)phosphinyl chloride (<NUM> mmol) was dissolved in anhydrous THF (<NUM>), cooled to -<NUM>, and (<NUM>-methoxy)phenyl lithium (<NUM> eq) was added. After the reaction was stirred for <NUM> hour, it was quenched with dilute hydrochloric acid at -<NUM>. After the reaction was returned to room temperature, EtOAc (<NUM>) was added. The reaction mixture was washed with water, dried, filtered, and spun-dried. The crude product was purified on a silica gel column, and the mobile phase was <NUM>-<NUM>% MeOH/DCM (v/v).

Compound <NUM> (<NUM> eq), methyl <NUM>-amino-<NUM>,<NUM>-dichlorobenzoate (<NUM> eq) was dissolved in anhydrous DMF (<NUM>), sodium iodide (<NUM> eq) was added and cooled to <NUM> and sodium hydrogen (<NUM> eq) was added. The reaction was stirred at room temperature until Compound <NUM> disappeared and was quenched with saturated aqueous NH4Cl solution at -<NUM>. After the reaction was returned to room temperature, EtOAc (<NUM>) was added, washed with water three times, dried, filtered and spun-dried. The crude product was purified on a silica gel column, and the mobile phase was <NUM>-<NUM>% MeOH/DCM (v/v).

Compound <NUM> was dissolved in DCM and <NUM> mol/L of boron tribromide (<NUM> eq) was added at <NUM>. The reaction was stirred at <NUM> for <NUM> minutes, then quenched at -<NUM>, extracted with EA <NUM> times, the organic phases were combined and spun-dried. The obtained crude product was ready for direct use in the further step.

Compound <NUM> was dissolved in DMF and methyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride (<NUM> eq) was added, followed by DIPEA (<NUM> eq) and HATU (<NUM> eq). After stirring at normal temperature for <NUM> hours, <NUM> of dilute hydrochloric acid solution was added, and extracted with EA three times, and the organic phases were combined and spun-dried. Purification was made by reverse phase, and spun-dried under reduced pressure at <NUM> to obtain the target product.

Compound <NUM> was dissolved in THF and LiOH (<NUM> eq) was added. After stirring at normal temperature for <NUM> hours, the dilute hydrochloric acid solution was added until pH was about <NUM>-<NUM>, and extracted with EA <NUM> times, the organic phases were combined, and spun-dried. The crude product was purified by reverse phase HPLC to yield the pure target product.

Chiral preparative HPLC was used to resolve the compound obtained in Example <NUM>. The chiral column was Chiralcel OZ-H model, the mobile phase was Hexane/EtOH/TFA, and the ratio was <NUM>/<NUM>/<NUM> (V/V/V). The two isomers were well separated. LCMS and <NUM>HNMR data were the same as compound <NUM>.

<NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-aldehyde benzoate and <NUM> of tetraethyl methylene diphosphate were dissolved in <NUM> of DMF, <NUM> of K<NUM>CO<NUM> solid was added, stirred for <NUM>, the solvent was removed, and the product was obtained after purification.

<NUM> Compound <NUM> was dissolved in <NUM> of SOCl2, heated to <NUM> for <NUM>, and the solvent was removed to yield the product.

<NUM> Compound <NUM> was dissolved in <NUM> of THF, cooled to <NUM>, and m-methoxyphenylmagnesium bromide was added, stirred at room temperature for <NUM> hours, THF was removed and the product was obtained after purification.

<NUM> of Compound <NUM> was dissolved in <NUM> CH2Cl2, cooled to <NUM>, and BBr3 was added, after <NUM> of reaction, water was added, extracted with EA, and spun-dried to give the product.

<NUM> of Compound <NUM> and <NUM> of benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride and <NUM> of DIPEA were dissolved in <NUM> DMF, <NUM> HATU was added, stirred overnight, and DMF was removed, and the product was obtained after purification.

<NUM> of Compound <NUM> was dissolved in <NUM> of THF, and <NUM> of aqueous LiOH solution was added thereto, and the mixture was stirred for <NUM> minutes. The solvent was removed and the product was obtained after purification.

<NUM>H-NMR(<NUM>,DMSO) δ9. <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>) <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(t,J=<NUM> , <NUM>).

