5-HT2A RECEPTOR INHIBITOR OR INVERSE AGONIST, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF

Abstract

The present invention relates to a novel compound as a 5-HT.sub.2A receptor inhibitor or inverse agonist, a preparation method therefor, and a pharmaceutical composition thereof. The present invention also relates to an application of the compound or the pharmaceutical composition in the preparation of a drug for treating 5-HT.sub.2A receptor-related diseases, the diseases comprising: non-motor symptoms caused by Parkinson's disease: delusion, illusion, depression, anxiety, cognitive disorder, and sleep disorder; dementia-related mental diseases; major depressive disorder; or negative symptoms of schizophrenia, etc.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, ##STR00152## wherein at least one of X.sub.1 and X.sub.4 is N, and the other one is optionally CR.sub.1 or N; X.sub.2 and X.sub.3 are each independently selected from CR.sub.1 and N; X.sub.5 is independently selected from CR.sub.3a or N; X.sub.6 is independently selected from CR.sub.3b or N; X.sub.7 is independently selected from CR.sub.3c or N; X.sub.8 is independently selected from CR.sub.3d or N; group B is linear or branched C.sub.1-6 alkyl or a 5-6-membered nitrogen heterocyclic group, and the linear or branched C.sub.1-6 alkyl or the 5-6-membered nitrogen heterocyclic group is optionally substituted with one or more deuterium atoms; each R.sub.1 is the same or different and is independently selected from a hydrogen atom, linear or branched C.sub.1-10 alkyl or halogen; each R.sub.2 is the same or different and is independently selected from a hydrogen atom, a deuterium atom, linear or branched C.sub.1-10 alkyl, (linear or branched C.sub.1-6 alkyl).sub.2 amine or 3-8-membered cycloalkyl, and the linear or branched C.sub.1-10 alkyl, the (linear or branched C.sub.1-6 alkyl).sub.2 amine or the 3-8-membered cycloalkyl is optionally substituted with one or more deuterium atoms; R.sub.3, R.sub.3a, R.sub.3b, R.sub.3c and R.sub.3d are the same or different and are each independently selected from a hydrogen atom, halogen, hydroxyl, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy and linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, halogen, hydroxyl and linear or branched C.sub.1-10 alkoxy; or when X.sub.6 is CR.sub.3b, X.sub.6 and R.sub.3 together with the atoms to which they are attached form a ring system which is selected from dihydrofuran, dihydropyrrole or dihydrothiophene and are substituted with one or more of the same or different R.sub.4, and each R.sub.4 is independently selected from a hydrogen atom, halogen, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy or linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, hydroxyl and linear or branched C.sub.1-10 alkoxy; X is selected from —NH— or —(CH.sub.2).sub.1-4NH—; Y is selected from O or S; m and n are independently selected from 0, 1, 2 and 3; s is independently selected from 1, 2, 3, 4, 5 and 6; and y is independently selected from 0, 1, 2, 3, 4 and 5.

2. The compound of claim 1, wherein the compound is represented by formula (II) ##STR00153## and wherein, X.sub.3 and X.sub.4 are each independently selected from CR.sub.1 and N; X.sub.5 is independently selected from CR.sub.3a or N; X.sub.7 is independently selected from CR.sub.3c or N; X.sub.8 is independently selected from CR.sub.3d or N; each R.sub.1 is the same or different and is independently selected from a hydrogen atom, linear or branched C.sub.1-10 alkyl or halogen; R.sub.2 is independently selected from a hydrogen atom, a deuterium atom, linear or branched C.sub.1-10 alkyl, (linear or branched C.sub.1-6 alkyl).sub.2 amine or 3-8-membered cycloalkyl, and the linear or branched C.sub.1-10 alkyl, the (linear or branched C.sub.1-6 alkyl).sub.2 amine or the 3-8-membered cycloalkyl is optionally substituted with one or more deuterium atoms; R.sub.3, R.sub.3a, R.sub.3c and R.sub.3d are the same or different and are each independently selected from a hydrogen atom, halogen, hydroxyl, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy and linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, halogen, hydroxyl and linear or branched C.sub.1-10 alkoxy; or R.sub.3 and the carbon atom to which it is attached together with adjacent carbon atoms form a ring system which is selected from dihydrofuran, pyrroline or dihydrothiophene and are substituted with one or more of the same or different R.sub.4, and each R.sub.4 is independently selected from a hydrogen atom, halogen, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy or linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, hydroxyl and linear or branched C.sub.1-10 alkoxy; X is selected from —NH— or —(CH.sub.2).sub.1-4NH—; Y is selected from O or S; m and n are independently selected from 0, 1, 2 and 3; and s is independently selected from 1, 2, 3, 4, 5 and 6.

3. The compound of claim 1, wherein the compound is represented by formula (III) ##STR00154## and wherein, X.sub.3 and X.sub.4 are each independently selected from CR.sub.1 and N; X.sub.5 is independently selected from CR.sub.3a or N; X.sub.7 is independently selected from CR.sub.3c or N; X.sub.8 is independently selected from CR.sub.3d or N; each R.sub.1 is the same or different and is independently selected from a hydrogen atom, linear or branched C.sub.1-10 alkyl or halogen; R.sub.2 is independently selected from a hydrogen atom, a deuterium atom, linear or branched C.sub.1-10 alkyl, (linear or branched C.sub.1-6 alkyl).sub.2 amine or 3-8-membered cycloalkyl, and the linear or branched C.sub.1-10 alkyl, the (linear or branched C.sub.1-6 alkyl).sub.2 amine or the 3-8-membered cycloalkyl is optionally substituted with one or more deuterium atoms; R.sub.3, R.sub.3a, R.sub.3c and R.sub.3d are the same or different and are each independently selected from a hydrogen atom, halogen, hydroxyl, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy and linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, halogen, hydroxyl and linear or branched C.sub.1-10 alkoxy; or R.sub.3 and the carbon atom to which it is attached together with adjacent carbon atoms form a ring system which is selected from dihydrofuran, dihydropyrrole or dihydrothiophene and are substituted with one or more of the same or different R.sub.4, and each R.sub.4 is independently selected from a hydrogen atom, halogen, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy or linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, hydroxyl and linear or branched C.sub.1-10 alkoxy; and s is independently selected from 1, 2, 3, 4, 5 and 6.

4. The compound of claim 1, wherein the compound is represented by formula (IV) ##STR00155## and wherein, X.sub.7 is independently selected from CR.sub.3c or N; X.sub.8 is independently selected from CR.sub.3d or N; R.sub.1 is independently selected from a hydrogen atom, linear or branched C.sub.1-10 alkyl or halogen; R.sub.2 is independently selected from a hydrogen atom, a deuterium atom, linear or branched C.sub.1-10 alkyl, (linear or branched C.sub.1-6 alkyl).sub.2 amine or 3-8-membered cycloalkyl, and the linear or branched C.sub.1-10 alkyl, the (linear or branched C.sub.1-6 alkyl).sub.2 amine or the 3-8-membered cycloalkyl is optionally substituted with one or more deuterium atoms; R.sub.3, R.sub.3c and R.sub.3d are the same or different and are each independently selected from a hydrogen atom, halogen, hydroxyl, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy and linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, halogen, hydroxyl and linear or branched C.sub.1-10 alkoxy; or R.sub.3 and the carbon atom to which it is attached together with adjacent carbon atoms form a ring system which is selected from dihydrofuran, dihydropyrrole or dihydrothiophene and are substituted with one or more of the same or different R.sub.4, and each R.sub.4 is independently selected from a hydrogen atom, halogen, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy or linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, hydroxyl and linear or branched C.sub.1-10 alkoxy; and s is independently selected from 1, 2, 3, 4, 5 and 6.

5. The compound of claim 1, wherein the compound is represented by formula (V) ##STR00156## and wherein, X.sub.3 is independently selected from CR.sub.5 or N; X.sub.4 is independently selected from CR.sub.6 or N; X.sub.7 is independently selected from CR.sub.3c or N; X.sub.8 is independently selected from CR.sub.3d or N; R.sub.1, R.sub.5 and R.sub.6 are the same or different and are each independently selected from a hydrogen atom, linear or branched C.sub.1-10 alkyl and halogen; R.sub.2 is independently selected from a hydrogen atom, a deuterium atom, linear or branched C.sub.1-10 alkyl, (linear or branched C.sub.1-6 alkyl).sub.2 amine or 3-8-membered cycloalkyl, and the linear or branched C.sub.1-10 alkyl, the (linear or branched C.sub.1-6 alkyl).sub.2 amine or the 3-8-membered cycloalkyl is optionally substituted with one or more deuterium atoms; and R.sub.3, R.sub.3c and R.sub.3d are the same or different and are each independently selected from a hydrogen atom, halogen, hydroxyl, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy and linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, halogen, hydroxyl and linear or branched C.sub.1-10 alkoxy.

6. The compound of claim 1, wherein the compound is represented by formula (VI) ##STR00157## and wherein, X.sub.3 is independently selected from CR.sub.5 or N; X.sub.4 is independently selected from CR.sub.6 or N; R.sub.1, R.sub.5 and R.sub.6 are the same or different and are each independently selected from a hydrogen atom, linear or branched C.sub.1-10 alkyl and halogen; R.sub.2 is independently selected from a hydrogen atom, a deuterium atom, linear or branched C.sub.1-10 alkyl, (linear or branched C.sub.1-6 alkyl).sub.2 amine or 3-8-membered cycloalkyl, and the linear or branched C.sub.1-10 alkyl, the (linear or branched C.sub.1-6 alkyl).sub.2 amine or the 3-8-membered cycloalkyl is optionally substituted with one or more deuterium atoms; and R.sub.4a, R.sub.4b and R.sub.4c and R.sub.4d are the same or different and are each independently selected from a hydrogen atom, halogen, hydroxyl, linear or branched C.sub.1-10 alkyl, linear or branched C.sub.1-10 alkoxy and linear or branched C.sub.1-10 haloalkoxy, wherein the linear or branched C.sub.1-10 alkyl and the linear or branched C.sub.1-10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, halogen, hydroxyl and linear or branched C.sub.1-10 alkoxy.

7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1, R.sub.5 and R.sub.6 are the same or different and are each independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; group B is —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, -CD.sub.2-, -(CD.sub.2).sub.2-, -(CD.sub.2).sub.3- or -(CD.sub.2).sub.4-, and R.sub.2 is independently selected from dimethylamine or diethylamine, wherein the dimethylamine or the diethylamine is optionally substituted with one or more deuterium atoms; or group B is selected from piperidinyl, wherein the piperidinyl is optionally substituted with one or more deuterium atoms, and R.sub.2 is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, the ethyl, the propyl, the isopropyl, the butyl, the isobutyl, the sec-butyl, the tert-butyl, the cyclopropyl, the cyclobutyl, the cyclopentyl or the cyclohexyl is optionally substituted with one or more deuterium atoms; R.sub.3, R.sub.3a, R.sub.3b, R.sub.3c and R.sub.3d are the same or different and are each independently selected from a hydrogen atom, F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3,3-difluoropropoxy, 2,2′-difluoroisopropoxy, 3,3,3-trifluoropropoxy, 4-fluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 2-methyl-3-hydroxy-butyl and i-Pr—O—CH.sub.2—; and R.sub.4 and/or R.sub.4a, R.sub.4b, R.sub.4c and R.sub.4d are the same or different and are each independently selected from a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

8. A compound or a pharmaceutically acceptable salt thereof or a deuterated analog thereof, which is selected from the following: ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186##

9. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

10. A method for treating 5-HT receptor-related diseases, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 9 to a subject in need thereof, wherein preferably the 5-HT receptor-related diseases comprise: schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety disorder, sleep disorder, dysorexia, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tics, depression, major depressive disorder, anxiety, sleep disturbance, eating disorder, non-motor symptoms caused by Parkinson's disease, delusion, illusion, cognitive disorder, dementia-related mental diseases, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar ataxia, Tourette's syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, dyskinesia, dysmyotonia, myoclonus, tremor or progressive supranuclear paralysis and frontotemporal dementia.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0166] FIG. 1: Comparison diagram of drug-time curves of pimavanserin and compound 59 after intragastric administration

DETAILED DESCRIPTION OF EMBODIMENTS

[0167] The present invention is further described below in conjunction with specific examples and test examples, but the scope of the present invention is not limited in any way.

