Fluoroallylamine Derivative And Use Thereof

Abstract

The present invention relates to a fluoroallylamine derivative and use thereof. In particular, the present invention relates to a compound as shown in Formula I, a prodrug, an isomer, an isotope-labeled compound, a solvate or a pharmaceutically acceptable salt thereof, which has VAP-1/SSAO inhibitory activity, and can be used for treating a disease associated with VAP-1/SSAO overactivity.

##STR00001##

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof: ##STR00075## Wherein: R.sub.1 is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, 3-10-membered cycloalkyl-CH.sub.2NHC(O), 3-8-membred aliphatic heterocyclyl-CH.sub.2NHC(O), 6-20-membered aryl-CH.sub.2NHC(O), 5-20-membered heteroaryl-CH.sub.2NHC(O), 5-20-membered fused heteroaryl-CH.sub.2NHC(O), benzo-fused 3-10-membered cycloalkyl-NHC(O), 3-8-membered aliphatic heterocyclyl-NHC(O), 6-20-membered aryl-NHC(O), 5-20-membered heteroaryl-NHC(O), and 5-20-membered fused heteroaryl-NHC(O); and wherein the C.sub.1-6 alkyl, 3-10-membered cycloalkyl-CH.sub.2NHC(O), 3-8-membered aliphatic heterocyclyl-CH.sub.2NHC(O), 6-20-membered aryl-CH.sub.2NHC(O), 5-20-membered heteroaryl-CH.sub.2NHC(O), 5-20-membered fused heteroaryl-CH.sub.2NHC(O), benzo-fused 3-10-membered cycloalkyl-NHC(O), 3-8-membered aliphatic heterocyclyl-NHC(O), 6-20-membered aryl-NHC(O), 5-20-membered heteroaryl-NHC(O), and 5-20-membered fused heteroaryl-NHC(O) are unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxyl, NRR, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, and cyano; each of R.sub.2 is independently selected from the group consisting of hydrogen, cyano, nitro, hydroxyl, halogen, C.sub.1-6 alkyl, 3-10-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, and halogenated C.sub.1-6 alkoxyl; n=1, 2 or 3; R.sub.3 and R.sub.4 are such that (a) R.sub.3 is selected from the group consisting of 3-10-membered cycloalkyl-CH.sub.2, 3-8-membered aliphatic heterocyclyl-CH.sub.2, 6-20-membered aryl-CH.sub.2, 5-20-membered heteroaryl-CH.sub.2, 5-20-membered fused heteroaryl-CH.sub.2, benzo-fused 3-10-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, phenyl-3-10-membered cycloalkyl, 5-20-membered heteroaryl-phenyl, 5-20-membered fused heteroaryl phenyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; and wherein the 3-10-membered cycloalkyl-CH.sub.2, 3-8-membered aliphatic heterocyclyl-CH.sub.2, 6-20-membered aryl-CH.sub.2, 5-20-membered heteroaryl-CH.sub.2, 5-20-membered fused heteroaryl-CH.sub.2, benzo-fused 3-10-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, phenyl-3-10-membered cycloalkyl, 5-20-membered heteroaryl-phenyl, 5-20-membered fused heteroaryl phenyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl are unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxyl, NRR, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, cyano, 3-10-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, 5-20-membered fused heteroaryl, halogenated C.sub.1-3 alkyl, halogenated C.sub.1-3 alkoxyl, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkoxyl, and C.sub.1-3 alkoxy-C.sub.1-3 alkoxy-C.sub.1-3 alkyl; R.sub.4 is selected from hydrogen, C.sub.1-6 alkyl, and halogenated C.sub.1-6 alkyl; (b) R.sub.3 and R.sub.1 are linked together to form a ring X, wherein the ring X is a 5-8-membered aliphatic ring or a 5-8-membered aliphatic heterocycle; and wherein the 5-8-membered aliphatic ring or 5-8-membered aliphatic heterocycle is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of O, halogen, cyano, NRR, nitro, hydroxyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; or the aforementioned 5-8-membered aliphatic ring or 5-8-membered aliphatic heterocycle is fused with a 3-8-membred aliphatic ring to form a spiro structure; R.sub.4 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; and wherein the C.sub.1-6 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl or 5-10-membered fused heteroaryl is optionally substituted by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, NRR, cyano, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; wherein the C.sub.14 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl or 5-10-membered fused heteroaryl is optionally substituted by one or more (for example, 1, 2, 3 or 4) substituents selected from halogen, NRR, C.sub.1-3 alkyl, and C.sub.1-3 alkoxyl; (c) R.sub.3 and R.sub.4 are linked together to form a ring Y, wherein the ring Y is a 5-8-membered aliphatic ring or a 5-8-membered aliphatic heterocycle; and wherein the 5-8-membered aliphatic ring or 5-8-membered aliphatic heterocycle is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, nitro, hydroxyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; wherein each of C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl is unsubstituted or substituted independently by one or more (for example, 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; or the aforementioned 5-8-membered aliphatic ring or 5-8-membered aliphatic heterocycle is fused with a 6-20-membered aromatic ring or a 5-20-membered aromatic heterocycle to form a fused ring system, wherein the fused ring system is unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; or (d) R.sub.3 is linked together with M to form a ring Z, wherein the ring Z is a 3-10-membered aliphatic heterocycle, a 6-20-membered aromatic ring or a 5-20-membered aromatic heterocycle; and wherein the 3-10-membered aliphatic heterocycle, 6-20-membered aromatic ring or 5-20-membered aromatic heterocycle is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, nitro, hydroxyl, O, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroary; or the aforementioned 3-10-membered aliphatic heterocycle, 6-20-membered aromatic ring or 5-20-membered aromatic heterocycle is fused with a 6-20-membered aromatic ring or a 5-20-membered aromatic heterocycle to form a fused ring system, wherein the fused ring system is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; R.sub.4 is selected from hydrogen, C.sub.1-6 alkyl, and C.sub.1-6 alkoxyl, or R.sub.4 is absent or forms a covalent bond; R.sub.5 is halogen; R.sub.6 is selected from hydrogen, C.sub.1-6 alkyl, and COOR; wherein C.sub.1-6 alkyl is unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from halogen, hydroxyl, amino, and cyano; atom A is selected from C, N, O and S; M is selected from C, N, O, H.sub.2 and NR; R and R are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; preferably, R.sub.1 is not a hydrogen, and ##STR00076## as a whole is independently a hydrogen; preferably, the compound is a mixture of the cis-configuration and the trans-configuration in any ratio; preferably, the compound is in cis (Z)-configuration; preferably, the compound is in trans (E)-configuration.