"Example <NUM>" was converted to Example <NUM> using the exact same procedure as in Example <NUM>.

<NUM>H-NMR(<NUM>,DMSO)δ10. <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>, <NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>).

Example <NUM> was prepared by replacing <NUM>-thiophenecarboxylic acid in Example <NUM> with <NUM>-hydroxybenzoic acid.

<NUM>H NMR (<NUM>, CD3OD): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Example <NUM> was prepared by replacing <NUM>-thiophenecarboxylic acid in Example <NUM> with <NUM>,<NUM>-dihydroxybenzoic acid.

<NUM>H NMR (<NUM>, CD<NUM>OD): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> -<NUM> (m, J = <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>) <NUM> (d, J = <NUM>, <NUM>).

Benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride in Examples <NUM> and <NUM> was replaced by benzyl <NUM>-amino-<NUM>-(<NUM>,<NUM>-(dimethylsulfonyl)phenyl)propionate hydrochloride to give Example <NUM>. LCMS ESI(+)m/z:<NUM>(M+<NUM>).

<NUM>H-NMR (<NUM>,DMSO) δ <NUM> (d,J=<NUM>,<NUM>), <NUM> (d,J=<NUM>,<NUM>), <NUM> (s,<NUM>), <NUM> (m,<NUM>) , <NUM> (m,<NUM>) , <NUM> (m,<NUM>), <NUM> (dd, J=<NUM>, J=<NUM>, <NUM>), <NUM> (s,<NUM>), <NUM> (dd, J=<NUM>, J=<NUM>, <NUM>), <NUM> (m,<NUM>), <NUM> (m,<NUM>) , <NUM> (d, J=<NUM>, <NUM>).

Benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propanoate hydrochloride in Examples <NUM> and <NUM> was replaced by methyl (<NUM>)-<NUM>-amino-<NUM>-(methylsulfonamide)hexanoate hydrochloride to give Example <NUM>. LC-MS: m/z <NUM> (M+H)+<NUM>H NMR (<NUM>, CD<NUM>OD): δ <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m,<NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>).

Benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride in Examples <NUM> and <NUM> was replaced by (<NUM>)-<NUM>-amino-<NUM>-(<NUM> -(methanesulfonyl)pyridin-<NUM>-yl)propionic acid hydrochloride to give Example <NUM>. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,MeOD) δ <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(m,H), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(m, <NUM>), <NUM>(m,<NUM>), <NUM>(m, <NUM>), <NUM>(d, J=<NUM>,<NUM>).

Benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride in Examples <NUM> and <NUM> was replaced by (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methanesulfonyl)-<NUM>-pyrrol-<NUM>-yl)propionic acid hydrochloride to give Example <NUM>.

Benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride in Examples <NUM> and <NUM> was replaced by (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methanesulfonyl)-<NUM>-pyrazol-<NUM>-yl)propionic acid hydrochloride to give Example <NUM>.

Benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride in Examples <NUM> and <NUM> was replaced by (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methanesulfonyl)pyrrolidin-<NUM>-yl)propionic acid hydrochloride to give Example <NUM>. LC-MS: m/z <NUM> (M+H)+.

<NUM>H NMR (<NUM>, CD<NUM>OD): δ <NUM>-<NUM> (m, <NUM>), <NUM>(s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>),<NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (m, <NUM>).

Example <NUM> was prepared by replacing <NUM>-thiophenecarboxylic acid in Example <NUM> with (s)-<NUM>-hydroxypyrrolidine-<NUM>-carbonyl chloride.

<NUM>HNMR (<NUM>, CD3OD): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride in Examples <NUM> and <NUM> was replaced by methyl (<NUM>)-<NUM>-amino-<NUM> (methylsulfonamide)valerate hydrochloride to give Example <NUM>.

<NUM>H NMR (<NUM>, CD<NUM>OD): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(d, J = <NUM>, <NUM>) <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m , <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

Example <NUM> was prepared by replacing (R)-<NUM>-pyrrolidinol in Example <NUM> with (trans)-<NUM>,<NUM>-pyrrolidine diol.

