TRIAZOLE COMPOUNDS AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Certain triazole compounds have good LPAR1 antagonistic activity and selectivity, low toxicity, and good metabolic stability, and can be used for preventing or treating the LPAR1-related disease or disorder. The IC.sub.50 value of some triazole compounds can be below 300 nM, even 50 nM. The range of CC.sub.50 of the triazole compounds can be greater than 200 μM. They also show good metabolic stability in human, fancy rats, and house mice.

Claims

1. A triazole compound of formula (I) or a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, ##STR00295## Formula (I) wherein, R.sub.1 is selected from H, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.a: C.sub.1-40 alkyl, —C.sub.6-20 aryl-O—C.sub.3-20 cycloalkyl and C.sub.3-20 cycloalkyl; R.sub.2 is selected from CN, NO.sub.2, halogen and the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.1-40 haloalkyl, ##STR00296##  —C.sub.6-20 aryl-X—R.sub.4, -5-20 membered heteroaryl-X—R.sub.4, —C.sub.3-20 cycloalkyl-X—R.sub.4, —C.sub.1-40 alkyl-X—R.sub.4, —C.sub.2-40 alkenyl-X—R.sub.4 and —C.sub.2-40 alkynyl-X—R.sub.4; X is selected from NH and O, and R.sub.4 is selected from C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.3-20 cycloalkyl and C.sub.6-20 aryl; R.sub.5′ is selected from C.sub.1-40 alkyl; R.sub.6′ is selected from C.sub.1-40 alkyl; R.sub.7′ is selected from C.sub.3-20 cycloalkyl and C.sub.1-40 alkyl-C.sub.6-20 aryl; or, R.sub.6′ and R.sub.7′ may, together with an N atom connected thereto, form 3-20 membered heterocyclyl unsubstituted or optionally substituted with one, two or more R.sub.e; R.sub.3 is selected from H, CN, NO.sub.2, halogen and the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.1-40 haloalkyl, ##STR00297##  R.sub.5 is selected from C.sub.1-40 alkyl, C.sub.2-40 alkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl and C.sub.6-20 aryl; R.sub.6 is selected from H, C.sub.1-40 alkyl and C.sub.3-20 cycloalkyl; R.sub.7 is selected from C.sub.1-40 alkyl, C.sub.1-40 alkyl-C.sub.6-20 aryl and C.sub.3-20 cycloalkyl; R.sub.8 is selected from C.sub.1-40 alkyl-C.sub.6-20 aryl-, —C.sub.1-40 alkyl-C.sub.6-20 aryl, C.sub.2-40 alkenyl-C.sub.6-20 aryl-, —C.sub.2-40 alkenyl-C.sub.6-20 aryl, C.sub.6-20 aryl, C.sub.3-20 cycloalkyl, —C.sub.1-40 alkyl-C.sub.3-20cycloalkyl, C.sub.1-40 alkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 5-20 membered heteroaryl-C.sub.3-20 cycloalkyl- and -5-20 membered heteroaryl-C.sub.3-20 cycloalkyl; R.sub.9 is selected from C.sub.1-40 alkyl-C.sub.6-20 aryl and C.sub.6-20 aryl; or, any two of R.sub.6, R.sub.7 and R.sub.8 may, together with an N atom connected thereto, form 3-20 membered heterocyclyl unsubstituted or optionally substituted with one, two or more R.sub.d; R.sub.a is selected from halogen, COOH, NH.sub.2 and OH; preferably, when selected from halogen, NH.sub.2, and OH, R.sub.a is not directly connected to position C.sub.1 of alkyl; R.sub.b and R.sub.e are the same or different, and are independently selected from COOH, CN, NO.sub.2, halogen, C.sub.1-40 alkyl and C.sub.1-40 haloalkyl; R.sub.c is selected from ═O, COOH, CN, NO.sub.2, C.sub.1-40 alkyl and C.sub.1-40 haloalkyl; and R.sub.d is selected from ═O, COOH, CN, NO.sub.2, C.sub.1-40 alkyl, C.sub.1-40 haloalkyl, halogen and C.sub.3-20 cycloalkyl.

2. The compound according to claim 1, wherein, R.sub.1 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.a: C.sub.1-6 alkyl, —C.sub.6-14 aryl-O—C.sub.3-14 cycloalkyl and C.sub.3-14 cycloalkyl; R.sub.2 is selected from CN, NO.sub.2, halogen and the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, ##STR00298##  —C.sub.6-14 aryl-X—R.sub.4, -5-14 membered heteroaryl-X—R.sub.4, —C.sub.3-14 cycloalkyl-X—R.sub.4, —C.sub.1-6 alkyl-X—R.sub.4, —C.sub.2-10 alkenyl-X—R.sub.4 and —C.sub.2-10 alkynyl-X—R.sub.4; X is selected from NH and O, and R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.2-10 alkenyl, C.sub.3-14 cycloalkyl and C.sub.6-14 aryl; R.sub.5′ is selected from C.sub.1-6 alkyl; R.sub.6′ is selected from C.sub.1-6 alkyl; R.sub.7′ is selected from C.sub.3-14 cycloalkyl and C.sub.1-6 alkyl-C.sub.6-14 aryl; or, R.sub.6′ and R.sub.7′ may, together with an N atom connected thereto, form 3-10 membered heterocyclyl unsubstituted or optionally substituted with one, two or more R.sub.e; R.sub.3 is selected from H, CN, NO.sub.2, halogen and the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, ##STR00299##  R.sub.5 is selected from C.sub.1-6 alkyl, C.sub.2-10 alkenyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl and C.sub.6-14 aryl; R.sub.6 is selected from H, C.sub.1-6 alkyl and C.sub.3-14 cycloalkyl; R.sub.7 is selected from C.sub.1-6 alkyl, —C.sub.1-6 alkyl-C.sub.6-14 aryl, C.sub.1-6 alkyl-C.sub.6-14 aryl- and C.sub.3-14 cycloalkyl; R.sub.8 is selected from C.sub.1-6 alkyl-C.sub.6-14 aryl-, —C.sub.1-6 alkyl-C.sub.6-14 aryl, C.sub.2-10 alkenyl-C.sub.6-14 aryl-, —C.sub.2-10 alkenyl-C.sub.6-14 aryl, C.sub.6-14 aryl, C.sub.3-14 cycloalkyl, —C.sub.1-6 alkyl-C.sub.3-14 cycloalkyl, C.sub.1-6 alkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, 5-14 membered heteroaryl-C.sub.3-14 cycloalkyl- and -5-14 membered heteroaryl-C.sub.3-14 cycloalkyl; R.sub.9 is selected from C.sub.1-6 alkyl-C.sub.6-14 aryl and C.sub.6-14 aryl; or, any two of R.sub.6, R.sub.7 and R.sub.8 may, together with an N atom connected thereto, form 3-10 membered heterocyclyl unsubstituted or optionally substituted with one, two or more R.sub.d; R.sub.a is selected from halogen, COOH, NH.sub.2 and OH; preferably, when selected from halogen, NH.sub.2, and OH, R.sub.a is not directly connected to position C.sub.1 of alkyl; R.sub.b and R.sub.e are the same or different, and are independently selected from COOH, CN, NO.sub.2, halogen, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; R.sub.c is selected from ═O, COOH, CN, NO.sub.2, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; and R.sub.d is selected from ═O, COOH, CN, NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halogen and C.sub.3-14 cycloalkyl.

3. The compound according to claim 1, wherein, R.sub.1 is selected from H, CH.sub.3, ##STR00300## R.sub.2 is selected from the following groups: ##STR00301## ##STR00302## R.sub.3 is selected from H and the following groups: ##STR00303## ##STR00304## ##STR00305##

4. The compound according to claim 1, wherein the compound of formula (I) is selected from the following compounds: ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314##

5. A preparation method for the compound according to claim 1, wherein the preparation method comprises any one of the following schemes: ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## wherein, R.sub.1, R.sub.2, R.sub.5, R.sub.6, R.sub.6′, R.sub.7, R.sub.7′, R.sub.8 and R.sub.9 are defined as in claim 1.

6. The preparation method according to claim 5, wherein the preparation method comprises any one of the following schemes: ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## wherein, R.sub.1, R.sub.2, R.sub.5, R.sub.6, R.sub.6′, R.sub.7, R.sub.7′, R.sub.8 and R.sub.9 are defined as in claim 1.

7. Compounds of formulas M-1, M-2, M-3, M-4, M-5, M-6, M-7, M-8, M-9, M-10, M-11, M-12, M-13, M-14, M-15, M-16, M-17, M-18, M-19, M-20, M-21, M-22, M-23, M-24, M-25, M-26, M-27, M-28, M-29, M-30, M-31, M-32, M-33, M-34, M-35, M-36, M-37 and M-38, wherein, the compounds described above are defined as in claim 5.

8. Compounds of formulas 1-3A, 1-4A, 1-6A, 2-5A, 2-6A, 2-7A, 2-9A, 3-1A, 4-1A, 4-2A, 4-3A, 4-4A, 4-5A, 5-5A, 5-6A, 6-2, 6-3, 6-5A, 6-6A, 6-9A, 7-2, 7-4, 7-5, 7-6, 7-7, 7-8A, 9-1A, 9-2A, 9-3A, 9-4A, 10-2A, 10-4A, 10-6A, 10-7A, 10-8A, 13-2, 13-3, 13-4, 13-5, 13-6A, 13-7A, 13-9A, 14-2A, 14-3A, 14-4A, 14-5A, 15-2A, 15-3A, 15-4A, 15-5A, 15-7A, 16-5A, 16-6A, 16-7B, 16-8A, 16-9A, 16-10A, 16-11A, 16-12A, 16-13A, 17-2A, 17-3A, 17-5A, 18-2A, 18-3A, 18-5A, 18-6A, 20-2A, 20-3A, 20-5A, 20-6A, 21-3A, 21-4A, 21-6A, 23-1A, 23-2A, 23-3A, 24-2A, 24-3A, 24-4A, 24-5A, 26-2, 26-3, 26-4, 26-5A, 28-2A, 30-1A, 30-2A, 30-3A, 31-1A, 31-2A, 31-3A, 31-4A, 31-5A and 31-6A, wherein, the compounds described above are defined as in claim 6.

9. The compound according to claim 8, wherein the compound is selected from the following compounds: ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391##

10. Use of one, two or more of the triazole compound of formula (I) and the pharmaceutically acceptable salt, the solvate, the polymorph, the metabolite, the ester, the stereoisomer, the tautomer, the isotopically labeled compound, the nitrogen oxide and the prodrug thereof according to claim 1 in preparing a drug, wherein preferably, the drug is an LPAR1 inhibitor; preferably, the drug is used for preventing and/or treating LPAR1-mediated diseases; and preferably, the drug can be used for preventing and/or treating organ fibrotic diseases, respiratory diseases, renal diseases, hepatic diseases, inflammatory diseases, neurological diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pains, urinary system diseases, ophthalmic diseases, metabolic diseases, cancers and rejection of transplanted organs.

11. A pharmaceutical composition comprising one, two or more of the triazole compound of formula (I) and the stereoisomer, the tautomer, the isotopically labeled compound, the nitrogen oxide, the solvate, the polymorph, the metabolite, the ester, the pharmaceutically acceptable salt and the prodrug thereof according to claim 1, wherein preferably, the pharmaceutical composition may also optionally comprise at least one pharmaceutically acceptable excipient; preferably, the pharmaceutical composition may also optionally comprise at least one additional active ingredient; specifically, the pharmaceutical composition may also comprise one or more active ingredients besides the triazole compound of formula (I) and the stereoisomer, the tautomer, the isotopically labeled compound, the nitrogen oxide, the solvate, the polymorph, the metabolite, the ester, the pharmaceutically acceptable salt and the prodrug thereof; preferably, the pharmaceutical composition is an LPAR1 inhibitor; and preferably, the pharmaceutical composition is used for preventing and/or treating organ fibrotic diseases, respiratory diseases, renal diseases, hepatic diseases, inflammatory diseases, neurological diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pains, urinary system diseases, ophthalmic diseases, metabolic diseases, cancers and rejection of transplanted organs.

12. A method for treating and/or preventing LPAR1-mediated conditions or diseases, comprising administering a therapeutically effective amount of the triazole compound of formula (I) according to claim 1 or the pharmaceutically acceptable salt, the solvate, the polymorph, the metabolite, the ester, the stereoisomer, the tautomer, the isotopically labeled compound, the nitrogen oxide and the prodrug thereof to a subject.

13. The method according to claim 12, wherein the conditions or diseases are organ fibrotic diseases, respiratory diseases, renal diseases, hepatic diseases, inflammatory diseases, neurological diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pains, urinary system diseases, ophthalmic diseases, metabolic diseases, cancers and rejection of transplanted organs.

Description

DETAILED DESCRIPTION

[0096] The present invention is further illustrated by the following examples; however, these examples should not be construed as limiting the present invention. Experimental procedures without specified conditions in the following examples are conducted in accordance with conventional procedures and conditions, or in accordance with the manufacturer's manual.

[0097] The following abbreviations are used throughout the present invention: DMF (N,N-dimethylformamide); DCM (dichloromethane); PE (petroleum ether); EA (ethyl acetate); DIPEA (N,N-diisopropylethylamine); THF (tetrahydrofuran); Ac (acetyl); MeOH (methanol); Boc (tert-butoxycarbonyl); B2Pin2 (bis(pinacolato)diboron); rt (room temperature); reflux (refluxing conditions); eq (equivalent); Rf (retardation factor); g (gram); mg (milligram); mol (mole); mmol (millimole); h (hour); min (minute); mL (milliliter); μL (microliter).

[0098] Overnight refers to 8-15 h, for example 12 h; the room temperature refers to 10-30° C.; solvent ratio such as PE/EA refers to the volume ratio.

[0099] Unless otherwise indicated, all temperatures in the examples described below are given in Celsius degrees. Unless otherwise indicated, reagents are purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and used without further purification. General reagents are purchased from Shantou Xilong Chemical Plant Co. Ltd., Guangdong Guanghua Sci-Tech Co., Ltd., Guangzhou Chemical Reagent Factory, Tianjin Yuyu Fine Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Co., Ltd.

[0100] Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing and drying with sodium metal. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are pre-dried over anhydrous sodium sulfate before use.

[0101] The following reactions are generally preformed under a positive pressure of nitrogen or argon or by placing a drying tube over an anhydrous solvent (unless otherwise indicated), the reaction flask is stoppered with a suitable rubber stopper and the substrate is driven in by syringe. Each piece of glassware is dried.

[0102] Chromatographic columns are silica gel columns. Silica gel (300-400 mesh) is purchased from Qingdao Haiyang Chemical Co., Ltd. NMR spectral data are measured on a Bruker Avance 400 NMR spectrometer or a Bruker Avance III HD 600 NMR spectrometer using CDCl.sub.3, DMSO-d.sub.6, CD.sub.3OD or Acetone-d.sub.6 as solvents (reported in ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are present, the following abbreviations will be used: s (singlet); d (doublet); t (triplet); m (multiplet); br (broadened); dd (doublet of doublets); dt (doublet of triplets); ddd (doublet of doublet of doublets); ddt (doublet of doublet of triplets); dddd (doublet of doublet of doublet of doublets). Coupling constants are expressed in hertz (Hz).

[0103] Low-resolution mass spectrometry (MS) data are determined on an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and an aG1316ATCC (column temperature maintained at 30° C.), with a G1329A autosampler and a G1315BDAD detector applied to the analysis and an ESI source applied to the LC-MS spectrometer.