Example 1

[0168] ##STR00044##

Synthesis Route:

[0169] ##STR00045## [0170] 1. Under nitrogen protection, in an ice-water bath, 2-(aminomethyl)-5-fluoropyridine (504 mg, 4.0 mmol) was dissolved in 10 ml of methanol. N-methyl-4-piperidone (452 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1a (538 mg), which was directly used in the next reaction without purification. [0171] 2. Under nitrogen protection, compound 1a (446 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 ml of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 1 (414 mg, a light yellow solid, yield: 480). MS m/z (ESI): 429.3 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (d, 1H), 7.38-7.32 (m, 1H), 7.31-7.28 (m, 1H), 7.18-7.14 (m, 2H), 6.85-6.80 (m, 2H), 6.64-6.58 (m, 1H), 4.37 (s, 2H), 4.34 (d, 2H), 3.70 (d, 2H), 2.93-2.87 (m, 2H), 2.28 (s, 3H), 2.13-1.98 (m, 4H), 1.81-1.64 (m, 4H), 1.02 (d, 6H).

[0172] Compounds 2-3, 12-13, 16, 19-20, 23-31, 33-52, 58, 61, 64, 66-68, 70-72, 75-77, 80-81 and 83-101 were prepared in a similar manner to example 1.

TABLE-US-00001 TABLE 1 Structures and characterization data of compounds 2-3, 12-13, 16, 19-20, 23-31, 33-52, 58, 61, 64, 66-68, 70-72, 75-77, 80-81 and 83-101 Compound number Structural formula Characterization data 2 [00046] MS m/z (ESI): 429.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.1(s, 1H), 7.69-7.65(m, 1H), 7.06-7.02(m, 2H), 6.90-6.87(m, 1H), 6.81-6.77(m, 2H), 4.69-4.60(m, 2H), 4.46(s, 2H), 4.29(d, 2H), 3.68(d, 2H), 3.45-3.38(m, 2H), 2.84-2.74(m, 2H), 2.70(s, 3H), 2.52- 2.41(m, 2H), 2.09-2.02(m, 1H), 1.88- 1.81(m, 2H), 1.01(d,6H). 3 [00047] MS m/z (ESI): 373.2[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.23 (s, 1H), 8.48 (d, 1H), 7.81-7.48 (m, 1H), 7.33 (m, 1H), 7.03 (m, 3H), 6.67 (d, 2H), 4.46 (s, 2H), 4.25-4.17 (m, 1H), 4.14 (d, 2H), 2.76 (d, 2H), 2.62-2.46 (m, 3H), 1.88 (m, ,2H), 1.68-1.58 (m, 2H), 1.25 (d, 2H). 12 [00048] MS m/z (ESI): 447.3 [M + 1]; .sup.1H NMR(400 MHz,CDCl.sub.3) δ 8.15-8.13(m, 1H), 7.23-7.17(m, 3H), 6.96-6.92(m, 1H), 6.85-6.80(m, 2H), 4.46(s, 2H), 4.35-4.32(m, 2H), 4.30-4.22(m, 1H), 3.68(d, 2H), 3.04-2.98(m, 2H), 2.37(s, 3H), 2.26-2.20(m, 2H), 2.09-2.02(m, 1H), 1.96-1.88(m, 2H), 1.70-1.65(m, 2H), 1.01(d, 6H) 13 [00049] MS m/z (ESI): 430.3 [M + 1]; .sup.1H NMR(400 MHz,CDCl.sub.3) δ 8.48(s, 2H), 7.16-7.13(m, 2H), 6.85-6.80(m, 2H), 6.42-6.37(m, 1H), 4.56(s, 2H), 4.52- 4.47(m, 1H), 4.33(d, 2H), 3.70(d, 2H), 3.40-3.36(m, 2H), 2.74-2.71(m, 1H), 2.65(s, 3H), 2.50-2.41(m, 3H), 2.09- 2.02(m, 1H), 1.88-1.81(m, 2H), 1.01(d, 6H). 16 [00050] MS m/z (ESI): 455.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.23(s, 1H), 7.72-7.68(m, 1H), 7.45-7.38(m, 1H), 7.25-7.20(m, 2H), 6.87-6.84(m, 2H), 4.67-4.62(m, 1H), 4.44(s, 2H), 4.35- 4.30(d, 2H) 3.71(d, 2H), 3.63-3.58(m, 1H), 3.47-3.44(m, 1H), 2.74-2.71(m, 1H), 2.64-2.60(m, 2H), 2.50(s, 3H), 2.25-2.17(m, 3H), 2.13-2.05(m, 2H), 1.65-1.61(m, 2H), 1.03(d, 6H). 19 [00051] MS m/z (ESI): 429.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.10(s, 1H), 7.25-7.20(m, 2H), 7.10-7.05(m, 2H), 6.99-6.89(m, 2H), 5.50-5.42(m, 1H), 4.45-4.35(m, 4H), 4.30-4.20(m, 1H), 3.70(d, 2H), 2.88-2.85(m, 2H), 2.26(s, 3H), 2.09-2.00(m, 3H), 1.75-1.60(m, 4H), 1.02(d, 6H). 20 [00052] MS m/z (ESI): 429.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 7.91(s, 1H), 7.38-7.33(m, 1H), 7.24-7.20(m, 2H), 7.05-6.95(m, 2H), 6.69-6.65(m, 1H), 4.55-4.45(m, 1H), 4.40-4.20(m, 5H), 3.99(d, 2H), 2.98(d, 2H), 2.30(s, 3H), 2.19-2.00(m, 3H), 1.75-1.65(m, 4H), 1.01(d, 6H). 21 [00053] MS m/z (ESI): 428.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 7.25- 7.15(m, 4H), 7.10-6.97(m, 4H), 4.55- 4.45(m, 1H), 4.42(s, 2H), 4.40-4.25(m, 5H), 3.70-3.63(m, 1H), 2.88(d, 2H), 2.28(s, 3H), 2.19-2.09(m, 2H), 1.75- 1.65(m, 4H), 1.01(d, 6H). 23 [00054] MS m/z (ESI): 413.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 9.49- 9.34(m, 2H), 8.26(s, 1H), 7.41-7.38(m, 2H), 7.07-7.02(m, 2H), 6.68-6.66(m, 1H), 4.58-4.44(m, 1H), 4.41-4.32(m, 4H), 3.45(d, 2H), 3.00-2.88(m, 4H), 2.30-2.24(m, 2H), 1.75-1.68(m, 2H), 1.47(s, 6H). 24 [00055] MS m/z (ESI): 427.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.51(s, 1H), 7.62-7.54(m, 2H), 7.24-7.20(m, 1H), 6.89-6.77(m, 2H), 4.63(s, 2H), 4.58- 4.44(m, 3H), 3.25-3.10(m, 4H), 2.80- 2.71(m, 1H), 2.52(s, 3H), 2.30-2.24(m, 2H), 2.08-1.88(m, 4H), 1.70(s, 6H). 25 [00056] MS m/z (ESI): 442.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.25- 7.21(m, 2H), 7.15-7.03(m, 6H), 6.94- 6.82(m, 1H), 4.42(s, 2H), 4.38-4.29(m, 1H), 4.24-4.18(m, 2H), 3.94-3.81(m, 1H), 3.48-3.32(m, 1H), 2.74(d, 2H), 2.70-2.58(m, 2H), 2.10(s, 3H), 1.90- 1.75(m, 2H), 1.59-1.41(m, 5H), 0.87(d, 6H). 26 [00057] MS m/z (ESI): 473.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.28(d, 1H), 7.88(s, 1H), 7.70-7.65(m, 1H), 7.46- 7.42(m, 1H), 7.13-7.08(m, 1H), 7.05- 6.97(m, 2H), 4.60-4.53(m, 1H), 4.50- 4.45(s, 2H), 4.43-4.37(m, 4H), 3.46- 3.40(m, 2H), 2.80-2.69(m, 5H), 2.67- 2.58(m, 2H), 1.79-1.73(m, 2H). 27 [00058] MS m/z (ESI): 453.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.27(s, 1H), 7.42-7.34(m, 2H), 7.05-6.98(m, 2H), 6.67-6.64(m, 1H), 4.43-4.34(m, 5H), 3.25-3.10(m, 2H), 3.00-2.95(m, 2H), 2.50-2.31(m, 2H), 1.82-1.60(m, 5H), 1.48(s, 6H), 0.63-0.35(m, 4H). 28 [00059] MS m/z (ESI): 515.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.33(d, 1H), 7.44-7.29(m, 3H), 7.17-7.13(m, 1H), 6.94-6.90(m, 1H), 4.50-4.44(m, 3H), 4.42-4.34(m, 4H), 3.26-3.10(m, 2H), 2.40-2.30(m, 2H), 1.89-1.63(m, 5H), 0.58-0.38(m, 4H). 29 [00060] MS m/z (ESI): 480.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.38(d, 1H), 7.45-7.28(m, 4H), 7.22-7.16(m, 1H), 6.99-6.90(m, 1H), 4.43-4.24(m, 4H), 3.96-3.90(m, 2H), 3.17-3.08(m, 2H), 2.40-2.30(m, 2H), 1.95-1.85(m, 1H), 1.79-1.60(m, 5H), 0.52-0.40(m, 4H). 30 [00061] MS m/z (ESI): 473.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.23(d, 1H), 7.98(s, 1H), 7.80-7.75(m, 1H), 7.43- 7.40(m, 1H), 7.32-7.27(m, 2H), 6.95- 6.90(m, 2H), 4.61-4.55(m, 1H), 4.53- 4.49(s, 2H), 4.41-4.32(m, 4H), 3.44- 3.38(m, 3H), 2.90-2.78(m, 4H), 1.79- 1.73(m, 2H), 1.42(d, 6H). 31 [00062] MS m/z (ESI): 426.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 7.22- 7.17(m, 2H), 7.02-6.98(m, 2H), 6.84- 6.81(m, 2H), 6.62-6.58(m, 1H), 4.55- 4.47(m, 1H), 4.37(s, 2H), 4.26-4.24(m, 2H), 3.15-3.08(m, 2H), 2.96-2.91(m, 2H), 2.45(s, 3H), 2.40-2.34(m, 2H), 2.04-1.94(m, 2H), 1.82-1.76(m, 2H), 1.46(s, 6H). 33 [00063] MS m/z (ESI): 442.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.28- 7.22(m, 2H), 7.19-7.08(m, 4H), 6.88- 6.76(m, 2H), 4.58-4.41(m, 4H), 4.24- 4.20(m, 2H), 3.71(d, 2H), 2.35-2.20(m, 2H), 2.17(s, 6H), 2.06-1.92(m, 3H), 1.70-1.52(m, 2H), 1.44-1.38(m, 1H), 0.97(d, 6H). 34 [00064] MS m/z (ESI): 455.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.47(s, 1H), 7.72-7.64(m, 1H), 7.35-7.28(m, 1H), 7.07-6.94(m, 3H), 6.68-6.65(m, 1H), 4.50(s, 1H), 4.23-4.04(m, 3H), 2.95(s, 2H), 2.80-2.60(m, 3H), 2.30- 2.11(m, 2H), 1.62-1.45(m, 4H), 1.38(s, 6H), 0.97(d, 6H). 35 [00065] MS m/z (ESI): 441.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.21- 8.12(m, 1H), 7.82-7.76(m, 2H), 7.26- 7.20(m, 4H), 7.12-7.01(m, 3H), 4.45- 4.29(m, 4H), 4.18-3.94(m, 2H), 2.78- 2.68(m, 2H), 2.11(s, 3H), 1.87-1.65(m, 2H), 1.60-1.42(m, 4H), 0.99(d, 6H). 36 [00066] MS m/z (ESI): 441.