2. The compound of claim 1, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the compound has a structure as represented by Formula II: ##STR00077## wherein, in the compound of Formula II, R3 is selected from the group consisting of 3-10-membered cycloalkyl-CH.sub.2, 3-8-membered aliphatic heterocyclyl-CH.sub.2, 6-20-membered aryl-CH.sub.2, 5-20-membered heteroaryl-CH.sub.2, 5-20-membered fused heteroaryl-CH.sub.2, benzo-fused 3-10-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, phenyl-3-10-membered cycloalkyl, 5-20-membered heteroaryl-phenyl, 5-20-membered fused heteroaryl-phenyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; and wherein the 3-10-membered cycloalkyl-CH.sub.2, 3-8-membered aliphatic heterocyclyl-CH.sub.2, 6-20-membered aryl-CH.sub.2, 5-20-membered heteroaryl-CH.sub.2, 5-20-membered fused heteroaryl-CH.sub.2, benzo-fused 3-10-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, phenyl-3-10-membered cycloalkyl, 5-20-membered heteroaryl-phenyl, 5-20-membered fused heteroaryl-phenyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered hetebroaryl, and 5-20-membered fused heteroaryl are unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxyl, NRR, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, cyano, 3-10-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, 5-20-membered fused heteroaryl, halogenated C.sub.1-3 alkyl, halogenated C.sub.1-3 alkoxyl, C.sub.1-3 alkoxyl-C.sub.1-3 alkyl, C.sub.1-3 alkoxyl-C.sub.1-3 alkoxyl, and C.sub.1-3 alkoxyl-C.sub.1-3 alkoxyl-C.sub.1-3 alkyl; R.sub.4 is selected from hydrogen, C.sub.1-6 alkyl, and halogenated C.sub.1-6 alkyl; R.sub.1, R.sub.2, R.sub.5, R.sub.6, R, R and n are as defined in Formula I; preferably, in the compound of Formula II, R.sub.3 is selected from the group consisting of 3-10-membered cycloalkyl-CH.sub.2, 3-8-membered aliphatic heterocyclyl-CH.sub.2, 6-20-membered aryl-CH.sub.2, 5-20-membered heteroaryl-CH.sub.2, 5-20-membered fused heteroaryl-CH.sub.2, benzo-fused 3-10-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, phenyl-3-10-membered cycloalkyl, 5-20-membered heteroaryl-phenyl, 5-20-membered fused heteroaryl-phenyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; and wherein the 3-10-membered cycloalkyl-CH.sub.2, 3-8-membered aliphatic heterocyclyl-CH.sub.2, 6-20-membered aryl-CH.sub.2, 5-20-membered heteroaryl-CH.sub.2, 5-20-membered fused heteroaryl-CH.sub.2, benzo-fused 3-10-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, phenyl-3-10-membered cycloalkyl, 5-20-membered heteroaryl-phenyl, 5-20-membered fused heteroaryl-phenyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl are unsubstituted or substituted independently by one or more (for example 1 or 2) substituents selected from the group consisting of halogen, hydroxyl, NRR, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, cyano, 3-10-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-20-membered aryl, 5-20-membered heteroaryl, 5-20-membered fused heteroaryl, halogenated C.sub.1-3 alkyl, halogenated C.sub.1-3 alkoxyl, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkoxyl, and C.sub.1-3 alkoxy-C.sub.1-3 alkoxy-C.sub.1-3 alkyl; R.sub.4 is selected from H and methyl; R.sub.1 is selected from H, halogen, and C.sub.1-3 alkyl; R.sub.2 is selected from the group consisting of hydrogen, cyano, nitro, halogen, C.sub.1-3 alkyl, and C.sub.1-3 alkoxyl; and n=1; R.sub.5, R.sub.6, R and R are as defined in Formula I; preferably, in the compound of Formula II, R.sub.3 is selected from the group consisting of 6-15-membered aryl, benzo-fused 3-8-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, 3-8-membered aliphatic heterocyclyl, 5-10-membered heteroaryl-CH.sub.2, 5-10-membered fused heteroaryl-CH.sub.2, 3-8-membered cycloalkyl-CH.sub.2, 3-8-membered aliphatic heterocyclyl-CH.sub.2, 6-10-membered aryl-CH.sub.2, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; and wherein the 6-15-membered aryl, benzo-fused 3-8-membered cycloalkyl, benzo-fused 3-8-membered aliphatic heterocyclyl, 3-8-membered aliphatic heterocyclyl, 5-10-membered heteroaryl-CH.sub.2, 5-10-membered fused heteroaryl-CH.sub.2, 3-8-membered cycloalkyl-CH.sub.2, and 3-8-membered aliphatic heterocyclyl-CH.sub.2 are unsubstituted or substituted independently by one or more (for example 1 or 2) substituents selected from the group consisting of halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl-C.sub.1-3 alkoxyl, and NRR, wherein R and R are independently selected from H and C.sub.1-3 alkyl; R.sub.4 is H or methyl; R.sub.1 is selected from H and halogen; R.sub.2 is selected from the group consisting of H, halogen, C.sub.1-3 alkyl, and C.sub.1-3 alkoxyl, and n=1; R.sub.5 and R.sub.6 are as defined in Formula I; preferably, R.sub.3 is selected from the group consisting of 3-7-membered cycloalkyl-CH.sub.2, 3-7-membered aliphatic heterocyclyl-CH.sub.2, 6-10-membered aryl-CH.sub.2, 5-6-membered heteroaryl-CH.sub.2, benzo-fused 3-7-membered cycloalkyl, 3-7-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl-CH2; R.sub.4 is H; R.sub.1 is H; R.sub.2 is H or halogen, and n=1; R.sub.5 is F; R.sub.6 is H.