Example 1

[0104] ##STR00109##

Step (1): preparation of 1-benzyl-3-(2,4-dimethoxybenzyl)-3-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1-methylurea

[0105] ##STR00110##

[0106] Compound 1-1 (340 mg, 0.82 mmol) was dissolved in dichloromethane (20 mL), and then triethylamine (165 mg, 1.63 mmol) was added. The reaction system was cooled to 0° C., added with benzyl(methyl)carbamic chloride (184 mg, 0.977 mmol), and then slowly warmed to room temperature and reacted for 16 h. Then the reaction system was quenched with water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 1-3 (190 mg, 42% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 546.1.

Step (2): preparation of 1-benzyl-3-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1-methylurea

[0107] ##STR00111##

[0108] Compound 1-3 (190 mg, 0.35 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 1-4 (93 mg, 74% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 352.4.

Step (3): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-((3-phenyl-3-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylate

[0109] ##STR00112##

[0110] Compound 1-4 (50 mg, 0.14 mmol), isopropyl 3-hydroxycyclohexane-1-carboxylate (109 mg, 0.57 mmol), DTAD (131 mg, 0.57 mmol) and PPh.sub.3 (150 mg, 0.57 mmol) were dissolved in THF (10 mL), and the reaction system was stirred overnight at 60° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=50/1) to give Compound 1-6 (130 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 520.2.

Step (4): preparation of (+/−)-(1S,3S)-3-(4-(5-((3-phenyl-3-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylic acid

[0111] ##STR00113##

[0112] Compound 1-6 (130 mg, crude product) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 1 (38 mg) in the form of a white solid.

[0113] LC-MS [M+H].sup.+: 478.2. .sup.1H NMR (400 MHz, MeOD) δ 7.64-7.56 (m, 2H), 7.37-7.20 (m, 3H), 7.16 (d, J=7.1 Hz, 2H), 7.08-7.01 (m, 2H), 4.69-4.67 (m, 1H), 4.64 (s, 2H), 4.47 (s, 2H), 4.11 (s, 3H), 2.82-2.73 (m, 1H), 2.76 (s, 3H), 2.06-2.04 (m, 1H), 1.92-1.78 (m, 3H), 1.74-1.44 (m, 4H).

Example 2

[0114] ##STR00114## ##STR00115##

Step (1): preparation of N-benzyl-N-methylacrylamide

[0115] ##STR00116##

[0116] N-methyl-1-phenylmethanamine (1.5 g, 12.4 mmol) and triethylamine (2.5 g, 24.8 mmol) were dissolved in dichloromethane (50 mL), and then the reaction system was cooled to 0° C., added with acryloyl chloride (126 mL, 2.4 M) dropwise, and then reacted at 0° C. for 2 h. Then the reaction system was slowly warmed to room temperature, washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give Compound 2-3 (1.7 g, 78% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 176.2.

Step (2): preparation of 5-iodo-4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole

[0117] ##STR00117##

[0118] Compound 2-4 (800 mg, 3.65 mmol) was dissolved in tetrahydrofuran (30 mL), and then the reaction system was cooled to −78° C. and added with n-butyl lithium (1.82 mL, 2.4 M) dropwise. After reaction at −78° C. for 1 h, the reaction system was added with a solution of iodine (1.4 g, 5.47 mmol) in tetrahydrofuran (5 mL) dropwise, and then reacted at −78° C. for 1 h. Then the reaction system was quenched with saturated ammonium chloride (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/EA=4/1) to give Compound 2-5 (1.2 g, 90% yield) in the form of a white solid. LC-MS [M+H].sup.+: 346.4.

Step (3): preparation of (E)-N-benzyl-3-(4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylacrylamide

[0119] ##STR00118##

[0120] Compound 2-5 (518 mg, 1.5 mmol), Compound 2-3 (290 mg, 1.65 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (105 mg, 0.15 mmol) and potassium carbonate (105 mg, 0.15 mmol) were added to anhydrous N,N-dimethylformamide (10 mL), and the reaction system was heated to 120° C. and reacted for 2 h under nitrogen atmosphere. Then the reaction system was quenched with water (30 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/MeOH=40/1) to give Compound 2-6 (470 mg, 79% yield) in the form of a white solid. LC-MS [M+H].sup.+: 393.2.

Step (4): preparation of (E)-N-benzyl-3-(4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylacrylamide

[0121] ##STR00119##

[0122] Compound 2-6 (470 mg, 1.2 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 2-7 (400 mg, 95% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 349.2.

Step (5): preparation of (+/−)-methyl (1S,3S)-3-((4-(5-((((E)-benzyl(methyl)carbamoyl)-1-en-1-yl) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylate

[0123] ##STR00120##

[0124] Compound 2-7 (300 mg, 0.31 mmol), methyl (3S)-3-hydroxycyclohexane-1-carboxylate (272 mg, 0.63 mmol), DIAD (142 mg, 63 mmol) and PPh.sub.3 (162 mg, 0.63 mmol) were dissolved in THF (10 mL), and the reaction system was stirred overnight at room temperature under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=5/1) to give Compound 2-9 (300 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 489.1.

Step (6): preparation of (+/−)-(1S,3S)-3-((4-(5-((((E)-benzyl(methyl)carbamoyl)-1-en-1-yl) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylic acid

[0125] ##STR00121##

[0126] Compound 2-9 (300 mg, crude product) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 2 (20 mg) in the form of a white solid. LC-MS [M+H].sup.+: 475.4.

Example 3

[0127] ##STR00122##

Step (1): preparation of (+/−)-methyl (1S,3S)-3-((4-(5-(3-(benzyl(methyl)amino)-3-carbonylpropyl)-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylate

[0128] ##STR00123##

[0129] Compound 2-9 (610 mg, crude product) was dissolved in tert-butanol (20 mL), and then palladium on carbon (61 mg) was added. Hydrogen gas was introduced, and the reaction system was reacted at room temperature for 2 h. Palladium on carbon was filtered out, and the filtrate was concentrated to give Compound 3-1 (510 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 491.8.

Step (2): preparation of (+/−)-(1S,3S)-3-((4-(5-(3-(benzyl(methyl)amino)-3-carbonylpropyl)-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylic acid

[0130] ##STR00124##

[0131] Compound 3-1 (510 mg, crude product) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 3 (20 mg) in the form of a white solid.

[0132] LC-MS [M+H].sup.+: 477.2. .sup.1H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 7.60-7.50 (m, 2H), 7.33-7.26 (m, 3H), 7.15-6.99 (m, 4H), 4.69 (s, 1H), 4.48 (s, 1.4H), 4.46 (s, 0.7H), 4.04 (s, 2H), 3.98 (s, 1H), 3.12 (dd, J=17.0, 9.0 Hz, 2H), 2.80 (s, 1H), 2.79 (s, 2H), 2.74-2.61 (m, 3H), 1.98-1.46 (m, 8H).

Example 4

[0133] ##STR00125## ##STR00126##

Step (1): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-2-phenylacetamide

[0134] ##STR00127##

[0135] Compound 1-1 (1.3 g, 3.25 mmol) and triethylamine (0.7 g, 6.50 mmol) were dissolved in dichloromethane (25 mL), and then the reaction system was put in an ice water bath, added with phenylacetyl chloride (172 mg, 0.98 mmol) dropwise and then stirred overnight at room temperature. Then the reaction system was diluted with dichloromethane (25 mL), washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE/EA=4//1) to give Compound 4-2 (0.86 g, 50% yield) in the form of a white solid. LC-MS [M+H].sup.+: 517.2.

Step (2): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-2-phenylacetamide

[0136] ##STR00128##

[0137] Compound 4-2 (800 mg, 1.55 mmol) was dissolved in tetrahydrofuran (5 mL), and then HCl (1 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with H.sub.2O (20 mL) and extracted with ethyl acetate (15 mL×2). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE/EA=1/1) to give Compound 4-3 (550 mg, 75% yield) in the form of a white solid.

[0138] LC-MS [M+H].sup.+: 473.2.

Step (3): isopropyl (1S,3S)-3-(4-(5-((N-(2,4-dimethoxybenzyl)-2-N-phenylacetamido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0139] ##STR00129##

[0140] Compound 4-3 (260 mg, 0.55 mmol) was dissolved in tetrahydrofuran solution (15 mL), and then triphenylphosphonium (444 mg, 1.65 mmol), di-tert-butyl azodicarboxylate (380 mg, 1.65 mmol) and Compound 1-5 (307 mg, 1.65 mmol) were added under nitrogen atmosphere. Then the reaction system was warmed to 60° C. and stirred overnight. The reaction system was quenched with water (50 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (P/EA=2/1) to give Compound 4-4 (160 mg, 45% yield) in the form of a pale yellow oil.

[0141] LC-MS [M+H].sup.+: 627.3.

Step (4): preparation of isopropyl (1S,3S)-3-((4-(5-(2-N-phenylacetamido))-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylate

[0142] ##STR00130##

[0143] Compound 4-4 (160 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (5 mL) was added dropwise, and the reaction system was stirred overnight at room temperature. After concentration under reduced pressure, the reaction system was diluted with H.sub.2O (20 mL) and extracted with dichloromethane (15 mL×2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE/EA=1/1) to give Compound 4-5 (120 mg, 97% yield) in the form of a white solid. LC-MS [M+H].sup.+: 491.2.

Step (5): preparation of (1S,3S)-3-((4-(5-(2-N-phenylacetamido))-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylic acid

[0144] ##STR00131##

[0145] Compound 4-5 (120 mg, 0.24 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL), and then lithium hydroxide hydrate (30 mg, 0.72 mmol) was added, and the reaction system was stirred at room temperature for 15 h. Then the reaction system was concentrated, diluted with H.sub.2O (10 mL), adjusted to pH 2-3 with diluted HCl (1 N), and then extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by thin layer chromatography (DCM/MeOH=30/1) and lyophilized to give Compound 4 (90 mg, 84% yield) in the form of a white solid.

[0146] LC-MS [M+H].sup.+: 449.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38 (d, J=8.7 Hz, 2H), 7.33-7.28 (m, 3H), 7.18 (dd, J=7.5, 1.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 6.38 (brs, 1H). 4.67-4.62 (m, 1H), 4.56 (d, J=5.3 Hz, 2H), 3.92 (s, 3H), 3.57 (s, 2H), 2.97-2.84 (m, 1H), 2.14-2.06 (m, 1H), 2.02-1.58 (m, 7H).

Example 5

[0147] ##STR00132## ##STR00133##

Step (1): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-cinnamamide

[0148] ##STR00134##

[0149] Compound 1-1 (324 mg, 0.814 mmol) was dissolved in dichloromethane (20 mL), and then triethylamine (165 mg, 1.63 mmol) was added. The reaction system was cooled to 0° C., added with cinnamoyl chloride (163 mg, 0.977 mmol), and then slowly warmed to room temperature and reacted for 16 h. Then the reaction system was quenched with water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 5-2 (320 mg, 76% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 529.1.

Step (2): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-cinnamamide

[0150] ##STR00135##

[0151] Compound 5-2 (320 mg, 0.605 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 5-3 (170 mg, 58% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 485.2.

Step (3): preparation of (+/−)-methyl (1S,3S)-3-(4-(5-((N-(2,4-dimethoxybenzyl)cinnamamido) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0152] ##STR00136##

[0153] Compound 5-3 (170 mg, 0.35 mmol), Compound 5-4 (219 mg, 0.7 mmol) and cesium carbonate (286 mg, 0.875 mmol) were dissolved in DMF (10 mL), and then the reaction system was heated to 100° C. and reacted for 7 h under nitrogen atmosphere. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (10 mL×2) and saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 5-5 (190 mg, 86% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 625.4.

Step (4): preparation of (+/−)-methyl (1S,3S)-3-(4-(5-(cinnamidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0154] ##STR00137##

[0155] Compound 5-5 (190 mg, 0.3 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (10 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was concentrated, and the residue was diluted with ethyl acetate (20 mL), washed successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 5-6 (75 mg, 53% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 475.3.

Step (5): preparation of (+/−)-(1S,3S)-3-((4-(5-((((E)-benzyl(methyl)carbamoyl)-1-en-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-phenoxy)cyclohexane-1-carboxylic acid

[0156] ##STR00138##

[0157] Compound 5-6 (75 mg, 0.157 mmol) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with water (10 mL) and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1), separated by preparative chromatography, and then lyophilized to give Compound 5 (30 mg, 41% yield) in the form of a white solid.

[0158] LC-MS [M+H].sup.+: 461.2. .sup.1H NMR (400 MHz, MeOD) δ 7.66-7.52 (m, 5H), 7.46-7.35 (m, 3H), 7.09 (d, J=8.8 Hz, 2H), 6.59 (d, J=15.8 Hz, 1H), 4.76 (s, 2H), 4.74-4.75 (s, 1H), 4.17 (s, 3H), 2.79-2.76 (m, 1H), 2.08-2.06 (m, 1H), 2.00-1.85 (m, 3H), 1.84-1.56 (m, 4H).

Example 6

[0159] ##STR00139##

Step (1): preparation of 4-azidophenol

[0160] ##STR00140##

[0161] (4-hydroxyphenyl)boronic acid (4.96 g, 35.96 mmol) was dissolved in acetonitrile (25 mL) and water (25 mL), and then sodium azide (3.5 g, 53.94 mmol) and copper acetate (1.3 g, 7.192 mmol) were added, and the reaction system was reacted overnight at room temperature. After the reaction was completed, the reaction system was added with water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation to give Compound 6-2 (3.59 g, 72% yield) in the form of a brown oil.

Step (2): preparation of 4-(4-(((tetrahydro-2H-pyran-2-yl)oxo)methyl)-1H-1,2,3-triazol-1-yl)phenol

[0162] ##STR00141##

[0163] Compound 6-2 (3.59 g, 26.569 mmol) and copper(I) iodide (1.01 g, 5.314 mmol) were added to N,N-dimethylformamide (20 mL), and then 2-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (4.47 g, 31.883 mmol) was added, and the reaction system was reacted at 100° C. for 15 h under nitrogen atmosphere. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (150 mL×3), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=10/1-3/1) to give Compound 6-3 (4 g, 54% yield) in the form of a purple oil. MS [M−H].sup.−: 274.1.

Step (3): preparation of (+/−)-methyl (1S,3S)-3-(4-(4-(((tetrahydro-2H-pyran-2-yl)oxo)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)cyclohexane-carboxylate

[0164] ##STR00142##

[0165] Compound 6-3 (260 mg, 0.94 mmol) and cesium carbonate (923 mg, 2.33 mmol) were dissolved in anhydrous DMF (5 mL), and then Compound 6-4 (354 mg, 1.13 mmol) was added. After reaction at 100° C. for 5 h, the reaction system was cooled to room temperature, added with water (20 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation to give a crude product, which was separated by column chromatography (PE/EA=1/1) to give Compound 6-5 (118 mg, 30% yield) in the form of a yellow oil.

[0166] MS [M+H].sup.+: 416.8.

Step (4): preparation of (+/−)-methyl (1S,3S)-3-(4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) phenoxy)cyclohexane-carboxylate

[0167] ##STR00143##

[0168] Compound 6-5 (118 mg, 0.28 mmol) was added to absolute methanol (5 mL), and then pyridinium p-toluenesulfonate (72 mg, 0.28 mmol) was added, and the reaction system was stirred at 60° C. for 3 h under nitrogen atmosphere. Then the reaction system was concentrated, and the residue was separated by thin layer chromatography (PE/EA=2/1) to give Compound 6-6 (60 mg, 63.7% yield) in the form of a yellow oil. LC-MS [M+H].sup.+: 332.8.