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 9.76(s, 1H), 7.52-7.46(m, 2H), 7.26-7.22(m, 2H), 7.12-7.01(m, 4H), 6.93-6.88(m, 1H), 4.45-4.39(m, 2H), 4.18-4.14(m, 2H), 3.99-3.90(m, 1H), 2.78-2.73(m, 2H), 2.60-2.52(m, 1H), 2.15(s, 3H), 2.01-1.88(m, 2H), 1.61-1.42(m, 4H), 1.01 (d, 6H). 37 [00067] MS m/z (ESI): 429.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.46(d, 1H), 7.68-7.62(m, 1H), 7.31-7.28(m, 1H), 7.22-7.10(m, 6H), 4.50-4.40(m, 4H), 4.24(d, 2H), 4.00-3.87(m, 1H), 3.70-3.60(m, 1H), 2.83-2.77(m, 2H), 2.21(s, 3H), 2.03-1.88(m, 2H), 1.61- 1.44(m, 4H), 1.12(d, 6H). 38 [00068] MS m/z (ESI): 491.2 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.49(d, 1H), 7.66-7.61(m, 1H), 7.36-7.18(m, 6H), 4.50(s, 2H), 4.36-4.30(m, 2H), 4.00-3.87(m, 1H), 2.81-2.72(m, 2H), 2.11(s, 3H), 2.03-1.88(m, 2H), 1.63- 1.45(m, 4H). 39 [00069] MS m/z (ESI): 428.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 7.25- 7.02(m, 7H), 6.88-6.76(m, 2H), 4.58- 4.41(m, 4H), 4.26-4.21(m, 2H), 3.65(d, 2H), 2.45-2.30(m, 3H), 2.13(s, 6H), 2.06-1.99(m, 1H), 1.44-1.38(m, 1H), 0.97(d, 6H). 40 [00070] MS m/z (ESI): 456.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.27- 7.23(m, 2H), 7.20-7.06(m, 4H), 6.85- 6.76(m, 2H), 4.44-4.25(m, 3H), 4.20- 4.07(m, 2H), 3.73(d, 2H), 3.30-3.21(m, 1H), 2.17(s, 6H), 2.06-1.97(m, 1H), 1.80-1.52(m, 4H), 1.47-1.31(m, 3H), 0.98(d, 6H). 41 [00071] MS m/z (ESI): 441.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.23(d, 1H), 7.90-7.60(s, 1H), 7.50-7.32(m, 3H), 7.08-6.86(m, 2H), 6.65-6.60(m, 1H), 4.50-4.31(m, 4H), 4.26-4.21(m, 2H), 3.25(d, 2H), 3.12-2.92(m, 2H), 2.69- 2.55(m, 4H), 2.46-2.29(m, 2H), 1.84- 1.68(m, 3H), 0.95(d, 6H). 42 [00072] MS m/z (ESI): 442.2 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.28- 7.12(m, 6H), 7.01-6.95(m, 1H), 6.88- 6.79(m, 2H), 4.48-4.31(m, 3H), 4.26- 4.21(m, 2H), 3.72(d, 2H), 3.25-3.15(m, 2H), 2.75(s, 3H), 2.35-2.20(m, 2H), 2.01-1.79(m, 2H), 1.64-1.58(m, 1H), 0.95(d, 6H). 43 [00073] MS m/z (ESI): 445.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 7.98(d, 1H), 7.48-7.36(m, 3H), 7.01-6.95(m, 3H), 4.68-4.54(m, 4H), 4.01-3.85(m, 3H), 3.22(d, 2H), 2.55(s, 3H), 2.39-2.20(m, 5H), 1.79-1.73(m, 2H), 1.15(d, 6H). 44 [00074] MS m/z (ESI): 487.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.22(d, 1H), 7.38-7.32(m, 1H), 7.21-7.05(m, 3H), 6.80-6.73(m, 2H), 4.48-4.34(m, 5H), 3.71(d, 2H), 3.52(d, 2H), 2.95-2.75(m, 5H), 2.45(s, 3H), 2.39-2.33(m, 2H), 2.12-2.00(m, 1H), 1.79-1.73(m, 2H), 1.00(d, 6H). 45 [00075] MS m/z (ESI): 451.2 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.48(d, 1H), 7.70-7.65(m, 1H), 7.32-7.27(m, 1H), 7.18-7.07(m, 3H), 6.95-6.88(m, 2H), 4.94-4.60(m, 5H), 4.44(s, 2H), 4.23(d, 2H), 3.96-3.86(m, 1H), 2.72(d, 2H), 2.12(s, 3H), 1.89-1.75(m, 2H), 1.55-1.43(m, 4H). 46 [00076] MS m/z (ESI): 399.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.21(d, 1H), 7.35-7.30(m, 2H), 7.10-6.92(m, 3H), 6.65-6.60(m, 1H), 4.52-4.41(m, 2H), 4.36-4.14(m, 5H), 3.15-2.99(m, 4H), 2.42(s, 3H), 2.35-2.20(m, 2H), 2.06- 1.86(m, 2H), 1.64-1.58(m, 2H). 47 [00077] MS m/z (ESI): 447.3 [M + 1]; .sup.1H NMR(400 MHz, MeOD-d.sub.4) δ 8.38(d, 1H), 7.55-7.48(m, 1H), 7.32-7.28(m, 1H), 7.25-7.17(m, 2H), 6.85-6.78(m, 2H), 4.51(s, 2H), 4.27(s, 2H), 4.20- 4.11(m, 1H), 3.92(s, 2H), 2.98(d, 2H), 2.34(s, 3H), 2.28-2.22(m, 2H), 1.79- 1.65(m, 4H), 1.45(d, 6H). 48 [00078] MS m/z (ESI): 441.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.26(s, 1H), 7.42-7.34(m, 2H), 7.04-6.90(m, 2H), 6.75-6.65(m, 2H), 4.43(s, 2H), 4.35- 4.27(m, 3H), 3.10(d, 2H), 2.95(s, 2H), 2.60-2.51(m, 2H), 2.20-2.11(m, 2H), 1.98-1.78(m, 2H), 1.74-1.67(m, 2H), 1.48(s, 6H), 1.14(t, 3H). 49 [00079] MS m/z (ESI): 401.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.25(d, 1H), 7.39-7.29(m, 2H), 7.21-7.13(m, 2H), 6.85-6.80(m, 2H), 6.74-6.64(m, 1H), 4.37-4.24(m, 5H), 3.99(q, 2H), 2.93- 2.85(d, 2H), 2.27(s, 3H), 2.13-1.98(m, 2H), 1.81-1.64(m, 4H), 1.42(t, 3H). 50 [00080] MS m/z (ESI): 439.3 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.25(d, 1H), 7.40-7.32(m, 4H), 7.09-7.06(m, 1H), 6.79-6.70(m, 1H), 6.29(s, 1H), 4.50- 4.44(d, 2H), 4.41-4.25(m, 3H), 3.12- 3.04(m, 1H), 2.93(d, 2H), 2.30(s, 3H), 2.16-2.09(m, 2H), 1.84-1.65(m, 4H), 1.29(d, 6H). 51 [00081] MS m/z (ESI): 426.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 7.22- 7.16(m, 2H), 7.09-6.88(m, 7H), 4.54- 4.47(m, 1H), 4.36-4.24(m, 5H), 2.91(d, 2H), 2.65-2.52(m, 2H), 2.27(s, 3H), 2.20-2.05(m, 2H), 1.80-1.66(m, 4H), 1.60-1.42(m, 3H), 0.91(d, 6H). 52 [00082] MS m/z (ESI): 427.2 [M + 1]; .sup.1H NMR(400 MHz, CDCl.sub.3) δ 8.24(d, 1H), 7.55-7.50(m, 1H), 7.45-7.35(m, 2H), 7.20-7.10(m, 4H), 4.55-4.47(m, 1H), 4.42-4.34(m, 4H), 3.28(d, 2H), 2.65- 2.52(m, 7H), 2.40-2.31(m, 2H), 1.76- 1.70(m, 2H), 1.60-1.45(m, 3H), 0.93(d, 6H). 58 [00083] MS m/z (ESI): 442.3 [M + 1]; .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.28- 7.24(m, 2H), 7.15-6.97(m, 4H), 6.85- 6.75(m, 2H), 4.25-4.15(m, 4H), 3.70(d, 2H), 2.80-2.70(m, 2H), 2.63(s, 3H), 2.08(s, 3H), 2.05-1.90(m, 2H), 1.88- 1.68(m, 4H), 1.61-1.49(m, 2H), 0.99(d, 6H). 61 [00084] MS m/z (ESI): 445.2[M + 1], 467.23[M + 23].sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.13 (d, 1H), 7.23 (m, 1H), 7.04 (d, 1H), 7.01-6.98 (m, 1H), 6.93 (s, 1H), 6.65 (d, 1H), 4.48 (d, 2H), 4.30 (d, 2H), 3.48 (s, 1H), 3.34 (d, 2H), 2.97 (s, 2H), 2.62 (s, 5H), 2.37- 2.30 (m, 2H), 1.82-1.76 (m, 2H), 1.46 (s, 6H). 64 [00085] MS m/z (ESI): 489.2[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.49 (d, 1H), 7.74-7.56 (m, 1H), 7.33 (m, 1H), 7.22- 7.16 (m, 3H), 7.02 (s, 1H), 4.83 (d, 2H), 4.48 (s, 2H), 4.19 (d, 2H), 4.13 (d, 1H), 3.43-3.28 (m, 2H), 3.09-2.96 (m, 2H), 2.41 (s, 3H), 1.83-1.75 (m, 2H), 1.69- 1.48 (m, 2H). 66 [00086] MS m/z (ESI): 534.2[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (m, 1H), 7.71-7.60 (m, 1H), 7.32 (m, 1H), 7.26- 7.11 (m, 3H), 7.02-6.94 (m, 1H), 4.82 (d, 1H), 4.71 (d, 1H), 4.47 (d, 2H), 4.19 (t, 2H), 4.06 (s, 1H), 3.32 (s, 1H), 2.94 (s, 2H), 2.31 (s, 4H), 1.70 (d, 2H), 1.52 (d, 2H). 67 [00087] MS m/z (ESI): 523.4[M + 1], 545.2[M + 23] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 7.65 (m, 1H), 7.54-7.47 (m, 1H), 7.35-7.29 (m, 1H), 6.97 (m, 3H), 4.91 (d, 1H), 4.70 (d, 1H), 4.48 (d, 2H), 4.24 (d, 1H), 4.17 (d, 1H), 4.07 (s, 1H), 3.37-3.30 (m, 1H), 3.07 (s, 2H), 2.43 (s, 3H), 2.13 (s, 1H), 1.79 (d, 2H), 1.58 (d, 2H). 68 [00088] MS m/z (ESI): 452.5 [M + 1] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.22 (m, 2H), 7.15-7.01 (m, 2H), 6.98-6.87 (m, 2H), 6.81 (t, 1H), 6.58 (d, 1H), 4.39 (s, 2H), 4.15 (d, 2H), 4.05 (d, 1H), 2.95 (d, 3H), 2.88 (s, 2H), 2.78 (s, 1H), 2.16 (s, 1H), 1.44 (s, 4H), 1.38 (d, 10H). 70 [00089] MS m/z (ESI): 469.1[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.49 (d, 1H), 7.69 (d, 1H), 7.34 (d, 1H), 7.23-7.15 (m, 3H), 7.03-6.94 (m, 2H), 4.71 (t, 2H), 4.48 (s, 2H), 4.20 (d, 3H), 3.32 (s, 2H), 2.81(m, 2H), 2.50 (m, 2H), 2.00- 1.81 (m, 2H), 1.62 (s, 2H), 1.18-1.07 (m, 3H). 71 [00090] MS m/z (ESI): 461.1[M + 1], 483.0[M + 23] .sup.1H NMR (600 MHz, Methanol-d.sub.4) δ 8.39 (d, 1H), 7.57 (d, 1H), 7.42 (m, 1H), 6.97 (d, 2H), 4.56 (s, 2H), 4.34-4.26 (m, 1H), 4.24 (s, 2H), 3.40-3.34 (m, 2H), 3.06 (s, 2H), 2.90 (s, 2H), 2.71 (s, 3H), 2.05-1.96 (m, 2H), 1.89-1.83 (m, 2H), 1.47 (s, 6H). 72 [00091] MS m/z (ESI): 413.4[M + 1], 435.4[M + 23] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (d, 1H), 7.68 (m, 1H), 7.35 (m, 1H), 7.16 (t, 1H), 7.11 (d, 2H), 7.06 (d, 2H), 4.48 (s, 2H), 4.26 (d, 1H), 4.23 (d, 2H), 3.28-3.16 (m, 2H), 2.82 (s, 2H), 2.57 (s, 3H), 2.40 (d, 2H), 2.06- 1.88 (m, 2H), 1.79 (m, 1H), 1.70-1.59 (m, 2H), 0.84 (d, 6H). 