SULFO-SUBSTITUTED BIARYL COMPOUND OR SALT THEREOF, PREPARATION METHOD THEREFOR, AND USE THEREOF

Abstract

The present disclosure relates to a sulfo-substituted biaryl derivative compound or a salt thereof, a preparation method and use thereof, in particular to the compound of formula (I) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.5′, R.sub.6, R.sub.7 and X as defined in the specification or its stereoisomers, tautomers, stable isotopic derivatives, pharmaceutically acceptable salts or solvates, a method for their preparation, a pharmaceutical composition comprising the same, and use of the compounds in the manufacture of a medicament for the treatment or prevention of a disease associated with RORγt.

##STR00001##

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, ##STR00103## wherein: R.sub.1 is selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with a substituent independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, mercapto, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio and C.sub.3-C.sub.6 cycloalkyl; R.sub.2, R.sub.3, R.sub.4 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, mercapto, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio, wherein C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio are each optionally substituted with a substituent independently selected from halogen, hydroxyl, mercapto, nitro and cyano; R.sub.5 and R.sub.5′ are each independently selected from hydrogen, hydroxy, halogen, nitro, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio and C.sub.3-C.sub.6 cycloalkyl, wherein C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6alkylthio and C.sub.3-C.sub.6 cycloalkyl are each optionally substituted with a substituent independently selected from halogen, nitro, cyano, hydroxyl, mercapto, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio; R.sub.6 is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio, wherein C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio are each optionally substituted with a substituent independently selected from halogen, nitro, cyano, hydroxyl and mercapto; R.sub.7 is selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, 3-6 membered heterocycloalkyl, and an amino optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein when R.sub.7 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio it is optionally substituted with a substituent independently selected from halogen, cyano, nitro, hydroxyl, mercapto, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.3-C.sub.6 cycloalkyl and an amino optionally substituted with C.sub.1-C.sub.6 alkyl; and X is selected from CH and N.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl, wherein C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl are each optionally substituted with a substituent independently selected from halogen, C.sub.3-C.sub.6 cycloalkyl and C.sub.1-C.sub.6 alkoxy.

3. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is selected from H and halogen.

4. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.3 and R.sub.4 are each independently selected from hydrogen, halogen, cyano, C.sub.1-C.sub.6 alkyl optionally substituted by halogen, and C.sub.1-C.sub.6alkoxy optionally substituted by halogen.

5. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.5 and R.sub.5′ are each independently selected from hydrogen, halogen, substituted C.sub.1-C.sub.3 alkyl and substituted C.sub.3-C.sub.6 cycloalkyl, wherein each of the substituents is independently selected from hydroxy, C.sub.1-C.sub.3 alkoxy and halogen.

6. The compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R.sub.5 is selected from hydrogen, —CH.sub.2OH, —CH.sub.2OCH.sub.3 ##STR00104## and R.sub.5′ is H.

7. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.6 is selected from hydrogen and halogen.

8. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.7 is selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkyl substituted by hydroxyl or C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl.

9. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the formula (II): ##STR00105##

10. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds: ##STR00106## ##STR00107## ##STR00108## ##STR00109##

11. (canceled)

12. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

13. (canceled)

14. A method of preventing or treating a disease associated with RORγt comprising administering to an individual in need thereof an effective dose of a compound according to claim 1.

15. The method according to claim 14, wherein the disease associated with RORγt is selected from tumor or cancer.

16. The method according to claim 15, wherein the tumor or cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, pemphigus cancer, liver cancer, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and eye cancer.

17. The compound according to claim 2, wherein R.sub.1 is selected from the group consisting of methyl, ethyl, propyl and cyclopropyl.

18. The compound according to claim 3, wherein R.sub.2 is selected from the group consisting of hydrogen and fluorine.

19. The compound according to claim 4, wherein R.sub.3 and R.sub.4 are each independently selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy.

20. The compound according to claim 6, wherein R.sub.5 is selected from the group consisting of hydrogen, —CH.sub.2OH, —CH.sub.2OCH.sub.3 ##STR00110## and R.sub.5′ is H.

21. The compound according to claim 8, wherein R.sub.7 is selected from the group consisting of methyl, ethyl, cyclopropylmethyl and —CH.sub.2CH.sub.2—OH.

22. The method according to claim 14 wherein the disease is treatable or preventable by activation of RORγt.

Description

EMBODIMENTS OF CARRYING OUT THE INVENTION

[0087] The technical solutions of the present disclosure are illustrated below with reference to specific embodiments, but the protection scope of the present disclosure is not limited to these embodiments. All modifications or equivalent substitutions that do not depart from the concept of the present disclosure are included in the protection scope of the present disclosure.

[0088] The experimental methods without specific conditions in the following examples are generally in accordance with the conventional conditions of this type of reaction, or in accordance with the conditions suggested by manufacturers. Percentages and parts are weight percentages and parts unless otherwise specified. Unless otherwise stated, ratios of liquids are by volume.

[0089] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods analogous to those disclosed in this application.

[0090] Abbreviations used herein have the meanings commonly understood in the art unless clearly defined otherwise in the specification. The meanings of the abbreviations used in the specification are listed below:

[0091] PdCl.sub.2 (dtbpf): 1,1′-di-tert-butylphosphinoferrocene palladium dichloride

[0092] Pd(dppf)Cl.sub.2: [1,1′-bis(diphenylphosphino)ferrocene] palladium dichloride

[0093] xantphos: 4,5-Bisdiphenylphosphine-9,9-dimethylxanthene

[0094] pd.sub.2(dba).sub.3: Tri(dibenzylideneacetone) dipalladium

[0095] HATU: 2-(7-Azobenzotriazole)-N,N,N′,N′,-tetramethylurea hexafluorophosphate

[0096] DIEA: N,N-diisopropylethylamine

[0097] DMF: N,N-dimethylformamide

[0098] DCM: dichloromethane

[0099] EA: Ethyl acetate

[0100] PE: Petroleum ether

[0101] rt: room temperature

[0102] LC-MS: Liquid Chromatography Mass Spectrometry

[0103] ESI: Electrospray ionization

[0104] m/z: mass-to-charge ratio

[0105] DTT: Dithiothreitol

[0106] EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0107] DCC: Dicyclohexylcarbodiimide

[0108] HOBt: 1-Hydroxybenzotriazole

[0109] TLC: Thin Layer Chromatography

Synthesis Examples

[0110] In the preparation of the target compounds provided by the present disclosure, column chromatography was carried out with silica gel (300-400 mesh) produced by Rushan Sun Desiccant Co., Ltd.; thin-layer chromatography was carried out with GF254 (0.25 mm); nuclear magnetic resonance spectroscopy (NMR) was carried out with Varian-400 nuclear magnetic resonance spectrometer; liquid mass spectrometry (LC/MS) was carried out with Agilent TechnologiESI 6120 liquid mass spectrometer.

[0111] In addition, all operations involving easily oxidizable or easily hydrolyzed raw materials are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present disclosure are all commercially available which can be used directly without further purification, and the temperatures used in the present disclosure are all in degrees Celsius ° C.

[0112] Where the structure of the compound of the present disclosure is inconsistent with the name thereof, the structural formula generally controls, unless it can be determined from the context that the name of the compound is correct.

Example 1: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) phenyl)acetamide

[0113] ##STR00012##

[0114] The title compound was synthesized according to the following scheme:

##STR00013##

Step 1: Synthesis of 2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-amine

[0115] ##STR00014##

[0116] 4-Ethylsulphonylbenzeneboronic acid (514 mg, 2.4 mmol), 4-bromo-3,5-dichloroaniline (482 mg, 2 mmol), PdCl.sub.2(dtbpf) (65 mg, 0.1 mmol), potassium carbonate (816 mg, 6 mmol) were added to 1,4-dioxane/water (5 mL/1 mL). The resulting mixture was stirred at 110° C. for 3 hours under nitrogen protection, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column (PE:EA=3:2) to obtain the target compound (320 mg, yield 48.5%, white solid). LC-MS (ESI) m/z: 330.0 [M+H].sup.+.

Step 2: Synthesis of N-(2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0117] ##STR00015##

[0118] 2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-amine (30 mg, 0.091 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (24.9 mg, 0.109 mmol), HATU (41.4 mg, 0.109 mmol), DIEA (35.3 mg, 0.273 mmol) were added sequentially to DMF (1.5 mL). The reaction mixture was stirred at room temperature for 2.5 hours. Water (10 mL) was added to the reaction mixture, which was extracted with EA (10 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by preparative plate (silica gel, EA:PE=1.5:1) gave the target compound (13.3 mg, yield 27.0%, white solid). LC-MS (ESI) m/z: 538.17 [M−H].sup.−. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.91-7.82 (m, 4H), 7.62 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 3.87 (s, 2H), 3.38 (q, J=7.4 Hz, 2H), 3.30-3.26 (m, 2H), 1.17-1.08 (m, 6H).

Example 2: N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) phenyl)acetamide

[0119] ##STR00016##

[0120] The title compound was synthesized according to the following scheme:

##STR00017##

Step 1: Synthesis of 2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-amine

[0121] ##STR00018##

[0122] 4-Methylsulfonylphenylboronic acid (240 mg, 1.2 mmol), 4-bromo-3,5-dichloroaniline (241 mg, 1 mmol), PdCl.sub.2 (dtbpf) (33 mg, 0.05 mmol) and potassium carbonate (408 mg, 3 mmol) were added to a mixture of 1,4-dioxane/water (5 mL/1 mL). The resulting mixture was stirred at 110° C. for 3 hours under nitrogen protection. The reaction was completed, and was cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (20 mL×3), and the solvent was removed under reduced pressure. The residue was separated and purified on a silica gel column (PE:EA=3:2) to obtain the target compound (168 mg, yield 53.1%, yellow solid). LC-MS (ESI) m/z: 317.9[M+H].sup.+.

Step 2: Synthesis of N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0123] ##STR00019##

[0124] 2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-amine (58 mg, 0.18 mmol), HATU (84 mg, 0.22 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (50 mg, 0.22 mmol) and DIEA (70 mg, 0.54 mmol) were successively added to DCM (3 mL). The reaction solution was reacted at room temperature overnight. TLC showed that the raw materials had been run out of and the reaction was completed. The reaction was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated sodium chloride (20 mL) successively, and the crude product was separated via an automated chromatographic system using silica gel column (PE:EA=1:4), to obtain the target product (70 mg, 71.4% yield, white solid). LC-MS (ESI) m/z: [M+H].sup.+/[M+18].sup.+ 526.0/543.0.

[0125] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.87 (d, J=8.2 Hz, 2H), 7.85 (s, 2H), 7.62 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 3.87 (s, 2H), 3.31 (s, 3H), 3.31-3.25 (m, 2H), 1.11 (t, J=7.3 Hz, 3H).

Example 3: N-(2,6-Dichloro-4′-(isopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0126] ##STR00020##

[0127] The title compound was synthesized according to the following scheme:

##STR00021##

Step 1: Synthesis of 2,6-dichloro-4′-(isopropylsulfonyl)-[1,1′-biphenyl]-4-amine

[0128] ##STR00022##

[0129] 4-Isopropanesulfonylbenzeneboronic acid (252 mg, 1.2 mmol), 4-bromo-3,5-dichloroaniline (241 mg, 1 mmol), PdCl.sub.2 (dtbpf) (33 mg, 0.05 mmol) and potassium carbonate (408 mg, 3 mmol) were added to a mixture of 1,4-dioxane/water (5 mL/1 mL). The resulting mixture was stirred at 110° C. for 3 hours under nitrogen protection. The reaction was completed, and was cooled to room temperature, added with water (20 mL), and extracted with EA (20 mL×3). The solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column (PE:EA=3:2) to obtain the target compound (230 mg, yield 66.8%, yellow solid). LC-MS (ESI) m/z: 344.0[M+H].sup.+.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(isopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) phenyl)acetamide

[0130] ##STR00023##

[0131] 2,6-Dichloro-4′-(isopropylsulfonyl)-[1,1′-biphenyl]-4-amine (62 mg, 0.18 mmol), HATU (84 mg, 0.22 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (50 mg, 0.22 mmol) and DIEA (70 mg, 0.54 mmol) were successively added in DCM (3 mL). The reaction solution was reacted at room temperature overnight. TLC showed that the raw materials had been run out of and the reaction was completed. The reaction was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated sodium chloride (20 mL) successively, and the crude product was separated by chromatography using silica gel column (PE:EA=1:2) to obtain the target product (70 mg, 70.0% yield, white solid). LC-MS (ESI) m/z: 571.0[M+18].sup.+.