3. The compound of claim 1, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the compound has a structure as represented by Formula III: ##STR00078## wherein, the ring X is a 5-8-membered aliphatic ring or a 5-8-membered aliphatic heterocyclic ring; and wherein each of 5-8-membered aliphatic ring or the 5-8-membered aliphatic heterocyclic ring is unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of O, halogen, cyano, NRR, C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, halogenated C.sub.1-4 alkyl, halogenated C.sub.1-4 alkoxyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; or the aforementioned 5-8-membered aliphatic ring or the 5-8-membered aliphatic heterocyclic ring is fused with a 3-8-membered aliphatic ring to form a Spiro structure; R.sub.4 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl and 5-10-membered fused heteroaryl; and wherein the C.sub.1-6 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl or 5-10-membered fused heteroaryl is optionally substituted by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; R.sub.2, R.sub.5, R.sub.6, R, R and A are as defined in Formula I; preferably, in the compound of Formula III, the ring X is a 5-7-membered aliphatic ring or a 5-7-membered aliphatic heterocyclic ring; and wherein the 5-7-membered aliphatic ring or the 5-7-membered aliphatic heterocyclic ring is unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of O, halogen, C.sub.1-4 alkyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; or the aforementioned 5-7-membered aliphatic ring or the 5-7-membered aliphatic heterocyclic ring is fused with a 3-6-membered aliphatic ring to form a spiro structure; A is selected from N and C; R.sub.2 is selected from F, Cl, and H; R.sub.4 is selected from H, CH.sub.3, and CH.sub.2CH.sub.3; R.sub.5 is F; R.sub.6 is H; preferably, in the compound of Formula III, the ring X is a 5-6-membered aliphatic ring or a 5-6-membered aliphatic heterocyclic ring; and wherein the 5-6-membered aliphatic ring or the 5-6-membered aliphatic heterocyclic ring is unsubstituted or substituted by one or more (for example 1, 2 or 3) substituents selected from the group consisting of O, halogen, and C.sub.1-3 alkyl; A is selected from N and C; R.sub.2 is selected from F and H; R.sub.4 is selected from H, CH.sub.3, and CH.sub.2CH.sub.3;