<NUM>H NMR (<NUM>, CD<NUM>OD): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

Example <NUM> was prepared by replacing (R)-<NUM>-pyrrolidinol in Example <NUM> with diethanolamine.

<NUM>H NMR (<NUM>, CD<NUM>OD): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

<NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-ethynylbenzoate was dissolved in <NUM> of tetrahydrofuran, protected with nitrogen, and <NUM> of <NUM> mol/L of isopropylmagnesium chloride was added at <NUM>, and stirred for <NUM> minutes; Compound <NUM> was dissolved in <NUM> of tetrahydrofuran and reacted for <NUM> minutes. The reaction was quenched with <NUM> mol/L dilute hydrochloric acid solution, and extracted three times with <NUM> ethyl acetate, the organic phases were combined, spun-dried, and purified to yield the product (<NUM>, <NUM>%). LCMS ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) and lithium iodide (<NUM>) were dissolved in <NUM> of pyridine, protected with nitrogen, stirred at <NUM> for <NUM> hours, cooled and spun-dried, and <NUM> of <NUM> mol/L dilute hydrochloric acid solution was added. It was extracted three times with <NUM> of ethyl acetate, and the organic phases were combined, and spun-dried without purification.

Compound <NUM> was dissolved in DMF and benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionate hydrochloride (<NUM> eq) was added, then followed by DIPEA (<NUM> eq) and HATU (<NUM> eq). After stirring at normal temperature for <NUM>, <NUM> of dilute hydrochloric acid solution was added, and extracted with EA three times, and the organic phases were combined and spun-dried. Purification was made by reverse phase, and spun-dried at <NUM> under reduced pressure to give the target product, <NUM>.

Compound <NUM> (<NUM>) was dissolved in <NUM> of methanol, and trimethylsilyldiazomethane (<NUM> eq) was added and stirred at room temperature for <NUM> minutes. Appropriate amount of acetic acid was added for quenching, spun-dried, and <NUM> dilute hydrochloric acid solution was added. It was extracted <NUM> times with EA, and the organic phases were combined and spun-dried. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) was dissolved in DCM, and <NUM> mol/L of boron tribromide (<NUM> eq) was added at -<NUM>, stirred at <NUM> for <NUM> minutes and then quenched with water at -<NUM>. It was extracted <NUM> times with EA, and the organic phases were combined, dried and spun-dried to give <NUM> of the target product. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO), δ <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>).

Example <NUM> was prepared by the same procedure as in Example <NUM> except that "diethyl m-methoxyphosphate" was replaced with "diethyl <NUM>-methoxy-<NUM>-chlorophosphate". LCMS ESI (+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO)δ11. <NUM>(s,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM> (m, <NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>).

<NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-ethynylbenzoate was dissolved in <NUM> of tetrahydrofuran, protected with nitrogen, and <NUM> of <NUM> mol/L of isopropylmagnesium chloride was added at <NUM>, and stirred for <NUM> minutes; Compound <NUM> was dissolved in <NUM> of tetrahydrofuran and reacted for <NUM> minutes. The reaction was quenched with <NUM> mol/L dilute hydrochloric acid solution, extracted three times with <NUM> of ethyl acetate, and the organic phases were combined, spun-dried, and purified to give the target product (<NUM>, <NUM>%). LCMS ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> (<NUM>) and lithium iodide (<NUM>) were dissolved in <NUM> of pyridine, protected under nitrogen, stirred at <NUM> for <NUM> hours, cooled and spun-dried, and <NUM> of <NUM> mol/L dilute hydrochloric acid solution was added. It was extracted three times with <NUM> ethyl acetate, and the organic phases were combined and spun-dried without further purification.

Compound <NUM> was dissolved in DMF, and benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propionic acid hydrochloride (<NUM> eq) was added, followed by DIPEA (<NUM> eq) and HATU (<NUM>. After stirring at normal temperature for <NUM> hours, <NUM> of dilute hydrochloric acid solution was added, and extracted with EA three times, and the organic phases were combined and spun-dried. Purification was made by reverse phase, and spun-dried at <NUM> under reduced pressure to give the target product, <NUM>. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR (<NUM>, DMSO) δ <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>),
<NUM>(s,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>-<NUM>(m, <NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>).