[0132] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 7.96 (d, J=8.2 Hz, 2H), 7.91-7.81 (m, 4H), 7.62 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 3.87 (s, 2H), 3.55-3.46 (m, 1H), 3.31-3.25 (m, 2H), 1.19 (d, J=6.8 Hz, 6H), 1.11 (t, J=7.3 Hz, 3H).

Example 4: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl) phenyl)acetamide

[0133] ##STR00024##

[0134] The title compound was synthesized according to the following scheme:

##STR00025##

[0135] 2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-amine (30 mg, 0.091 mmol), 2-(4-(methylsulfonyl)phenyl)acetic acid (23.4 mg, 0.109 mmol), 1-propylphosphoric anhydride (50% in ethyl acetate, 139 mg, 0.218 mmol), triethylamine (33.2 mg, 0.328 mmol) were successively added to EA (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours. Water (10 mL) and EA (10 mL) were added to the reaction mixture. The aqueous phase was separated and extracted with EA (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by preparative plate (silica gel, dichloromethane:methanol=30:1) to obtain the target compound (30.0 mg, yield 62.6%, white solid). LC-MS (ESI) m/z: 543.0 [M+18].sup.+.

[0136] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.85 (s, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 3.86 (s, 2H), 3.38 (q, J=14.7, 7.3 Hz, 2H), 3.21 (s, 3H), 1.14 (t, J=7.3 Hz, 3H).

Example 5: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylsulfonyl)pyridin-2-yl)acetamide

[0137] ##STR00026##

[0138] The title compound was synthesized according to the following scheme:

##STR00027##

Step 1: Synthesis of 2-(5-Bromopyridin-2-yl)-N-(2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl) acetamide

[0139] ##STR00028##

[0140] 2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-amine (120 mg, 0.35 mmol), HATU (160 mg, 0.42 mmol), 2-(5-Bromopyridin-2-yl)acetic acid (91 mg, 0.42 mmol) and DIEA (135 mg, 1.05 mmol) were successively added in DCM (3 mL). The reaction solution was reacted at room temperature overnight. TLC showed that the raw materials had been run out of and the reaction was completed. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated sodium chloride (20 mL) successively, and the crude product (200 mg) was directly used in the next step.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylthio)pyridine-2-yl)acetamide

[0141] ##STR00029##

[0142] 2-(5-Bromopyridin-2-yl)-N-(2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide crude (200 mg) synthesized in the previous step, DIEA (135 mg, 1.05 mmol), xantphos (9.8 mg, 0.017 mmol), Pd.sub.2(dba).sub.3 (16 mg, 0.017 mmol) and 1,4-dioxane (3 mL) were added to a microwave reaction tube, bubbled with nitrogen for 5 minutes, and then reacted under microwave at 120° C. for 2 hours. TLC showed that the reaction was completed, and the reaction was separated via an automated chromatographic system using silica gel column (PE:EA=1:2) to obtain the target product (130 mg, 70.3% over two steps, yellow solid). LC-MS (ESI) m/z: 509.0[M+H].sup.+.

Step 3: Synthesis of N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylsulfonyl)pyridine-2-yl)acetamide

[0143] ##STR00030##

[0144] At room temperature, N-(2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylthio)pyridine-2-yl)acetamide (130 mg, 0.27 mmol), m-chloroperoxybenzoic acid (107 mg, 0.53 mmol, 85% content) were added to DCM (5 mL), and the reaction solution was reacted at room temperature for 1 hour. The reaction was completed, and was washed once with 2N sodium carbonate solution (10 mL), and separated via an automated chromatographic system using silica gel column (PE:EA=1:3) to obtain the target product (42 mg, yield 28.8%, yellow solid). LC-MS (ESI) m/z: 541.0 [M+H].sup.+.

[0145] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.77 (s, 1H), 8.98 (d, J=2.3 Hz, 1H), 8.29 (dd, J=8.2, 2.4 Hz, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.85 (s, 2H), 7.73 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 4.08 (s, 2H), 3.45-3.35 (m, 4H), 1.17-1.12 (m, 6H).

Example 6: N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-ethylsulfonyl) phenyl)acetamide

[0146] ##STR00031##

[0147] The title compound was synthesized according to the following scheme:

##STR00032##

Step 1: Synthesis of 1-bromo-4-cyclopropylthiobenzene

[0148] ##STR00033##

[0149] Potassium tert-butoxide (1.48 g, 13.2 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 4-bromobenzenethiol (1.64 mL, 13.2 mmol) was added dropwise to the reaction solution at room temperature. Upon the dropwise addition was completed, the reaction mixture was stirred at room temperature for reaction for 15 minutes, and then bromocyclopropane (3.18 mL, 39.7 mmol) was added to the reaction solution. The tube was sealed and the reaction mixture was stirred at 80° C. for reaction for 24 hours. TLC showed that the raw materials was reacted completely, and a new main spot was formed (R.sub.f=0.7, PE:EA=10:1). The reaction solution was poured into ice water (50 mL) and extracted with methyl tert-butyl ether (50 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2.8 g, yield 92.4%, brown liquid).

Step 2: Synthesis of 1-bromo-4-cyclopropylsulfonylbenzene

[0150] ##STR00034##

[0151] 1-Bromo-4-cyclopropylthiobenzene (6-3) (3.00 g, 13.1 mmol) was dissolved in DCM (50 mL) and m-chloroperoxybenzoic acid (5.65 g, 32.7 mmol) was slowly added to the reaction solution under ice bath. After the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. TLC showed that the raw materials were reacted completely, and a new main spot was formed (R.sub.f=0.5, PE:EA=10:1). The reaction solution was filtered, the filtrate was poured into saturated aqueous sodium bicarbonate solution (50 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified on a silica gel column (PE:EA=100:1-30:1) to obtain the target compound (1.50 g, 43.9% yield, yellow solid).

Step 3: Synthesis of 2-(4-(cyclopropylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0152] ##STR00035##

[0153] 1-Bromo-4-cyclopropylsulfonylbenzene (6-4) (500 mg, 1.91 mmol), Bis(pinacolato)diboron (729 mg, 2.87 mmol), potassium acetate (564 mg, 5.74 mmol)) and Pd(dppf)Cl.sub.2 (140 mg, 0.192 mmol) were added to 1,4-dioxane (5 mL). Under nitrogen protection, the reaction mixture was stirred at 90° C. overnight. Then the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was separated and purified by silica gel column (PE:EA=100:1-30:1) to obtain the target compound (200 mg, yield 3.39%, yellow liquid).

Step 4: Synthesis of 2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine

[0154] ##STR00036##

[0155] 2-(4-(cyclopropylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.649 mmol), 4-bromo-3,5-dichloroaniline (130 mg, 0.541 mmol), potassium carbonate (187 mg, 1.35 mmol) and PdCl.sub.2 (dtbpf) (59.1 mg, 0.081 mmol) were added to a mixed solvent of 1,4-dioxane (8 mL) and water (1 mL). Under nitrogen protection, the reaction mixture was stirred at 110° C. for 1.5 hours, and monitored by TLC for completion. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was separated and purified by silica gel column (PE:EA=8:1-4:1) to obtain the target compound (64.0 mg, yield 34.6%, brown solid). LC-MS (ESI) m/z 342.0 [M+H].sup.+.

Step 5: Synthesis of N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-ethylsulfonyl)phenyl)acetamide

[0156] ##STR00037##

[0157] 2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (50.0 mg, 0.146 mmol), 2-[4-(ethylsulfonyl))phenyl]acetic acid (40.0 mg, 0.175 mmol), DIEA (0.0724 mL, 0.438 mmol) and HATU (83.3 mg, 0.219 mmol) were added to DMF (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction solution was poured into water (20 mL) and extracted with EA (10 mL×2). The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Crystallization from methanol gave the target compound (20.0 mg, 24.8% yield, white solid). LC-MS (ESI) m/z 550.0 [M−1].sup.−.

[0158] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.97 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.67 (s, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J=8.3 Hz, 2H), 3.84 (s, 2H), 3.14 (q, J=7.5 Hz, 2H), 2.59-2.50 (m, 1H), 1.44-1.37 (m, 2H), 1.30 (t, J=7.5 Hz, 3H), 1.13-1.05 (m, 2H).

Example 7: N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl) phenyl)acetamide

[0159] ##STR00038##

[0160] 2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-amine (64 mg, 0.2 mmol), HATU (91 mg, 0.24 mmol), 2-(4-(methylsulfonyl)phenyl)acetic acid (52 mg, 0.24 mmol) and DIEA (77 mg, 0.6 mmol) were successively added in DCM (3 mL), and the reaction solution was reacted at room temperature overnight. TLC showed that the raw materials had been run out of and the reaction was completed. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated sodium chloride (20 mL) successively, and the crude product was separated via automated chromatographic system using silica gel column (PE:EA=1:2) to obtain the target product (90 mg, 86.5% yield, white solid). LC-MS (ESI) m/z: 529.0 [M+18].sup.+.

[0161] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.85 (s, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 3.86 (s, 2H), 3.32 (s, 3H), 3.22 (s, 3H).

Example 8: N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylsulfonyl) pyridin-2-yl)acetamide

[0162] ##STR00039##

[0163] The title compound was synthesized according to the following scheme:

##STR00040##

Step 1: Synthesis of N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(6-(ethylthio)pyridine-3-yl)acetamide

[0164] ##STR00041##

[0165] 2-(5-Bromopyridin-2-yl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide (60.0 mg, 0.117 mmol), pd.sub.2(dba).sub.3 (10.7 mg, 0.0117 mmol), xantphos (6.77 mg, 0.0117 mmol), triethylamine (0.0324 mL, 0.233 mmol) and ethanethiol (0.0437 mL, 0.584 mmol) were added to 1,4-dioxane (1.5 mL). Under nitrogen protection, the reaction mixture was reacted under microwave at 120° C. for 1.5 hours, and monitored by LC-MS for completion. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was separated and purified by silica gel column (PE:EA=4:1-2:1) to obtain the target compound (29.0 mg, yield 50.2%, yellow oil). LC-MS (ESI) m/z: 495.0 [M+H].sup.+.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylsulfonyl)pyridin-2-yl)acetamide

[0166] ##STR00042##

[0167] N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(6-(ethylthio)pyridin-3-yl) acetamide (8-3) (29.0 mg, 0.0585 mmol) was dissolved in DCM (2 mL) and m-chloroperoxybenzoic acid (23.8 mg, 0.117 mmol) was slowly added to the reaction under ice bath. Upon the addition was complete, the ice bath was removed, and the reaction was continued under stirring at room temperature for 1.5 hours, and monitored by LC-MS for completion. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (10 mL), extracted with DCM (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative plate (PE:EA=1:3) to obtain the target compound (10.0 mg, yield 32.4%, white solid). LC-MS (ESI) m/z 527.0 [M+H].sup.+.

[0168] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.65 (s, 1H), 9.14 (d, J=2.1 Hz, 1H), 8.24 (dd, J=8.1, 2.3 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.71 (s, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 4.03 (s, 2H), 3.20 (q, J=7.4 Hz, 2H), 3.13 (s, 3H), 1.36 (t, J=7.4 Hz, 3H).