75 [00092] MS m/z (ESI): 436.4[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.24-7.17 (m, 2H), 7.17-7.13 (m, 2H), 7.11 (t, 1H), 7.03 (m, 1H), 6.91-6.85 (m, 2H), 4.79- 4.74 (m, 1H), 4.70-4.67 (m, 1H), 4.41 (s, 2H), 4.24-4.21 (m, 1H), 4.19 (s, 2H), 4.17 (d, 2H), 3.23-3.08 (m, 2H), 2.51 (m, 3H), 2.49(s, 2H), 1.85 (s, 2H), 1.66- 1.59 (m, 2H). 76 [00093] MS m/z (ESI): 444.3[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.25-7.15 (m, 2H), 7.03 (m, 2H), 6.99 (d, 1H), 6.94- 6.86 (m, 1H), 6.58 (d, 1H), 4.41 (s, 2H), 4.27-4.18 (m, 1H), 4.15 (d, 2H), 3.17 (d, 2H), 2.94 (s, 2H), 2.51 (m, 3H), 2.47 (m, 2H), 1.85 (d, 2H), 1.61 (d, 2H), 1.38 (s, 6H). 77 [00094] MS m/z (ESI): 505.3[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (d, 1H), 7.68 (m, 1H), 7.33 (m, 1H), 6.97 (d, 1H), 6.91 (m, 1H), 6.58 (d, 1H), 4.46 (s, 2H), 4.24-4.17 (m, 1H), 4.15 (d, 2H), 3.16 (d, 2H), 2.94 (s, 2H), 2.55-2.51 (m, 2H), 2.50 (m, 3H), 1.89 (s, 2H), 1.62 (d, 2H), 1.38 (s, 6H). 80 [00095] MS m/z (ESI): 429.2[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.16 (m, 2H), 6.89- 6.68 (m, 2H), 4.63 (t, 1H), 4.34 (d, 2H), 4.21-4.18 (m, 2H), 3.91(m, 1H), 3.69 (m, 2H), 2.88(m, 2H), 2.26 (s, 2H), 2.22 (s, 3H), 2.17 (s, 3H), 2.04 (m, 2H), 1.68 (d, 4H), 1.01 (d, 7H). 81 [00096] MS m/z (ESI): 447.0[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.11 (d, 1H), 7.22 (m, 1H), 7.19-7.14 (m, 2H), 7.04 (t, 1H), 6.95-6.89 (m, 2H), 4.49 (d, 2H), 4.38 (d, 3H), 3.24(s, 2H), 2.55 (s, 5H), 2.23 (s, 2H), 1.84-1.70 (m, 2H), 1.33 (s, 9H). 83 [00097] MS m/z (ESI): 526.4[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.17 (m, 2H), 7.02- 6.91 (m, 4H), 6.77 (d, 2H), 4.51 (s, 2H), 4.37 (s, 2H), 4.26 (d, 2H), 3.98 (d, 2H), 3.96-3.90 (m, 1H), 3.67 (d, 2H), 3.35 (d, 3H), 2.73 (t, 1H), 2.57-2.42 (m, 1H), 2.11-1.95 (m, 1H), 1.86-1.72 (m, 3H), 1.62-1.53 (m, 5H), 1.48 (tq, 1H), 1.38-1.25 (m, 3H), 1.00 (d, 6H). 84 [00098] MS m/z (ESI): 642.5[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.18 (dd, 2H), 7.02- 6.95 (m, 4H), 6.77 (d, 2H), 4.48 (dd, 2H), 4.38 (s, 2H), 4.27 (d, 2H), 4.07 (s, 1H), 3.98-3.83 (m, 2H), 3.68 (d, 2H), 3.39-2.49 (m, 6H), 2.35 (s, 5H), 2.12 (m, 1H), 2.06 (m, 1H), 2.00-1.91 (m, 1H), 1.88-1.79 (m, 2H), 1.75 (m, 2H), 1.65-1.47 (m, 1H), 1.26 (d, 1H), 1.01 (d, 6H). 85 [00099] MS m/z (ESI): 687.1[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.23-7.10 (m, 2H), 6.99 (td, 4H), 6.84-6.50 (m, 2H), 4.39 (d, 3H), 4.27 (d, 2H), 3.86-3.73 (m, 1H), 3.68 (d, 2H), 3.26 (s, 1H), 2.90 (d, 2H), 2.72-2.65 (m, 2H), 2.58 (s, 2H), 2.46 (s, 1H), 2.06 (m, 3H), 1.88- 1.51 (m, 9H), 1.48 (d, 2H), 1.39-1.30 (m, 2H), 1.29-1.07 (m, 6H), 1.01 (d, 6H), 0.98-0.83 (m, 2H). 86 [00100] MS m/z (ESI): 463.1[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.13-7.06 (m, 2H), 7.05-6.98 (m, 2H), 6.80 (d, 2H), 4.54-4.42 (m, 2H), 4.36 (s, 2H), 4.29 (d, 2H), 3.68 (d, 2H), 3.16 (d, 2H), 2.49 (s, 3H), 2.43 (s, 2H), 2.06 (s, 3H), 1.92- 1.71 (m, 2H), 1.01 (d, 6H). 87 [00101] MS m/z (ESI): 411.3[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.22 (s, 1H), 7.45 (d, 1H), 7.18 (t, 3H), 6.81 (d, 2H), 4.51 (s, 1H), 4.34 (t, 5H), 2.99-2.90 (m, 2H), 2.31 (d, 6H), 2.19-2.10 (m, 2H), 1.91- 1.79 (m, 2H), 1.69 (d, 2H), 1.32 (d, 6H). 88 [00102] MS m/z (ESI): 466.4[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.25 (m, 2H), 7.15-7.10 (m, 2H), 7.06 (s, 1H), 7.03- 6.97 (m, 1H), 6.90 (t, 1H), 6.82 (d, 1H), 5.46 (m, 1H), 4.41 (s, 2H), 4.19 (d, 2H), 4.00 (d, 1H), 3.53 (m, 1H), 3.23 (m, 1H), 2.93-2.85 (m, 2H), 2.26 (s, 5H), 1.70-1.60 (m, 2H), 1.50 (d, 2H). 89 [00103] MS m/z (ESI): 465.2 [M + 1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (d, 1H), 7.39- 7.36 (m, 2H), 7.21-7.08 (m, 3H), 6.84- 6.81(m, 2H), 6.07-5.75 (m, 1H), 4.47- 4.32 (m, 5H), 4.03 (t, 2H), 3.03 (d, 2H), 2.41-2.15 (m, 5H), 2.11-1.96(m, 4H), 1.75-1.56(m, 4H). 90 [00104] MS m/z (ESI): 453.5[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (d, 1H), 7.68 (m, 1H), 7.33 (m, 1H), 7.20 (d, 2H), 7.14 (m, 3H), 4.48 (s, 2H), 4.23 (d, 2H), 4.11-4.02 (m, 1H), 2.98 (d, 2H), 2.81-2.73 (m, 2H), 2.55 (m, 2H), 2.35 (s, 5H), 1.71 (m, 2H), 1.55 (m, 2H). 91 [00105] MS m/z (ESI): 430.3 [M + 1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.69-7.65 (m, 1H), 7.17-7.13 (m, 3H), 6.83-6.81 (m, 2H), 5.67-5.62(m, 1H), 4.65 (s, 2H), 4.31 (d, 2H), 4.10-4.01(m, 1H), 3.69(d, 2H), 2.88 (d, 2H), 2.26 (s, 3H), 2.14-1.97 (m, 3H), 1.76-1.66 (m, 4H), 1.01 (d, 6H). 92 [00106] MS m/z (ESI): 451.2 [M + 1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.27 (d, 1H), 7.39- 7.36 (m, 2H), 7.21 (d, 2H), 6.86-6.82 (m, 3H), 6.24-5.96 (m, 1H), 4.42-4.33 (m, 5H), 4.11 (t, 2H), 3.02 (d, 2H), 2.38- 2.21 (m, 7H), 1.95-1.72(m, 4H). 93 [00107] MS m/z (ESI): 469.2 [M + 1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16 (d, 1H), 7.25- 7.22 (m, 3H), 7.11-6.98 (m, 3H), 6.23- 5.95 (m, 1H), 4.42-4.23 (m, 4H), 4.19- 4.10 (m, 3H), 2.92 (d, 2H), 2.38-2.11 (m, 7H), 1.85-1.62(m, 4H). 94 [00108] MS m/z (ESI): 465.2 [M + 1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (d, 1H), 7.39- 7.36 (m, 2H), 7.21-7.08 (m, 3H), 6.84- 6.81(m, 2H), 6.07-5.75 (m, 1H), 4.47- 4.32 (m, 5H), 4.03 (t, 2H), 3.03 (d, 2H), 2.41-2.15 (m, 5H), 2.11-1.96(m, 4H), 1.75-1.56(m, 4H). 95 [00109] MS m/z (ESI): 483.2 [M + 1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16 (d, 1H), 7.25- 7.22 (m, 3H), 7.11-6.98 (m, 3H), 6.23- 5.95 (m, 1H), 4.47-4.36 (m, 4H), 4.23- 4.03 (m, 3H), 2.93 (d, 2H), 2.31 (s, 3H), 2.11-1.96(m, 6H), 1.85-1.66(m, 4H). 96 [00110] MS m/z (ESI): 430.2 [M + 1]; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (d, 1H), 8.16 (d, 1H), 7.69-7.66 (m, 1H), 7.37- 7.34 (m, 2H), 7.19-7.15 (m, 2H), 4.48(s, 2H), 4.28 (d, 2H), 3.95-3.79(m, 3H), 2.72 (d, 2H), 2.13 (s, 3H), 2.04-1.87 (m, 3H), 1.61-1.46 (m, 4H), 0.95 (d, 6H). 97 [00111] MS m/z (ESI): 430.2 [M + 1]; .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.30-8.23 (m, 1H), 8.06 (d, 1H), 7.69 (s, 1H), 7.53 (dd, 1H), 7.11 (d, 2H), 6.69 (d, 1H), 4.41-4.32 (m, 5H), 4.03 (d, 2H), 3.08 (d, 2H), 2.43 (s, 3H), 2.34-2.27 (m, 2H), 2.11-2.02 (m, 3H), 1.69 (d, 2H), 1.01 (d, 6H). 98 [00112] MS m/z (ESI): 441.3 [M + 1]; .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.25 (d, 1H), 7.48- 7.35 (m, 2H), 7.15-7.08 (m, 1H), 7.02- 6.93 (m, 2H), 6.71 (d, 1H), 4.51-4.38 (m, 3H), 4.30 (d, 2H), 3.24-3.14 (m, 2H), 2.73 (t, 2H), 2.51 (s, 5H), 2.29- 2.16 (m, 2H), 1.81-1.68 (m, 4H), 1.31 (s, 6H). 99 [00113] MS m/z (ESI): 439.3 [M + 1]; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.47 (d, 1H), 7.75-7.60 (m, 2H), 7.34 (m, 1H), 7.04 (d, 1H), 6.95 (m, 1H), 6.91-6.84 (m, 1H), 6.63 (m, 1H), 6.34 (d, 1H), 4.47 (s, 2H), 4.14 (m, 3H), 3.05 (d, 2H), 2.50 (m, 3H), 2.41 (s, 2H), 1.75 (m, 2H), 1.62-1.50 (m, 2H), 1.30 (d, 6H). 100 [00114] MS m/z (ESI): 454.3 [M + 1]; .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.14 (d, 1H), 7.26- 7.20 (m, 3H), 7.10-7.04 (m, 1H), 6.90- 6.85 (m, 2H), 6.08 (tt, 1H), 4.48 (d, 2H), 4.39-4.30 (m, 3H), 4.17 (td, 2H), 3.12 (d, 2H), 2.46 (s, 3H), 2.36 (s, 2H), 1.74- 1.68 (m, 2H). 101 [00115] MS m/z (ESI): 437.2 [M + 1]; .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.14 (d, 1H), 7.25- 7.20 (m, 3H), 7.04 (t, 1H), 6.90-6.86 (m, 2H), 4.81-4.77 (m, 1H), 4.73-4.70 (m, 1H), 4.48 (d, 2H), 4.36 (d, 3H), 4.21 (ddd, 2H), 3.29-3.14 (m, 2H), 2.51 (d, 5H), 2.19 (s, 2H), 1.77-1.71(m, 2H).