<NUM> of ethyl methyl(<NUM>-methoxyphenyl)phosphonate was weighed and dissolved in <NUM> of dry tetrahydrofuran under protection of nitrogen, and <NUM> (<NUM>) of LDA was added thereto, stirred for <NUM> hour in an ice bath, <NUM> of methyl <NUM>,<NUM>-dichloro-<NUM>-formylbenzoate was added, stirred at room temperature for <NUM> hours, quenched with the saturated NH<NUM>Cl in an ice bath. It was extracted three times with <NUM> of ethyl acetate, and the organic phases were combined, spun-dried, and purified with columns to give the product (<NUM>, <NUM>%). LCMS ESI(+) m/z: <NUM>.

Compound <NUM> (<NUM>) was dissolved in <NUM> of dichloromethane under protection with nitrogen. At -<NUM>, <NUM> of boron tribromide was added, stirred at -<NUM> for <NUM> hours, quenched with <NUM> of water. It was extracted three times with <NUM> of ethyl acetate, and the organic phases were combined, spun-dried without purification to give <NUM> of the crude product. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> was dissolved in DMF, and benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>,<NUM>-(dimethylsulfonyl)phenyl)propanoic acid hydrochloride (<NUM> eq) was added, followed by DIPEA (<NUM> eq) and HATU (<NUM> eq). After stirring at normal temperature for <NUM> hours, <NUM> of dilute hydrochloric acid solution was added, and extracted with EA three times, and the organic phases were combined and spun-dried. Purification was made by reverse phase, and spun-dried at <NUM> under reduced pressure to yield <NUM> of the target product. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

Compound <NUM> was dissolved in <NUM> of methanol and <NUM> of water, <NUM> eq of lithium hydroxide monohydrate was added under ice bath, stirred at room temperature for <NUM>, and pH was adjusted with 1N hydrochloric acid to pH=<NUM>, and <NUM> of ethyl acetate for extracting three times, washed with water, dried, rotary evaporated and prepared by reversed phase to yield <NUM> of the lyophilized product.

<NUM>H-NMR (<NUM>,CD<NUM>OD-d<NUM>) δ <NUM> (s,<NUM>), <NUM> (d,J=<NUM>,<NUM>), <NUM> (d,J=<NUM>,<NUM>), <NUM> (t,J=<NUM>,<NUM>), <NUM> (m,<NUM>), <NUM> (s,<NUM>) , <NUM> (dd,J=<NUM>, J=<NUM>,<NUM>), <NUM> (d,J=<NUM>,<NUM>) ,<NUM> (t,J=<NUM>,<NUM>) ,<NUM> (m,<NUM>), <NUM> (m,<NUM>),<NUM>(dd, J=<NUM>, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, J=<NUM>, <NUM>), <NUM> (s,<NUM>), <NUM> (m,<NUM>).

Compound <NUM> was dissolved in <NUM> of tetrahydrofuran, and <NUM> of aqueous LiOH solution was added thereto, stirred at room temperature for <NUM> hr, spun-dried and purified to obtain the product.

<NUM>H-NMR(<NUM>,DMSO) δ9. <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t, J=<NUM>,<NUM>),<NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>).

<NUM> Compound <NUM> was dissolved in <NUM> of THF, cooled to <NUM>, and <NUM> equivalents of m-methoxyphenylmagnesium bromide solution was added, stirred at room temperature for <NUM>, and THF was removed and the product was obtained after purification.

<NUM> Compound <NUM>, dissolved in <NUM> CH2CI2, cooled to <NUM>, and BBr3 was added, after <NUM> of reaction, water was added, extracted with EA, then dried, and spun-dried to give the product.

<NUM> Compound <NUM>, <NUM> of benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propanoic acid hydrochloride and <NUM> of DIPEA was dissolved in <NUM> DMF, <NUM> HATU was added, stirred overnight, and DMF was removed, and the product was obtained after purification.

<NUM> Compound <NUM> was dissolved in <NUM> of THF, and <NUM> of aqueous LiOH solution was added thereto, stirred for <NUM> hour, and the solvent was removed to obtain a product.