Example 9: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylsulfonyl)pyridin-2-yl)acetamide

[0169] ##STR00043##

[0170] The title compound was synthesized according to the following scheme:

##STR00044##

Step 1: Synthesis of N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylthio)pyridin-2-yl)acetamide

[0171] ##STR00045##

[0172] 2-(5-Bromopyridin-2-yl)-N-(2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide (100 mg, 0.189 mmol), methyl mercaptan (18.2 mg, 0.379 mmol), xantphos (10.9 mg, 0.019 mmol), Pd.sub.2(dba).sub.3 (10.9 mg, 0.019 mmol) and DIEA (48.9 mg, 0.379 mmol) were dissolved in 1,4-dioxane (4 mL). The reaction mixture was stirred under microwave at 100° C. for 1 hour, and monitored by LC-MS for completion. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative plate (EA:PE=1:1) to obtain the target compound (36.0 mg, yield 38.4%, white solid). LC-MS (ESI) m/z: 495.0 [M+H].sup.+.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylsulfonyl)pyridin-2-yl)acetamide

[0173] ##STR00046##

[0174] N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylthio)pyridin-2-yl)acetamide (9-1) (30.0 mg, 0.06 mmol) was dissolved in DCM (3 mL), and m-chloroperoxybenzoic acid (21.0 mg, 0.121 mmol) was slowly added to the reaction solution under ice bath. The ice bath was removed and the reaction mixture was stirred for an additional 1.5 hours at room temperature, and monitored by LC-MS for completion. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (15 mL), extracted with DCM (15 mL×2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative plate (EA:PE=2:1) to obtain the target compound (10.0 mg, yield 31.3%, white solid). LC-MS (ESI) m/z: 527.0 [M+H].sup.+.

[0175] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.60 (s, 1H), 9.19 (s, 1H), 8.28 (d, J=6.1 Hz, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.71 (s, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 4.03 (s, 2H), 3.27-3.11 (m, 5H), 1.33 (t, J=7.4 Hz, 3H).

Example 10: N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylsulfonyl)pyridin-2-yl)acetamide

[0176] ##STR00047##

Step 1: Synthesis of N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylthio)pyridin-2-yl) acetamide

[0177] ##STR00048##

[0178] 2-(5-Bromopyridin-2-yl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide (60.0 mg, 0.117 mmol), Pd.sub.2(dba).sub.3 (10.7 mg, 0.0117 mmol), xantphos (6.77 mg, 0.0117 mmol), triethylamine (0.0487 mL, 0.350 mmol) and methyl mercaptan (281 mg, 0.584 mmol) were added to 1,4-dioxane (1.5 mL). Under nitrogen protection, the reaction mixture was stirred under microwave at 100° C. for 1.5 hours, and monitored by LC-MS for completion. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=4:1-2:1) to obtain the target compound (30.0 mg, yield 53.4%, yellow oil). LC-MS (ESI) m/z: 480.9 [M+H].sup.+.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylsulfonyl)pyridin-2-yl)acetamide

[0179] ##STR00049##

[0180] N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(methylthio)pyridin-2-yl) acetamide (10-1) (30.0 mg, 0.0623 mmol) was dissolved in DCM (2 mL) and m-chloroperoxybenzoic acid (25.3 mg, 0.125 mmol) was slowly added to the reaction solution under ice bath. Upon the addition was complete, the ice bath was removed, and the reaction was continued under stirring at room temperature for 1.5 hours, and monitored by LC-MS for completion. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (10 mL), extracted with DCM (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative plate (PE:EA=1:3) to obtain the target compound (3.00 mg, yield 9.38%, white solid). LC-MS (ESI) m/z 513.0 [M+H].sup.+.

[0181] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.61 (s, 1H), 9.19 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.1, 2.2 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.71 (s, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 4.03 (s, 2H), 3.15 (s, 3H), 3.13 (s, 3H).

Example 11: N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0182] ##STR00050##

[0183] 2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (70.0 mg, 0.205 mmol), 2-[4-(methylsulfonyl)phenyl]acetic acid (52.6 mg, 0.245 mmol), HATU (117 mg, 0.307 mmol) and DIEA (79.3 mg, 0.614 mmol) were added to DCM (3 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with DCM (15 mL×2). The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative plate (EA:PE=3:1) to obtain the target compound (14.5 mg, yield 13.2%, white solid). LC-MS (ESI) m/z 536.0 [M−H].sup.−.

[0184] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03 (s, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 7.68 (s, 2H), 7.53 (d, J=7.9 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 3.82 (s, 2H), 3.07 (s, 3H), 2.61-2.49 (m, 1H), 1.43-1.37 (m, 2H), 1.17-1.06 (m, 2H).

Example 12: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionamide

[0185] ##STR00051##

[0186] N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (450 mg, 0.83 mmol) and paraformaldehyde (25 mg, 0.83 mmol) were added to anhydrous dimethylsulfoxide (5 mL). To the reaction mixture was added sodium methoxide (1.78 mg, 0.03 mmol). The reaction mixture was stirred at room temperature overnight. EA (10 mL) and water (10 mL) were added. The organic phase was separated, the aqueous phase was extracted with EA (10 mL×2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, EA/(DCM/PE=1/2)=0˜100%) to obtain the target compound (200 mg, yield 42.4%, white solid). LC-MS (ESI) m/z: 586.9 [M+NH.sub.4].sup.+.

[0187] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.76 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.98-7.91 (m, 4H), 7.74 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 5.22 (t, J=5.2 Hz, 1H), 4.23-4.13 (m, 1H), 4.09-4.03 (m, 1H), 3.83-3.68 (m, 1H), 3.45 (q, J=7.3 Hz, 2H), 3.34 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.3 Hz, 3H), 1.17 (t, J=7.3 Hz, 3H).

Example 12-1: 3-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-amino)-2-(4-(ethylsulfonyl) phenyl)propionic acid

[0188] ##STR00052##

[0189] Dichloromethane (1 mL), 2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-amine (45 mg, 0.139 mmol), 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionic acid (30 mg, 0.116 mmol), EDC (33 mg, 0.174 mmol), HOBt (24 mg, 0.174 mmol) and DIEA (45 mg, 0.348 mmol) were successively added to a 25 mL single-necked flask. The resulting reactant was stirred at room temperature for 48 hours under nitrogen protection, the solvent was then removed under reduced pressure, and the residue was purified by preparative chromatography to obtain the target compound (18.0 mg, yield 27.2%, white solid). LC-MS (ESI) m/z: 570.0[M+H].sup.+.

[0190] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.93 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.78 (s, 2H), 6.53 (s, 1H), 3.92 (t, J=6.8 Hz, 1H), 3.78-3.73 (m, 1H), 3.44 (dd, J=12.2, 5.4 Hz, 1H), 3.39-3.34 (m, 2H), 3.29-3.25 (m, 2H), 1.16-1.07 (m, 6H).

Example 13: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) phenyl)-3-methoxypropionamide

[0191] ##STR00053##

Step 1: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionic acid

[0192] ##STR00054##

[0193] To a 250 mL there-necked flask were added 4-ethylsulfonyl phenylacetic acid (2.50 g, 10.9 mmol) and tetrahydrofuran (35 mL), the reaction solution was cooled to −20° C. and then added dropwise isopropylmagnesium bromide (32.8 mL, 32.8 mmol, 1 mol/L). Upon the addition was complete, the reaction solution was reacted at room temperature for 6 hours, and then paraformaldehyde (2.95 g, 32.8 mmol) was added. The reaction continued at room temperature for 18 hours, then cooled to 0° C., quenched with saturated aqueous ammonium chloride solution (40 mL), and acidified to pH=2˜3 with hydrochloric acid (1 mol/L) at 0° C. The separated aqueous phase was extracted again with EA (50 mL×2), the organic layers were combined, and the solvent was rotary dried under reduced pressure to obtain a crude product. The crude product was separated with a silica gel column (dichloromethane:methanol=1:0-4:1) to obtain the target product (2.00 g, yield 71.0%, colorless oil). LC-MS (ESI) m/z 276.1 [M+18].sup.+.

[0194] .sup.1H NMR (400 MHz, McOH-d.sub.4) δ 7.90-7.85 (m, 2H), 7.65-7.60 (m, 2H), 4.13-4.07 (m, 1H), 3.94-3.87 (m, 1H), 3.87-3.81 (m, 1H), 3.20 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.4 Hz, 3H).

Step 2: Synthesis of methyl 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropanoate

[0195] ##STR00055##

[0196] 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionic acid (1.88 g, 7.27 mmol) and 3 mol/L hydrogen chloride methanol solution (60 mL) were added to a 100 mL single-necked flask. The reaction was carried out at 60° C. for 18 hours, and rotary dried under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column (EA:PE=0:1-1:1) to obtain the target product (1.30 g, yield 65.6%, white solid). LC-MS (ESI) m/z: 290.1 [M+18].sup.+.

Step 3: Methyl 2-(4-(ethylsulfonyl)phenyl)-3-methoxypropanoate

[0197] ##STR00056##

[0198] To a 50 mL single-necked flask were successively added methyl 2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionate (1.10 g, 4.03 mmol), acetonitrile (10 mL), silver oxide (1.21 g, 5.25 mmol), then cooled to 0° C. Methyl iodide (1.72 g, 12.1 mmol) was added, and the reaction solution was stirred at room temperature for 7 days. The solvent was removed under reduced pressure by rotary evaporation, and the crude product was separated by silica gel column (EA:PE=0:1-2:1) to obtain the target product (800 mg, yield 69.3%, oil). LC-MS (ESI) m/z: 287.0 [M+H].sup.+.

Step 4: 2-(4-(Ethylsulfonyl)phenyl)-3-methoxypropionic acid

[0199] ##STR00057##

[0200] To a 50 mL single-necked flask were added methyl 2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionate (800 mg, 2.79 mmol), methanol (5 mL), water (5 mL), lithium hydroxide (200 mg, 8.38 mmol), and the reaction solution was stirred at 50° C. for 2 hours. The solvent was removed under reduced pressure by rotary evaporation, and the crude product was re-diluted with EA (20 mL) and water (20 mL). The separated aqueous phase was acidified with hydrochloric acid (1 mol/L) to pH=3, and then extracted with EA (20 mL×3). The organic phases from the last three extractions were combined, and the filtrate was rotary dried under reduced pressure to obtain a crude product. The crude product was prepared by high pressure liquid chromatography to obtain the target product (270 mg, yield 35.5%, white solid). LC-MS (ESI) m/z: 273.0 [M+H].sup.+.

[0201] .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 7.90-7.84 (m, 2H), 7.65-7.60 (m, 2H), 4.04-3.98 (m, 1H), 3.97-3.92 (m, 1H), 3.73-3.68 (m, 1H), 3.34 (s, 3H), 3.20 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H).

Step 5: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionamide

[0202] ##STR00058##

[0203] To a 50 mL single-necked flask were added 2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionic acid (12-5) (40 mg, 0.146 mmol), DCM (3 mL) and thionyl chloride (87 mg, 0.734 mmol), the reaction solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure by rotary evaporation, and the crude product was re-dissolved in DCM (3 mL), added with DIEA (113 mg, 0.881 mmol), 3,5-dichloro-4-(4-ethylsulfonylphenyl)aniline (58 mg, 0.176 mmol). The reaction solution was further stirred at room temperature for 4 hours. The crude product was obtained by rotary evaporation under reduced pressure, which was subject to high pressure liquid chramatography to obtain the target product (40 mg, yield 46.7%, white solid). LC-MS (ESI) m/z: 584.0 [M+H].sup.+.