Example 2

[0173] ##STR00116##

[0174] Under nitrogen protection, in an ice-water bath, 1-methylpyrazole-4-carbaldehyde (440 mg, 4.0 mmol) was dissolved in 10 ml of methanol. N-methyl-4-piperidone (452 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 4a (617 mg).

[0175] Under nitrogen protection, compound 4a (208 mg, 1.0 mmol) was dissolved in 5 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 10 ml of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 4 (172 mg, yield: 43%). MS m/z (ESI): 414.3 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38 (s, 1H), 7.17 (s, 1H), 7.12-7.07 (m, 2H), 6.82-6.77 (m, 2H), 4.69 (m, 1H), 4.30-4.25 (m, 2H), 4.23-4.20 (m, 2H), 3.78 (s, 3H), 3.69-3.64 (d, 2H), 2.98-2.88 (m, 2H), 2.32 (s, 3H), 2.18-2.02 (m, 3H), 1.80-1.65 (m, 4H), 1.04-0.99 (d, 6H).

[0176] Compounds 5, 8 and 22 were prepared in a similar manner to compound 4.

TABLE-US-00002 TABLE 2 Structures and characterization data of compounds 5, 8 and 22 Compound number Structural formula Characterization data 5 [00117] MS m/z (ESI): 466.2 [M + 1]; .sup.1H NMR(400 MHZ, CDCl.sub.3) δ 7.79(d, 1H), 7.52(d, 1H), 7.40-7.37(m, 1H), 7.30- 7.27(m, 1H), 7.25-7.23(m, 1H), 7.02- 6.98(m, 2H), 6.78-6.75(m, 2H), 4.75(s, 3H), 4.68-4.59(m, 2H), 4.26(d, 2H), 3.70(d, 2H), 3.20-3.05(m, 3H), 2.50- 2.34(m, 4H), 2.10-1.98(m, 2H), 1.89- 1.82(m, 2H), 1.41-1.35(m, 2H), 1.02- 0.98(d, 6H). 8 [00118] MS m/z (ESI): 450.3 [M + 1]; .sup.1H NMR(400 MHZ, CDCl.sub.3) δ 7.82(d, 1H), 7.51(d, 1H), 7.20-7.09(m, 5H), 6.78- 6.73(m, 2H), 4.75(s, 2H), 4.28(d, 2H), 3.68(d, 2H), 3.20-3.05(m, 2H), 2.50- 2.34(m, 5H), 2.15-1.95 (m, 4H), 1.69- 1.52(m, 2H), 1.00-0.95(d, 6H). 22 [00119] MS m/z (ESI): 400.3 [M + 1]; .sup.1H NMR(400 MHZ, CDCl.sub.3) δ 7.42(s, 2H), 7.12-7.06(m, 2H), 6.84-6.79(m, 2H), 4.73(m, 1H), 4.41(m, 1H), 4.31- 4.25(m, 4H), 3.70-3.66(d, 2H), 3.18- 3.10(m, 2H), 2.47(s, 3H), 2.44-2.34(m, 2H), 2.10-1.98(m, 3H), 1.80-1.72(m, 2H), 1.03-0.98(d, 6H).

Example 3

[0177] ##STR00120## ##STR00121##

[0178] N-Boc-bromoethylamine (2.23 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-Piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80° C. and reacted under stirring for 8 h. The reaction solution was cooled to room temperature. 60 mL of water was added, and then the resulting solution was extracted with dichloromethane (60 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6a (1.97 g).

[0179] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. Compound 6a (968 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6b (912 mg).

[0180] Under nitrogen protection, compound 6b (702 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 6c (467 mg).

[0181] Under nitrogen protection, compound 6c (278 mg, 0.5 mmol) was dissolved in 5 mL of dichloromethane. Trifluoroacetic acid (285 mg, 2.5 mmol) was added, and the resulting mixture was reacted at room temperature for 2 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (5 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6 (201 mg, yield: 88%). MS m/z (ESI): 457.2 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25-7.23 (m, 2H), 7.02-6.98 (m, 4H), 6.78-6.75 (m, 2H), 4.48-4.27 (m, 5H), 3.62-3.59 (m, 2H), 3.51-3.29 (m, 2H), 2.94-2.89 (m, 2H), 2.84-2.80 (m, 2H), 2.47-2.41 (m, 2H), 2.18-2.02 (m, 3H), 1.75-1.68 (m, 4H), 1.02-0.98 (d, 6H).

Example 4

[0182] ##STR00122## ##STR00123##

[0183] 1-(2-Bromoethyl)imidazolidine-2-one (1.93 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-Piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80° C. and reacted under stirring for 8 h. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was extracted with dichloromethane (60 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 7a (1.56 g).

[0184] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. Compound 7a (844 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 7b (812 mg).

[0185] Under nitrogen protection, compound 7b (640 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 7 (494 mg, yield: 47%). MS m/z (ESI): 526.3 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.24-7.22 (m, 2H), 7.02-6.98 (m, 4H), 6.78-6.75 (m, 2H), 4.60-4.54 (m, 2H), 4.32-4.26 (m, 4H), 3.72-3.62 (m, 4H), 3.51-3.44 (m, 2H), 3.41-3.32 (m, 2H), 3.30-3.26 (m, 2H), 2.98-2.92 (m, 2H), 2.47-2.41 (m, 2H), 2.18-2.02 (m, 3H), 1.74-1.65 (m, 4H), 1.02-0.99 (d, 6H).

Example 5

[0186] ##STR00124## ##STR00125##

[0187] Tert-butyl dimethyl bromoethoxysilane (2.38 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-Piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80° C. and reacted under stirring for 8 h. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was extracted with dichloromethane (60 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 9a (1.72 g).

[0188] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. Compound 9a (1028 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 9b (812 mg).

[0189] Under nitrogen protection, compound 9b (732 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 9c (327 mg).

[0190] Under nitrogen protection, compound 9c (286 mg, 0.5 mmol) was dissolved in 5 ml of THF. A 1 M tetrabutylammonium fluoride tetrahydrofuran solution (1 ml, 1.0 mmol) was added, and the resulting mixture was reacted at room temperature for 2 h. The organic phase was concentrated and then extracted with dichloromethane (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 9 (118 mg, yield: 52%). MS m/z (ESI): 458.3 [M+1]; H NMR (400 MHz, CDCl.sub.3) δ 7.23-7.20 (m, 2H), 7.02-6.98 (m, 4H), 6.81-6.76 (m, 2H), 4.70-4.50 (m, 2H), 4.38-4.27 (m, 4H), 3.78-3.69 (m, 4H), 3.41-3.19 (m, 2H), 2.84-2.74 (m, 2H), 2.67-2.51 (m, 2H), 2.18-2.02 (m, 2H), 1.81-1.58 (m, 3H), 1.02-0.98 (d, 6H).

Example 6

[0191] ##STR00126##

[0192] 2-Bromo-N,N-dimethylacetamide (1.66 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-Piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80° C. and reacted under stirring for 8 h. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was extracted with dichloromethane (60 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 10a (1.15 g).