<NUM>H-NMR(<NUM>, DMSO) δ <NUM> (s,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(t,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(t,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>).

<NUM> of Compound <NUM> was dissolved in <NUM> of MeOH, <NUM> of <NUM>% palladium carbon was added, and H2 was added thereto, reacted for <NUM> hours, filtered, and the product was obtained after purification. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>, DMSO) δ <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>),
<NUM>(d,J=<NUM>,<NUM>), <NUM>(t,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>) , <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>, <NUM>,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>).

The exact same procedure as in Preparation Example <NUM> was used to prepare Example <NUM>, wherein p-methoxymagnesium bromide was replaced by m-methoxymagnesium bromide. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(t,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>, <NUM>,<NUM>), <NUM>(m,<NUM>),<NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(s,<NUM>), <NUM>(t,J=<NUM>, <NUM>).

<NUM> of methyl (benzofuran-<NUM>-yl)phosphonoyl chloride was dissolved in <NUM> of tetrahydrofuran, protected with nitrogen, and <NUM> of <NUM> mol/L methyl magnesium bromide was added at <NUM> and stirred for <NUM> minutes. The reaction was quenched with <NUM> mol/L dilute hydrochloric acid solution. It was extracted three times with <NUM> of ethyl acetate, and the organic phases were combined, spun-dried, and purified to give the target product. LCMS ESI (+) m/z: <NUM> (M+<NUM>).

Using the exact same procedure as in Example <NUM>, replacing "methyl (<NUM>-methoxyphenyl)phosphonate" with "dimethyl(benzofuran-<NUM>-yl)phosphine oxide" to prepare Compound <NUM>.

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(t,J=<NUM>,<NUM>) , <NUM>(s,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>).

The exact same procedure as in Preparation Example <NUM> was used to prepare Example <NUM>, wherein the ethyl Grignard reagent was replaced by the isopropyl Grignard reagent. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM> (s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(dd, J=<NUM>,<NUM>,<NUM>), <NUM>(dd, J=<NUM>,<NUM>,<NUM>).

<NUM> Compound <NUM> was dissolved in <NUM> of SOCl2, heated at <NUM> for <NUM> hours, concentrated to give the product.

<NUM> of <NUM> cyclopropylmagnesium chloride solution in THF, <NUM> of cesium chloride was added, and <NUM> of Compound <NUM> was added thereto, and reacted at room temperature for <NUM> hour, and then quenched with ammonium chloride solution to obtain a product after extraction and purification.

<NUM> Compound <NUM> was dissolved in <NUM> CH2Cl2, cooled to <NUM>, BBr3 was added, after <NUM> of reaction, water was added, extracted with EA, dried, and spun-dried to give the product.

<NUM> Compound <NUM>, benzyl (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-(methylsulfonyl)phenyl)propanoic acid hydrochloride and <NUM> of DIPEA were dissolved in <NUM> DMF, <NUM> HATU was added, stirred overnight to remove DMF, and the product was obtained after purification.

<NUM> Compound <NUM> was dissolved in <NUM> of THF, and <NUM> of aqueous LiOH solution was added thereto, stirred for <NUM> hour, and the solvent was removed, the product was obtained after purification.

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>-<NUM>(m,<NUM>).

The exact same procedure as in Preparation Example <NUM> was used to prepare Example <NUM>, wherein the cyclopropyl Grignard reagent was replaced by the methyl Grignard reagent. LCMS ESI(+) m/z: <NUM> (M+<NUM>).

<NUM>H-NMR(<NUM>,DMSO) δ <NUM>(s,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>(t,J=<NUM>,<NUM>), <NUM>(m,<NUM>), <NUM>(d,J=<NUM>,<NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(m,<NUM>), <NUM>(dd,J=<NUM>,J=<NUM>,<NUM>), <NUM>(s,<NUM>), <NUM>(dd,J=<NUM>,<NUM>,<NUM>), <NUM>(d, ,J=<NUM> <NUM>).