[0204] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.73 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.84 (s, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 4.17-4.11 (m, 1H), 4.00 (t, J=9.0 Hz, 1H), 3.66-3.60 (m, 1H), 3.38 (q, J=7.4 Hz, 2H), 3.31-3.26 (m, 5H), 1.18-1.06 (m, 6H).

Example 14: N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(2-hydroxyethyl sulfonyl)phenyl)acetamide

[0205] ##STR00059##

Step 1: Synthesis of 2-(4-Bromophenyl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide

[0206] ##STR00060##

[0207] 2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-amine (100 mg, 0.316 mmol), 2-(4-bromophenyl) acetic acid (81.6 mg, 0.379 mmol), DIEA (0.157 mL, 0.949 mmol) and HATU (180 mg, 0.474 mmol) were successively added to DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours and monitored by LC-MS for completion. The reaction solution was poured into water (20 mL) and extracted with DCM (15 mL×2). The organic phases were combined, washed successively with saturated ammonium chloride (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (196 mg, crude product, white solid). LC-MS (ESI) m/z: 509.9 [M−H].sup.−.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(2-hydroxyethylthio)phenyl)acetamide

[0208] ##STR00061##

[0209] 2-(4-Bromophenyl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide (196 mg, 0.382 mmol), Pd.sub.2(dba).sub.3 (35.0 mg, 0.0382 mmol), xantphos (22.1 mg, 0.0382 mmol), triethylamine (0.159 mL, 1.15 mmol) and 2-mercaptoethanol (0.0538 mL, 0.764 mmol) were added into 1,4-dioxane (3 mL). Under nitrogen protection, the reaction mixture was stirred at 100° C. overnight, and monitored by TLC for completion. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (600 mg, crude, yellow oil).

Step 3: Synthesis of N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(2-hydroxyethylsulfonyl)phenyl)acetamide

[0210] ##STR00062##

[0211] N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(2-hydroxyethylthio)phenyl)acetamide (600 mg, 1.18 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (507 mg, 2.94 mmol) was slowly added to the reaction under ice bath. Upon the addition was complete, the ice bath was removed, and the reaction was continued under stirring at room temperature for 2 hours, and monitored by LC-MS for completion. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (30 mL), extracted with DCM (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified on silica gel column (PE:EA=2:1-1:2) to obtain the target compound (30.0 mg, 17.5% yield over three steps, white solid). LC-MS (ESI) m/z: 541.9 [M+H].sup.+.

[0212] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02 (d, J=8.0 Hz, 2H), 7.94 (d, J=7.9 Hz, 2H), 7.66 (s, 2H), 7.60-7.53 (m, 3H), 7.45 (d, J=7.9 Hz, 2H), 4.06-4.00 (m, 2H), 3.84 (s, 2H), 3.42-3.33 (m, 2H), 3.14 (s, 3H).

Example 15: N-(2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) phenyl)-3-methoxypropionamide

[0213] ##STR00063##

[0214] 2-[4-(Ethylsulfonyl)phenyl]-3-methoxypropionic acid (40.0 mg, 0.147 mmol) was dissolved in dry DCM (3 mL), and thionyl chloride (0.0533 mL, 0.735 mmol) was added dropwise to the reaction solution at room temperature. Upon the addition was complete, the reaction was continued under stirring at room temperature for 3 hours. The intermediate obtained by concentrating the reaction solution under reduced pressure was dissolved in dry DCM (3 mL), and 2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-amine (46.5 mg, 0.147 mmol) and DIEA (0.159 mL, 0.955 mmol) were added successively. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (20 mL) and extracted with DCM (15 mL×2). The organic phases were combined, washed successively with saturated ammonium chloride (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=1:9) to obtain the target compound (20.0 mg, yield 23.9%, white solid). LC-MS (ESI) m/z: 569.9 [M+H].sup.+.

[0215] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.47 (s, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 7.70 (s, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 4.07-3.99 (m, 1H), 3.98-3.92 (m, 1H), 3.82-3.74 (m, 1H), 3.49 (s, 3H), 3.19-3.07 (m, 5H), 1.30 (t, J=7.4 Hz, 3H).

Example 16: N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionamide

[0216] ##STR00064##

[0217] 2-[4-(Ethylsulfonyl)phenyl]-3-methoxypropionic acid (40.0 mg, 0.147 mmol) was dissolved in dry DCM (3 mL), and thionyl chloride (0.0533 mL, 0.735 mmol) was added dropwise to the reaction solution at room temperature. Upon the addition was complete, the reaction was continued under stirring at room temperature for 3 hours. The intermediate obtained by concentrating the reaction solution under reduced pressure was dissolved in dry DCM (3 mL), and 2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (50.3 mg, 0.147 mmol) and DIEA (0.158 mL, 0.955 mmol) were added successively. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (20 mL) and extracted with DCM (15 mL×2). The organic phases were combined, washed successively with saturated ammonium chloride (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=1:9) to obtain the target compound (27.0 mg, yield 30.8%, white solid). LC-MS (ESI) m/z: 596.1 [M+H].sup.+.

[0218] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.72 (s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.82 (s, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 4.15-4.08 (m, 1H), 3.98 (t, J=9.0 Hz, 1H), 3.65-3.57 (m, 1H), 3.29-3.25 (m, 5H), 2.98-2.89 (m, 1H), 1.18-1.13 (m, 2H), 1.11-1.04 (m, 5H).

Example 17: 2-(4-((Cyclopropylmethyl)sulfonyl)phenyl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide

[0219] ##STR00065##

Step 1: Synthesis of methyl 2-(4-(benzylthio)phenyl)acetate

[0220] ##STR00066##

[0221] Methyl 2-(4-bromophenyl)acetate (9.00 g, 39.3 mmol), pd.sub.2(dba).sub.3 (2.88 g, 3.14 mmol), xantphos (1.82 g, 3.14 mmol), DIEA (13.0 mL, 78.6 mmol) and benzyl mercaptan (9.22 mL, 78.6 mmol) were added to 1,4-dioxane (120 mL). Under nitrogen protection, the reaction mixture was stirred at 100° C. overnight, and monitored by TLC for completion. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=20:1-10:1) to obtain the target compound (10.2 g, yield 95.3%, yellow oily).

Step 2: Synthesis of methyl 2-[4-(chlorosulfonyl)phenyl]acetate

[0222] ##STR00067##

[0223] Methyl 2-(4-(benzylthio)phenyl)acetate (10.2 g, 37.4 mmol) was dissolved in a mixed solvent of acetic acid (100 mL) and water (25 mL). Under an ice bath, N-chlorosuccinimide (20.0 g, 150 mmol) was slowly added to the reaction solution. After the addition was complete, the ice bath was removed, and the reaction was continued under stirring at room temperature for 2 hours, and monitored by TLC for completion. The reaction solution was poured into water (200 mL), extracted with EA (50 mL×2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=10:1-5:1) to obtain the target compound (8.5 g, yield 91.3%, colorless oil).

Step 3: Synthesis of methyl 2-(4-cyclopropylmethylsulfonylphenyl)acetate

[0224] ##STR00068##

[0225] Methyl 2-[4-(chlorosulfonyl)phenyl]acetate (5.00 g, 20.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran (60 mL) and water (40 mL). Sodium bicarbonate (3.38 g, 40.2 mmol) and sodium sulfite (3.04 g, 24.1 mmol) were added to the reaction at room temperature. Upon the addition was complete, the reaction solution was heated to 70° C. and stirred for 2 hours, and monitored by LC-MS for completion. The reaction solution was concentrated under reduced pressure to obtain the intermediate, which was dissolved in anhydrous dimethylsulfoxide (90 mL), and added with (bromomethyl)cyclopropane (5.90 mL, 60.3 mmol). Under nitrogen protection, the reaction mixture was stirred at 100° C. for 3 hours, and monitored by TLC for completion. The reaction solution was poured into water (150 mL), extracted with EA (80 mL×2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=7:3) to obtain the target compound (2.80 g, yield 51.9%, light brown solid).

Step 4: Synthesis of 2-(4-cyclopropylmethylsulfonylphenyl)acetic acid

[0226] ##STR00069##

[0227] Methyl 2-(4-cyclopropylmethylsulfonylphenyl)acetate (58.0 mg, 0.216 mmol) was dissolved in methanol (3 mL). At room temperature, a 1M aqueous sodium hydroxide solution (1 mL) was added dropwise to the reaction solution. Upon the addition was complete, the reaction was continued under stirring at room temperature for 2 hours, and monitored by LC-MS for completion. The reaction solution was poured into water (10 mL) and adjusted to pH-4 with 1M dilute hydrochloric acid. The reaction was extracted with EA (15 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (45.0 mg, crude product, colorless oil). LC-MS (ESI) m/z 507.1 [2M−H].sup.−.

Step 5: Synthesis of 2-(4-((Cyclopropylmethyl)sulfonyl)phenyl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide

[0228] ##STR00070##

[0229] 2,6-Dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-amine (56.0 mg, 0.177 mmol), 2-(4-cyclopropylmethylsulfonylphenyl)acetic acid (45.0 mg, 0.177 mmol), DIEA (0.0878 mL, 0.531 mmol) and HATU (101 mg, 0.266 mmol) were successively added to DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours and monitored by LC-MS for completion. The reaction solution was poured into water (20 mL) and extracted with DCM (15 mL×2). The organic phases were combined, washed successively with saturated ammonium chloride (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by reverse phase column (20% water/80% acetonitrile) to obtain the target compound (35.0 mg, 29.4% over two steps, white solid). LC-MS (ESI) m/z: 550.0 [M−H].sup.−.

[0230] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.69 (s, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.85 (d, J=8.1 Hz, 2H), 7.82 (s, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 3.85 (s, 2H), 3.29 (s, 3H), 3.23 (d, J=7.0 Hz, 2H), 0.86-0.76 (m, 1H), 0.48-0.39 (m, 2H), 0.14-0.06 (m, 2H).

Example 18: 2-(4-((Cyclopropylmethyl)sulfonyl)phenyl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-methoxypropionamide

[0231] ##STR00071##

Step 1: Synthesis of methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-hydroxypropanoate

[0232] ##STR00072##

[0233] Methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate (1000 mg, 3.73 mmol) and paraformaldehyde (302 mg, 3.35 mmol) were dissolved in anhydrous dimethylsulfoxide (10 mL). Sodium methoxide (8.05 mg, 0.149 mmol) was added to the reaction solution at room temperature. Upon the addition was complete, the reaction solution was stirred at room temperature overnight. The reaction solution was poured into ice water (25 mL), and neutralized with 1M dilute hydrochloric acid to pH-7. The resultant mixture was extracted with EA (15 mL×3), the combined organic phases was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=10:1-1:1) to obtain the target compound (765 mg, yield 65.7%, light brown solid), and the raw material (196 mg) was recovered. LC-MS (ESI) m/z: 297.1 [M−H].sup.−.

Step 2: Synthesis of methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-methoxypropanoate

[0234] ##STR00073##

[0235] Methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-hydroxypropanoate (490 mg, 1.64 mmol) and silver oxide (457 mg, 1.97 mmol) were dissolved in acetonitrile (4 mL) under a condition protected from light. Under an ice bath, iodomethane (0.153 mL, 2.46 mmol) was added dropwise to the reaction solution. Upon the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 3 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which wad separated and purified by silica gel column (PE:EA=10:1-1:1) to obtain the target compound (70.0 mg, yield 13.6%, pale yellow solid), and the raw material (255 mg) was recovered. LC-MS (ESI) m/z: 313.1 [M+H].sup.+.

Step 3: Synthesis of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-methoxypropionic acid

[0236] ##STR00074##

[0237] Methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-methoxypropanoate (70.0 mg, 0.224 mmol) was dissolved in methanol (2 mL). At room temperature, a 1M aqueous sodium hydroxide solution (2 mL) was added dropwise to the reaction solution. Upon the addition was complete, the reaction was continued under stirring at room temperature for 2 hours, and monitored by LC-MS for completion. The reaction solution was poured into water (10 mL) and adjusted to pH-4 with 1M dilute hydrochloric acid. The reaction was extracted with EA (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (60.0 mg, crude product, pale yellow oil). LC-MS (ESI) m/z: 297.0 [M−H].sup.−.