[0193] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. Compound 10a (736 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 10b (832 mg).

[0194] Under nitrogen protection, compound 10b (586 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 10 (535 mg, yield: 54%). MS m/z (ESI): 499.3 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.20-7.13 (m, 2H), 7.02-6.95 (m, 4H), 6.77-6.73 (m, 2H), 4.48-4.43 (m, 1H), 4.38-4.27 (m, 3H), 4.26-4.23 (m, 2H), 3.66 (d, 2H), 3.15 (d, 2H), 3.02-2.88 (m, 8H), 2.30-2.20 (m, 2H), 2.10-2.00 (m, 1H), 1.80-1.65 (m, 4H), 1.01-0.96 (d, 6H).

Example 7

[0195] ##STR00127## ##STR00128##

[0196] 7-(4-Bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (2.98 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-Piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80° C. and reacted under stirring for 8 h. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was extracted with dichloromethane (60 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 11a (2.26 g).

[0197] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. Compound 11a (1.26 g, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 11b (1.03 g).

[0198] Under nitrogen protection, compound 11b (425 mg, 1.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 11 (311 mg, yield: 49%). MS m/z (ESI): 631.3 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.96 (s, 1H), 7.20-7.15 (m, 2H), 7.04-6.96 (m, 4H), 6.79-6.75 (m, 2H), 6.50-6.43 (m, 1H), 6.32-6.28 (m, 1H), 4.70-4.52 (m, 2H), 4.48-4.43 (m, 2H), 4.31-4.27 (m, 2H), 3.98-3.90 (m, 2H), 3.64 (d, 2H), 3.50-3.20 (d, 2H), 2.82-2.58 (m, 4H), 2.56-2.44 (m, 4H), 2.10-2.00 (m, 2H), 1.90-1.65 (m, 7H), 1.02-0.97 (d, 6H).

Example 8

[0199] ##STR00129##

[0200] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. N,N-dimethyl-1,3-diaminopropane (408 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 14a (587 mg).

[0201] Under nitrogen protection, compound 14a (210 mg, 1.0 mmol) was dissolved in 5 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 10 ml of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (5 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 13 (202 mg, yield: 48%). MS m/z (ESI): 416.3 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.26-7.20 (m, 4H), 7.02-6.97 (m, 2H), 6.81-6.76 (m, 2H), 4.47 (s, 2H), 4.38-4.35 (m, 2H), 3.71 (s, 2H), 3.30-3.24 (m, 2H), 2.35-2.25 (m, 2H), 2.15-2.00 (m, 7H), 1.65-1.58 (m, 2H), 1.02-0.98 (d, 6H).

Example 9

[0202] ##STR00130##

[0203] (2-Bromomethyl)dimethylamine (1.52 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-Piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80° C. and reacted under stirring for 8 h. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was extracted with dichloromethane (60 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 15a (1.17 g).

[0204] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. Compound 15a (680 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 15b (611 mg).

[0205] Under nitrogen protection, compound 15b (279 mg, 1.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 15 (287 mg, yield: 59%). MS m/z (ESI): 485.3 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.22-7.16 (m, 2H), 7.02-6.95 (m, 4H), 6.77-6.75 (m, 2H), 4.55-4.46 (m, 1H), 4.38-4.32 (m, 2H), 4.26-4.23 (m, 2H), 3.67 (d, 2H), 3.19 (d, 1H), 2.98-2.68 (m, 6H), 2.61 (s, 6H), 2.45-2.35 (m, 2H), 2.10-2.00 (m, 2H), 1.80-1.65 (m, 2H), 1.01-0.96 (d, 6H).

Example 10

[0206] ##STR00131##

[0207] Under nitrogen protection, compound 3 (372 mg, 1.0 mmol) was dissolved in 10 ml of acetonitrile. 1-Bromo-3-fluoropropane (211 mg, 1.5 mmol) and cesium carbonate (652 mg, 2.0 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 5 h. The reaction solution was cooled to room temperature and filtered. 10 ml of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 17 (238 mg, yield: 54%). MS m/z (ESI): 433.2 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.22 (s, 1H), 7.45-7.35 (m, 2H), 7.22-7.14 (m, 2H), 7.15-7.07 (m, 1H), 6.85-6.81 (m, 2H), 4.67 (t, 1H), 4.60 (t, 1H), 4.44-4.34 (m, 3H), 4.34 (d, 2H), 4.07 (t, 2H), 3.12 (d, 2H), 2.46 (s, 3H), 2.40-2.32 (m, 2H), 2.19-2.05 (m, 4H), 1.75-1.67 (m, 2H).

[0208] Compounds 18, 55-57, 59-60, 62, 65, 69, 73-74, 78 and 82 were prepared in a similar manner to compound 17.

TABLE-US-00003 TABLE 3 Structures and characterization data of compoundes 18, 55-57, 59-60, 62, 65, 69, 73-74, 78 and 82 Compound number Structural formula Characterization data 18 [00132] MS m/z (ESI): 429.3 [M + 1]; .sup.1H NMR(400 MHz,CDCl.sub.3) δ 8.23(s, 1H), 7.39-7.34(m, 2H), 7.17-7.14(m, 2H), 6.98-6.90(m, 3H), 4.37(s, 2H), 4.41(s, 2H), 4.38-4.34(m, 2H), 3.06-3.00(m, 2H), 2.39(s, 3H), 2.30-2.24(m, 2H), 2.02-1.93(m, 2H), 1.73-1.68(m, 2H), 1.32(s, 9H). 55 [00133] MS m/z (ESI): 469.2 [M + 1]; 1H NMR(400 MHz, CDCl3) δ 8.27(d, 1H), 7.44-7.35(m, 2H), 7.25-7.19(m, 2H), 7.17-7.08(m, 1H), 6.85-6.80(m, 2H), 4.42-4.34(m, 5H), 4.18(t, 2H), 3.10(d, 2H), 2.65-2.58(m, 2H), 2.45(s, 3H), 2.37-2.30(m, 2H), 2.11-2.02(m, 2H), 1.73-1.67(m, 2H). 56 [00134] MS m/z (ESI): 418.2 [M + 1]; 1H NMR(400 MHz, CDCl3) δ 7.20-7.15(m, 2H), 7.04- 6.94(m, 4H), 6.85-6.77(m, 2H), 4.77(t, 1H), 4.68(t, 1H), 4.54-4.38(m, 2H), 4.34(s, 2H), 4.27(d, 2H), 4.22-4.14(m, 2H), 3.02(d, 2H), 2.36(s, 3H), 2.30-2.18(m, 2H), 1.95-1.73(m, 4H). 57 [00135] MS m/z (ESI): 436.2 [M + 1]; 1H NMR(400 MHz, CDCl3) δ 7.21-7.15(m, 2H), 7.05- 6.96(m, 4H), 6.83-6.77(m, 2H), 6.15- 5.97(m, 1H), 4.55(t, 1H), 4.50-4.35(m, 3H), 4.28(d, 2H), 4.15(dt, 2H), 3.03(d, 2H), 2.38(s, 3H), 2.31-2.22(m, 2H), 1.92-1.73(m, 4H). 59 [00136] MS m/z (ESI): 455.5[M + 1], 477.5[M + 23]1H NMR (600 MHz, DMSO-d6) δ 8.49 (d, 1H), 7.74-7.65 (m, 1H), 7.33 (m, 1H), 7.23-7.17 (m, 2H), 7.13 (s, 1H), 7.00-6.95 (m, 2H), 4.72 (q, 2H), 4.47 (s, 2H), 4.21 (d, 2H), 4.16- 4.05 (m, 1H), 3.07 (s, 2H), 2.50 (d, 3H), 2.44 (s, 2H), 1.77 (d, 2H), 1.58 (d, 2H). 60 [00137] MS m/z (ESI): 419.48[M + 1]1H NMR (600 MHz, CDCl3) δ 8.24 (d, 1H), 7.52 (m, 1H), 7.40 (m, 2H), 7.23 (d, 2H), 6.88 (d, 2H), 4.81-4.77 (m, 1H), 4.72-4.69 (m, 1H), 4.52- 4.45 (m, 1H), 4.43 (s, 2H), 4.36 (d, 2H), 4.25-4.21 (m, 1H), 4.20-4.16 (m, 1H), 3.29- 3.23 (m, 2H), 2.58 (s, 3H), 2.56 (s, 2H), 2.33 (d, 2H), 1.74 (m, 2H). 62 [00138] MS m/z (ESI): 447.26[M + 1]1H NMR (600 MHz, DMSO-d6) δ 8.48 (d, 1H), 7.68 (d, 1H), 7.33 (m, 1H), 7.16-7.07 (m, 3H), 6.85 (d, 2H), 4.54 (t, 1H), 4.46 (q, 3H), 4.18 (d, 2H), 3.97 (t, 1H), 3.09 (s, 2H), 2.50 (m, 3H), 2.47-2.41 (m, 2H), 1.86-1.73 (m, 6H), 1.62- 1.54 (m, 2H), 1.29-1.19 (m, 2H). 65 [00139] MS m/z (ESI): 454.2[M + 1], 476.3[M + 23].sup.1H NMR (600 MHZ, DMSO-d.sub.6) δ 7.24 (m, 2H), 7.19-7.15 (m, 2H), 7.14-7.10 (m, 2H), 6.98 (m, 3H), 4.72 (q, 2H), 4.41 (s, 2H), 4.20 (d, 2H), 4.04 (s, 1H), 2.93 (s, 2H), 2.50 (t, 3H), 2.30 (s, 2H), 1.82-1.65 (m, 2H), 1.50 (d, 2H). 69 [00140] MS m/z (ESI): 480.4[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.25-7.20 (m, 2H), 7.19- 7.15 (m, 2H), 7.14-7.07 (m, 2H), 7.00-6.96 (m, 2H), 6.93 (t, 1H), 4.72 (q, 2H), 4.39 (s, 2H), 4.20 (d, 2H), 3.96 (s, 1H), 2.88 (d, 2H), 2.17 (d, 2H), 1.43 (d, 4H), 1.24 (d, 1H), 0.36 (d, 2H), 0.21 (s, 2H). 73 [00141] MS m/z (ESI): 472.2[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.24-7.15 (m, 4H), 7.15- 7.08 (m, 1H), 7.03 (m, 1H), 6.97 (d, 2H), 4.72 (d, 2H), 4.40 (s, 2H), 4.19 (d, 2H), 4.14- 4.04 (m, 1H), 2.97 (s, 2H), 2.50 (m, 3H), 2.34 (s, 2H), 1.71 (s, 2H), 1.56 (d, 2H). 74 [00142] MS m/z (ESI): 454.1[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.24-7.18 (m, 2H), 7.16 (d, 2H), 7.13 (s, 1H), 7.04 (td, 1H), 6.93 (d, 2H), 6.38 (m, 1H), 4.41 (s, 2H), 4.28 (d, 2H), 4.19 (d, 3H), 3.21-3.08 (m, 2H), 2.64 (d, 2H), 2.51 (p, 3H), 1.94-1.80 (m, 2H), 1.62 (d, 2H). 78 [00143] MS m/z (ESI): 437.2[M + 1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.23 (d, 1H), 7.56 (m, 2H), 7.40 (m, 1H), 7.26-7.22 (m, 2H), 6.88-6.82 (m, 2H), 6.07 (s, 1H), 4.50 (t, 1H), 4.43 (s, 2H), 4.36 (d, 2H), 4.16 (m, 2H), 3.37-3.29 (m, 2H), 2.67(s, 2H), 2.64 (s, 2H), 2.43 (m, 3H), 1.78-1.66 (m, 2H). 82 [00144] MS m/z (ESI): 483.2[M + 1].sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (d, 1H), 7.77-7.57 (m, 1H), 7.33 (m, 1H), 7.21-7.08 (m, 3H), 6.96-6.82 (m, 2H), 4.46 (s, 2H), 4.18 (d, 2H), 4.16-4.12 (m, 1H), 4.00 (t, 2H), 3.07 (s, 2H), 2.50 (m, 3H), 2.48-2.36 (m, 2H), 1.96-1.88 (m, 2H), 1.87-1.75 (m, 2H), 1.58 (d, 2H), 1.42-1.21 (m, 2H).