T-cell adhesion assay was performed using human T lymphocyte strain Jurkat (ATCC TIB-<NUM>): goat Anti-Human IgG (Fc specific) (Sigma I8885) was diluted to <NUM>µg/ml in PBS, incubated 100µL per well /<NUM> well plate at <NUM> for <NUM> hours. Liquid in the well plate was poured off, blocked with <NUM>µL of <NUM>% BSA at <NUM> for <NUM> minutes, and washed three times with PBS. <NUM>µL of <NUM>µg/mL ICAM-<NUM> (containing <NUM>% BSA, <NUM>% Tween <NUM>) was added to each well and incubated at <NUM> for <NUM> hours. The plate was washed <NUM> times with assay buffer (<NUM> HEPES pH <NUM>, <NUM> NaCl, <NUM> MgCl<NUM>, <NUM> MnCl<NUM>, <NUM>% glucose).

The Jurkat cytometer was centrifuged at <NUM>-G, and cells were resuspended in an assay buffer (<NUM> HEPES pH <NUM>, <NUM> NaCl, <NUM> MgCl<NUM>, <NUM> MnCl<NUM>, <NUM>% glucose) at <NUM>.

<NUM>µl of <NUM> of BCECF-AM per mL of the cell suspension was added. Incubated at <NUM> for <NUM> minutes, stirred up every <NUM> minutes during the incubation. After the incubation, the cells were washed with assay buffer at <NUM>. The cells were suspended to a concentration of <NUM> x <NUM><NUM>/mL.

The inhibitor was diluted to a final concentration of 2X in assay buffer, and <NUM>µL of the compound solution and <NUM>µL of Jurkat cells were mixed at room temperature, and incubated at <NUM> for <NUM> minutes. <NUM>µL/well of cells and inhibitors were added to the plate and incubated for <NUM> hour at room temperature. The total fluorescence was measured by a fluorometer: ex: <NUM>; em: <NUM>; cutoff: <NUM> to measure the total fluorescence. The plate was washed once with the assay buffer and the fluorescence was measured with a fluorometer: ex: <NUM>; em: <NUM>; cutoff:. The results are plotted as inhibition-concentration plots and EC<NUM> is calculated using standard methods.

Table <NUM> shows the EC<NUM> values of selected compounds measured by this method.

Claim 1:
A phosphorus-containing compound characterized in that it is a compound represented by the following structure:
<CHM>
R<NUM> is selected from alkyl, aryl, benzyl, aryl derivatives and benzyl derivatives;
R<NUM> is selected from hydroxyl, alkyl, hydrogen, alkoxy;
n is selected from <NUM> or <NUM>;
X is selected from carbon, oxygen, and nitrogen;
wherein when X is carbon, it is -CH<NUM>-, or -C(R<NUM>R<NUM>)-, wherein R<NUM>, and R<NUM> are the same or different substituents independently selected from an alkyl group, benzyl group, an aromatic group, a hydroxyl group, an alkoxy group, and a halogen;
wherein when X is nitrogen, it is -NH-, or -N(RN)-, wherein RN is selected from an alkyl group, a benzyl group and an aromatic group;
Z is selected from carbonyl, alkylenyl, sulfonyl, nitrogen, oxygen and sulfur;
wherein when Z is nitrogen, it is -NH-, or -N(RN)-, wherein RN is selected from an alkyl group, a benzyl group and an aromatic group;
R<NUM> is one or more substituents on the benzene ring independently selected from hydrogen and halogen;
Y is selected from carbon, oxygen, and nitrogen;
wherein when Y is carbon, it is -CH<NUM>-, or -C(R<NUM>R<NUM>)-, wherein R<NUM>, and R<NUM> are the same or different substituents independently selected from an alkyl group, a benzyl group, an aromatic group, and a halogen;
wherein when Y is nitrogen, it may be -NH-, or -N(RN)-, wherein RN is selected from an alkyl group, a benzyl group and an aromatic group;
R<NUM> is selected from alkyl, aryl, benzyl, aryl derivatives and benzyl derivatives;
R<NUM> is hydrogen;
the substituent groups represented by G1 and G2 are disposed on the benzene ring in meta, para or ortho position,
wherein, the above derivatives refer to the aromatic ring having one or more independently substituted hydrogen, alkyl, alkoxy, halogen, amino, cyano, hydroxy, nitro, aryl, alkylsulfonyl or phenylsulfonyl thereon.