4. The compound of claim 1, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the compound has a structure as represented by the Formula IV: ##STR00079## wherein, the ring X is a 5-8-membered aliphatic ring or a 5-8-membered aliphatic heterocyclic ring; and wherein the 5-8-membered aliphatic ring or the 5-8-membered aliphatic heterocyclic ring is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of O, halogen, cyano, NRR, C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, halogenated C.sub.1-4 alkyl, halogenated C.sub.1-4 alkoxyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; or the aforementioned 5-8-membered aliphatic ring or the 5-8-membered aliphatic heterocyclic ring is fused with a 3-8-membered aliphatic ring to form a Spiro structure; R.sub.4 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; and wherein the C.sub.1-6 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl are optionally substituted by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; wherein the C.sub.1-4 alkyl, 3-8-membered cycloalkyl, 3-8-membered aliphatic heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl or 5-10-membered fused heteroaryl is optionally substituted by one or more (for example 1, 2 or 3) substituents selected from halogen, NRR, and C.sub.1-3 alkyl; R.sub.2, R.sub.5, R.sub.6, R, R, A and n are as defined in Formula I; preferably, in the compound of Formula IV, the ring X is a 5-7-membered aliphatic ring or a 5-7-membered aliphatic heterocyclic ring; and wherein the 5-7-membered aliphatic ring or the 5-7-membered aliphatic heterocyclic ring is unsubstituted or substituted by one or more(for example 1, 2, 3 or 4) substituents selected from the group consisting of O, halogen, C.sub.1-4 alkyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; or the aforementioned 5-7-membered aliphatic ring or the 5-7-membered aliphatic heterocyclic ring is fused with a 3-6-membered aliphatic ring to form a Spiro structure; A is selected from N and C; each of R.sub.2 is independently selected from F, Cl, and H, and n=1 or 2; R.sub.4 is selected from the group consisting of H, C.sub.1-4 alkyl, benzyl, and halogenated benzyl; R.sub.5 is F; R.sub.6 is H; preferably, in the compound of Formula IV, the ring X is a 5-6-membered aliphatic ring or a 5-6-membered aliphatic heterocyclic ring; and wherein the 5-6-membered aliphatic ring or the 5-6-membered aliphatic heterocyclic ring is unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from O, halogen, and C.sub.1-4 alkyl; A is selected from N and C; each of R.sub.2 is independently is selected from F, Cl, and H, and n=1; R.sub.4 is selected from H, C.sub.1-4 alkyl, benzyl and chloro benzyl; R.sub.5 is F; R.sub.6 is H; preferably, in the compound of Formula IV, the ring X is a 6-membered aliphatic heterocyclic ring (for example a 6-membered nitrogen-containing aliphatic heterocyclic ring, such as piperidine ring); and wherein the 6-membered aliphatic heterocyclic ring is unsubstituted or substituted by one or more (for example 1, 2 or 3) substituents selected from O, halogen, and C.sub.1-3 alkyl; A is N; each of R.sub.2 is independently is selected from F and H, and n=1; R.sub.4 is selected from H, CH.sub.3, and CH.sub.2CH.sub.3; R.sub.5 is F; R.sub.6 is H.

5. The compound of claim 1, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the compound has a structure as represented by formula V: ##STR00080## wherein, the ring Y is a 5-8-membered aliphatic heterocyclic ring or a 5-8-membered aliphatic ring; and wherein the 5-8-membered aliphatic heterocyclic ring or the 5-8-membered aliphatic ring is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, nitro, hydroxyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl are unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-6 alkyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; or the aforementioned 5-8-membered aliphatic heterocyclic ring or the 5-8-membered aliphatic ring is fused with a 6-20-membered aromatic ring or a 5-20-membered aromatic heterocycle to form a fused ring system, wherein the fused ring system is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; R.sub.1, R.sub.2, R.sub.5, R.sub.6, R and R are as defined in Formula I; A is selected from N and C; preferably, in the compound of formula V, the ring Y is a 5-7-membered aliphatic heterocyclic ring; and wherein the 5-7-membered aliphatic heterocyclic ring is unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, 6-15-membered aryl, and C.sub.1-4 alkyl, wherein the 6-15-membered aryl and C.sub.1-4 alkyl are unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, and 6-10-membered aryl; or the aforementioned 5-7-membered aliphatic heterocyclic ring is fused with a 6-10-membered aromatic ring or a 5-10-membered aromatic heterocycle to form a fused ring system, and wherein the fused ring system is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, and 6-10-membered aryl; R.sub.1, R.sub.2, R.sub.5, R.sub.6, R and R are as defined in Formula I; A is N; preferably, in the compound of formula V, the ring Y is a 5-7-membered aliphatic heterocyclic ring; and wherein the 5-7-membered aliphatic heterocyclic ring is unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from 6-10-membered aryl; A is N, R.sub.1 is H; R.sub.2 is H or F; R.sub.5 is F; R.sub.6 is H.