Example 11

[0209] ##STR00145##

[0210] Under nitrogen protection, compound 1a (446 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. Compound 32a (440 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol) and diisopropylethylamine (387 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered. 20 ml of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 32 (561 mg, yield: 66%). MS m/z (ESI): 426.2 [M+1]; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (s, 1H), 7.72-7.64 (m, 1H), 7.26-7.20 (m, 1H), 6.99-6.87 (m, 2H), 6.62-6.53 (m, 1H), 4.53 (s, 2H), 4.38-4.24 (m, 1H), 2.97-2.92 (d, 2H), 2.80-2.61 (m, 5H), 2.55-2.52 (m, 1H), 2.12 (s, 3H), 1.98-1.88 (m, 2H), 1.65-1.30 (m, 10H).

[0211] Compounds 53 and 54 were prepared in a similar manner to compound 32.

TABLE-US-00004 TABLE 4 Structures and characterization data of compounds 53 and 54 Compound number Structural formula Characterization data 53 [00146] MS m/z (ESI): 428.3 [M + 1]; .sup.1H NMR(400 MHZ, DMSO-d.sub.6) δ 7.34- 7.27(m, 2H), 7.18-7.09(m, 2H), 6.75- 6.68(m, 2H), 6.62-6.50(m, 2H), 4.99(s, 1H), 4.55(s, 2H), 3.96-3.76(m, 3H), 3.63(m, 2H), 2.72(d, 2H), 2.18(s, 3H), 2.03-1.85(m, 3H), 1.75-1.53(m, 4H), 0.92(d, 6H). 54 [00147] MS m/z (ESI): 454.2 [M + 1]; .sup.1H NMR(400 MHZ, DMSO-d.sub.6) δ 8.5(d, 1H), 7.74-7.67(m, 1H), 7.38-7.19(m, 2H), 7.12-7.07(m, 1H), 6.99-6.88(m, 2H), 4.75-4.65(m, 2H), 4.60-4.50(m, 2H), 4.40-4.31(m, 1H), 3.25-3.15(m, 2H), 2.90-2.75(m, 5H), 2.65-2.55(m, 4H), 1.85-1.75(m, 2H), 1.70-1.58(m, 2H).

Example 12

[0212] ##STR00148##

Synthesis Route:

[0213] ##STR00149##

[0214] Under nitrogen protection, compound 63a (1.212 g, 11.3 mmol) was dissolved in 10 ml of acetonitrile. Bromomethyl cyclohexane (2 g, 11.3 mmol) and potassium carbonate (4.68 g, 33.9 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered, and then the filtrate was extracted with dichloromethane (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 63b (1.49 g, a light yellow oily liquid).

[0215] Under nitrogen protection, compound 63b (1.49 g, 7.63 mmol) was dissolved in 20 ml of methanol. (5-Fluoropyridin-2-methyl)amine (962.4 mg, 7.63 mmol) and sodium triacetoxyborohydride (1.972 g, 9.31 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 h. An aqueous solution of NaHCO.sub.3 was added to adjust the pH value to alkaline. The organic phase was concentrated and then extracted with dichloromethane (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and subjected to column chromatography to obtain compound 63c (217 mg).

[0216] Under nitrogen protection, compound 63c (217 mg, 0.71 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-1-formamide (194 mg, 0.710 mmol) and potassium carbonate (107.9 mg, 0.781 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 12 h. The reaction solution was cooled to room temperature and filtered, and then the filtrate was extracted with dichloromethane (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 63 (50.5 mg, a light yellow oily liquid, yield: 14%). MS m/z (ESI): 511.69[M+1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.24 (d, 1H), 7.37 (d, 2H), 7.17 (d, 2H), 6.90-6.75 (m, 2H), 4.42 (s, 2H), 4.33 (d, 2H), 3.70 (d, 2H), 3.11 (s, 2H), 2.41-2.14 (m, 1H), 2.11-2.01 (m, 2H), 1.85-1.63 (m, 10H), 1.46-1.36 (m, 2H), 1.31 (d, 2H), 1.24 (d, 2H), 1.16 (s, 2H), 1.02 (s, 3H), 1.01 (s, 3H).

Example 13

[0217] ##STR00150##

Synthesis Route:

[0218] ##STR00151##

[0219] Under nitrogen protection, compound 79a (200 mg, 0.75 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazol-1-formamide (207 mg, 0.75 mmol) and potassium carbonate (105 mg, 0.75 mmol) were added, and the resulting mixture was heated to 60° C. and reacted under stirring for 5 h. The reaction solution was cooled to room temperature and filtered, and then the filtrate was extracted with dichloromethane (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 79 (166 mg, a light yellow oily liquid, yield: 47%). MS m/z (ESI): 471.2[M+1].sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.20 (m, 2H), 7.01 (m, 4H), 6.92 (s, 1H), 6.81-6.74 (m, 2H), 5.40 (s, 1H), 4.44 (t, 1H), 4.34 (s, 3H), 4.27 (d, 2H), 3.68 (d, 2H), 2.98 (s, 2H), 2.94-2.87 (m, 2H), 2.31 (m, 2H), 2.06 (m, 1H), 1.80-1.74 (m, 2H), 1.66 (m, 2H), 1.01 (d, J=6.7 Hz, 6H).

Test Example 1. In-Vitro Activity Test of 5-HT.SUB.2A .Receptor

1. Screening for 5-HT.SUB.2A .Inverse Agonistic Activity

1.1 Test Materials:

[0220] Cell lines: Adherent cells NIH3T3-5-HT.sub.2A R [0221] Cell culture medium: DMEM+10% FBS (purchased from GBICO) [0222] Cell culture plate: White-wall clear-bottom 96-well plate (purchased from Perkin Elmer) [0223] Detection kit: Bright-Glo™ Luciferase (purchased from Promega) [0224] Detection instrument: BioTek multifunctional microplate reader

1.2 Test Drugs

[0225] Pimavanserin: Purchased from MCE Corporation [0226] Other compounds: Prepared according to the preceding examples

1.3 Test Method:

[0227] NIH.sub.3T3-5HT.sub.2AR cells in the logarithmic growth phase were seeded into a white-wall clear-bottom 96-well plate at a density of 1000 cells per well, and cultured overnight in a 37° C., 5% CO.sub.2 incubator. The next day, a compound to be tested was added to the cells, wherein the compound to be tested was subjected to 3.16-fold gradient dilution with PBS to obtain 9 concentrations, with the highest concentration of 10 uM, and double replicate wells were set up for each concentration; and PBS was used as a negative control group, and pimavanserin with the same concentration was used as a positive control group. After the addition, the cells were cultured in a 37° C., 5% CO.sub.2 incubator for another 120 h. On the sixth day, a Bright-Glo™ Luciferase reagent with a volume equal to that of cell sap was added to the cells, and the cells were incubated at room temperature in the dark for 20 min. The plate was shaken every 5 min with a plate shaker, the luminescent intensity was detected by a microplate reader, and the cell inhibition rate was calculated. The data was processed with GraphPad Prism 7.0 to obtain a cell inhibition rate curve, and the IC.sub.50 was calculated. The test results were as shown in Table 5.

Cell inhibition rate (%)=[100−(Lum test drug−Lum culture solution)/(Lum cell control−Lum culture solution)×100]%

2. Test for 5-HT.SUB.2A .Antagonistic Activity (i.e., Calcium Ion Antagonism)

2.1 Test Materials:

[0228] Cell lines: CHO-K1/5-HT.sub.2A (Chempartner) [0229] Cell culture medium: DMEM/F12+10% FBS (purchased from GBICO) [0230] Cell culture plate: 384-well Assay Plate (purchased from Corning) [0231] Detection kit: FLIPR® Calcium 4 Assay Kit (purchased from Molecular Devices)

2.2 Test Drugs

[0232] Pimavanserin: Purchased from MCE Corporation [0233] Other compounds: Prepared according to the preceding examples

2.3 Test Method:

[0234] CHO-K1/5-HT.sub.2A cells in the logarithmic growth phase were seeded into a 384-well plate at a density of 10000 cells per well, and cultured in a 37° C., 5% CO.sub.2 incubator for 16-24 h. After that, centrifugation was performed to remove the culture medium in the cell culture plate. Dye was added, and the cells were incubated in a 37° C., 5% CO.sub.2 incubator for another 1 h. The cell culture plate was placed on the FLIPR. A compound to be tested was added, and the Ca.sup.2+ signal was detected, wherein the compound to be tested was subjected to 3-fold gradient dilution with PBS to obtain 10 concentrations, with the highest concentration of 10 uM, and double replicate wells were set up. 100 nM a-methyl-5-HT was added 15 min later, and the Ca.sup.2+ signal was detected again, wherein the value obtained by only adding 100 nM a-methyl-5-HT was taken as the maximum signal. In order to determine the test stability, risperidone was used as a positive control. The data were processed with GraphPad Prism 7.0 to obtain a cell inhibition rate curve, and the IC.sub.50 was calculated. The test results were as shown in Table 5.

Inhibition rate (%)=100%−[(signal value of the compound to be tested−signal value of the test solution)/(the maximum signal value−the signal value of the test solution)]×100%

Test Example 2. hERG Inhibitory Activity

1. Test Materials and Instruments

1.1 Positive Control Compound

[0235] Name: Cisapride

1.2 Solvent

[0236] Name: Dimethyl sulfoxide (DMSO)

1.3 Cells

[0237] Species & strains: CHO-hERG cell lines (Chinese hamster ovary cells stably expressing hERG channels) [0238] Culture medium: 90% F12, 10% fetal bovine serum, 100 μg/mL G418 and 100 μg/mL hygromycin B [0239] Culture conditions: 5% CO2, 37° C. incubator [0240] Freezing conditions: Liquid nitrogen

1.4 Test Instruments

[0241] Patch clamp amplifier (Axoclamp 200B, Multiclamp 700B, Axon, US) [0242] Digital analog converter (DigiData 1440A, DigiData 1550B, Axon, US) [0243] Inverted microscope (IX51, IX71, Olympus, Japan) [0244] Rapid drug delivery system (RSC-200, Bio-Logic, France) [0245] Micromanipulator (MX7600R, Syskiyou, US) [0246] Electrode puller (P-97, Sutter, US) [0247] Glass electrode (BF150-86-10, Sutter, US) [0248] Vibration isolation table and shielding mesh (63-534, TMC, US) [0249] Data acquisition and analysis software (pClamp 10, Axon, US) [0250] Carbon dioxide incubator (HERacell 150i, Thermo, US) [0251] Biological safety cabinet (MODEL 1384, Thermo, US) [0252] Water purifier (Milli Q, Millipore, US)

2. Test Method

2.1 Cell Culture and Treatment

[0253] CHO cells stably expressing hERG were cultured in a cell culture dish with the diameter of 35 mm in a 37° C., 5% CO2 incubator, and passaged at a ratio of 1:5 every 48 h. On the day of the test, the cell culture solution was pipetted, the cells were rinsed once with extracellular fluid, and then a 0.25% Trypsin-EDTA (Invitrogen) solution was added. Digestion was performed at room temperature for 3-5 min. The digestion solution was pipetted, and the cells were resuspended in extracellular fluid and transferred to an experimental dish for electrophysiological recording for later use.