Step (5): preparation of (+/−)-methyl (1S,3S)-3-(4-(4-(((benzyl(methyl)carbamoyl)oxo)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)cyclohexane-carboxylate

[0169] ##STR00144##

[0170] Compound 6-6 (60 mg, 0.18 mmol) and pyridine (72 mg, 0.91 mmol) were dissolved in dichloromethane (5 mL) under nitrogen atmosphere, and then the reaction system was cooled to 0° C., added with 4-nitrophenyl chloroformate (112 mg, 0.55 mmol), and then warmed to room temperature and stirred for 2 h. Then the reaction system was added with N-methylbenzylamine (134 mg, 1.1047 mmol) and diisopropylethylamine (47 mg, 0.36 mmol) and stirred overnight at room temperature. The reaction system was then washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated by thin layer chromatography (PE/EA=2/1) to give Compound 6-9 (60 mg, 69% yield) in the form of a yellow oil. LC-MS [M+H].sup.+: 479.7.

Step (6): preparation of (+/−)-(1S,3S)-3-(4-(4-(((benzyl(methyl)carbamoyl)oxo)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)cyclohexane-1-carboxylic acid

[0171] ##STR00145##

[0172] Compound 6-6 (60 mg, 0.1462 mmol) and lithium hydroxide (18 mg, 0.4386 mmol) were dissolved in methanol (3 mL) and water (3 mL). After reaction at room temperature for 10 h, the reaction system was concentrated, adjusted to pH 5 with diluted HCl (1 N), and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by chiral HPLC to give Compound 6 (4 mg, 7% yield) in the form of a white solid.

[0173] Compound 6: LC-MS [M−H].sup.−: 463.9. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.00 (d, J=51.9 Hz, 1H), 7.63 (t, 2H), 7.33 (m, 2H), 7.28 (m, 2H), 7.21 (s, 1H), 7.06 (d, J=8.0 Hz, 2H), 5.37 (s, 2H), 4.71 (s, 1H), 4.50 (d, J=8.8 Hz, 2H), 2.90 (d, J=23.7 Hz, 3H), 2.15 (d, J=14.0 Hz, 1H), 2.07-1.53 (m, 8H).

Example 7

[0174] ##STR00146##

Step (1): preparation of 4-(3-((tetrahydro-2H-pyran-2-yl)oxo)prop-1-yn-1-yl)phenol

[0175] ##STR00147##

[0176] 4-iodophenol (10 g, 45.45 mmol) and 2-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (9.56 g, 68.18 mmol) were dissolved in acetonitrile (20 mL), and then bis(triphenylphosphine)palladium(II) chloride (1.6 g, 2.273 mmol), triethylamine (13.8 g, 136.35 mmol) and copper(I) iodide (433 mg, 2.273 mmol) were added, and the reaction system was reacted overnight at room temperature. After the reaction was completed, the reaction system was filtered, concentrated, added with water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation, and the residue was purified by column chromatography (PE/EA=10/1-3/1) to give Compound 7-2 (8.5 g, 80% yield) in the form of a yellow oil. MS [M−H].sup.−: 231.1.

Step (2): preparation of methyl 4-chloro-2-(4-(3-((tetrahydro-2H-pyran-2-yl)oxo)prop-1-yn-1-yl) phenoxy)benzoate

[0177] ##STR00148##

[0178] Compound 7-2 (6.4 g, 27.6564 mmol) and methyl 2-bromo-4-chlorobenzoate (4.6 g, 18.4376 mmol) were added to anhydrous toluene (100 mL), and then triphenylphosphine (242 mg, 0.9219 mmol), copper(I) iodide (176 mg, 0.9219 mmol) and potassium carbonate (5.1 g, 36.8752 mmol) were added, and the reaction system was reacted at 100° C. for 24 h under nitrogen atmosphere. After the reaction was completed, the reaction system was filtered. The filtrate was concentrated, diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (150 mL×3), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=20/1-5/1) to give Compound 7-4 (2.5 g, 33.7% yield) in the form of a yellow oil. MS [M+H].sup.+: 401.0.

Step (3): preparation of methyl 4-chloro-2-(4-(5-(((tetrahydro-2H-pyran-2-yl)oxo)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)benzoate

[0179] ##STR00149##

[0180] Compound 7-4 (1.9 g, 4.74 mmol), trimethylsilylmethyl azide (1.84 g, 14.22 mmol) and anhydrous DMF (20 mL) were added into a sealed tube. After reaction at 100° C. for a week, the reaction system was concentrated to remove the DMF, added with water (30 mL) and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation to give a crude product, which was separated by column chromatography (PE/EA=30/1-5/1) to give Compound 7-5 (510 mg, 20% yield) in the form of a yellow oil. MS [M+H].sup.+: 530.1.

Step (4): methyl 4-chloro-2-(4-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxo)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)benzoate

[0181] ##STR00150##

[0182] Compound 7-5 (510 mg, 0.9621 mmol) was added to anhydrous tetrahydrofuran (5 mL), and then tetrabutylammonium fluoride (1 mL, 1 M) was added, and the reaction system was stirred overnight at room temperature. The reaction system was then concentrated and the residue was separated by column chromatography (PE/EA=3/1-EA) to give Compound 7-6 (350 mg, 79% yield) in the form of a yellow oil. LC-MS [M+H].sup.+: 458.6.

Step (5): preparation of methyl 4-chloro-2-(4-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl) phenoxy)benzoate

[0183] ##STR00151##

[0184] Compound 7-6 (300 mg, 0.6552 mmol) and pyridinium p-toluenesulfonate (165 mg, 0.6552 mmol) were dissolved in absolute methanol (5 mL), and the reaction system was stirred overnight at 60° C. Then the reaction system was concentrated to remove methanol, diluted with water (15 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=1/1) to give Compound 7-7 (213 mg) in the form of a white solid.

[0185] LC-MS [M+H].sup.+: 374.7.

Step (6): preparation of methyl 4-chloro-2-(4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)benzoate

[0186] ##STR00152##

[0187] Compound 7-7 (169 mg, 0.4521 mmol) and pyridine (179 mg, 2.2605 mmol) were dissolved in dichloromethane (10 mL) under nitrogen atmosphere, and then the reaction system was cooled to 0° C., added with 4-nitrophenyl chloroformate (274 mg, 1.3563 mmol), and then warmed to room temperature and stirred for 2 h. Then the reaction system was added with N-methylbenzylamine (329 mg, 2.7126 mmol) and diisopropylethylamine (117 mg, 0.9042 mmol) and stirred overnight at room temperature. The reaction system was then washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated by thin layer chromatography (PE/EA=1/1) to give Compound 7-8 (130 mg, 55% yield) in the form of a yellow oil. LC-MS [M+H].sup.+: 521.7.

Step (7): preparation of 4-chloro-2-(4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)benzoic acid

[0188] ##STR00153##

[0189] Compound 7-8 (130 mg, 0.2495 mmol) and lithium hydroxide (32 mg, 0.7486 mmol) were dissolved in methanol (3 mL) and water (3 mL). After reaction at room temperature for 10 h, the reaction system was concentrated, adjusted to pH 5 with diluted HCl (1 N), and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by thin layer chromatography (PE/EA=1/1) to give Compound 7 (70 mg, 44% yield) in the form of a white solid.

[0190] LC-MS [M−H].sup.−: 505.8. .sup.1H NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.73 (dd, J=26.3, 7.9 Hz, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.36-7.04 (m, 6H), 7.00 (d, J=8.2 Hz, 1H), 5.35 (d, J=26.2 Hz, 2H), 4.41 (s, 2H), 4.09 (d, J=45.6 Hz, 3H), 2.79 (d, J=36.7 Hz, 3H).

Example 8

[0191] ##STR00154##

[0192] Refer to the synthesis procedures in Example 9 below, LC-MS [M−H].sup.−: 473.6.

Example 9

[0193] ##STR00155## ##STR00156##

Step (1): 2-(benzylamino)-1-(4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl) ethan-1-ol

[0194] ##STR00157##

[0195] Compound 9-1 (190 mg, 0.56 mmol) was dissolved in tetrahydrofuran (10 mL), and then saturated sodium bicarbonate (0.5 mL) was added. The reaction system was cooled to 0° C. and then added with benzylamine (73 mg, 0.67 mmol). After reaction at 0° C. for 20 min, the reaction system was added with lithium borohydride (36 mg, 1.68 mmol), and then slowly warmed to room temperature and reacted for 1 h. Then the reaction system was quenched with water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 9-2 (65 mg, 31% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 369.2.

Step (2): preparation of 3-benzyl-5-(4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl) oxazolidin-2-one

[0196] ##STR00158##

[0197] Compound 9-2 (65 mg, 0.177 mmol) was dissolved in tetrahydrofuran (5 mL), and then diisopropylethylamine (91 mg, 0.7 mmol) was added. The reaction system was cooled to 0° C., added with a solution of triphosgene (26 mg, 0.088 mmol) in tetrahydrofuran (5 mL), and then slowly warmed to room temperature and reacted for 1 h. Then the reaction system was quenched with saturated ammonium chloride (10 mL), and extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 9-3 (51 mg, 74% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 395.3.

Step (3): preparation of 3-benzyl-5-(4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl) oxazolidin-2-one

[0198] ##STR00159##

[0199] Compound 9-3 (51 mg, 0.13 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 9-4 (35 mg, 78% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 351.2.

Step (4): preparation of methyl (1S,3S)-3-(4-(5-(3-benzyl-2-carbonyloxazolidin-5-yl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0200] ##STR00160##

[0201] Compound 9-4 (35 mg, 0.1 mmol), methyl (1S,3R)-3-(tosyloxo)cyclohexane-1-carboxylate (42 mg, 0.12 mmol) and cesium carbonate (65 mg, 0.2 mmol) were dissolved in DMF (5 mL), and then the reaction system was heated to 100° C. and reacted for 7 h under nitrogen atmosphere. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (10 mL×2) and saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 9-5 (32 mg, 65% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 491.2.

Step (5): preparation of (1S,3S)-3-(4-(5-(3-benzyl-2-carbonyloxazolidin-5-yl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0202] ##STR00161##

[0203] Compound 9-5 (32 mg, 0.065 mmol) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 9 (4.5 mg, 15% yield) in the form of a white solid.

[0204] LC-MS [M+H].sup.+: 477.2. .sup.1H NMR (400 MHz, MeOD) δ 7.43-7.29 (m, 5H), 7.25-7.23 (m, 2H), 7.08-7.01 (m, 2H), 6.01 (dd, J=9.5, 8.4 Hz, 1H), 4.77 (m, 1H), 4.39 (m, 2H), 4.11 (s, 3H), 3.81 (t, J=9.6 Hz, 1H), 3.44 (dd, J=9.3, 8.3 Hz, 1H), 2.81-2.83 (m, 1H), 2.09-2.11 (m, 1H), 2.00-1.86 (m, 3H), 1.83-1.58 (m, 4H).

Example 10

[0205] ##STR00162## ##STR00163##

Step (1): preparation of (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0206] ##STR00164##

[0207] Compound 10-1 (400 mg, 1.62 mmol) was dissolved in tetrahydrofuran (12 mL), and then the reaction system was cooled to 0° C., added with sodium borohydride (62 mg, 1.62 mmol) and stirred at room temperature for 2 h. Then the reaction system was quenched with water (1 mL), and dried by rotary evaporation, and the residue was separated by column chromatography (EA/PE=1/2) to give Compound 10-2 (326 mg, 81% yield) in the form of a white solid. LC-MS [M−H].sup.+: 250.1.

Step (2): preparation of (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl (4-nitro) carbonate diester

[0208] ##STR00165##

[0209] Compound 10-2 (326 mg, 1.31 mmol) and pyridine (310 mg, 3.92 mmol) were dissolved in dichloromethane (10 mL), and 4-nitrophenyl chloroformate (398 mg, 1.97 mmol) at 0° C. was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was extracted with dichloromethane (20 mL×2), and the organic phases were combined, washed with saturated brine (20 mL) and concentrated, and the residue was separated by column chromatography (wet loading, PE/EA=5/1) to give Compound 10-4 (380 mg, 70% yield) in the form of a pale yellow solid. LC-MS [M+H].sup.+: 415.2.

Step (3): preparation of (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl) methylbenzyl(methyl)carbamate

[0210] ##STR00166##

[0211] Compound 10-4 (380 mg, 0.92 mmol) and N,N-diisopropylethylamine (356 mg, 2.76 mmol) were added to anhydrous tetrahydrofuran (10 mL), and then N-methylbenzylamine (167 mg, 1.38 mmol) was added. The reaction system was reacted at room temperature overnight and extracted with ethyl acetate (30 mL×2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=1/1) to give Compound 10-6 (300 mg, 82% yield) in the form of a colorless oil. LC-MS [M+H].sup.+: 397.2.

Step (4): preparation of (4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methylbenzyl(methyl) carbamate

[0212] ##STR00167##

[0213] Compound 10-6 (300 mg, 0.76 mmol) was dissolved in dichloromethane (8 mL), and then a solution of HCl in methanol (1 mL) was added dropwise at room temperature. The reaction system was stirred at room temperature for 2 h and then concentrated to give Compound 10-7 (200 mg, 75% yield) in the form of a colorless oil. LC-MS [M+H].sup.+: 353.2.

Step (5): preparation of ethyl (E)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)acrylate

[0214] ##STR00168##

[0215] Compound 10-7 (70 mg, 0.20 mmol) and triethylenediamine (34 mg, 0.30 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and then ethyl propiolate (39 mg, 0.40 mmol) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (EA/PE=1/1) to give Compound 10-8 (55 mg, 62% yield) in the form of a colorless oil. LC-MS [M+H].sup.+: 451.2.

Step (6): preparation of (E)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)acrylic acid

[0216] ##STR00169##

[0217] Compound 10-8 (55 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), and then the reaction system was cooled to 0° C., added with aqueous lithium hydroxide solution (0.15 mL, 3 mol/L) dropwise, and stirred overnight at room temperature. The reaction system was then concentrated under reduced pressure, adjusted to pH 3 with diluted HCl (0.5 mL, 1 mol/L) and extracted with ethyl acetate (20 mL×2). After concentration, the residue was separated by preparative reverse phase chromatography (CH.sub.3CN (0.1% FA)-H.sub.2O (0.1% FA)) to give Compound 10 (23 mg, 45% yield) in the form of a white solid.

[0218] LC-MS [M+H].sup.+: 423.1. .sup.1H NMR (400 MHz, MeOD) δ 7.96-7.79 (m, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.24 (ddd, J=56.9, 31.0, 18.4 Hz, 7H), 5.58 (d, J=12.1 Hz, 1H), 5.43 (d, J=24.0 Hz, 2H), 4.48 (s, 2H), 4.17 (d, J=58.6 Hz, 3H), 2.88 (d, J=55.3 Hz, 3H).

Example 11

[0219] ##STR00170##

Step (1): preparation of ethyl 3-(4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)propionate

[0220] ##STR00171##

[0221] Compound 10-8 (200 mg, 0.44 mmol) was dissolved in ethyl acetate (8 mL), then palladium on carbon (20 mg) was added. Hydrogen was introduced, and then the reaction system was stirred at room temperature for 2 h, and filtered, and the filtrate was concentrated to give Compound 11-1 (190 mg, 94% yield) in the form of a colorless oil. LC-MS [M−H].sup.+: 453.3.

Step (2): preparation of 3-(4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)propionic acid

[0222] ##STR00172##

[0223] Compound 11-1 (190 mg, 0.42 mmol) was dissolved in tetrahydrofuran (5 mL), and then the reaction system was cooled to 0° C., added with aqueous lithium hydroxide solution (0.4 mL, 3 mol/L) dropwise, and stirred overnight at room temperature. The reaction system was then concentrated under reduced pressure, adjusted to pH 3 with diluted HCl (1.5 mL, 1 mol/L) and extracted with ethyl acetate (30 mL×2). After concentration, the residue was separated by preparative reverse phase chromatography (CH.sub.3CN (0.1% FA)-H.sub.2O (0.1% FA)) to give Compound 11 (42 mg, 23% yield) in the form of a white solid.