6. The compound of claim 1, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the compound has a structure as represented by Formula VI: ##STR00081## wherein, the ring Z is a 3-10-membered aliphatic heterocycle, a 6-20-membered aromatic ring or a 5-20-membered aromatic heterocycle; and wherein each of 3-10-membered aliphatic heterocycle, 6-20-membered aromatic ring or 5-20-membered aromatic heterocycle is unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, cyano, NRR, nitro, hydroxyl, O, C.sub.1-6 alkyl, C.sub.1-l alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; or the aforementioned 3-10-membered aliphatic heterocycle, 6-20-membered aromatic ring or 5-20-membered aromatic heterocycle is fused with a 6-20-membered aromatic ring or a 5-20-membered aromatic heterocycle to form a fused ring system, wherein the fused ring system is unsubstituted or each substituted independently by one or more (for example 1, 2, 3 or 4) subsituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, halogenated C.sub.1-6 alkyl, halogenated C.sub.1-6 alkoxyl, 6-20-membered aryl, 5-20-membered heteroaryl, and 5-20-membered fused heteroaryl; R.sub.4 is selected from hydrogen, C.sub.1-6 alkyl, and C.sub.1-6 alkoxyl, or R.sub.4 is absent or forms a covalent bond; R.sub.1, R.sub.2, R.sub.5, R.sub.6, R, R, A, M and n are as defined in Formula I; preferably, in the compound of formula VI, the ring Z is a 5-7-membered aliphatic heterocyclic ring, a 6-10-membered aromatic ring or a 5-10-membered aromatic heterocycle; and wherein each of 5-7-membered aliphatic heterocyclic ring, 6-10-membered aromatic ring or 5-10-membered aromatic heterocycle is unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) subsituents selected from the group consisting of halogen, cyano, NRR, nitro, hydroxyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, halogenated C.sub.1-3 alkyl, and halogenated C.sub.1-6 alkoxyl; or the aforementioned 5-7-membered aliphatic heterocyclic ring, 6-10-membered aromatic ring or 5-10-membered aromatic heterocycle is fused with a 6-10-membered aromatic ring or a 5-10-membered aromatic heterocycle to form a fused ring system, wherein the fused ring system is unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) subsituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, halogenated C.sub.1-3 alkyl, halogenated C.sub.1-3 alkoxyl, 6-10-membered aryl, 5-10-membered heteroaryl, and 5-10-membered fused heteroaryl; R.sub.4 is selected from hydrogen and C.sub.1-6 alkyl, or R.sub.4 is absent or forms a covalent bond; R.sub.1 is selected from hydrogen and halogen; each of R.sub.2 is independently selected from hydrogen, halogen, and cyano, and n=1 or 2; R.sub.5 is F or Cl; R.sub.6 is selected from hydrogen and C.sub.1-6 alkyl; A is selected from N and S; M is N; R and R are as defined in Formula I; preferably, in the compound of formula VI, the ring Z is a 5-7-membered aliphatic heterocyclic ring, a 6-10-membered aromatic ring or a 5-10-membered aromatic heterocycle; and wherein each of 5-7-membered aliphatic heterocyclic ring, 6-10-membered aromatic ring or 5-10-membered aromatic heterocycle is unsubstituted or substituted independently by one or more (for example 1, 2 or 3) subsituents selected from the group consisting of halogen, cyano, NRR, nitro, hydroxyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, halogenated C.sub.1-3 alkyl, and halogenated C.sub.1-6 alkoxyl; wherein R and R are independently selected from hydrogen and C.sub.1-3 alkyl; or the aforementioned 5-7-membered aliphatic heterocyclic ring, 6-10-membered aromatic ring or 5-10-membered aromatic heterocycle is fused with a 6-10-membered aromatic ring or a 5-10-membered aromatic heterocycle to form a fused ring system, wherein the fused ring system is unsubstituted or substituted independently by one or more (for example 1, 2, 3 or 4) subsituents selected from the group consisting of halogen, cyano, NRR, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, halogenated C.sub.1-3 alkyl, and halogenated C.sub.1-3 alkoxyl; wherein R and R are independently selected from hydrogen and C.sub.1-.sub.3 alkyl; R.sub.4 is selected from hydrogen and C.sub.1-6 alkyl, or R.sub.4 is absent or forms a covalent bond; R.sub.1 is selected from H and halogen; each of R.sub.2 independently is H or F, and n=1 or 2; R.sub.5 is F or Cl; R.sub.6 is selected from H and C.sub.1-6 alkyl; A is N; M is N.

7. The compound of claim 1, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the compound is selected from the group consisting of: ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101##

8. The compound of claim 1, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the pharmaceutically acceptable salt is a hydrochloride or a trifluoroacetate, and preferably, the pharmaceutically acceptable salt is a hydrochloride.

9. The compound of claim 8, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the pharmaceutically acceptable salt thereof is: ##STR00102##

10. The compound of claim 9, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the pharmaceutically acceptable salt thereof is: ##STR00103##

11. A pharmaceutical composition, comprising a compound of claim 1, a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, and one or more pharmaceutical excipients.

12. A process of preparing the compound of claim 1, wherein R.sub.6 in Formula I is hydrogen, the process consists in a route selected from: Route I: Subjecting compound SM-1 and compound INT-1 to a nucleophilic substitution reaction to afford compound INT-2; removing the protection of compound INT-2 to afford a target product; ##STR00104## Route II: Subjecting compound SM-1 and compound INT-3 to a Mitsunobu reaction to afford compound INT-2; removing the protection of compound INT-2 to afford a target product; ##STR00105## Route III: Subjecting compound SM-2 and compound INT-1 to a nucleophilic substitution reaction to afford compound INT-4; subjecting compound INT-4 to a coupling reaction to afford compound INT-2; removing the protection of compound INT-2 to afford a target product; ##STR00106## Route IV: Subjecting compound SM-2 and compound INT-3 to a Mitsunobu reaction to afford compound INT-4; subjecting compound INT-4 to a coupling reaction to afford compound INT-2; removing the protection of compound INT-2 to afford a target compound; ##STR00107## ##STR00108## Subjecting compound SM-3 and compound INT-3 to a Mitsunobu reaction to afford compound INT-5; removing the protection of compound INT-5 to afford a target product; wherein, Lg represents a leaving group, such as halogen, -OTs, etc.; P represents an amino protective group, such as Boc, Cbz, Fmoc, benzyl, etc.; the other atoms and groups are as defined in claim 1.

13.-14. (canceled)

15. A method for treating a disease or disorder associated with the overactivity of VAP-1/SSAO, comprising a step of administrating a patient in need of such treatment with an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, an ester, a hydrate, a solvate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof.