2.2 Compound Preparation

[0254] On the day of the test, the compound was diluted with DMSO to an intermediate concentration. 10 μL of compound with the intermediate concentration was taken, transferred to 4990 μL of extracellular fluid, and subjected to 500-fold dilution to obtain a final concentration to be tested.

[0255] Preparation of positive control compound Cisapride: 10 μL of 150 μM Cisapride DMSO mother liquor was taken, transferred to 4990 μL of extracellular fluid, and subjected to 500-fold dilution to obtain a final concentration 300 nM to be tested.

2.3 Electrophysiological Recording Process

[0256] CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were taken, and hERG potassium channel currents were recorded at room temperature by means of a whole-cell patch-clamp technique. A glass microelectrode was formed by pulling a glass electrode blank (BF150-86-10, Sutter) with a glass microelectrode puller. The tip resistance was about 2-5 MΩ after perfusion of a pippette solution. The glass microelectrode could be connected to a patch clamp amplifier by inserting the glass microelectrode into an amplifier probe. Clamping voltages and data recording were controlled and recorded by a computer with pClamp 10 software, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After the whole-cell recording was obtained, the cells were clamped at −80 mV, and the step voltage evoking hERG potassium current (I hERG) was changed from −80 mV to +20 mV by giving a 2 s depolarization voltage and then repolarized to −50 mV for 1 s, and returned to −80 mV. Such voltage stimulation was given every 10 s, and the administration process was started after it was determined that the hERG potassium currents were stable (1 min). The compound at each test concentration was given at least 1 min, and at least 2 cells (n≥2) were tested for each concentration.

2.4 Data Processing and Analysis

[0257] Data analysis was performed by means of pClamp 10 and GraphPad Prism 5.0 software.

[0258] The formula for calculating the degree of inhibition of different compound concentrations on hERG potassium currents (the hERG tail current peak value evoked at −50 mV) was:

Inhibition %=[1−(I/Io)]×10000

[0259] wherein Inhibition 0% represents the percentage of inhibition of hERG potassium currents by the compound, and I and Io represent the amplitudes of hERG potassium current after administration and before administration, respectively.

[0260] Compound IC.sub.50 was calculated via the following equation fitting by means of GraphPad Prism 5 software, and the test results were as shown in Table 5:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogIC.sub.50−X)*HillSlope))

[0261] wherein X is a Log value of a test concentration of a test sample, Y is the inhibition percentage at a corresponding concentration, and Bottom and Top are the minimum inhibition percentage and the maximum inhibition percentage, respectively.

Test Results

[0262]

TABLE-US-00005 TABLE 5 In-vitro test results of compounds of the present invention 5-HT.sub.2A 5-HT.sub.2A inverse antagonistic agonistic hERG inhibitory Compound activity IC.sub.50 activity IC.sub.50 activity IC.sub.50 number (nM) (nM) (μM) Pimavanserin 27.3 50 0.41 1 8.64 22.80 0.41 3 11.6 — >10 13 1.92 — 1.3 14 2.17 — — 17 1.93 3.05 1.55 18 5.75 1.12 0.85 19 6.94 49.85 0.48 20 9.14 — 0.68 21 2.1 34.15 0.91 23 6.02 5.64 >10 24 3.49 2.54 3.61 25 6.73 16.87 1.03 26 6.86 9.79 0.53 30 9.92 10.66 — 31 17.4 30.04 1.85 37 2.05 42.78 3.99 38 — 10.04 — 41 9.98 4.29 0.79 45 2.42 7.04 5.5 46 4.15 11.06 10.4 47 3.13 9.22 1.39 48 3.14 22.5 2.4 49 4.1 7.3 2.43 50 20.9 — 0.55 52 — 42.74 — 55 4.7 2.23 0.69 56 5.77 9.90 — 57 6.41 6.83 — 59 0.54 2.04 0.81 60 2.11 16.4 >10 61 3.32 31.21 2.55 62 2.35 32.8 1.43 63 — 20.84 — 65 7.98 18.4 0.67 66 12 8.85 — 70 8.09 12.33 0.5 71 9.52 — 3.32 74 8.95 — — 75 8.35 14.37 — 76 20.68 — — 77 6.59 6.44 — 78 2.17 6.01 1.74 81 2.78 30.06 0.68 82 3.78 1.95 0.5 89 7.72 — 2.05 91 14.7 — 0.58 92 4.64 6.54 — 93 4.26 10.58 — 94 4.29 7.59 — 95 5.13 27.92 — 96 11.39 26.38 — 98 21.25 — 1.46 99 17.27 33.34 0.65

[0263] The results show that: [0264] the compounds of the present invention have superior 5-HT.sub.2A antagonistic activity and/or 5-HT.sub.2A inverse agonistic activity to those of pimavanserin, and have lower cardiotoxicity.

Test Example 3. In-Vitro Stability Evaluation of Pimavanserin and Compound 59 in Liver Microsomes

1 Solution Formulation

[0265] 1) formulation of test sample working solution: the test sample was diluted to 100 μM with methanol; [0266] 2) formulation of liver microsome working solution: liver microsomes were diluted to 0.56 mg/ml with a 100 mM phosphate buffer; [0267] 3) formulation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: an appropriate amount of NADPH was weighted and diluted to 20 mM with a phosphate buffer, and then a 60 mM MgCl.sub.2 solution with the equal volume was added; [0268] 4) formulation of stop solution: tolbutamide was diluted to 20 ng/mL with acetonitrile to serve as a stop solution containing an internal standard.

2 Incubation Process

[0269] 1) anti-adsorption EP tubes for incubation were prepared, and species, test samples, reference substances (testosterone and dextromethorphan), time points (0 min, 5 min, 10 min, 20 min, 30 min, 60 min, Blank60 and NCF60), etc. were labeled; [0270] 2) 2 μL of test sample or reference substance working solution and 178 μL of liver microsome working solution were added to each tube, 2 μL of acetonitrile in place of the test samples was added to the Blank tube, and the mixture was placed in a 37° C. water bath kettle and pre-incubated for about 10 min, wherein each sample was divided in triplicate aliquots; [0271] 3) after the pre-incubation was completed, 20 μL of NADPH working solution was added to each tube except for 0 min and NCF60 to initiate the reaction, and 20 μL of phosphate buffer (containing 30 mM MgCl.sub.2) was added to the NCF60 tube, wherein in the incubation system, the test sample or the reference substance had a final concentration of 1 μM, the liver microsomes had a final concentration of 0.5 mg/mL, the NADPH had a final concentration of 1 mM, and the MgCl.sub.2 had a final concentration of 3 mM; [0272] 4) 600 μL of stop solution was added to the 0-min sample followed by an NADPH working solution, and 600 μL of stop solution was added to stop the reaction after each sample was incubated for a corresponding period of time; [0273] 5) each sample was vortexed for 30 s after the reaction was stopped and then centrifuged at 13500 rpm for 10 m; 100 L of supernatant was added to an EP tube, 100 μL of Milli-Q water was added, and the resulting mixture was vortexed and mixed uniformly; and LC-MS/MS analysis was performed by using the method in Table 6; and [0274] 6) testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

TABLE-US-00006 TABLE 6 LC-MS-MS analysis methods Analyte Pimavanserin, compound 59, testosterone and dextromethorphan Liquid-phase method Mobile phase A 0.1% formic acid in water Mobile phase B 0.1% formic acid in methanol Chromatographic ACQUITY UPLC BEH C18 2.1 × 50 mm, column particle size 1.7 uM Waters Internal standard Tolbutamide Injection volume 5 μL Gradient Time Flow rate A B (min) (μL/min) (%) (%) 0.00 0.5 80 20 1.00 0.5 80 20 1.10 0.5 10 90 2.00 0.5 10 90 2.30 0.5 80 20 3.00 0.5 80 20 Mass spectrometry method Scanning mode MRM Compound name Ion pair DP EP CE CXP (eV) (eV) (eV) (eV) Pimavanserin 428.2/223.2 84 11 24 18 Compound 59 429.2/224.2 50 6 23 8 Testosterone 289.1/97.0  99 14 29 8 Dextromethorphan 272.2/171.1 130 10 46 7 Tolbutamide 271.1/155.3 30 8 21 7

3 Data Analysis

[0275] The remaining percentage of the test sample was tested 60 min later. The test results were as shown in Table 7.

TABLE-US-00007 TABLE 7 Test data of compounds of the present invention in human and rat liver microsomes Remaining amount Compounds Species 60 min later % Pimavanserin Dog 29.72 Human 77.44 Compound 59 Dog 76.37 Human 89.19

[0276] The results show that: compound 59 has obviously superior stability to that of pimavanserin in dog and human liver microsomes in vitro, and has better druggability.

Test Example 4. In-Vivo Pharmacokinetic Test of Pimavanserin and Compound 59 in Rats

1 Test Drugs

[0277] Pimavanserin: Purchased from MCE Corporation. [0278] Compound 59: Prepared according to the previous examples

2 Test Method

[0279] Eight SD rats weighting about 220 g were randomly divided into 2 groups, 4 rats per group, fasted for 12 h before administration, and intragastrically given pimavanserin and compound 59 at a dose of 46.7 μmol/kg, respectively, with vehicles both being 20% Solutol. Blood was collected before administration and 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration, respectively and placed in a heparinized EP tube, and the plasma was centrifugally separated. After the plasma was pre-treated, the concentrations of compounds in the plasma were determined by LC-MS/MS, and the pharmacokinetic parameters were calculated. The test results were as shown in FIG. 1 and Table 8.

TABLE-US-00008 TABLE 8 Comparison of pharmacokinetic parameters of pimavanserin and compound 59 after intragastric administration Parameter Unit Pimavanserin Compound 59 T.sub.max h 2.75 ± 1.26 5.88 ± 5.14 C.sub.max nmol/L 536 ± 260 1135 ± 365  AUC.sub.last nmol/L * h 4286 ± 1664 16987 ± 2969  T.sub.1/2 h 2.38 ± 0.8  5.51 ± 1.33 MRT.sub.last h 5.61 ± 0.34 8.66 ± 0.89

[0280] The results show that: the T.sub.1/2 of compound 59 is higher than that of pimavanserin; the C.sub.max of compound 59 is 2 times that of pimavanserin; the AUC.sub.last of compound 59 is 4 times that of pimavanserin; and the in-vivo pharmacokinetic properties of compound 59 are obviously better than those of pimavanserin.