[0224] LC-MS [M+H].sup.+: 425.2. .sup.1H NMR (400 MHz, MeOD) δ 7.72-7.53 (m, 2H), 7.28 (t, J=16.7 Hz, 4H), 7.16-6.92 (m, 3H), 5.40 (d, J=22.2 Hz, 2H), 4.47 (d, J=8.3 Hz, 2H), 4.28 (s, 2H), 4.14 (d, J=61.5 Hz, 3H), 2.84 (dd, J=36.3, 30.5 Hz, 5H).

Example 12

[0225] ##STR00173##

[0226] Refer to the synthesis procedures in Example 13 below, LC-MS [M+H].sup.+: 469.4.

Example 13

[0227] ##STR00174##

Step (1): preparation of 2-((3-(4-nitrophenyl)prop-2-yn-1-yl)oxo)tetrahydro-2H-pyran

[0228] ##STR00175##

[0229] 1-iodo-4-nitrobenzene (5 g, 20 mmol) and 2-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (4.2 g, 30 mmol) were dissolved in acetonitrile (10 mL), and then bis(triphenylphosphine)palladium(II) chloride (702 g, 1 mmol), triethylamine (4.2 g, 60 mmol) and copper(I) iodide (191 mg, 1 mmol) were added, and the reaction system was reacted overnight at room temperature. After the reaction was completed, the reaction system was filtered, concentrated, added with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation, and the residue was purified by column chromatography (PE/EA=20/1) to give Compound 13-2 (3.6 g, 68% yield) in the form of a yellow oil. MS [M+H].sup.+: 262.4.

Step (2): preparation of 4-(4-nitrophenyl)-5-(((tetrahydro-2H-pyran-2-yl)oxo)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole

[0230] ##STR00176##

[0231] Compound 13-2 (3.1 g, 11.865 mmol) and trimethylsilylmethyl azide (4.6 g, 36.595 mmol) were dissolved in anhydrous toluene (50 mL). After reaction at 90° C. for 4 days, the reaction system was concentrated to remove the toluene, added with water (60 mL) and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation to give a crude product, which was separated by column chromatography (PE/EA=40/1) to give Compound 13-3 (1 g, 21% yield) in the form of a white solid. MS [M+H].sup.+: 390.8.

Step (3): preparation of 1-methyl-4-(4-nitrophenyl)-5-(((tetrahydro-2H-pyran-2-yl)oxo)methyl)-1H-1,2,3-triazole

[0232] ##STR00177##

[0233] Compound 13-3 (960 mg, 2.4583 mmol) was added to anhydrous tetrahydrofuran (10 mL), and then tetrabutylammonium fluoride (2.5 mL, 1 M) was added, and the reaction system was stirred at room temperature for 1 h. The reaction system was then diluted with water (30 mL) and extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=3/1) to give Compound 13-4 (530 mg, 67% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 318.8.

Step (4): (1-methyl-4-(4-nitrophenyl)-1H-1,2,3-triazol-5-yl)methanol

[0234] ##STR00178##

[0235] Compound 13-4 (500 mg, 1.57 mmol) and pyridinium p-toluenesulfonate (395 mg, 1.57 mmol) were dissolved in absolute methanol (10 mL), and the reaction system was stirred overnight at 60° C. Then the reaction system was concentrated to remove methanol, diluted with water (15 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=10/1-3/1) to give Compound 13-5 (300 mg) in the form of a yellow oil. LC-MS [M+H].sup.+: 234.8.

Step (5): preparation of (1-methyl-4-(4-nitrophenyl)-1H-1,2,3-triazol-5-yl)methylbenzyl(methyl) carbamate

[0236] ##STR00179##

[0237] Compound 13-5 (290 mg, 1.2382 mmol) and pyridine (489 mg, 6.1910 mmol) were dissolved in dichloromethane (5 mL) under nitrogen atmosphere, and then the reaction system was cooled to 0° C., added with 4-nitrophenyl chloroformate (345 mg, 1.7146 mmol), and then warmed to room temperature and stirred for 2 h. Then the reaction system was added with N-methylbenzylamine (900 mg, 7.4292 mmol) and diisopropylethylamine (320 mg, 2.4764 mmol) and stirred overnight at room temperature. The reaction system was then washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated by thin layer chromatography (PE/EA=1/1) to give Compound 13-6 (208 mg, 44% yield) in the form of a yellow oil. LC-MS [M+H].sup.+: 382.8.

Step (6): preparation of (4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methylbenzyl(methyl) carbamate

[0238] ##STR00180##

[0239] Compound 13-6 (180 mg, 0.472 mmol) was dissolved in ethanol (5 mL) and water (1 mL), and then zinc powder (309 mg, 4.72 mmol) and ammonium chloride (76 mg, 1.416 mmol) were added, and the reaction system was stirred under reflux for 6 h. The reaction system was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=2/1-1/1) to give Compound 13-7 (140 mg, 84% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 352.8.

Step (7): preparation of ethyl 3-((4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclohexanecarboxylate

[0240] ##STR00181##

[0241] Compound 13-7 (110 mg, 0.313 mmol), trimethylchlorosilane (85 mg, 0.7825 mmol) and ethyl 3-carbonylcyclohexanecarboxylate (59 mg, 0.344 mmol) were added to anhydrous DMF (5 mL), and under nitrogen atmosphere, the reaction system was cooled to 0° C., slowly added with a solution of borane in tetrahydrofuran (0.3 mL, 1 M), and reacted at 0° C. for 1 h. Then the reaction system was quenched with saturated aqueous sodium carbonate solution (15 mL), stirred for 10 min, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by thin layer chromatography (PE/EA=1/1) to give Compound 13-9 (100 mg, 63% yield) in the form of a yellow oil. LC-MS [M−H].sup.+: 506.9.

Step (8): preparation of (+/−)-3-((4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclohexanecarboxylic acid

[0242] ##STR00182##

[0243] Compound 13-9 (100 mg, 0.1978 mmol) and lithium hydroxide (25 mg, 0.5934 mmol) were dissolved in tetrahydrofuran (3 mL) and water (3 mL). After reaction at room temperature for 10 h, the reaction system was concentrated, adjusted to pH 3 with diluted HCl (1 N), and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the residue was separated by preparative HPLC to give Compound 13-10 (80 mg, 70% yield) in the form of a white solid. LC-MS [M−H].sup.−: 476.7.

Step (9) 3-((4-(5-(((benzyl(methyl)carbamoyl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclohexanecarboxylic acid was separated by chiral HPLC to give Compound 13 (50.1 mg)

[0244] ##STR00183##

[0245] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.57 (dd, J=26.4, 8.0 Hz, 2H), 7.34 (dd, J=15.7, 7.0 Hz, 3H), 7.27 (d, J=7.3 Hz, 1H), 7.14 (d, J=6.5 Hz, 1H), 6.65 (dd, J=23.9, 7.8 Hz, 2H), 5.33 (d, J=22.1 Hz, 2H), 4.48 (d, J=29.8 Hz, 2H), 4.10 (d, J=66.0 Hz, 3H), 3.34 (s, 1H), 2.92 (d, J=55.8 Hz, 3H), 2.49 (dd, J=25.8, 13.7 Hz, 2H), 2.16 (d, J=12.1 Hz, 1H), 2.11-2.01 (m, 1H), 1.95 (dd, J=9.8, 2.8 Hz, 1H), 1.45 (dd, J=20.3, 11.5 Hz, 2H), 1.33 (t, J=8.2 Hz, 1H), 1.14 (d, J=11.6 Hz, 1H).

Example 14

[0246] ##STR00184## ##STR00185##

Step (1): preparation of 1-(4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylethylamine

[0247] ##STR00186##

[0248] A solution of 4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-carbaldehyde and methylamine in ethanol (100 mg) was dissolved in methanol (10 mL), and then the reaction system was stirred at room temperature for 2 h, added successively with sodium cyanoborohydride and saturated sodium bicarbonate (48 mg, 0.75 mmol), and reacted at room temperature for 10 h. Then the reaction system was concentrated, and the residue was separated by column chromatography (DCM/MeOH=40/1) to give Compound 14-2 (120 mg, 90% yield) in the form of a yellow solid.

[0249] LC-MS [M+H].sup.+: 263.6.

Step (2): preparation of benzyl ((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-azol-5-yl) methyl)(methyl)carbamate

[0250] ##STR00187##

[0251] Compound 14-2 (120 mg, 0.46 mmol) and diisopropylethylamine (89 mg, 0.69 mmol) were dissolved in tetrahydrofuran (5 mL), and then benzyl chloroformate (86 mg, 0.5 mmol) was added, and the reaction system was heated to reflux and reacted for 16 h. Then the reaction system was concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 14-3 (160 mg, 95% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 397.2.

Step (3): preparation of benzyl ((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl) (methyl)carbamate

[0252] ##STR00188##

[0253] Compound 14-3 (160 mg, 0.45 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 14-4 (140 mg, 87% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 353.3.

Step (4): preparation of methyl (1S,3S)-3-(4-(5-((((benzyloxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0254] ##STR00189##

[0255] Compound 14-4 (110 mg, 0.31 mmol), methyl (1S,3R)-3-(tosyloxo)cyclohexane-1-carboxylate (198 mg, 1.25 mmol), DTAD (288 mg, 1.25 mmol) and PPh.sub.3 (328 mg, 1.25 mmol) were dissolved in THF (15 mL), and the reaction system was stirred overnight at room temperature under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=5/1) to give Compound 14-5 (260 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 521.5.

Step (5): preparation of (1S,3S)-3-(4-(5-((((benzyloxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0256] ##STR00190##

[0257] Compound 14-5 (260 mg, crude product) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 14 (20 mg) in the form of a white solid.

[0258] LC-MS [M+H].sup.+: 479.4. .sup.1H NMR (400 MHz, MeOD) δ 7.49-7.47 (m, 2H), 7.38-7.34 (m, 5H), 7.03 (d, J=8.3 Hz, 2H), 5.12 (s, 2H), 4.84 (s, 2H), 4.72 (s, 1H), 4.03 (s, 3H), 2.79-2.77 (m, 1H), 2.66 (s, 3H), 2.07-2.05 (m, 1H), 1.98-1.85 (m, 3H), 1.82-1.53 (m, 4H).

Example 15

[0259] ##STR00191## ##STR00192##

Step (1): preparation of 5-iodo-4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole

[0260] ##STR00193##

[0261] Compound 15-1 (2 g, 9.1 mmol) was dissolved in tetrahydrofuran (25 mL), and then the reaction system was cooled to −78° C., added with n-butyl lithium (2.4 N, 5.7 mL, 13.7 mmol) under nitrogen atmosphere and stirred at this temperature for 10 min. the reaction system was then added with iodine (3.5 g, 13.7 mmol) and stirred overnight at this temperature. Then the reaction system was quenched with water (50 mL), extracted with ethyl acetate (25 mL×3), and washed with saturated sodium chloride solution (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was dried by rotary evaporation, and the residue was purified by silica gel column chromatography (PE/EA=3/1) to give Compound 15-2 (1.3 g, 41.41% yield) in the form of a white solid. LC-MS [M+H].sup.+: 346.8.

Step (2): preparation of 5-(1-ethoxyvinyl)-4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole

[0262] ##STR00194##

[0263] Compound 15-2 (1.3 g, 3.76 mmol), tributyl(1-ethoxyvinyl)tin (1.5 g, 4.14 mmol), palladium acetate (42 mg, 0.19 mmol) and triphenylphosphine (197 mg, 0.75 mmol) were dissolved in 1,4-dioxane (25 mL), and then the reaction system was stirred overnight at 80° C., quenched with water (30 mL), and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give Compound 15-3 (1 g, 83.57% yield) in the form of a white solid. LC-MS [M+H].sup.+: 290.9.

Step (3): 2-bromo-1-(4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol

[0264] ##STR00195##

[0265] Compound 15-3 (1 g, 3.46 mmol) and N-bromosuccinimide (677 mg, 3.81 mmol) were dissolved in a mixed solvent of tetrahydrofuran (25 mL) and water (5 mL) under nitrogen atmosphere, and then the reaction system was stirred at room temperature for 1 h, diluted with water (20 mL) and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation The crude product was purified by silica gel column chromatography (PE/EA=5/1) to give Compound 15-4 (480 mg, 47.31% yield) in the form of a brown solid. LC-MS [M+H].sup.+: 339.6, 341.6.

Step (4): preparation of 4-(1-methyl-5-(2-methyloxazol-5-yl)-1H-1,2,3-triazol-4-yl)phenol

[0266] ##STR00196##

[0267] Compound 15-4 (230 mg, 0.68 mmol) and acetamide (828 mg, 14.02 mmol) were added to a microwave tube, and then the reaction system was heated in microwave at 160° C. for 30 min, cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (5 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/EA=2/1) to give Compound 15-5 (130 mg, 74.68% yield) in the form of a brown solid. LC-MS [M+H].sup.+: 257.9.

Step (5): (+/−)-methyl (1S,3S)-3-(4-(1-methyl-5-(2-methyloxazol-5-yl)-1H-1,2,3-triazol-4-yl) phenoxy)cyclohexane-1-carboxylate

[0268] ##STR00197##

[0269] Compound 15-5 (100 mg, 0.51 mmol), methyl (3S)-3-hydroxycyclohexane-1-carboxylate (320 mg, 2.03 mmol), DTAD (466 mg, 2.03 mmol) and triphenylphosphine (532 mg, 2.03 mmol) were dissolved in tetrahydrofuran (20 mL), and then the reaction system was stirred overnight at room temperature, quenched with water (20 mL), extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was dried by rotary evaporation, and the residue was purified by silica gel column chromatography (DCM/EA=5/1) to give Compound 15-7 (178 mg, 88.14% yield) in the form of a white solid. LC-MS [M+H].sup.+: 397.8.

Step (7): (+/−)-(1S,3S)-3-(4-(1-methyl-5-(2-methyloxazol-5-yl)-1H-1,2,3-triazol-4-yl)phenoxy) cyclohexane-1-carboxylic acid

[0270] ##STR00198##

[0271] Compound 15-7 (178 mg, 0.45 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), and then an aqueous lithium hydroxide solution was added, and the reaction system was stirred overnight at room temperature. Water (10 mL) was added to quench the reaction, and the organic solvent was removed by rotary evaporation. The reaction system was then adjusted to pH 2-3 with diluted HCl (1 N) and extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/EA=1/1) and lyophilized to give Compound 15 (10 mg, 36.95% yield) in the form of a white solid.

[0272] LC-MS [M+H].sup.+: 383.7.

[0273] .sup.1H NMR (400 MHz, MeOD) δ 8.04 (s, 1H), 7.53 (d, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.74-4.70 (m, 1H), 4.12 (s, 3H), 2.82-2.77 (m, J=9.5 Hz, 1H), 2.56 (s, 3H), 2.09-2.04 (m, J=13.1 Hz, 1H), 1.94-1.87 (m, J=10.4 Hz, 3H), 1.81-1.74 (m, J=12.0 Hz, 1H), 1.69-1.59 (m, 3H).

Example 16

[0274] ##STR00199## ##STR00200##

Step (1): preparation of 1-benzyl-1,3-dihydro-2H-imidazol-2-one

[0275] ##STR00201##

[0276] (isocyanatomethyl)benzene (2.0 g, 15 mmol) and 2,2-diethoxyethan-1-amine (2.0 g, 15 mmol) were dissolved in dichloromethane (20 mL). After reaction for 3 h, the reaction system was added dropwise with trifluoroacetic acid (2 mL) and then reacted at room temperature for another 3 h. The reaction system was then quenched with water (20 mL), and extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=5/1) to give Compound 16-3 (180 mg, 57.7% yield) in the form of a white solid. LC-MS [M+H].sup.+: 349.4.