Step 4: 2-(4-((Cyclopropylmethyl)sulfonyl)phenyl)-N-(2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl] Preparation of phenyl]-4-yl)-3-methoxypropionamide

[0238] ##STR00075##

[0239] 2-(4-((Cyclopropylmethyl)sulfonyl)phenyl)-3-methoxypropionic acid (60.0 mg, 0.201 mmol) was dissolved in dry DCM (3 mL). At room temperature, thionyl chloride (0.073 mL, 1.01 mmol) was added dropwise to the reaction solution. Upon the addition was complete, the reaction was continued under stirring at room temperature for 3 hours. The intermediate obtained by concentrating the reaction solution under reduced pressure was dissolved in dry DCM (3 mL), and 2,6-dichloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-amine (63.6 mg, 0.201 mmol) and DIEA (0.216 mL, 1.31 mmol) was added successively. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (20 mL) and extracted with DCM (15 mL×2). The organic phases were combined, washed successively with saturated ammonium chloride (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by reverse phase column (20% water/80% acetonitrile) to obtain the target compound (26.0 mg, 19.5% yield over two steps, white solid). LC-MS (ESI) m/z: 594.1 [M−H].sup.−.

[0240] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.88 (s, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.1 Hz, 2H), 7.84 (s, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 4.18-4.11 (m, 1H), 3.98 (t, J=8.9 Hz, 1H), 3.62-3.55 (m, 1H), 3.28 (s, 3H), 3.27 (s, 3H), 3.23 (d, J=7.1 Hz, 2H), 0.84-0.75 (m, 1H), 0.47-0.36 (m, 2H), 0.14-0.04 (m, 2H).

Example 19: N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propionamide

[0241] ##STR00076##

Step 1: Synthesis of methyl 2-(4-methylsulfonyl)phenylacetate

[0242] ##STR00077##

[0243] 2-(4-Methylsulfonyl) phenylacetic acid (9.00 g, 42.0 mmol) was dissolved in methanol (100.0 mL), and thionyl chloride (15.0 g, 126 mmol) was added at 0° C. The reaction solution was warmed to room temperature and stirred for 1 hour, and then was stopped. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA=3:1-2:1) to obtain the target compound (8.60 g, yield 89.7%, yellow solid). MS (ESI) m/z: 229.0 [M+H].sup.+.

[0244] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 3.73 (s, 2H), 3.72 (s, 3H), 3.05 (s, 3H).

Step 2: Synthesis of methyl 2-(4-methylsulfonyl)phenyl-3-hydroxypropionate

[0245] ##STR00078##

[0246] To a solution of methyl 2-(4-methylsulfonyl)phenylacetate (9.40 g, 41.2 mmol) and paraformaldehyde (1.17 g, 39.2 mmol) in anhydrous dimethyl sulfoxide (100.0 mL) was added sodium methoxide (89.0 mg, 1.65 mmol), and the reaction was stirred at room temperature for 16 hours, and then was stopped. The reaction solution was poured into ice water (300.0 mL), 1.0M hydrochloric acid solution was added, and extracted with EA (400 mL×2). The organic phase was washed with saturated brine (60.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA=3:1-1:1) to obtain the target compound (6.15 g, yield 57.8%, pale yellow oil). MS (ESI) m/z: 290.1 [M.sup.+NH.sub.4].sup.+.

[0247] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.87 (d, 2H), 7.57 (d, 2H), 5.08 (t, J=4.9 Hz, 1H), 3.95-3.90 (m, 2H), 3.72-3.65 (m, 1H), 3.61 (s, 3H), 3.18 (s, 3H).

Step 3: Synthesis of methyl 2-(4-(methylsulfonyl)phenyl)-3-methoxypropanoate

[0248] ##STR00079##

[0249] Methyl 2-(4-(methylsulfonyl)phenyl)-3-hydroxypropanoate (6.10 g, 23.6 mmol) was dissolved in DCM (140 mL) and cooled to 0° C. with an ice-water bath. Fluoroboric acid (4.14 g, 23.6 mmol, 48% aqueous solution) and trimethylsilyl diazomethane (11.8 mL, 23.6 mmol, 2M) were successively added to the reaction solution under a condition protected from light. After 20 minutes, trimethylsilane diazomethane (11.8 mL, 23.6 mmol) was added again. After 20 minutes, trimethylsilane diazomethane (11.8 mL, 23.6 mmol) was added once again. After 20 minutes, trimethylsilane diazomethane (11.8 mL, 23.6 mmol) was added again. The reaction solution was poured into water (80.0 mL), extracted with DCM (200 mL×3), and allowed to stand to separate the layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA=5:1-3:1) to obtain the target compound (4.62 g, yield 71.9%, colorless oil). MS (ESI) m/z: 273.2 [M+H].sup.+.

[0250] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (d, 2H), 7.53 (d, 2H), 4.00-3.92 (m, 2H), 3.71 (s, 3H), 3.69-3.65 (m, 1H), 3.35 (s, 3H), 3.04 (s, 3H).

Step 4: Synthesis of 2-(4-(methylsulfonyl)phenyl)-3-methoxypropionic acid

[0251] ##STR00080##

[0252] Methyl 2-(4-(methylsulfonyl)phenyl)-3-methoxypropanoate (1.00 g, 3.67 mmol) was dissolved in the mixture of 1,4-dioxane (30.0 mL) and 6.0 M hydrochloric acid (30.0 mL). The reaction solution was stirred at 80° C. for 2 hours, and then was stopped. The reaction solution was cooled to room temperature, carefully poured into water (80.0 mL), extracted with EA (150 mL×2), and allowed to stand to separate the layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase chromatography (acetonitrile/water containing 0.05% formic acid) to obtain the target compound (880 mg, yield 77.3%, white solid). MS (ESI) m/z: 276.0 [M+NH.sub.4].sup.+.

[0253] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 4.01-3.92 (m, 2H), 3.72-3.66 (m, 1H), 3.37 (s, 3H), 3.05 (s, 3H).

Step 5: Synthesis of N-(2,6-Dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propionamide

[0254] ##STR00081##

[0255] 2-(4-(Methylsulfonyl)phenyl)-3-methoxypropionic acid (105 mg, 0.407 mmol) was dissolved in DCM (3.00 mL), and thionyl chloride (52.4 mg, 118.97 mmol) was added at 0° C. The reaction solution was stirred at room temperature for 2 hours, dried under reduced pressure to remove the solvent to obtain a crude product. The crude product was redissolved in DCM (3.0 mL) and carefully added dropwise to the ice-water bath cooled solution of DIEA (131 mg, 1.02 mmol) and 2,6-dichloro-4′-(ethylsulfonyl)-[1,1′-biphenyl]-4-amine (112 mg, 0.339 mmol) in DCM (2.00 mL). The reaction solution was stirred for 20 minutes in an ice-water bath. The crude product was obtained by drying under reduced pressure and removing the solvent, which was subject to high pressure liquid chromatography (acetonitrile/water containing 0.05% ammonia water) to obtain the target compound (51.3 mg, yield 26.6%, pale yellow solid). MS (ESI) m/z: 570.2 [M+H].sup.+.

[0256] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.2 Hz, 2H), 7.70 (s, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 4.06-4.01 (m, 1H), 4.00-3.94 (m, 1H), 3.80-3.74 (m, 1H), 3.48 (s, 3H), 3.19 (q, J=7.4 Hz, 2H), 3.06 (s, 3H), 1.33 (t, J=7.4 Hz, 3H).

Example 20: N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propionamide

[0257] ##STR00082##

[0258] 3-Methoxy-2-(4-methylsulfonyl) phenyl)propanoic acid (105 mg, 0.407 mmol) was dissolved in DCM (3.00 mL), and thionyl chloride (52.4 mg, 0.441 mmol) was added at 0° C. The reaction solution was stirred at room temperature for 2 hours, dried under reduced pressure to remove the solvent, the crude product was redissolved in DCM (3.0 mL), and carefully added dropwise to the ice-water bath cooled solution of DIEA (131 mg, 1.02 mmol) and 2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (116 mg, 0.339 mmol) in DCM (2.0 mL). The reaction solution was stirred for 20 minutes in an ice-water bath. The crude product was obtained by drying under reduced pressure and removing the solvent, which was subject to high pressure liquid chromatography (acetonitrile/water containing 0.05% ammonia water) to obtain the target compound (52.9 mg, yield 26.9%, off-white solid). MS (ESI) m/z: 582.0 [M+H].sup.+.

[0259] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.65 (s, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.93 (d, J=7.6 Hz, 2H), 7.72 (s, 2H), 7.61 (d, J=7.7 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 4.08-3.98 (m, 2H), 3.79-3.74 (m, 1H), 3.48 (s, 3H), 3.06 (s, 3H), 2.57-2.50 (m, 1H), 1.43-1.38 (m, 2H), 1.13-1.05 (m, 2H).

Example 21: N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-1,1′-biphenyl-4-yl)-2-(5-(ethylsulfonyl)pyridin-2-yl)acetamide

[0260] ##STR00083##

Step 1: Synthesis of 2-(5-Bromopyridin-2-yl)-N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide

[0261] ##STR00084##

[0262] 2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (150 mg, 0.438 mmol), 2-(5-bromopyridine-2-yl)acetic acid (114 mg, 0.526 mmol), DIEA (0.217 mL, 1.31 mmol) and HATU (250 mg, 0.658 mmol) were added to DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours and monitored by LC-MS for completion. The reaction solution was poured into water (20 mL) and extracted with DCM (10 mL×2). The organic phases were combined, washed successively with saturated ammonium chloride (15 mL) and saturated aqueous sodium bicarbonate solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (283 mg, crude product, yellow oil). LC-MS (ESI) m/z: 538.9 [M+H].sup.+.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylthio)pyridin-2-yl)acetamide

[0263] ##STR00085##

[0264] 2-(5-Bromopyridin-2-yl)-N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)acetamide (283 mg, 0.524 mmol), Pd.sub.2(dba).sub.3 (48.0 mg, 0.0524 mmol), xantphos (30.3 mg, 0.0524 mmol), DIEA (0.173 mL, 1.05 mmol) and ethanethiol (0.0784 ML, 1.05 mmol) were added to 1,4-dioxane (2 mL). Under nitrogen protection, the reaction mixture was stirred in a sealed tube at 100° C. overnight, and monitored by LC-MS for completion. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=4:1-2:1) to obtain the target compound (170 mg, yield 74.6% over two steps, yellow oil). LC-MS (ESI) m/z: 520.9 [M+H].sup.+.

Step 3: Synthesis of N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylsulfonyl)pyridin-2-yl)acetamide

[0265] ##STR00086##

[0266] N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(5-(ethylthio)pyridin-2-yl)acetamide (170 mg, 0.326 mmol) was dissolved in DCM (5 mL), and m-chloroperoxybenzoic acid (132 mg, 0.652 mmol) was slowly added to the reaction solution under ice bath. Upon the addition was complete, the ice bath was removed, and the reaction was continued under stirring at room temperature for 1.5 hours, and monitored by LC-MS for completion. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (20 mL), extracted with DCM (10 mL×2), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA=1:9) to obtain crude product (120 mg). Further separation and purification by reverse phase column (water:acetonitrile=3:7) gave the target compound (76.0 mg, yield 42.1%, white solid). LC-MS (ESI) m/z: 552.9 [M+H].sup.+.