16. The compound of claim 4, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the pharmaceutically acceptable salt is a hydrochloride or a trifluoroacetate, and preferably, the pharmaceutically acceptable salt is a hydrochloride.

17. The compound of claim 7, or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, wherein the pharmaceutically acceptable salt is a hydrochloride or a trifluoroacetate, and preferably, the pharmaceutically acceptable salt is a hydrochloride.

18. A pharmaceutical composition, comprising a compound of claim 4, a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, and one or more pharmaceutical excipients.

19. A pharmaceutical composition, comprising a compound of claim 7, a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof, and one or more pharmaceutical excipients.

20. The method according to claim 15, wherein the disease or disorder associated with the overactivity of VAP-1/SSAO is selected from the group consisting of an inflammatory disease (for example a liver-related inflammatory disease, such as hepatitis, hepatomegaly, hepatic fibrosis, cirrhosis or ascites; a respiratory tract-related inflammatory disease, such as tracheitis, pneumonia, pulmonary fibrosis, asthma, acute lung injury, acute respiratory distress syndrome, bronchitis or chronic obstructive pulmonary disease; an eye-related inflammatory disease, for example Le uveitis; other inflammation, for example synovitis or peritonitis), organ and/or tissue transplantation rejection, an autoimmune disease (for example rheumatoid arthritis or multiple sclerosis (for example chronic multiple sclerosis)), a skin disease (for example eczema or psoriasis), a diabetes mellitu and stroke.

21. A method for treating a disease or disorder associated with the overactivity of VAP-1/SSAO, comprising a step of administrating a patient in need of such treatment with an effective amount of the compound of claim 4, or a pharmaceutically acceptable salt, an ester, a hydrate, a solvate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof.

22. A method for treating a disease or disorder associated with the overactivity of VAP-1/SSAO, comprising a step of administrating a patient in need of such treatment with an effective amount of the compound of claim 7, or a pharmaceutically acceptable salt, an ester, a hydrate, a solvate, an isomer, or an isotope-labeled compound thereof; any crystal form or racemate thereof; a metabolite thereof; or a mixture thereof.

23. A method for treating a disease or disorder associated with the overactivity of VAP-1/SSAO, comprising a step of administrating a patient in need of such treatment with an effective amount of the pharmaceutical composition according to claim 11.

Description

EXAMPLE 1

Preparation of 4-((2-(aminomethyl)-3-fluoroallyl)oxy)-N-(naphthyl)benzoamide trifluoroacetate (TM8)

[0220] ##STR00037##

Step I: Preparation of N-naphthyl-4-hydroxybenzoamide (1-1)

[0221] Para-hydroxybenzoic acid (200 mg, 1.45 mmol) was dissolved in DMF (10 mL), and in an ice bath, HOBT (294 mg, 2.17 mmol), DIEA (374 mg, 2.90 mmol) and EDCI (417 mg, 2.17 mmol) were added in order and stirred for 30 min, and then, 2-naphthylamine (248 mg, 1.74 mmol) was added thereto. The mixture was raised to room temperature and stirred overnight. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed twice with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration and concentration, the crude product was purified by column chromatograph to give white solids (240 mg, 65%).

[0222] MS m/z(ESI): 264 [M+H].sup.+

Step II: Preparation of tert-butyl (2-(4-(naphthyl-2-carbamoyl) phenoxy)methyl-3-fluoroallyl)amino formate (1-2)

[0223] The compound 1-1 (240 mg, 0.91 mmol) was dissolved in DMF (10 mL) and added with the Int-1 (293 mg, 1.09 mmol) and potassium carbonate (450 mg, 3.27 mmol), the mixture was stirred overnight at room temperature. Then water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, the organic phases were combined. Then the organic phase was washed with saturated saline solution three times, dried over magnesium sulfate, fitered, concentrated, and purified by preparative TLC to give the target product (206 mg, 50%).

[0224] MS m/z(ESI): 451 [M+H].sup.+

Step III: Preparation of N-naphthyl-4-(2-aminomethyl-3-fluoroallyloxy)-benzamide trifluoroacetate (TM8)

[0225] The compound 1-2 (206 mg, 0.5mmo1) was dissolved in dichloromethane (6 mL) and then added with TFA (2 mL), the mixture was stirred at room temperature for 30 min. After LC-MS monitored the completion of the reaction, the reaction mixture was concentrated under vacuum and then lyophilized to afford the target product TM8 (60 mg, 39%).

[0226] MS m/z (ESI): 351 [M+H].sup.+

[0227] .sup.1HNMR (400 MHz, DMSO-d.sub.6) : 10.31 (s, 1H), 8.44 (s, 1H), 8.07-7.99 (m, 4H), 7.89-7.82 (m, 4H), 7.49-7.42 (m, 2H), 7.18-7.14 (m, 2H), 4.82 (s, 2H), 4.70 (d, J=2.8 Hz, 2H), 3.66 (s, 2H), 3.58 (d, J=2.0 Hz, 2H).

[0228] According to general empirical analyses, it was deduced that the chemical shifts 4.82, 3.58 may be the characteristic peaks of the Z-configuration, and the chemical shifts 4.70, 3.66 may be the characteristics peaks of the E-configuration.