Step (2): preparation of 1-iodo-4-(methoxymethoxy)benzene

[0277] ##STR00202##

[0278] p-iodophenol (30.0 g, 136.4 mmol) was dissolved in tetrahydrofuran (300 mL), and then the reaction system was cooled to 0° C., added with sodium hydride (9.8 g, 163.6 mmol) in portions, and maintained at this temperature. After reaction for 20 min, the reaction system was added dropwise with bromomethyl methyl ether (17.8 g, 143.2 mmol) and then reacted for 2 h. The reaction system was then quenched with ammonium chloride solution (200 mL), and extracted with ethyl acetate (250 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 16-5 (30.0 g) in the form of a yellow oil.

Step (3): preparation of 1-ethynyl-4-(methoxymethoxy)benzene

[0279] ##STR00203##

[0280] Compound 16-5 (30 g, 113.7 mmol), trimethylsilylacetylene (13.4 g, 136.3 mmol), Pd(PPh.sub.3)Cl.sub.2 (2.5 g, 3.5 mmol), copper(I) iodide (1.3 g, 6.8 mmol) and triethylamine (45.8 g, 544.7 mmol) were dissolved in DMF (30 mL), and then the reaction system was reacted at 50° C. for 4 h, quenched with water (30 mL), and extracted with ethyl acetate (45 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The resulting solid was dissolved in methanol (30 mL), and then potassium carbonate (24.4 g, 176.7 mmol) was added. The reaction system was reacted overnight at room temperature, quenched with water (30 mL), and extracted with ethyl acetate (45 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=5/1) to give Compound 16-6 (15 g, 81.1% yield over two steps) in the form of a white solid.

Step (4): preparation of 4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole

[0281] ##STR00204##

[0282] Compound 16-6 (15.0 g, 92.2 mmol), sodium azide (18 g, 276.8 mmol), iodomethane (39 g, 267.8 mmol), copper sulfate pentahydrate (4.7 g, 18.8 mmol), sodium vitamin C (7.3 g, 36.8 mmol) and potassium carbonate (46.5 g, 461.25 mmol) were dissolved in water and tert-butanol (1/1, 40 mL), and then the reaction system was reacted at room temperature for 24 h, quenched with water (40 mL), and extracted with ethyl acetate (45 mL×3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=5/1) to give Compound 16-7 (25.0 g, 83.3% yield) in the form of a white solid. LC-MS [M+H].sup.+: 220.6.

Step (5): 4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde

[0283] ##STR00205##

[0284] Compound 16-7 (25.0 g, 114 mmol) was dissolved in tetrahydrofuran (40 mL), and then the reaction system was cooled to −78° C. and slowly added with n-butyl lithium (71.3 mL, 171 mmol) dropwise. After reaction at this temperature for 1 h, the reaction system was added with DMF (12.5 g, 171 mmol) and reacted for 2 h. The reaction system was then quenched with water (40 mL), and extracted with ethyl acetate (45 mL×3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=3/1) to give Compound 16-8 (20.0 g, 71.4% yield) in the form of a white solid. LC-MS [M+H].sup.+: 248.2.

Step (6): preparation of (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0285] ##STR00206##

[0286] Compound 16-8 (2.0 g, 8.1 mmol) and sodium borohydride (367 mg, 9.7 mmol) were dissolved in tetrahydrofuran (20 mL), and then the reaction system was reacted overnight at room temperature, quenched with water (20 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 16-9 (2.0 g) in the form of a yellow oil.

[0287] LC-MS [M+H].sup.+: 250.4.

Step (7): preparation of (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl methanesulfonate

[0288] ##STR00207##

[0289] Compound 16-9 (2.0 g, 8.0 mmol) and triethylamine (2.4 g, 24 mmol) were dissolved in tetrahydrofuran (20 mL), and then the reaction system was cooled to 0° C. and added with methylsulfonyl chloride (2.7 g, 24 mmol) dropwise. The reaction system was then warmed to room temperature, reacted over overnight at room temperature, quenched with water, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 16-10 (2.0 g) in the form of a yellow oil. LC-MS [M+H].sup.+: 328.4.

Step (8): 1-benzyl-3-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1,3-dihydro-2H-imidazol-2-one

[0290] ##STR00208##

[0291] Compound 16-10 (500 mg, 1.53 mmol) was dissolved in tetrahydrofuran (5 mL), and then the reaction system was cooled to 0° C., slowly added with sodium hydride (180 mg, 4.6 mmol), and maintained at this temperature. After reaction for 20 min, the reaction system was added with 1-benzyl-1,3-dihydro-2H-imidazol-2-one (320 mg, 1.84 mmol) and warmed to room temperature. The reaction system was then reacted overnight at room temperature, quenched with water, and extracted with ethyl acetate (15 mL×3). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 16-11 (500 mg) in the form of a yellow oil. LC-MS [M+H].sup.+: 406.4.

Step (9): preparation of 1-benzyl-3-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1,3-dihydro-2H-imidazol-2-one

[0292] ##STR00209##

[0293] Compound 16-11 (500 mg, 1.2 mmol) was dissolved in a solution of HCl in methanol (5 mL), and then the reaction system was stirred at room temperature for 2 h and concentrated. The residue was separated by column chromatography (PE/MA=4/1) to give Compound 16-12 (150 mg, 34.6% yield) in the form of a white solid.

Step (10): preparation of (+/−)-methyl (1S,3S)-3-(4-(5-((3-benzyl-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0294] ##STR00210##

[0295] Compound 16-12 (150 mg, 0.42 mmol), methyl (1S,3S)-3-(tosyloxo)cyclohexane-1-carboxylate (262 mg, 0.84 mmol) and cesium carbonate (273 mg, 0.84 mmol) were dissolved in anhydrous DMF (5 mL), and then the reaction system was warmed to 100° C., reacted for 3 h under nitrogen atmosphere, quenched with water, and extracted with ethyl acetate (15 mL×3). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=1/1) to give Compound 16-13 (55 mg, 26.2% yield) in the form of a yellow oil. LC-MS [M+H].sup.+: 502.2.

Step (11): preparation of (+/−)-(1S,3S)-3-(4-(5-((3-benzyl-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0296] ##STR00211##

[0297] Compound 16-13 (55 mg, 0.1 mmol) and lithium hydroxide (21 mg, 0.5 mmol) were dissolved in a mixed solvent of THF (3 mL), MeOH (1 mL) and H.sub.2O (1 mL), and then the reaction system was stirred overnight at room temperature, quenched with water (10 mL), and extracted with ethyl acetate (5 mL×3). The organic phase was dried over Na.sub.2SO.sub.4 and filtered, and the filtrate was dried by rotary evaporation and concentrated. The residue was separated by column chromatography (DCM/MeOH=40/1) and lyophilized to give Compound 16 (10 mg, 27.8% yield) in the form of a white solid.

[0298] .sup.1H NMR (400 MHz, MeOD) δ 7.55-7.51 (m, 2H), 7.37-7.28 (m, 3H), 7.24-7.20 (m, 2H), 7.07-7.03 (m, 2H), 6.38 (d, J=3.0 Hz, 1H), 6.16 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.78 (s, 2H), 4.74 (s, 1H), 4.17 (s, 3H), 2.84-2.78 (m, 1H), 2.08-2.12 (m, 1H), 1.91-1.97 (m, 3H), 1.77-1.60 (m, 4H).

Example 17

[0299] ##STR00212##

Step (1): preparation of 1-benzyl-3-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl) methyl)imidazolidin-2-one

[0300] ##STR00213##

[0301] Compound 16-10 (200 mg, 0.61 mmol) was dissolved in tetrahydrofuran (5 mL), and then the reaction system was cooled to 0° C., slowly added with sodium hydride (73 mg, 1.83 mmol), and maintained at this temperature. After reaction for 20 min, the reaction system was added with 1-benzylimidazolidin-2-one (128 mg, 0.73 mmol) and warmed to room temperature. The reaction system was then reacted overnight at room temperature, quenched with water, and extracted with ethyl acetate (15 mL×3). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 17-2 (200 mg) in the form of a yellow oil. LC-MS [M+H].sup.+: =408.2.

Step (2): preparation of 1-benzyl-3-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl) imidazolidin-2-one

[0302] ##STR00214##

[0303] Compound 17-2 (200 mg, 0.49 mmol) was dissolved in a solution of HCl in methanol (5 mL), and then the reaction system was stirred at room temperature for 2 h and concentrated. The residue was separated by column chromatography (PE/MA=4/1) to give Compound 17-3 (100 mg) in the form of a white solid. LC-MS [M+H].sup.+: 364.2.

Step (3): preparation of (+/−)-methyl (1S,3S)-3-(4-(5-((3-benzyl-2-carbonylimidazolidin-1-yl) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0304] ##STR00215##

[0305] Compound 17-3 (100 mg, 0.28 mmol), methyl (1S,3R)-3-(tosyloxo)cyclohexane-1-carboxylate (175 mg, 0.56 mmol) and cesium carbonate (273 mg, 0.84 mmol) were dissolved in anhydrous DMF (5 mL), and then the reaction system was warmed to 90° C., reacted for 3 h under nitrogen atmosphere, quenched with water, and extracted with ethyl acetate (15 mL×3). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=1/1) to give Compound 17-5 (100 mg, 70.9% yield) in the form of a yellow oil. LC-MS [M+H].sup.+: 504.2.

Step (4): preparation of (+/−)-(1S,3S)-3-(4-(5-((3-benzyl-2-carbonylimidazolidin-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0306] ##STR00216##

[0307] Compound 17-5 (100 mg, 0.19 mmol) and lithium hydroxide (40 mg, 0.95 mmol) were dissolved in a mixed solvent of THF (3 mL), MeOH (1 mL) and H.sub.2O (1 mL), and then the reaction system was stirred overnight at room temperature, quenched with water (10 mL), and extracted with ethyl acetate (5 mL×3). The organic phase was dried over Na.sub.2SO.sub.4 and filtered, and the filtrate was dried by rotary evaporation and concentrated. The residue was separated by column chromatography (DCM/MeOH=40/1) and lyophilized to give Compound 17 (20 mg, 27.8% yield) in the form of a white solid.

[0308] .sup.1H NMR (400 MHz, MeOD) δ 7.60-7.54 (m, 2H), 7.34-7.37 (m, 2H), 7.31-7.22 (m, 3H), 7.10-7.03 (m, 2H), 4.73 (s, 3H), 4.37 (s, 2H), 4.14 (s, 3H), 3.18-3.04 (m, 4H), 2.83-2.76 (m, J=9.8 Hz, 1H), 2.13-2.05 (m, 1H), 1.98-1.87 (m, 3H), 1.80-1.58 (m, 4H).

Example 18

[0309] ##STR00217## ##STR00218##

Step (1): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-benzenesulfonamide

[0310] ##STR00219##

[0311] Compound 1-1 (324 mg, 0.814 mmol) and N,N-diisopropylethylamine (210 mg, 1.63 mmol) were dissolved in dichloromethane (10 mL), and then benzenesulfonyl chloride (172 mg, 0.98 mmol) was added, and the reaction system was stirred overnight at room temperature. The reaction system was then quenched with water (15 mL) and extracted with dichloromethane (15 mL×2). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/CH.sub.3OH=25/1) to give Compound 18-2 (370 mg, 85% yield) in the form of a colorless oil. LC-MS [M+H].sup.+: 539.2.

Step (2): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-benzenesulfonamide

[0312] ##STR00220##

[0313] Compound 18-2 (370 mg, 0.69 mmol) was dissolved in tetrahydrofuran (5 mL), and then HCl (5 mL, 1 N) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with H.sub.2O (20 mL) and extracted with ethyl acetate (15 mL×2). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/CH.sub.3OH=100/1) to give Compound 18-3 (277 mg, 81% yield) in the form of a colorless oil.

[0314] LC-MS [M+H].sup.+: 495.1.

Step (3): preparation of (+/−)-methyl (1S,3S)-3-(4-(5-((N-(2,4-dimethoxybenzyl)benzenesulfonamido) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0315] ##STR00221##

[0316] Compound 18-3 (277 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then methyl (1S,3S)-3-(tosyloxo)cyclohexane-1-carboxylate (300 mg, 1.1 mmol) and cesium carbonate (454 mg, 1.4 mmol) were added, and the reaction system was warmed to 100° C. and stirred overnight. Then the reaction system was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/CH.sub.3OH=100/1) to give Compound 18-5 (210 mg, 59% yield) in the form of a colorless oil. LC-MS [M+H].sup.+: 635.4.

Step (4): preparation of (+/−)-methyl (1S,3S)-3-(4-(1-methyl-5-(benzenesulfonamidomethyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0317] ##STR00222##

[0318] Compound 18-5 (210 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (5 mL) was added dropwise, and the reaction system was stirred overnight at room temperature. After concentration under reduced pressure, the reaction system was then diluted with H.sub.2O (20 mL) and extracted with dichloromethane (15 mL×2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/CH.sub.3OH=100/1) to give Compound 18-6 (140 mg, 93% yield) in the form of a white solid. LC-MS [M+H].sup.+: 485.2.

Step (5): preparation of (+/−)-(1S,3S)-3-(4-(1-methyl-5-(benzenesulfonamidomethyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0319] ##STR00223##

[0320] Compound 18-6 (140 mg, 0.29 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), and then lithium hydroxide hydrate (42 mg, 0.87 mmol) was added, and the reaction system was stirred at room temperature for 5 h. Then the reaction system was concentrated, diluted with H.sub.2O (10 mL), adjusted to pH 2-3 with diluted HCl (1 N), and then extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative reverse phase chromatography and lyophilized to give Compound 18 (52 mg, 38% yield) in the form of a white solid.

[0321] LC-MS [M+H].sup.+: 471.4. .sup.1H NMR (400 MHz, MeOD) δ7.79 (d, J=7.7 Hz, 2H), 7.67 (t, J=7.5 Hz, 1H) 7.56 (t, J=7.7 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.75-4.70 (m, 1H), 4.28 (s, 2H), 4.08 (s, 3H), 2.82-2.78 (m, 1H) 2.06-1.97 (m, 1H), 1.95-1.92 (m, 3H), 1.80-1.63 (m, 4H).

Example 19

[0322] ##STR00224##

[0323] Refer to the synthesis procedures in Example 20 below, LC-MS [M+H].sup.+: 441.2.

Example 20

[0324] ##STR00225## ##STR00226##

Step (1): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-cyclopentanecarboxamide

[0325] ##STR00227##

[0326] Compound 1-1 (320 mg, 0.806 mmol) was dissolved in dichloromethane (20 mL), and then triethylamine (165 mg, 1.63 mmol) was added. The reaction system was cooled to 0° C., added with cyclopentanylcarbonyl chloride (127 mg, 0.96 mmol), and then slowly warmed to room temperature and reacted for 16 h. Then the reaction system was quenched with water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 20-2 (300 mg, 75% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 495.4.

Step (2): preparation of N-(2,4-dimethoxybenzyl)-N-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-cyclopentanecarboxamide

[0327] ##STR00228##

[0328] Compound 20-2 (300 mg, 0.605 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 20-3 (130 mg, 48% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 451.2.

Step (3): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-((N-(2,4-dimethoxybenzyl) cyclopentanecarboxamido<oxalylamino>)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0329] ##STR00229##

[0330] Compound 20-3 (130 mg, 0.29 mmol), (+/−)-isopropyl 3-hydroxycyclohexane-1-carboxylate (219 mg, 1.15 mmol), DTAD (265 mg, 1.15 mmol) and PPh.sub.3 (301 mg, 1.15 mmol) were dissolved in THF (10 mL), and the reaction system was stirred overnight at 60° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=50/1) to give Compound 20-5 (370 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 619.4.