[0267] .sup.1H NMR (500 MHz, MeOD) δ 8.90 (d, J=2.4 Hz, 1H), 8.20 (dd, J=8.2, 2.4 Hz, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.73 (s, 2H), 7.62 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 3.25-3.20 (m, 2H), 2.71 (s, 2H), 2.68-2.63 (m, 1H), 1.21-1.19 (m, 2H), 1.17 (t, J=7.4 Hz 3H), 1.03-1.01 (m, 2H).

Example 22: 3-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amino)-2-(4-(ethylsulfonyl)phenyl)propionic acid

[0268] ##STR00087##

[0269] 2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (30 mg, 0.0877 mmol) and 4-(ethylsulfonyl)phenyl)-3-hydroxypropionic acid (27.1 mg, 0.105 mmol) were added to DCM (3 mL), and HOBt (17.8 mg, 0.132 mmol), EDC (25.3 mg, 0.132 mmol) and DIEA (0.043 mL, 0.263 mmol) were added successively. The reaction mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL). The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative plate (silica gel, dichloromethane:methanol=15:1), to obtain the target compound (6 mg, yield 11.7%, white solid). LC-MS (ESI) m/z 582.0 [M+H].sup.+.

[0270] .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 7.95 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 6.70 (s, 2H), 4.09-4.04 (m, 1H), 3.90-3.84 (m, 1H), 3.60-3.54 (m, 1H), 3.20 (q, J=7.6 Hz, 2H), 2.78-2.72 (m, 1H), 1.31-1.27 (m, 2H), 1.23 (t, J=7.4 Hz, 3H), 1.15-1.08 (m, 2H).

Example 22-1: N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionamide

[0271] ##STR00088##

Step 1: Synthesis of N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0272] ##STR00089##

[0273] 2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (100 mg, 0.292 mmol) and 2-(4-(ethylsulfonyl)phenyl) acetic acid (79.9 mg, 0.350 mmol) were added to DCM (5 mL). To the reaction mixture was added successively HATU (133 mg, 0.350 mmol) and DIEA (0.145 mL, 0.876 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, EA:PE=0˜40%), to obtain the target compound (150 mg, yield 93.2%, colorless oil). LC-MS (ESI) m/z: 569.0 [M+NH.sub.4].sup.+.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionamide

[0274] ##STR00090##

[0275] N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl) acetamide (60 mg, 0.109 mmol) and paraformaldehyde (2.94 mg, 0.098 mmol) were added to anhydrous dimethylsulfoxide (2 mL). To the reaction mixture was added sodium methoxide (0.24 mg, 0.004 mmol). The reaction mixture was stirred at room temperature for 2 hours. EA (10 mL) and water (10 mL) were added. The organic phase was separated, the aqueous phase was extracted with EA (10 mL×2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, EA/(DCM/PE=1/2)=0˜100%), to obtain the target compound (30 mg, yield 47.6%, white solid). LC-MS (ESI) m/z: 599.0 [M+NH.sub.4].sup.+.

[0276] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.68 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.91-7.84 (m, 4H), 7.66 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 5.14 (t, J=5.2 Hz, 1H), 4.11-4.06 (m, 1H), 4.00-3.95 (m, 1H), 3.70-3.65 (m, 1H), 3.28 (q, J=7.3 Hz, 2H), 2.99-2.94 (m, 1H), 1.20-1.15 (m, 2H), 1.13-1.06 (m, 5H).

Example 33: N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl)-3-hydroxypropionamide

[0277] ##STR00091##

Step 1: Synthesis of N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl) acetamide

[0278] ##STR00092##

[0279] 2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-amine (100 mg, 0.292 mmol) and 2-(4-(methylsulfonyl)phenyl)acetic acid (75.0 mg, 0.350 mmol) were added to DCM (5 mL). To the reaction mixture was successively added HATU (133 mg, 0.350 mmol) and DIEA (0.145 mL, 0.876 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, EA:PE=0˜40%), to obtain the target compound (145 mg, yield 92.4%, yellow solid). LC-MS (ESI) m/z: 555.0 [M+NH.sub.4].sup.+.

Step 2: Synthesis of N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl)-3-hydroxypropionamide

[0280] ##STR00093##

[0281] N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl) acetamide (60 mg, 0.111 mmol) and paraformaldehyde (3.0 mg, 0.100 mmol) were added to anhydrous dimethylsulfoxide (2 mL). To the reaction mixture was added sodium methoxide (0.24 mg, 0.004 mmol). The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (10 mL) and water (10 mL) were added. The separated aqueous phase was extracted with EA (10 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, EA: (DCM:PE=1:2)=0˜100%), to obtain the target compound (35 mg, yield 55.6%, white solid). LC-MS (ESI) m/z: 585.0 [M+NH.sub.4].sup.+.

[0282] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.68 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.86 (s, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 5.14 (t, J=5.2 Hz, 1H), 4.13-4.06 (m, 1H), 4.01-3.94 (m, 1H), 3.70-3.63 (m, 1H), 3.20 (s, 3H), 3.00-2.93 (m, 1H), 1.20-1.16 (m, 2H), 1.12-1.07 (m, 2H).

Examples 34 and 35: (S)—N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propanamide or (R)—N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propanamide

[0283] ##STR00094##

[0284] Racemate N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propanamide (Example 20, 500 mg dissolved in about 80 mL methanol, injection volume 5.0 mL) was separated through a Waters SFC 150 (room temperature, 100 bar, 214 nm) and 250*25 mm 10 μm Dr. maish Reprosil Chiral-OM (similar to DAICELCHIRALCEL® OD) (supercritical carbon dioxide:methanol, 50:50, 3.0 min, 70 mL/min) to obtain Example 34 (212 mg, white solid, Ret.time=1.284 min, ee 99%), LC-MS (ESI) m/z: 582.1 [M+H].sup.+/584.1 [M+2+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.41 (s, 1H), 8.05-7.87 (m, 4H), 7.69 (s, 2H), 7.64-7.53 (m, 2H), 7.43 (d, J=6.9 Hz, 2H), 4.09-3.91 (m, 2H), 3.85-3.75 (m, 1H), 3.51 (s, 3H), 3.07 (s, 3H), 2.60-2.49 (m, 1H), 1.47-1.36 (m, 2H), 1.16-1.03 (m, 2H); and Example 35 (208 mg, white solid, Ret. time=1.711 min, ee 9.8%); LC-MS (ESI) m/z: 582.1 [M+H].sup.+/584.1 [M+2+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (s, 1H), 8.00-7.91 (m, 4H), 7.69 (s, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 4.07-4.00 (m, 1H), 3.99-3.93 (m, 1H), 3.82-3.75 (m, 1H), 3.50 (s, 3H), 3.06 (s, 3H), 2.59-2.50 (m, 1H), 1.45-1.38 (m, 2H), 1.13-1.06 (m, 2H).

Examples 36 and 37: (S)—N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl)-3-hydroxypropionamide or (R)—N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl)-3-hydroxypropionamide

[0285] ##STR00095##

[0286] Racemate N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl)-3-hydroxypropionamide (Example 33, 500 mg dissolved in about 120 mL methanol, injection volume 2.5 mL) was separated through a Waters SFC 150 (room temperature, 100 bar, 214 nm) and a 250*25 mm 10% m Dr. maish Reprosil Chiral-OM (similar to DAICELCHIRALCEL® OD) (supercritical carbon dioxide:methanol, 55:45, 3.0 min, 70 mL/min) to obtain Example 36 (158 mg, white solid, Ret.time=1.373 min, ee 99%), LC-MS (ESI) m/z: 567.9 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.14 (s, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.70 (s, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 4.23-4.16 (m, 1H), 4.05-3.99 (m, 1H), 3.98-3.92 (m, 1H), 3.07 (s, 3H), 2.58-2.50 (m, 1H), 1.44-1.38 (m, 2H), 1.13-1.06 (m, 2H); and Example 37 (102 mg, white solid, Ret.time=1.701 min, ee 99%), LC-MS (ESI) m/z: 567.9 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.00 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.69 (s, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 4.26-4.17 (m, 1H), 4.07-3.99 (m, 1H), 3.98-3.91 (m, 1H), 3.07 (s, 3H), 2.59-2.48 (m, 1H), 1.44-1.38 (m, 2H), 1.13-1.07 (m, 2H).

Examples 38 and 39: (S)—N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionamide or (R)—N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-hydroxypropionamide

[0287] ##STR00096##

[0288] Racemate N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) phenyl)-3-hydroxypropionamide (Example 22, 500 mg dissolved in about 150 mL methanol, injection volume 5.0 mL) was separated through a Waters SFC 150 (room temperature, 100 bar, 214 nm) and a 250*25 mm 10 m Dr. maish Reprosil Chiral-OM (similar to DAICELCHIRALCEL®OD) (supercritical carbon dioxide:methanol, 55:45, 3.2 min, 70 mL/min) to obtain Example 38 (165 mg, white solid, Ret. time=1.370 min, ee 99%), LC-MS (ESI) m/z: 581.9 [M+H].sup.+/583.9 [M+2+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.01 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.70 (s, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.24-4.16 (m, 1H), 4.06-3.99 (m, 1H), 3.99-3.91 (m, 1H), 3.14 (q, J=7.4 Hz, 2H), 2.59-2.50 (m, 1H), 1.44-1.38 (m, 2H), 1.31 (t, J=7.4 Hz, 3H), 1.13-1.06 (m, 2H); and Example 39 (117 mg, white solid, Ret. time=1.759 min, ee 99%), LC-MS (ESI) m/z 581.9 [M+H].sup.+/583.9 [M+2+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.2 Hz, 2H), 7.71 (s, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.24-4.17 (m, 1H), 4.06-3.99 (m, 1H), 3.98-3.90 (m, 1H), 3.13 (q, J=7.4 Hz, 2H), 2.59-2.49 (m, 1H), 1.44-1.38 (m, 2H), 1.31 (t, J=7.4 Hz, 3H), 1.13-1.06 (m, 2H).

Examples 40 and 41: (S)—N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionamide or (R)—N-(2,6-dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)-3-methoxypropionamide

[0289] ##STR00097##

[0290] Racemate N-(2,6-Dichloro-4′-(cyclopropylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-(4-(ethylsulfonyl) phenyl)-3-methoxypropionamide (Example 16, 500 mg dissolved in about 100 mL methanol, injection volume 8.0 mL) was separated through a Waters SFC 150 (room temperature, 100 bar, 214 nm) and 250*25 mm 10 m Dr. maish Reprosil Chiral-OM (similar to DAICELCHIRALCEL® OD) (supercritical carbon dioxide:methanol, 50:50, 3.5 min, 70 mL/min) to obtain Example 40 (175 mg, white solid, Ret. time=1.287 min, ee 99%), LC-MS (ESI) m/z 596.1[M+H].sup.+/598.1 [M+2+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.40 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.3 Hz, 2H), 7.69 (s, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 4.06-3.99 (m, 1H), 3.97-3.92 (m, 1H), 3.82-3.77 (m, 1H), 3.50 (s, 3H), 3.13 (q, J=7.4 Hz, 2H), 2.58-2.51 (m, 1H), 1.44-1.38 (m, 2H), 1.30 (t, J=7.4 Hz, 3H), 1.12-1.06 (m, 2H); and Example 41 (153 mg, white solid, Ret. time=1.797 min, ee 99%), LC-MS (ESI) m/z 596.1 [M+H].sup.+/598.1 [M+2+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.71 (s, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 4.07-4.00 (m, 1H), 4.00-3.94 (m, 1H), 3.80-3.73 (m, 1H), 3.48 (s, 3H), 3.13 (q, J=7.4 Hz, 2H), 2.59-2.50 (m, 1H), 1.45-1.37 (m, 2H), 1.30 (t, J=7.4 Hz, 3H), 1.15-1.06 (m, 2H).