EXAMPLE 2

Preparation of N-methyl-N-p-methylphenyl-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM67)

[0229] ##STR00038##

[0230] Except for, that N-methyl-p-methylaniline in Step I of this example replaced the 2-naphthylamine in Step I of Example 1, the title compound was prepared according to a similar method to that described in Example 1, with the total yield of 19%.

[0231] MS m/z (ESI): 329 [M+H].sup.+

[0232] .sup.1HNMR (400 MHz, DMSO-d.sub.6) : 7.97 (s, 2H), 7.38-7.18 (m, 3H), 7.09-7.01 (m, 4H), 6.84-6.82 (m, 2H), 4.64 (d, J=2.0 Hz, 2H), 4.52 (d, J=3.6 Hz, 2H), 3.57 (d, J=7.6 Hz, 2H), 3.51 (s, 2H), 3.32 (s, 3H), 2.23 (s, 3H).

[0233] According to general empirical analyses, it was deduced that the chemical shifts 4.64, 3.51 may be the characteristic peaks of the Z-configuration, and the chemical shifts 4.52, 3.57 may be the characteristics peaks of the E-configuration.

EXAMPLE 3

Preparation of N-(4-fluorophenyl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM61)

[0234] ##STR00039##

Step I: Preparation of methyl 4-(2-(tert-butoxycarbonylaminomethyl)-3-fluoroallyl)oxy)benzoate (3-1)

[0235] Except for that methyl hydroxybenzoate in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1. The resultant crude product was directly applied in the next step.

[0236] MS m/z (ESI): 340 [M+H].sup.+

Step II: Preparation 4-(2-(tert-butoxycarbonylaminomethyl)-3-fluoroallyloxy) benzoic acid (3-2)

[0237] The compound 3-1 (2.71 g, 7.99 mmol) was dissolved in tetrahydrofuran (18 mL) and water (9 mL) and added with lithium hydroxide (2.02 g, 48.08 mmol), the mixture was reacted overnight at 45 C. The reaction solution was adjusted with diluted hydrochloric acid aqueous solution to pH=2-3, then extracted twice with ethyl acetate, washed with saturated saline solution and dried over anhydrous sodium sulfate, followed by concentration under vacuum, to afford the product (1.78 g, 69%).

[0238] MS m/z (ESI): 326 [M+H].sup.+

Step III: Preparation tert-butyl (2-(4-(4-fluorophenylaminoformyl)phenoxy) methyl-3-fluoroallyl)carbamate (3-3)

[0239] The compound 3-2 (150 mg, 0.44 mmol) was dissolved in DMF (4 mL) and added with DIEA (114 mg, 0.88 mmol) and HATU (252 mg, 0.66 mmol), the mixture was stirred for half an hour in ice bath under the protection of nitrogen gas. Then para-fluoroaniline (49 mg, 0.44 mmol) was added at the same temperature. After 15 minute, the ice bath was removed, and the mixture was allowed to react for 2 hours at room temperature. After the completion of the reaction, the mixture was quenched by adding saturated sodium bicarbonate, and the resulting mixture was extracted twice with ethyl acetate. The organic phase was collected and washed twice with saturated saline solution, dried over anhydrous sodium sulfate and concentrated in vacuum, then purified by preparative TLC to afford the product (168 mg, 87%).

[0240] MS m/z (ESI): 419 [M+H].sup.+

Step IV: Preparation of N-(4-fluorophenyl)-4-((2-aminomethyl-3-fluoroallyl) oxy)-benzamide trifluoroacetate (TM61)

[0241] Except for that the intermediate 3-3 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of about 100%.

[0242] MS m/z (ESI): 319 [M+H].sup.+

[0243] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.97-7.94 (m, 2H), 7.68-7.65 (m, 2H), 7.35-7.02 (m, 5H), 4.89 (d, J=2.4 Hz, 2H), 4.69 (d, J=3.2 Hz, 2H), 3.83 (d, J=2.0 Hz, 2H), 3.71 (d, J=2.4 Hz; 2H,).

[0244] According to general empirical analyses, it was deduced that the chemical shifts 4.89, 3.71 may be the characteristic peaks of the Z-configuration, and the chemical shifts 4.69, 3.83 may be the characteristics peaks of the E-configuration.

EXAMPLE 4

Preparation of (4-(2-aminomethyl-3-fluoroallyloxy)phenyl)-(6-trifluoromethyl-3,4-dihydroisoquinol-2(1H)-yl)-methanone trifluoroacetate (TM68)

[0245] ##STR00040##

[0246] Except for that 1,2,3,4-tetrahydro-6-trifluoromethylisoquinoline in the first step of the example replaced the para-fluoroaniline in Step III of Example 3, the title compound was prepared according to processes similar to those described in Steps III and IV of Example 3, with the total yield of 16%.

[0247] MS m/z (ESI): 409 [M+H].sup.+

[0248] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.76-7.47 (m, 4H), 7.40-6.92 (m, 4H), 5.06-4.67 (m, 2H), 4.87 (d, J=2.4 Hz, 2H), 4.67 (d, J=3.2 Hz, 2H), 3.83 (d, J=1.6 Hz, 2H), 3.83-3.70 (m, 2H), 3.70 (d, J=2.4 Hz, 2H), 3.01 (s, 2H).