Step (4): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-(cyclopentanecarboxamido<oxalylamino>methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane- 1-carboxylate

[0331] ##STR00230##

[0332] Compound 20-5 (370 mg, crude product) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (10 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was concentrated, and the residue was diluted with ethyl acetate (20 mL), washed successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 20-6 (220 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 469.2.

Step (5): preparation of (+/−)-(1S,3S)-3-(4-(5-(cyclopentanecarboxamido<oxalylamino>methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0333] ##STR00231##

[0334] Compound 20-6 (220 mg, crude product) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=30/1), separated by preparative chromatography, and then lyophilized to give Compound 20 (50 mg) in the form of a white solid.

[0335] LC-MS [M+H].sup.+: 427.2. .sup.1H NMR (400 MHz, MeOD) δ 7.68-7.54 (m, 2H), 7.15-7.02 (m, 2H), 4.85-4.64 (m, 1H), 4.63 (s, 2H), 4.12 (s, 3H), 2.81-2.68 (m, 1H), 2.61-2.58 (m, 1H), 2.07-2.05 (m, 1H), 2.02-1.91 (m, 3H), 1.91-1.44 (m, 12H).

Example 21

[0336] ##STR00232##

Step (1): preparation of 5-((cyclopentyloxy)methyl)-4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole

[0337] ##STR00233##

[0338] Compound 21-1 (300 mg, 1.12 mmol) was dissolved in tetrahydrofuran (5 mL), and then the reaction system was cooled to 0° C., slowly added with sodium hydride (224 mg, 5.6 mmol), and maintained at this temperature. After reaction for 20 min, the reaction system was added with cyclopentanol (280 mg, 3.36 mmol) and warmed to room temperature. The reaction system was then reacted overnight at room temperature, quenched with water, and extracted with ethyl acetate (15 mL×3). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 21-3 (1200 mg) in the form of a yellow oil. LC-MS [M+H].sup.+: 318.2.

Step (2): preparation of 4-(5-((cyclopentyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenol

[0339] ##STR00234##

[0340] Compound 21-3 (120 mg, 0.38 mmol) was dissolved in a solution of HCl in methanol (5 mL), and then the reaction system was stirred at room temperature for 2 h and concentrated. The residue was separated by column chromatography (PE/MA=4/1) to give Compound 21-4 (100 mg) in the form of a white solid. LC-MS [M+H].sup.+: 274.4.

Step (3): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-((cyclopentyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0341] ##STR00235##

[0342] Compound 21-4 (216 mg, 1.12 mmol), di-tert-butyl azodicarboxylate (267 mg, 1.12 mmol) and triphenylphosphine (304 mg, 1.12 mmol) were dissolved in tetrahydrofuran (5 mL), and then the reaction system was reacted at 60° C. for 12 h under nitrogen atmosphere, quenched with water, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (PE/EA=2/1) to give Compound 21-6 (100 mg) in the form of a yellow oil. LC-MS [M+H].sup.+: 442.4.

Step (4): preparation of (+/−)-(1S,3S)-3-(4-(5-((cyclopentyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl) phenoxy)cyclohexane-1-carboxylic acid

[0343] ##STR00236##

[0344] Compound 21-6 (200 mg, 0.46 mmol) and lithium hydroxide (96 mg, 0.23 mmol) were dissolved in a mixed solvent of THF (3 mL), MeOH (1 mL) and H.sub.2O (1 mL), and then the reaction system was stirred overnight at room temperature, quenched with water (10 mL), and extracted with ethyl acetate (5 mL×3). The organic phase was dried over Na.sub.2SO.sub.4 and filtered, and the filtrate was dried by rotary evaporation and concentrated. The residue was separated by column chromatography (DCM/MeOH=40/1) and lyophilized to give Compound 21 (40 mg, 21.7% yield) in the form of a white solid. LC-MS [M+H].sup.+: 400.4.

[0345] .sup.1H NMR (400 MHz, MeOD) δ 7.57 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 4.78-4.73 (m, 1H), 4.65 (s, 2H), 4.14 (s, 3H), 4.11-4.05 (m, 1H), 2.86-2.77 (m, 1H), 2.08-2.12 (d, J=13.4 Hz, 1H), 1.99-1.88 (m, 3H), 1.84-1.55 (m, 12H).

Example 22

[0346] ##STR00237##

Step (1): preparation of 5-(isopropoxymethyl)-4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole

[0347] ##STR00238##

[0348] Propan-2-ol (402 mg, 6.7 mmol) was dissolved in tetrahydrofuran solution (15 mL), and then the reaction system was put in an ice water bath and added with sodium hydride (540 mg, 13.5 mmol) under nitrogen atmosphere. After reaction for 30 min, the reaction system was added with Compound 21-1 (300 mg, 1.1 mmol) and stirred overnight at room temperature. Then the reaction system was quenched with saturated aqueous ammonium chloride solution (5 mL), diluted with water (25 mL), and extracted with ethyl acetate (25 mL×2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/EA=2/1) to give Compound 22-2 (98 mg, 31% yield) in the form of a pale yellow oil.

[0349] LC-MS [M+H].sup.+: 292.1.

Step (2: preparation of 4-(5-(isopropoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenol

[0350] ##STR00239##

[0351] Compound 22-2 (98 mg, 0.34 mmol) was dissolved in methanol (5 mL), and then a solution of hydrogen chloride in methanol (2 mL, 4 N) was added, and the reaction system was reacted at room temperature for 2 h. Then the reaction system was dried by rotary evaporation, diluted with H.sub.2O (10 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/EA=3/1) to give Compound 22-3 (62 mg, 74% yield) in the form of a pale yellow oil. LC-MS [M+H].sup.+: 248.1.

Step (3): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-(isopropoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0352] ##STR00240##

[0353] Compound 22-3 (10 mL) was added with triphenylphosphonium (262 mg, 1.0 mmol), di-tert-butyl azodicarboxylate (230 mg, 1.0 mmol) and isopropyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (186 mg, 1.0 mmol) under nitrogen atmosphere, and then the reaction system was warmed to 60° C. and stirred overnight. The reaction system was then quenched with water (25 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (DCM/EA=8/1) to give Compound 22-4 (37 mg, 36% yield) in the form of a pale yellow oil. LC-MS [M+H].sup.+: 416.2.

Step (4): preparation of (+/−)-(1S,3S)-3-(4-(5-(isopropoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl) phenoxy)cyclohexane-1-carboxylic acid

[0354] ##STR00241##

[0355] Compound 22-4 (37 mg, 0.089 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), and then lithium hydroxide hydrate (18.7 mg, 0.44 mmol) was added, and the reaction system was stirred at room temperature for 5 h. The reaction system was concentrated, diluted with water (10 mL), adjusted to pH 2-3 with diluted HCl (1 N), and then extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative reverse phase chromatography and lyophilized to give Compound 22 (5.9 mg, 14% yield) in the form of a white solid.

[0356] LC-MS [M+Na]: 396.2. .sup.1H NMR (400 MHz, MeOD) δ 7.57 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 4.78-4.74 (m, 1H), 4.69 (s, 2H), 4.14 (s, 3H), 3.79-3.74 (m, 1H), 2.79-2.75 (m, 1H), 1.96-1.64 (m, 8H), 1.23 (d, J=6.1 Hz, 6H).

Example 23

[0357] ##STR00242##

Step (1): preparation of 5-((benzyloxy)methyl)-4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazole

[0358] ##STR00243##

[0359] Compound 16-9 (200 mg, 0.8 mmol) was dissolved in DMF (20 mL), and then the reaction system was cooled to 0° C., added with sodium hydride (39 mg, 0.96 mmol), and reacted at room temperature for half an hour. The reaction system was then added with benzyl bromide (274 mg, 1.6 mmol), slowly warmed to room temperature and reacted for 16 h. Then the reaction system was quenched with water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 23-1 (240 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 340.2.

Step (2): preparation of 4-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenol

[0360] ##STR00244##

[0361] Compound 23-1 (220 mg, crude product) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 23-2 (140 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 296.2.

Step (3): preparation of (+/−)-methyl (1S,3S)-3-(4-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0362] ##STR00245##

[0363] Compound 23-2 (140 mg, 0.47 mmol), methyl (1S,3R)-3-(tosyloxo)cyclohexane-1-carboxylate (296 mg, 0.95 mmol) and cesium carbonate (337 mg, 1.03 mmol) were dissolved in DMF (10 mL), and then the reaction system was heated to 100° C. and reacted for 7 h under nitrogen atmosphere. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (10 mL×2) and saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 23-3 (160 mg, 78% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 436.2.

Step (4): preparation of (+/−)-(1S,3S)-3-(4-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl) phenoxy)cyclohexane-1-carboxylic acid

[0364] ##STR00246##

[0365] Compound 23-3 (160 mg, 0.367 mmol) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (77 mg, 1.8 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 23 (33 mg, 21% yield) in the form of a white solid.

[0366] LC-MS [M+H].sup.+: 422.4.

[0367] .sup.1H NMR (400 MHz, MeOD) δ 7.66-7.45 (m, 2H), 7.45-7.30 (m, 5H), 7.10-6.99 (m, 2H), 4.89 (s, 1H), 4.71 (s, 2H), 4.60 (s, 2H), 4.11 (s, 3H), 2.83-2.81 (m, 1H), 2.09-2.08 (m, 1H), 1.86-1.81 (m, 3H), 1.72-1.49 (m, 4H).

Example 24

[0368] ##STR00247## ##STR00248##

Step (1): preparation of tert-butyl (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl) carbamate

[0369] ##STR00249##

[0370] Compound 24-1 (700 mg, 2.66 mmol) was dissolved in toluene (15 mL), and then tert-butyl alcohol (5 mL), diphenylphosphoryl azide (878 mg, 3.19 mmol) and triethylamine (537 mg, 5.32 mmol) were added, and then the reaction system was heated to reflux and reacted for 16 h under nitrogen atmosphere. The reaction system was concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 24-2 (0.29 g, 32.5% yield) in the form of a white solid. LC-MS [M+H].sup.+: 335.4.

Step (2): preparation of tert-butyl benzyl (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0371] ##STR00250##

[0372] Compound 24-2 (0.29 g, 0.87 mmol) was dissolved in tetrahydrofuran (15 mL), and the reaction system was cooled to 0° C. and added with sodium hydride (35 mg, 0.86 mmol). The reaction system was then warmed to room temperature, reacted for 0.5 h, added with benzyl bromide (222 mg, 1.3 mmol) and reacted overnight at room temperature. Then the reaction system was quenched with saturated ammonium chloride (10 mL), and extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 24-3 (320 mg, 86% yield) in the form of a white solid. LC-MS [M+H].sup.+: 425.2.

Step (3): preparation of 4-(5-(benzylamino)-1-methyl-1H-1,2,3-triazol-4-yl)phenol

[0373] ##STR00251##

[0374] Compound 24-3 (320 mg, 0.75 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 24-4 (120 mg, 57% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 281.2.

Step (4): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-(benzylamino)-1-methyl-1H-1,2,3-triazol-4-yl) phenoxy)cyclohexane-1-carboxylate

[0375] ##STR00252##

[0376] Compound 24-4 (90 mg, 0.32 mmol), (+/−)-isopropyl 3-hydroxycyclohexane-1-carboxylate (238 mg, 1.28 mmol), DTAD (295 mg, 1.28 mmol) and PPh.sub.3 (335 mg, 1.28 mmol) were dissolved in THF (10 mL), and the reaction system was stirred overnight at 60° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=50/1) to give Compound 24-5 (290 mg, crude product) in the form of a yellow solid. LC-MS [M+H].sup.+: 449.2.

Step (5): preparation of (+/−)-(1S,3S)-3-(4-(5-(benzylamino)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy) cyclohexane-1-carboxylate

[0377] ##STR00253##

[0378] Compound 24-5 (290 mg, crude product) was dissolved in THF (18 mL), and MeOH (6 mL), H.sub.2O (6 mL) and lithium hydroxide (52 mg, 1.25 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 24 (38 mg, 29% yield over two steps) in the form of a white solid. LC-MS [M+H].sup.+: 407.4.

[0379] .sup.1H NMR (400 MHz, MeOD) δ 7.53-7.51 (m, 2H), 7.21-7.19 (m, 3H), 7.10-7.07 (m, 2H), 7.04-7.01 (m, 2H), 4.73-4.72 (m, 1H), 4.12 (s, 2H), 3.73 (s, 3H), 2.80-2.76 (m, 1H), 2.13-2.08 (m, 1H), 1.96-1.90 (m, 3H), 1.85-1.77 (m, 1H), 1.73-1.64 (m, 3H).

Example 25

[0380] ##STR00254##

[0381] The synthetic route is similar to that in Example 1, LC-MS [M+H].sup.+: 474.2.

Example 26

[0382] ##STR00255##

Step (1): preparation of (+/−)-isopropyl (1S,3S)-3-((6-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate

[0383] ##STR00256##

[0384] Compound 26-1 (3.3 g, 10.5 mmol), (+/−)-isopropyl 3-hydroxycyclohexane-1-carboxylate (3.64 g, 20 mmol), DTAD (4.6 g, 20 mmol) and PPh.sub.3 (5.25 g, 2 mmol) were dissolved in THF (50 mL), and the reaction system was stirred overnight at 60° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (PE/EA=5/1) to give Compound 26-2 (4.8 g, 95.3% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 485.3.

Step (2): preparation of (+/−)-isopropyl (1S,3S)-3-((6-(5-(((tert-butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate

[0385] ##STR00257##

[0386] Compound 26-2 (4.8 g, 10 mmol) was dissolved in DMF (20 mL), and then (azidomethyl)trimethylsilane (4.26 g, 33 mmol) was added, and the reaction system was heated to 90° C. and stirred for 96 h under nitrogen atmosphere. Then the reaction system was quenched with water (100 mL), extracted with ethyl acetate (10 mL×2) and washed with saturated brine (10 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove solids, and the filtrate was dried by rotary evaporation. The residue was dissolved in tetrahydrofuran (20 mL), and then the reaction system was added with tetrabutylammonium fluoride (33 mL) and reacted at room temperature for 2 h. Then the reaction system was quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (50 mL×2) and washed with saturated brine (30 mL×2). The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (PE/EA=4/1) to give Compound 26-3 (840 mg, 12% yield over two steps) in the form of a yellow solid. LC-MS [M+H].sup.+: 542.5.

Step (3): preparation of (+/−)-isopropyl (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate

[0387] ##STR00258##

[0388] Compound 26-3 (840 mg, 1.55 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with water (20 mL), adjusted to pH 8-9 with saturated sodium carbonate and extracted with dichloromethane (30 mL×2). The organic phase was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=20/1) to give Compound 26-4 (580 mg, 84.5% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 442.3.

Step (4): preparation of (+/−)-isopropyl (1S,3S)-3-((6-(5-((3-cyclopentyl-3-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate

[0389] ##STR00259##

[0390] Triphosgene (410 mg, 1.38 mmol) was dissolved in tetrahydrofuran (5 mL), and then the reaction system was cooled to 0° C. and slowly added with a solution of triethylamine (958 mg, 9.48 mmol) and N-methylcyclopentylamine (536 mg, 3.95 mmol) in tetrahydrofuran (10 mL) dropwise. After reaction at 0° C. for 1 h, the reaction system was added with Compound 26-4 (350 mg, 0.79 mmol), slowly warmed to room temperature and reacted for 16 h. Then the reaction system was quenched with water (10 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 26-5 (600 mg, crude product) in the form of a yellow solid.

[0391] LC-MS [M+H].sup.+: 567.4.