Example 42: N-(4′-(Cyclopropylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propionamide

[0291] ##STR00098##

Step 1: Synthesis of 4′-(cyclopropylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-amine

[0292] ##STR00099##

[0293] To a solution of 4-bromo-3-(trifluoromethyl)-aniline (1.00 g, 4.17 mmol) and 2-(4-(cyclopropylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.93 g, 6.23 mmol) in 1,4-dioxane (40.0 mL) was added Pd(dppf)Cl.sub.2 (305 mg, 0.417 mmol) and potassium carbonate (1.15 g, 8.32 mmol). Under argon protection, the reaction mixture was stirred at 100° C. for 12 hours, and then the reaction was stopped. After cooling the reaction solution to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA=10:1, 5:1-3:1) to obtain the target compound (820 mg, yield 57.7%, yellow solid). LC-MS (ESI) m/z 342.1 [M+H].sup.+.

[0294] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.15-7.06 (m, 2H), 6.94 (d, J=7.5 Hz, 1H), 2.63-2.39 (m, 1H), 1.45-1.34 (m, 2H), 1.10-1.05 (m, 2H).

Step 2: N-(4′-(Cyclopropylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propionamide

[0295] ##STR00100##

[0296] To a solution of 4′-(cyclopropylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-amine (200 mg, 0.586 mmol), 2-(4-(methylsulfonyl)phenyl)-3-methoxypropionic acid (303 mg, 1.17 mmol) and N-methylimidazole (241 mg, 2.93 mmol) in acetonitrile (4.00 mL) was added N,N,N′,N′-tetra methylchloroformamidine hexafluorophosphate (493 mg, 1.76 mmol). The reaction solution was stirred at room temperature for 16 hours, and then the reaction was stopped. The reaction solution was directly preoperatively purified by high pressure liquid chromatography (acetonitrile/water containing 0.05% formic acid) to obtain the target compound (91.4 mg, yield 26.8%, white solid). LC-MS (ESI) m/z: 581.9 [M+H].sup.+.

[0297] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.45 (s, 1H), 7.98-7.90 (m, 5H), 7.81 (dd, J=8.3, 2.1 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H), 7.28-7.26 (d, J=8.4, 1H), 4.09-4.02 (m, 1H), 4.01-3.95 (m, 1H), 3.83-3.78 (m, 1H), 3.51 (s, 3H), 3.06 (s, 3H), 2.56-2.48 (m, 1H), 1.43-1.37 (m, 2H), 1.12-1.05 (m, 2H).

Examples 43 and 44: (S)—N-(4′-(cyclopropylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propionamide or (R)—N-(4′-(cyclopropylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propanamide

[0298] ##STR00101##

[0299] Racemate N-(4′-(cyclopropylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methoxy-2-(4-(methylsulfonyl)phenyl)propanamide (Example 42, 90 mg dissolved in about 30 mL methanol, injection volume 2.0 mL) was separated through a Waters SFC 150 (room temperature, 100 bar, 214 nm) and 250*25 mm 10 m Dr. maish Reprosil Chiral-OM (similar to DAICELCHIRALCEL® OD) (supercritical carbon dioxide:methanol, 55:45, 4.2 min, 70 mL/min) to obtain Example 43 (37.7 mg, white solid, Ret.time=2.080 min, ee 100%), LC-MS (ESI) m/z: 581.9 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.15 (d, J=2.0 Hz, 1H), 7.97-7.93 (m, 4H), 7.86 (dd, J=8.4, 1.9 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 4.15-4.07 (m, 2H), 3.69-3.65 (m, 1H), 3.39 (s, 3H), 3.11 (s, 3H), 2.77-2.70 (m, 1H), 1.30-1.24 (m, 2H), 1.13-1.06 (m, 2H); and Example 44 (32.3 mg, white solid, Ret.time=2.972 min, ee 98%), LC-MS (ESI) m/z: 581.9 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.15 (d, J=1.9 Hz, 1H), 7.98-7.92 (m, 4H), 7.86 (dd, J=8.4, 1.9 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 4.16-4.06 (m, 2H), 3.69-3.65 (m, 1H), 3.39 (s, 3H), 3.11 (s, 3H), 2.77-2.69 (m, 1H), 1.30-1.25 (m, 2H), 1.13-1.07 (m, 2H).

Activity Examples

Activity Example 1: In Vitro Determination of Agonistic Activity of Compound on RORγ Receptors

[0300] A time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used for the compounds of the present disclosure, to determine the agonistic activity of the compounds on the RORγ protein receptor. The agonistic activity is expressed by the concentration for 50% of maximal effect (EC.sub.50). The experiment was performed basically with reference to the methods described in ONCOIMMUNOLOGY, 2016, VOL. 5, NO. 12, e1254854.

[0301] Experimental Methods:

[0302] 1. Preparation of RORγ Basal Buffer

[0303] A 100 mL basal buffer was prepared, mixed homogeneously and stored for use;

TABLE-US-00001 Tris-HCl, pH7.5  20 mM EDTA, pH8.0  1 mM CHAPS 0.01% KF 100 mM BSA 0.01% DTT  5 mM

[0304] 2. Preparation of Solutions of Test Compounds

[0305] The compounds of the examples shown in the table below were prepared into solutions with DMSO as the solvent, serially diluted at 3-fold dilution to 10 concentrations starting from 10 mM, and added to the corresponding wells of a 384-well plate with each concentration of each compound in duplicate;

[0306] The solution of reference substance LYC-55716 was similarly prepared, starting from 10 mM, serially diluted at 3-fold dilution to 10 concentrations, and added to the corresponding control wells of 384-well plate;

[0307] 3. Preparation of Protein Solution Mixture

a. A 75 nM solution of GST-RORγ LBD ((263-509) (produced at ChemPartner)) and a 4 nM solution of Biotin-SRC1 (Glsbiochem) were prepared with the above basal buffer. The two solutions were 1:1 mixed evenly, and 10 μL of the mixed solution was added into each well of the above 384-well plate. The plate was immediately centrifugated at 1000 rpm for 10 seconds;
b. A 1 nM solution of Anti-GST Eu (Cisbio, #61GSTKLA) and a 50 nM solution of SA-APC (Cisbio, #61GSTKLA) were prepared with the above basal buffer. The two solutions were 1:1 mixed evenly, and 10 μL of the mixed solution was added into each well of the above 384-well plate. The plate was immediately centrifugated at 1000 rpm for 10 seconds;
c. The resulting 384-well plate was incubated at room temperature for 15 minutes. Data were read on an Envision microplate reader, EC.sub.50 values and E max % were calculated.

[0308] 4. Analysis of Experimental Results

a. Readings were taken at 665 nm and 615 nm wavelengths respectively on the Envision Microplate Reader, and the ratios between them were normalized.
b. Calculation was carried out with the following equation:

[00001]$\%\mathrm{Activation}=\left(\frac{X-\mathrm{Min}}{\mathrm{Max}-\mathrm{Min}}\right)\times 100\%$

wherein X is the reading of compounds, Min is the reading of the blank solution, and Max is the reading of 10 μM SRC.
c. The concentration-response curve data were fitted by a four-parameter logistic nonlinear regression model, and Emax was the TOP value of the fitted curve.

TABLE-US-00002 TABLE 1 RORγt protein receptor agonistic activity of Example compounds Examples EC50(nM) Emax %  1 14.5 212.7  2 9.1 209.9  3 14 222.9  4 9.6 219.9  5 8.5 222  6 3.7 171.4  7 10 168.8  8 10.1 169.8  9 22.2 159.7 10 114.4 158.8 11 6.8 167.4 12-1 6.8 185.6 13 12.1 170.8 16 16.6 186.6 20 19.5 192.3 22-1 7.0 179.0 33 13.3 201.9 34 5.1 191.0 36 4.3 200.0 37 27.4 197.0 38 5.9 190.2 39 13.5 181.3 40 9.9 199.3 41 24.6 174.7 42 12.6 194.0 43 6.2 193.8 LYC-55716 27.9 226.2 (Control compound) Note: Emax % is the maximum activation rate.

[0309] The test results in the above table show that the compounds of the present disclosure have good agonistic activity on the RORγ protein receptor.

Activity Example 2: In Vitro Assay of Agonistic Activity of Compounds on RORγt in Luciferase Reporter Gene Assay

[0310] This assay was basically carried out according to the method described in the literature ONCOIMMUNOLOGY, 2016, VOL. 5, NO. 12, e1254854.

[0311] The RORγ-LBD coding sequence was inserted into pBIND plasmid (Promega, E1581). This expression vector and a reporter vector (pGL4.35 carrying a stably integrated luciferase reporter gene driven by GAL4 promoter) were co-expressed in HEK293T host cells. When the agonist binds to the corresponding chimeric receptor, the chimeric receptor binds to the GAL4 binding site on the reporter gene carrier and stimulates reporter gene expression. The agonistic activity of the compound on RORγ was determined according to the intensity of the chemiluminescence signal.

[0312] Experimental Procedure:

[0313] 1. Preparation of test compounds

1.1 All test compounds were serially diluted at 3-fold dilution with DMSO, with 10 serial dilutions starting from 10 mM; LIT-00093 solution was prepared similarly.
1.2 The positive control LYC-55716 was serially diluted at 3-fold dilution with DMSO, with 10 serial dilutions starting from 5 mM.
1.3 1000× positive control (5 mM LYC-55716) and 1000× negative control (100% DMSO) were prepared.
1.4 The compound plate was sealed and shaken for 5 min.

[0314] 2. Test procedure

[0315] Cells were cultured according to ATCC standard operation, and 6*10.sup.6 HEK293T cells were seeded into 100 mm cell culture dishes, cultured overnight in a 37° C., 5% CO.sub.2 incubator, and then transfected. Compounds of corresponding concentrations were added for treatment, and the Steady-Glo™ kit (Lot E 2520) was used for further detection.

[0316] Chemiluminescence values were detected with Envision 2104; EC50 values were calculated.

[0317] % Activity was calculated with the following equation:

[00002]$\%\mathrm{Activity}=.Math.\frac{{\mathrm{RLU}}_{\mathrm{cmpd}}-{\stackrel{\_}{\mathrm{RLU}}}_{\mathrm{vehicle}}}{{\stackrel{\_}{\mathrm{RLU}}}_{\mathrm{positive}}-{\stackrel{\_}{\mathrm{RLU}}}_{\mathrm{vehicle}}}.Math.*100$

RLU: Fluorescence value
R L Upositive: average value of positive control
R L Uvehicle: average value of negative control

[0318] The log values of the compound concentration and % Activity were fitted using Graphad 8.0, to calculate EC50s of the compounds. The results are shown in Table 2.

TABLE-US-00003 TABLE 2 Luciferase reporter gene assay of RORγt agonistic activity of Example compounds Example EC50 (nM) Emax %  1 47 87.07  2 19 43.04  3 14 50.53  4 17 63.96  5 37 69.62  6 13 42.08  7 41 39.44  8 44 37.89  9 53 51.47 10 1461 58.96 11 15 45.04 12-1 >3000 13 69 71.86 14 225 40.7 15 202 79.49 16 181 85.57 17 25 33.86 18 784 136.9 19 123 91.37 20 81 63.49 21 72 51.25 22-1 139 73.84 33 93 69.77 34 67 70.7 36 54 71.28 38 124 103.3 40 93 77.5 42 105 60.71 43 57 64.08 LIT-00093 116 83.86 LYC-55716 157 94.19 Note: Emax % is the relative maximum activation rate relative to LYC-55716 at 5 μM.

[0319] The test results in the above table show that the compounds of the present disclosure have good agonistic activity on the RORγt luciferase reporter gene.