Step (5): preparation of (+/−)-(1S,3S)-3-((6-(5-((3-cyclopentyl-3-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylic acid

[0392] ##STR00260##

[0393] Compound 26-5 (600 mg, crude product) was dissolved in THF (18 mL), and MeOH (6 mL), H.sub.2O (6 mL) and lithium hydroxide (218 mg, 5.3 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1), subjected to chiral resolution, and then lyophilized to give Compound 26 (34 mg) in the form of a white solid. LC-MS [M+H].sup.+: 525.4.

[0394] .sup.1H NMR (400 MHz, MeOD) δ 8.35 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 5.02-4.97 (m, 1H), 4.69 (s, 2H), 4.45-4.34 (m, 1H), 4.24 (s, 2H), 2.79-2.68 (m, 1H), 2.68 (s, 3H), 2.17-2.13 (m, 1H), 1.97-1.92 (m, 3H), 1.75-1.45 (m, 12H).

Example 27

[0395] ##STR00261## ##STR00262##

Step (1): preparation of N-cyclopentyl-N-methylpent-acetamide

[0396] ##STR00263##

[0397] N-methylcyclopentylamine (1.0 g, 7.4 mmol) was dissolved in dichloromethane (20 mL), and then the reaction system was cooled to 0° C., added with acetyl chloride (0.7 g, 8.9 mmol), and stirred overnight at room temperature. Then the reaction system was diluted with dichloromethane (50 mL), washed with saturated sodium carbonate (30 mL×2) and washed with saturated brine (30 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give Compound 27-2 (0.74 g, crude product) in the form of a yellow oil. LC-MS [M+H].sup.+: 142.6.

Step (2): preparation of N-cyclopentyl-N-methylpent-4-ynamide

[0398] ##STR00264##

[0399] Compound 27-2 (0.74 g, 5.2 mmol) was dissolved in tetrahydrofuran (20 mL), and then the reaction system was cooled to −78° C. and added with lithium diisopropylamide (3.9 mL, 7.8 mmol). After reaction at −78° C. for 1 h, the reaction system was added with propargyl bromide (1.24 g, 10.4 mmol) and reacted for 1 h. Then the reaction system was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (50 mL×2) and washed with saturated sodium carbonate (30 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give Compound 27-3 (0.54 g, crude product) in the form of a yellow oil. LC-MS [M+H].sup.+: 180.3.

Step (3): preparation of (+/−)-isopropyl (1S,3S)-3-((6-bromo-2-(trifluoromethyl)pyridin-3-yl)oxo) cyclohexane-1-carboxylate

[0400] ##STR00265##

[0401] Compound 27-4 (1.5 g, 6.2 mmol), Compound 1-5 (2.31 g, 12.4 mmol), DTAD (2.86 g, 12.4 mmol) and PPh.sub.3 (3.25 g, 12.4 mmol) were dissolved in THF (50 mL), and the reaction system was stirred overnight at 60° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=50/1) to give Compound 27-5 (1.7 g, 68% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 410.4.

Step (4): preparation of (+/−)-isopropyl (1S,3S)-3-((6-(5-(cyclopentyl(methyl)amino)-5-carbonylpent-1-yn-1-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate

[0402] ##STR00266##

[0403] Compound 27-5 (641 mg, 1.56 mmol) was dissolved in DMF (15 mL), and then N-cyclopentyl-N-methylpent-4-ynamide (280 mg, 1.56 mmol), copper(I) iodide (18 mg, 0.09 mmol), bis(triphenylphosphine)palladium(II) chloride (33 mg, 0.047 mmol) and triethylamine (643 mg, 4.68 mmol) were added successively, and the reaction system was stirred overnight at 80° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (PE/EA=4/1) to give Compound 27-6 (0.63 g, 75.6% yield) in the form of a yellow solid.

[0404] LC-MS [M+H].sup.+: 509.2.

Step (5): preparation of (+/−)-isopropyl (1S,3S)-3-((6-(5-(3-(cyclopentyl(methyl)amino)-3-carbonylpropyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate and (+/−)-isopropyl (1S,3S)-3-((6-(4-(3-(cyclopentyl(methyl)amino)-3-carbonylpropyl)-1-methyl-1H-1,2,3-triazol-5-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate

[0405] ##STR00267##

[0406] Compound 27-6 (0.74 g, 1.46 mmol) was dissolved in DMF (10 mL), and then (azidomethyl)trimethylsilane (567 mg, 4.38 mmol) was added, and the reaction system was heated to 90° C. and stirred for 48 h under nitrogen atmosphere. Then the reaction system was quenched with water (50 mL), extracted with ethyl acetate (40 mL×2) and washed with saturated brine (30 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove solids, and the filtrate was dried by rotary evaporation. The residue was dissolved in tetrahydrofuran (20 mL), and then the reaction system was added with tetrabutylammonium fluoride (1 mL) and reacted at room temperature for 2 h. Then the reaction system was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (20 mL×2) and washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (PE/EA=4/1) to give a crude compound (a mixture of two isomers, 220 mg, 13% yield over two steps) in the form of a yellow solid. LC-MS [M+H].sup.+: 566.4.

Step (6): preparation of (+/−)-(1S,3S)-3-((6-(5-(3-(cyclopentyl(methyl)amino)-3-carbonylpropyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylic acid and (+/−)-(1S,3S)-3-((6-(4-(3-(cyclopentyl(methyl)amino)-3-carbonylpropyl)-1-methyl-1H-1,2,3-triazol-5-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylic acid

[0407] ##STR00268##

[0408] The product of the last step (220 mg, mixture) was dissolved in THF (18 mL), and then MeOH (6 mL), H.sub.2O (6 mL) and lithium hydroxide (63 mg, 1.5 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=15/1), separated by preparative chromatography, and then lyophilized to give a white solid.

[0409] Compound 27-A: white solid, 29 mg, LC-MS [M+H].sup.+: 524.6.

[0410] .sup.1H NMR (400 MHz, MeOD) δ 8.26-8.23 (m, 1H), 7.93-7.77 (m, 1H), 4.97-4.95 (m, 1H), 4.84-4.52 (m, 1H), 4.13-4.12 (d, 3H), 3.31-3.30 (m, 2H), 3.08 (t, J=7.1 Hz, 1H), 2.93 (t, J=7.3 Hz, 1H), 2.76-2.73 (m, 4H), 2.16-2.12 (m, 1H), 1.93-1.71 (m, 3H), 1.82-1.34 (m, 12H).

[0411] Compound 27-B: white solid, 34 mg, LC-MS [M+H].sup.+: 524.6.

[0412] .sup.1H NMR (400 MHz, MeOD) δ 8.01-7.96 (m, 1H), 7.92-7.87 (m, 1H), 5.02-4.98 (m, 0.6H), 4.84-4.57 (m, 1H), 4.33-4.19 (m, 0.4H), 4.16 (d, 3H), 3.11-3.06 (m, 2H), 2.98-2.68 (m, 6H), 2.20-2.13 (m, 1H), 1.98-1.92 (m, 3H), 1.84-1.38 (m, 12H).

Example 28

[0413] ##STR00269##

Step (1): preparation of (+/−)-isopropyl (1S,3S)-3-((6-(5-((((cyclopentyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate

[0414] ##STR00270##

[0415] Triphosgene (120 mg, 0.42 mmol) was dissolved in tetrahydrofuran (5 mL), and then the reaction system was cooled to 0° C. and slowly added with a solution of triethylamine (158 mg, 1.56 mmol) and cyclopentylmethylamine (103 mg, 1.2 mmol) in tetrahydrofuran (5 mL) dropwise. After reaction at 0° C. for 1 h, the reaction system was added with Compound 28-1 (50 mg, 0.12 mmol), slowly warmed to room temperature and reacted for 16 h. Then the reaction system was quenched with water (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 28-2 (60 mg, 85% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 554.2.

Step (2): preparation of (+/−)-(1S,3S)-3-((6-(5-((((cyclopentyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxo)cyclohexane-1-carboxylic acid

[0416] ##STR00271##

[0417] Compound 28-2 (60 mg, 0.11 mmol) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (23 mg, 0.55 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1), separated by preparative chromatography, and then lyophilized to give Compound 28 (25 mg, 45.4% yield) in the form of a white solid.

[0418] LC-MS [M+H].sup.+: 512.6. .sup.1H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.9 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 5.03-5.01 (m, 2H), 4.76 (s, 2H), 4.21 (s, 3H), 2.80-2.74 (m, 1H), 2.17-2.15 (m, 1H), 2.03-1.88 (m, 3H), 1.72-1.44 (m, 12H).

Example 29

[0419] ##STR00272##

[0420] The preparation process is similar to that in Example 9, LC-MS [M+H].sup.+: 524.5.

Example 30

[0421] ##STR00273##

Step (1): preparation of 3-(2,4-dimethoxybenzyl)-3-((4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1-cyclopentyl-1-methylurea

[0422] ##STR00274##

[0423] Triphosgene (232 mg, 0.78 mmol) was dissolved in dichloromethane (10 mL), and then the reaction system was cooled to 0° C. and slowly added with a solution of triethylamine (394 mg, 3.91 mmol) and cyclopentylmethylamine (318 mg, 2.34 mmol) in dichloromethane (10 mL) dropwise. After reaction at 0° C. for 1 h, the reaction system was added with Compound 1-1 (300 mg, 0.78 mmol), slowly warmed to room temperature and reacted for 16 h. Then the reaction system was quenched with water (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=30/1) to give Compound 30-1 (400 mg, crude product).

[0424] LC-MS [M+H].sup.+: 524.2.

Step (2): preparation of 3-((4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1-cyclopentyl-1-methylurea

[0425] ##STR00275##

[0426] Compound 30-1 (400 mg, crude product) was dissolved in tetrahydrofuran (10 mL), and then HCl (5 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=15/1) to give Compound 30-2 (60 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 330.4.

Step (3): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-((3-cyclopentyl-3-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0427] ##STR00276##

[0428] Compound 30-2 (60 mg, 0.18 mmol), (+/−)-isopropyl 3-hydroxycyclohexane-1-carboxylate (135 mg, 0.73 mmol), DTAD (168 mg, 0.73 mmol) and PPh.sub.3 (192 mg, 0.73 mmol) were dissolved in THF (10 mL), and the reaction system was stirred overnight at 60° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=50/1) to give Compound 30-3 (85 mg, crude product) in the form of a yellow solid. LC-MS [M+H].sup.+: 498.2.

Step (4): preparation of (+/−)-(1S,3S)-3-(4-(5-((3-cyclopentyl-3-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0429] ##STR00277##

[0430] Compound 30-3 (85 mg, crude product) was dissolved in THF (9 mL), and MeOH (3 mL), H.sub.2O (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 30 (35 mg) in the form of a white solid.

[0431] LC-MS [M+H].sup.+: 456.2. .sup.1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.76 (t, J=4.8 Hz, 1H), 4.72-4.67 (m, 1H), 4.45-4.41 (m, 3H), 4.03 (s, 3H), 2.71-2.63 (m, 1H), 2.62 (s, 3H), 1.96-1.94 (m, 1H), 1.87-1.77 (m, 3H), 1.65-1.59 (m, 6H), 1.55-1.37 (m, 6H).

Example 31

[0432] ##STR00278## ##STR00279##

Step (1): preparation of methyl 4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-carboxylate

[0433] ##STR00280##

[0434] Compound 2-4 (1.07 g, 4.88 mmol) was dissolved in tetrahydrofuran (20 mL), and then the reaction system was cooled to −78° C. and slowly added with n-butyl lithium (2.6 mL, 6.35 mmol) dropwise. After reaction at −78° C. for 1 h, the reaction system was added with ethyl chloroformate (600 mg, 6.34 mmol) and reacted at −78° C. for 1 h. Then the reaction system was quenched with saturated ammonium chloride (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/EA=5/1) to give Compound 31-1 (930 mg, 71.5% yield) in the form of a white solid. LC-MS [M+H].sup.+: 278.3.

Step (2): preparation of 4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-carboxylic acid

[0435] ##STR00281##

[0436] Compound 31-1 (930 mg, 3.35 mmol) was dissolved in tetrahydrofuran (20 mL), and MeOH (6 mL), H.sub.2O (6 mL) and lithium hydroxide (705 mg, 16.8 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (20 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=30/1) to give Compound 31-2 (860 mg, 96% yield) in the form of a white solid. LC-MS [M+H].sup.+: 264.2.

Step (3): preparation of cyclopentyl (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl) carbamate

[0437] ##STR00282##

[0438] Compound 31-2 (160 mg, 0.61 mmol) was dissolved in toluene (10 mL), and then cyclopentanol (105 mg, 1.21 mmol), diphenylphosphoryl azide (201 mg, 0.73 mmol) and triethylamine (123 mg, 1.21 mmol) were added, and the reaction system was heated to reflux and reacted for 16 h under nitrogen atmosphere. The reaction system was concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 31-3 (0.2 g, 94% yield) in the form of a white solid. LC-MS [M+H].sup.+: 347.2.

Step (4): preparation of cyclopentyl (4-(4-(methoxymethoxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl) (methyl)carbamate

[0439] ##STR00283##

[0440] Compound 31-3 (0.2 g, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL), and the reaction system was cooled to 0° C. and added with sodium hydride (35 mg, 0.86 mmol). The reaction system was then warmed to room temperature, reacted for 0.5 h, added with iodomethane (164 mg, 1.15 mmol) and reacted overnight at room temperature. Then the reaction system was quenched with saturated ammonium chloride (10 mL), and extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=50/1) to give Compound 31-4 (190 mg, 90% yield) in the form of a white solid. LC-MS [M+H].sup.+: 361.4.

Step (5): preparation of cyclopentyl (4-(4-hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)(methyl) carbamate

[0441] ##STR00284##

[0442] Compound 31-4 (190 mg, 0.53 mmol) was dissolved in tetrahydrofuran (10 mL), and then HCl (2 N, 5 mL) was added, and the reaction system was stirred overnight at room temperature. Then the reaction system was diluted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was separated by column chromatography (DCM/MeOH=15/1) to give Compound 31-5 (120 mg, 71% yield) in the form of a yellow solid. LC-MS [M+H].sup.+: 317.4.

Step (6): preparation of (+/−)-isopropyl (1S,3S)-3-(4-(5-(((cyclopentyloxy)carbonyl)(methyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylate

[0443] ##STR00285##

[0444] Compound 31-5 (120 mg, 0.38 mmol), (+/−)-isopropyl 3-hydroxycyclohexane-1-carboxylate (283 mg, 1.52 mmol), DTAD (350 mg, 1.52 mmol) and PPh.sub.3 (398 mg, 1.52 mmol) were dissolved in THF (10 mL), and the reaction system was stirred overnight at 60° C. under nitrogen atmosphere. Then the reaction system was purified by silica gel column chromatography (DCM/EA=50/1) to give Compound 31-6 (260 mg) in the form of a yellow solid. LC-MS [M+H].sup.+: 485.2.

Step (7): preparation of (+/−)-(1S,3S)-3-(4-(5-(((cyclopentyloxy)carbonyl)(methyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0445] ##STR00286##

[0446] Compound 31-6 (260 mg, crude product) was dissolved in THF (18 mL), and MeOH (6 mL), H.sub.2O (6 mL) and lithium hydroxide (52 mg, 1.25 mmol) were added successively, and the reaction system was stirred overnight at room temperature. Then water (10 mL) was added for dilution, and the organic solvent was removed by rotary evaporation under reduced pressure. The aqueous phase was adjusted to pH 5-6 with HCl (1 N), and extracted with dichloromethane (10 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) and then lyophilized to give Compound 31 (40 mg, 38% yield over two steps) in the form of a white solid.

[0447] LC-MS [M+H].sup.+: 443.6. .sup.1H NMR (400 MHz, MeOD) δ 7.54 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 5.22-5.09 (m, 1H), 4.75-4.73 (m, 1H), 3.93 (s, 3H), 3.16-3.13 (m, 3H), 2.79-2.76 (m, 1H), 1.91-1.79 (m, 1H), 1.76-1.71 (m, 4H), 1.64-1.19 (m, 11H).