Activity Example 3: Th17 Differentiation and Activation by the Present Compounds in Mouse Lymphocytes

[0320] Experiment Materials:

TABLE-US-00004 Materials Supplier Cat # Lot # mouse C57BL/6J male / RPMI1640 Gibco A10491-01 2037571 Mouse Lymphocyte Haoyang LTS1092PK 2018 Dec. 12 Isolation Kit Biologicals Purified NA/LE BD 553057 8172649 hamster anti-mouse CD3 Purified NA/LE BD 553294 8072791 mouse anti-mouse CD28 Recombinant R & D 7666-MB/CF DCKL0218101 mouse TGF-beta 1 Recombinant R & D 406-ML-005/CF NUQ2618011 mouse IL-6 Recombinant R & D 1887-ML-010/CF DFXU0418021 mouse IL-23 Ursolic acid (UA) Sigma U6753 BCBQ8542V Quantikine ® R & D SM1700 P198693 ELISA Mouse IL-17 Immunoassay

[0321] Test procedure: the mouse spleen lymphocytes were first isolated, and the lymphocytes were subject to the conditions of stimulating factors (anti-mCD28: 5 μg/mL; rmTGF-β1: 1 ng/mL; rmIL-6: 50 ng/mL; rmIL-23: 5 ng/mL) and differentiated to Th17, while adding different concentrations of compounds. All test compounds were serially diluted at 3-fold dilution with DMSO, with 8 serial dilutions starting from the maximum concentration 3 μM. The supernatants were collected after 48 hours for IL-17 ELISA detection, and compared with the solvent group, to determine the activation rate of the compounds on Th17 cells to secrete IL-17. EC.sub.50 values were fitted with Graphad 8.0, and the TOP values fitted by the software was Emax %.

[0322] The test results show that the compounds of the present disclosure have good ability to increase the differentiation of Th17 cells to secrete IL-17 on mouse lymphocytes (as shown in Table 3)

TABLE-US-00005 TABLE 3 Compound stimulated Th17 cells differentiate and secretion of IL-17 Example EC50 (nM) Emax %  2 114.2 203.2  4 111.8 156.4  5  11.4 147.3  8 370.1  85  9 942.8  65.4 11 317.7 123.0 13  5.7 133.5 Note: Emax % is the maximum activation rate.

Activity Example 4: Th17 Differentiation and Activation by the Present Compounds Inhuman PBMC

[0323] Experiment Materials:

TABLE-US-00006 Materials and Reagents supplier Item # batch number # hPBMC_ TPCS PB100C A19Z018001 RPMI1640 Gibco A10491-01 2037571 penicillin-streptomycin Gibco 15140-122 1953104 fetal bovine serum Gibco 10099-141C 2045686CP Phosphate Buffered Gibco 10010-031 2003918 Saline (PBS) DMSO Sigma D8418-1L SHBG3288V Purified NA/LE mouse BD 555336 8152611 anti-human CD3 Purified NA/LE mouse BD 555725 8152601 anti-human CD28 Recombinant human R & D 240-B AV7117011 TGF-beta 1 Recombinant R & D 7270-IL- DAOM0318061 human IL-6 025/CF Recombinant R & D 1290-IL- GBI6218031 human IL-23 010/CF Ursolic acid (UA) Sigma U6753 BCBQ8542V Quantikine ® ELISA R & D S1700 P192117 Human IL-17 Immunoassay

[0324] Test procedure: PBMC cells were first thawed and plated, and then stimulated with stimulating factors (anti-hCD28: 5 μg/mL; rhTGF-β1: 5 ng/mL; rhIL-6: 20 ng/mL; rhIL-23: 10 ng/Ml) to differentiate to Th17, while adding different concentrations of compounds. All test compounds were serially diluted at 3-fold dilution with DMSO, with 8 serial dilutions starting from the maximum concentration 3 μM. The supermatants were collected after 48 hours for IL-17 ELISA detection, and compared with the solvent group, to determine the activation rate of the compounds on Th17 cells to secrete IL-17. EC.sub.50 values were fitted with Graphad8.0, and the TOP values fitted by the software was Emax %.

[0325] The test results show that the compounds of the present disclosure have good ability to increase the differentiation of Th17 cells to secrete IL-17 on on human PBMCs (as shown in Table 4).

TABLE-US-00007 TABLE 4 Compound stimulated Th17 cells differentiate and secretion of IL-17 Example EC50 (nM)_ Emax % 2 61.61 137.8 4 30.4 152.4 5 33.2 122.9 6 49.23 254.0 8 346.9 128.9 9 359.7 167.1 11 52.76 149.2 13 6.2 138.8 15 45.1 196.7 16 27.3 202.3 17 112.6 294.6 18 29.4 193.1 19 32.1 232.5 20 18.9 227.8 21 182.9 296.8 34 57.2 195.2 36 36.2 168.7 38 22.8 178.6 40 25.8 224.1 43 134.9 264.6 Note: Emax % is the maximum activation rate.

Activity Example 5: Metabolic Stability of Human and Mouse Liver Microsomes

[0326] According to standard methods of in vitro metabolic stability studies in the art, eg., the methods described in Kerns, Edward H. and Di Li (2008). Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization. San Diego: Academic Press; Di, Li et al., Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates, J. Biomol. Screen. 2003, The method described in 8(4), 453, the liver microsomal metabolic stability test of the compounds of the present disclosure was carried out analogously as follows.

[0327] The incubation system contained 0.5 mg protein/mL microsomes, cofactors, and PBS, was pre-incubated at 37° C. for 3 min, and then added the substrate (i.e., the test compounds) to initiate the reaction. Samples were taken at 0, 1, 5, 10, 15, 20, 30 and 60 min from the start of the reaction, and an appropriate terminator was added to terminate the reaction.

[0328] The terminator was an ice acetonitrile solution containing 100 ng/mL tolbutamide and 100 ng/mL labetalol.

TABLE-US-00008 Product Species information Supplier Abbreviation Human Cat No. 452117 Coming HLM Lot No. 38292 CD-1 Cat No. BQM1000 Biopredic MLM mice Lot No. MIC255036

[0329] Sample treatment (n=3): each appropriate sample was added, vortexed and centrifuged at high speed. The supernatants were collected, and the substrate was detected by HPLC-MS/MS. The peak area at the 0 min was taken as 100%. The peak areas at other time points were converted to percentage of the remaining amount. The natural logarithms of the percentage of remaining amount at each time point was plotted against the incubation time, and the slope (−k) was calculated by linear regression. Then, Clint (uL/min/mg) and half-life (T½, min) of the compounds were calculated following the equation of the inherent clearance rate (Clint)=(k* volume of incubation solution)/mass of liver microsomes. The results are shown in Table 5.

TABLE-US-00009 TABLE 5 Test results of metabolic stability of human and mouse liver microsomes human liver microsomes mouse liver microsomes % % Clint (uL/ T1/2 Remaining Clint (uL/ T1/2 Remaining Example cLogP min/mg) (min) (T = 60 min) min/mg) (min) (T = 60 min) 1 3.7 33.1 41.8  32.4% 67.6 20.5 11.70% 2 3.1 <9.6 >145  75.7% <9.6 >145 89.30% 3 4.0 9 9.5 13.9   4.6% 4 3.1 <9.6 >145  83.4% 4 9.1 28.2 22.20% 5 2.8 <9.6 >145  76.7% 3 2.7 42.4 35.50% 6 3.7 <9.6 >145    82% <9.6 >145 78.60% 7 2.6 <9.6 >145  80.1% <9.6 >145 88.20% 8 2.3 <9.6 >145  95.6% <9.6 >145 107.80% 9 2.3 <9.6 >145 102.5% 1 4.1 98.6 64.20% 10 1.7 <9.6 >145  92.5% <9.6 >145 89.90% 11 3.2 <9.6 >145 110.5% <9.6 >145 97.10% 12-1 2.8 <9.6 >145 107.4% 1 0.9 126.8   71% 13 3.6 1 1.1 124.4  71.4% 4 2.6 32.6   28% 14 2.1 14.9 92.8  61.7% <9.6 >145  87.3% 15 3.0 17.8- 77.9  58.7% <9.6 >145 82.60% 16 3.6 <9.6 >145 100.7% 10.7 134.3 68.90% 17 3.6 415- 3.3     0% 61.2- 22.6 15.30% 18 3.5 120.9 11.5     2% 57.6 24.1 15.10% 19 3.0 13.0 106.6    60% 47.4 29.2 23.10% 20 3.1 17.3 80.2  53.9% 10.5 132.6 75.50% 21 2.8 <9.6 >145  79.6% 17.3 80.1    56% 34 3.1 15.6 88.6  62.4% <9.6 >145  74.5% 36 2.3 13.7 101.2  62.3% <9.6 >145  83.9% 38 2.9 <9.6 >145  77.2% 12.9 107.7  70.7% 40 3.6 9.6 143.8  71.1% 11.8 117.1  71.8% 43 3.2 13.8 100.8    69% 14.8 93.4  64.4% LIT-00093 5.8 295.4 4.7     0% (control)

Activity Example 6: Pharmacokinetic (PK) Assay of the Compounds of the Disclosure in Mice

[0330] The PK of each compound was determined as follows: 6 CD-1 mice (obtained from Shanghai Lingchang Biotechnology Co., Ltd.) were divided into two groups, 3 mice in each group. One group was administered intravenously at a dose of 1 mg/kg, and the vehicle was 5% DMSO/40% PEG400/55% (20% 3-CD); one group was administered by oral gavage at a dose of 5 mg/kg, and the vehicle was DMSO/1% methylcellulose (1:99). Blood samples were collected from saphenous vein of lower leg in each group at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration. Approximately 40 μL of the blood samples were collected into anticoagulant tubes containing EDTA-K2. Immediately after collection, the tubes were inverted at least 5 times to ensure uniform mixing, and then placed on ice. The blood samples collected at each time point were centrifuged at 4° C., 8000 rpm for 5 minutes to obtain plasma. Another 1.5 mL centrifuge tube was marked with the compound name, animal number, and time point, and the plasma was transferred to this tube. The plasma was stored at −80° C. until analysis.

[0331] Compound concentrations in plasma were determined by UPLC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNolin 6.4 pharmacokinetic software on the obtained data.

[0332] The specific test results are as follows, showing that the compounds have good pharmacokinetic absorption and have the PK advantages.

TABLE-US-00010 TABLE 6 In vivo PK results of Example compounds IV  1 mg/kg Po  5 mg/kg AUC0-last Cmax Vss CL_obs AUC0-last Cmax Ex. (ng/mL*hr) (ng/mL) t1/2(hr) (ml/kg) (mL/hr/kg) (ng/mL*hr) (ng/mL) t1/2(hr) F % 2 2250 737 1.76 1086 426.2 12622.9 3033.3 2.46 112.2 5 730.2 1360 0.45 892.9 1367 1415.97 1770 0.5 38.8 11 7246.9 709.3 6.33 1040.9 128.6 31190.6 3810 4.52 86.1 13 785.7 1323.3 0.63 712.7 1264.7 951.7 1218.7 0.54 24.2 15 2301 1435 1.23 0.71* 7 17** 4239 1061 2.32 40 16 3662 1169 3.88 1.10* 4.51** 10328 1417 3.3 56.3 19 647 932 0.63 1.09* 26.0** 924 419 1.51 29.7 20 8280 1164 4.85 0.75* 1.98** 21589 1657 6.95 57.3 21 3631 716 4.19 1.45* 4.55** 5629 611 3.83 30.9 35 6882 1335 3.56 0.83* 2.40** 9140 700 12.3 32.8 37 2170 1325 2.20 1.27* 7.21** 1440 294 2.60 15.8 39 2048 1084 3.70 1.53* 8.22** 1717 400 3.00 17.1 41 1061 601 1.70 2.02* 15.4** 6375 1450 2.72 116 43 3810 787 4.14 1.38* 4.31** 17145 3037 3.51 89.1 LYC-55716 256.5 352.7 2.63 7231.5 3654.6 269.3 52.6 5.35 21.0 *in L/kg **in mL/min/kg

[0333] The structures of the control compounds used in the above experiments are as follows:

##STR00102##