Example 32

[0448] ##STR00287##

[0449] Refer to the method in Example 1, LC-MS [M+H].sup.+:=443.21.

Example 33

[0450] ##STR00288##

[0451] Refer to the method in Example 18, LC-MS [M+H].sup.+: 463.17.

Example 34

[0452] ##STR00289##

[0453] Refer to the method in Example 31, LC-MS [M+H].sup.+: 443.20.

Example 35

[0454] ##STR00290##

[0455] Refer to the method in Example 31, LC-MS [M+H].sup.+: 483.21.

Example 36

[0456] ##STR00291##

[0457] Refer to the method in Example 31, LC-MS [M+H].sup.+: 399.20.

Example 37

[0458] ##STR00292##

[0459] Refer to the method in Example 31, LC-MS [M+H].sup.+: 435.19.

Example 38

[0460] ##STR00293##

[0461] Refer to the method in Example 31, LC-MS [M+H].sup.+: 466.17.

Example 39

[0462] ##STR00294##

[0463] Refer to the method in Example 1, LC-MS [M+H].sup.+: 398.12.

Biological Experiments

Example A: In Vitro Evaluation of Biological Activity

[0464] The antagonist property of the compounds disclosed herein was determined using the FLIPR (fluorescence imaging plate reader) method, wherein the compounds are inhibitors for the intracellular calcium increase induced by activation of hLPAR1 (human lysophosphatidic acid receptor 1, accession No. NM_001401.4) expressed in CHO-K1 cells (Chinese hamster ovary cells K1, ATCC).

[0465] CHO-K1 cells stably expressing hLPAR1 were cultured in F-12 medium containing 10% FBS (fetal bovine serum, Gibco, 10099-141), 1% penicillin-streptomycin (Gibco, 15140-122) and 0.4 mg/mL hygromycin B (Gibco, 10687010) in a cell incubator (37° C., 5% humidity). During 18-24 h prior to the FLIPR experiment, cells at 250,000 cells/mL were seeded into a 96-well plate (25,000 cells/well) and incubated overnight in the cell incubator. On the day of the experiment, the medium was discarded and the cells were washed in a FLIPR buffer (0.3 mL of probenecid (Thermo, P36400), 0.6 mL of 1 M HEPES (Invitrogen, 15630080) and 29.1 mL of HBSS (Invitrogen, 14065056) per 30 mL of buffer). Each well was added with 75 μL of 1 mM Fluo-4 AM fluorescent dye (Thermo, F14202) and then the cells were subjected to dye-loading incubation at 37° C. for 1.0 h. The 96-well plate was then washed once with buffer, added with a buffer containing a test compound or vehicle at 50 μL per well and then incubated for 30 min at room temperature. The cell plate was then placed in the FLIPR for baseline fluorescence measurements (excitation at 485 nm and emission at 525-535 nm). An agonist (oleoyl-L-α-lysophosphatidic acid sodium salt (Sigma, L7260) at a final concentration of 1 μM) or a vehicle (ultrapure water) was then added at 50 Lt/well, fluorescence values were measured for 2 min at 1-second intervals, and finally the output fluorescence counts were analyzed.

[0466] IC.sub.50 values obtained using the above method are shown in Table 1.

TABLE-US-00001 TABLE 1 IC.sub.50 values of compounds of Examples 1-39 for LPAR1 receptor LPAR1 IC.sub.50 LPAR1 IC.sub.50 Compound Example No. (μM) Compound Example No. (μM) Compound 1 Example 1 B Compound 2 Example 2 B Compound 3 Example 3 B Compound 4 Example 4 B Compound 5 Example 5 C Compound 6 Example 6 B Compound 7 Example 7 C Compound 8 Example 8 B Compound 9 Example 9 B Compound 10 Example 10 B Compound 11 Example 11 B Compound 12 Example 12 C Compound 13 Example 13 B Compound 14 Example 14 B Compound 15 Example 15 C Compound 16 Example 16 C Compound 17 Example 17 B Compound 18 Example 18 B Compound 19 Example 19 B Compound 20 Example 20 B Compound 21 Example 21 B Compound 22 Example 22 B Compound 23 Example 23 B Compound 24 Example 24 C Compound 25 Example 25 B Compound 26 Example 26 A Compound 27-A Example 27 A Compound 27-B Example 27 C Compound 28 Example 28 B Compound 29 Example 29 C Compound 30 Example 30 B Compound 31 Example 31 B Compound 32 Example 32 C Compound 33 Example 33 C Compound 34 Example 34 C Compound 35 Example 35 C Compound 36 Example 36 C Compound 37 Example 37 C Compound 38 Example 38 C Compound 39 Example 39 A A: IC.sub.50 ≤ 50 nM; B: 50 < IC.sub.50 ≤ 300 nM; C: 300 < IC.sub.50 ≤ 10,000 nM.

[0467] The results show that the above compounds have good inhibitory activity against LPAR1. The IC.sub.50 value of some of the compounds was 10,000 nM or less, 300 nM or less, or even 50 nM or less. In view of such excellent inhibitory activity, application thereof as LPAR1 inhibitors to treat the diseases or disorders described above is promising.

Example B: In Vitro Evaluation of Biological Activity (Cell Activity)

[0468] The activity of the compounds disclosed herein at the cell level in vitro is evaluated by A2058 (human melanoma cells, Beina Bio, BNCC341099) cell scratch assay. The inhibitory activity of the compounds against LPAR1 can be reflected by inhibition of cell scratch healing.

[0469] A2058 cells in a T75 cm.sup.2 cell culture flask were digested and gently pipetted into single cells, adjusted to a cell density of 4×10.sup.5 cells/mL, and then seeded into a 24-well plate. After the cell confluence reached 80%, the cell culture plate was taken out and the original medium was discarded. Serum-free medium was then added, and the cells were starved overnight in an incubator (37° C., 5% CO.sub.2). The cell culture plate was then taken out, and cell scratches were made along the diameter of the wells using a 200 μL pipette tip. The cell culture plate was then added with 500 μL of serum-free medium and then shaken gently to wash away the residual cells on the scratched surface, and this was repeated twice. The medium was discarded and 500 μL of 1% FBS medium containing the compound was then added, and the mixture was incubated at 37° C. for 30 min. The medium was discarded, and 500 μL of 1% FBS medium containing 10 μM compound and 10 μM LPA was added. Olympus CKX53 was used to observe the scratches, and MShot image analysis system was used to take pictures and measure the scratch area at 0 h. Then the cell culture plate was incubated in the incubator (37° C., 5% CO.sub.2). 24 h later, the scratches were observed again with Olympus CKX53, and MShot image analysis system was used to take pictures and measure the scratch area at 24 h. Cell migration inhibition rate was calculated according to the following formula:

[00001]$\mathrm{Cell}\mathrm{migration}\mathrm{inhibition}\mathrm{rate}\left(\%\right)=1-\frac{\begin{array}{c}\mathrm{scratch}\mathrm{area}\mathrm{of}\mathrm{compound}\mathrm{group}\mathrm{at}0h-\\ \mathrm{scratch}\mathrm{area}\mathrm{of}\mathrm{compound}\mathrm{group}\mathrm{at}24h\end{array}}{\begin{array}{c}\mathrm{scratch}\mathrm{area}\mathrm{of}\mathrm{control}\mathrm{group}\mathrm{at}0h-\\ \mathrm{scratch}\mathrm{area}\mathrm{of}\mathrm{control}\mathrm{group}\mathrm{at}24h\end{array}}$

TABLE-US-00002 TABLE 2 Inhibition rate of some of the compounds against scratch migration of A2058 cells Cell migration inhibition rate Compound Example No. (% 20 μM) Compound 1 Example 1 B Compound 2 Example 2 C Compound 3 Example 3 B Compound 4 Example 4 B Compound 5 Example 5 C Compound 6 Example 6 B Compound 7 Example 7 C Compound 8 Example 8 C Compound 9 Example 9 B Compound 10 Example 10 B Compound 11 Example 11 C Compound 12 Example 12 C Compound 13 Example 13 C Compound 14 Example 14 B Compound 15 Example 15 B Compound 16 Example 16 B Compound 17 Example 17 C Compound 18 Example 18 B Compound 19 Example 19 C Compound 20 Example 20 B Compound 21 Example 21 B Compound 22 Example 22 B Compound 23 Example 23 B Compound 24 Example 24 C Compound 25 Example 25 B Compound 26 Example 26 B Compound 27-A Example 27 A Compound 27-B Example 27 C Compound 28 Example 28 A Compound 29 Example 29 C Compound 30 Example 30 B Compound 31 Example 31 B A: 50-70%; B: 30-50%; C: 0-30%.

[0470] It can be seen from the data in Table 2 that the above-mentioned compounds of the present invention have relatively good inhibitory activity against LPAR1, wherein some compounds have an inhibitory rate of 300 against A2058 cell migration, some compounds have an inhibitory rate of 50-70%, and cell migration is remarkably inhibited.

Example C: In Vitro Cytotoxicity Assay

[0471] In vitro cytotoxicity assay for the compounds disclosed herein was performed in HepG2 cells using the CCK-8 method. HepG2 cells (Beina Bio) in the logarithmic growth phase were collected, the concentration of cell suspension was adjusted, and then the cells were plated on a 96-well cell culture plate at 50,000 cells/well. The cells were then incubated overnight in a cell incubator (500 CO.sub.2, 37° C.), and after 800 cell confluence was achieved, test compounds or vehicle (DMSO) at various concentration gradients were added after medium change. The resulting mixture was incubated in the cell incubator (500, 37° C.) for 48 h. After the treatment, the medium in the plate was discarded. The plate was washed twice with PBS, added with CCK-8 working solution (Beyotime) at 100 μL per well, and then incubated at 37° C. for 1.5 h in the dark. Absorbance at OD.sub.450 nm was measured for each well on a microplate reader, and CC.sub.50 value of each compound was analyzed and calculated.

[0472] CC.sub.50 values obtained using the above method are shown in Table 3.

TABLE-US-00003 TABLE 3 CC.sub.50 values obtained for some of the compounds HepG2 CC.sub.50 Compound Example No. (μM) Compound 1 Example 1 >200 Compound 2 Example 2 >200 Compound 3 Example 3 >200 Compound 4 Example 4 >200 Compound 5 Example 5 >200 Compound 6 Example 6 >200 Compound 7 Example 7 >200 Compound 8 Example 8 >200 Compound 9 Example 9 >200 Compound 10 Example 10 >200 Compound 11 Example 11 >200 Compound 12 Example 12 >200 Compound 13 Example 13 >200 Compound 14 Example 14 >200 Compound 15 Example 15 >200 Compound 16 Example 16 >200 Compound 17 Example 17 >200 Compound 18 Example 18 >200 Compound 19 Example 19 >200 Compound 20 Example 20 >200 Compound 21 Example 21 >200 Compound 22 Example 22 >200 Compound 23 Example 23 >200 Compound 24 Example 24 >200 Compound 25 Example 25 >200 Compound 26 Example 26 >200 Compound 27-A Example 27 >200 Compound 27-B Example 27 >200 Compound 28 Example 28 >200 Compound 29 Example 29 >200 Compound 30 Example 30 >200 Compound 31 Example 31 >200 It can be seen from the data in Table 3 that the compounds disclosed herein all have good safety, and the CC.sub.50 values of the compounds are all greater than 200 μM.

Example D: Test of In Vitro Metabolic Stability

[0473] The in vitro metabolic stability of the compounds disclosed herein was determined through incubation of liver microsomes of various species. A proper amount of test compound was added into a liver microsome reaction system (1 mg/mL liver microsome protein, 25 U/mL glucose-6 phosphate dehydrogenase, 1 mM NADP, 6 mM D-glucose 6-phosphate and 5 mM MgCl.sub.2), and then the mixture was incubated in a water bath kettle at 37° C. to start reaction. At each time point, 100 μL of the reaction system was added into a centrifuge tube containing 400 μL of internal standard working solution (containing a 200 ng/mL solution of dexamethasone, diclofenac, tolbutamide and labetalol in acetonitrile) precooled at 0° C. so as to stop the reaction, and the mixture was then centrifuged at 10,000 g for 10 min at 4° C. The supernatant was collected for LC-MS assay so as to obtain the values of in vitro metabolic half-life of the test compounds in liver microsomes of various species.

[0474] The metabolic half-life data obtained using the above method are shown in Table 4.

TABLE-US-00004 TABLE 4 Metabolic half-life values obtained for some the compounds Metabolic Metabolic Metabolic Metabolic Metabolic Metabolic half-life in half-life half-life in half-life in half-life half-life in human liver in rat liver mouse liver human liver in rat liver mouse liver Example microsome microsome microsome Example microsome microsome microsome Compound No. min min min Compound No. min min min Compound Example >30 >30 >30 Compound Example >30 >30 >30 2 2 3 3 Compound Example >30 <30 >30 Compound Example >30 >30 >30 7 7 25 25 Compound Example >30 >30 >30 Compound Example 231.83 57.05 192.02 26 26 27-A 27 Compound Example >30 >30 >30 31 31

[0475] The results show that the compounds disclosed herein have relatively good metabolic stability in human, rat, and mouse liver microsomes, wherein the T.sub.1/2 of some of the compounds in human liver microsome is more than 30 min, or even more than 90 min.

Example E: Pharmacodynamic Evaluation on Bleomycin-Induced Lung Fibrosis Models of Mice

[0476] Pharmacodynamic evaluation of the compounds disclosed herein was performed using bleomycin-induced lung fibrosis models of mice.

[0477] The bleomycin-induced pulmonary fibrosis models of C57BL/6 mice were established by administering 3 mg/kg of bleomycin in a single rapid spray (tracheal spray) with a nebulizer. For the normal control group, normal saline was used instead. Immediately after injection, the animals were erected at a 90-degree angle and rotated left and right for 2 min to allow the medical solution to be evenly distributed in the lungs. On day 0, the bleomycin induction group was randomly divided into a model group and an administration group (divided into low, medium, and high dosage groups) according to body weight. On days 0-20 of the experiment, animals in the normal control group and the model control group were intragastrically administered with vehicle (0.5% CMC-Na) once daily, and animals in the administration group was administered with a corresponding dosage of the compound. After 21 days of consecutive administration, the mice were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (0.06 mL/10 g) and then put to death by bleeding at abdominal aorta. The thoracic cavity was cut open, the whole lungs of the mice were taken out, and the residual blood on the surface was washed away with normal saline. The left lung was soaked in 4% paraformaldehyde for use in the detection of pulmonary inflammation and fibrosis using HE and Masson staining. After the upper bronchus and blood vessels was removed as much as possible, the remaining lung was weighed, added with 1×Ripa lysis buffer (containing protease inhibitor cocktail and PMSF) at a ratio of 2 mL/100 mg, homogenized with a homogenizer, and then stored in a refrigerator at −80° C. for use in the detection of the levels of hydroxyproline, Collagen I and α-SMA in lung tissue.

[0478] The results show that the compounds disclosed herein can alleviate bleomycin-induced lung fibrosis in mice by inhibiting the fibrogenic mechanism mediated by LPAR1.

[0479] In this specification, terms such as “one embodiment”, “some embodiments”, “examples”, “a specific example”, or “some examples” means that a particular feature, structure, material or characteristic described in reference to the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the schematic descriptions of the terms described above do not necessarily refer to the same embodiment or example. Moreover, the specific features, materials, structures and other characteristics described may be combined in any one or more embodiments or examples in an appropriate manner. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined by one skilled in the art to the extent that they do not contradict each other.

[0480] Although examples of the present invention are illustrated and described above, it will be appreciated that the above examples are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above examples by those of ordinary skill in the art within the scope of the present invention.