[0249] According to general empirical analyses, it was deduced that the chemical shifts 4.87, 3.70 may be the characteristic peaks of the Z-configuration, and the chemical shifts 4.67, 3.83 may be the characteristics peaks of the E-configuration.

EXAMPLE 5

Preparation of N-(3-dimethylaminophenyl)-4-(2-aminomethyl-3-fluoroallyloxy)-benzamide trifluoroacetate (TM62)

[0250] ##STR00041##

[0251] Except for that N,N-dimethyl-m-phenylenediamine in Step I of the example replaced the para-fluoroaniline in Step III of Example 3, the title compound was prepared according to processes similar to those described in Steps III and IV of Example 3, with the total yield of 49%.

[0252] MS m/z (ESI): 344 [M+H].sup.+

[0253] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.04-7.96 (m, 3H), 7.54-7.45 (m, 2H), 7.36-7.00 (m, 4H), 4.90 (d, J=2.4 Hz, 2H), 4.70 (d, J=3.2 Hz, 2H), 3.84 (d, J=1.6 Hz, 2H), 3.71 (d, J=1.6 Hz, 2H), 3.23 (s, 6H).

[0254] According to general empirical analyses, it was deduced that the chemical shifts 4.90, 3.71 may be the characteristic peaks of the Z-configuration, and the chemical shifts 4.70, 3.84 may be the characteristics peaks of the E-configuration.

EXAMPLE 6

Preparation of (S)-(4-(2-aminomethyl)-3-fluoroallyloxy)phenyl)-(1-phenyl-3,4-dihydroisoquinol-2(1H)-yl)-methanone trifluoroacetate (TM69)

[0255] ##STR00042##

[0256] Except for that (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in Step I of the example replaced the para-fluoroaniline in Step III of Example 3, the title compound was prepared according to processes similar to those described in Steps III and IV of Example 3, with the total yield of 52%.

[0257] MS m/z (ESI): 417 [M+H].sup.+

[0258] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.38 (dd, J=8.8 Hz, 2.4 Hz, 2H), 7.33-7.20 (m, 8H), 7.13-7.00 (m, 4H), 4.86 (d, J=2.8 Hz, 2H), 4.65 (d, J=3.2 Hz, 2H), 3.82 (d, J=1.2 Hz, 2H), 3.75 (br, 1H), 3.69 (d, J=2.4 Hz, 2H), 3.40 (m, 1H), 3.08-3.00 (m, 1H), 2.85-2.76 (m, 1H).

[0259] According to general empirical analyses, it was deduced that the chemical shifts 4.86, 3.69 may be the characteristic peaks of the Z-configuration, and the chemical shifts 4.65, 3.82 may be the characteristics peaks of the E-configuration.

EXAMPLE 7

Preparation of 2-(4-(4-methylthiazolyl-2-phenoxy)methyl)-3-fluoroallylamine trifluoroacetate (TM70)

[0260] ##STR00043##

Step I: Preparation of tert-butyl (3-fluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxymethyl)allyl)carbamate (7-1)

[0261] Except for that 4-hydroxyphenylboronic acid pinacol ester in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 83%.

[0262] MS m/z(ESI): 408 [M+H].sup.+

Step II: Preparation of tert-butyl (3-fluoro-2-(4-(4-methylthiazolyl-2-phenoxy) methyl)allyl)carbamate (7-2)

[0263] The compound 7-1 (100 mg, 0.25 mmol) was dissolved in 1,4-dioxane (3 mL), and added with 2-bromo-4-methylthiazole (52 mg, 0.30 mmol), [1,1-bis (diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (20 mg, 0.03 mmol) and 1mmol/L potassium carbonate aqueous solution (1.3 mL), and the mixture was reacted overnight at 90 C. under the protection of nitrogen gas. After the completion of the reaction, the mixture was quenched by adding water. The aqueous phase was extracted twice by ethyl acetate, the organic phase was collected. The organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified by TLC to afford the target product (62 mg, 67%).

[0264] MS m/z (ESI): 379 [M+H].sup.+

Step III: Preparation of 2-(4-(4-methylthiazolyl-2-phenoxy)methyl)-3-fluoroallylamine trifluoroacetate (TM70)

[0265] Except for that the intermediate 7-2 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared through a similar method to that described in Step III of Example 1, with the yield of about 100%.

[0266] MS m/z (ESI): 279 [M+H].sup.+

[0267] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.89 (dd, J=8.8 Hz, 2.4 Hz, 2H), 7.24 (d, J=81.2 Hz, 1H), 7.12 (d, J=80.8 Hz, 1H), 7.14-7.11 (m, 3H), 4.88 (d, J=2.4 Hz, 2H), 4.68 (d, J=3.2 Hz, 2H), 3.84 (d, J=2.6 Hz, 2H), 3.70 (d, J=2.0 Hz, 2H), 2.47 (s, 3H).

[0268] According to general empirical analyses, it was deduced that the chemical shifts 7.12, 4.88, 3.70 may be the characteristic peaks of the Z-configuration, and the chemical shifts 7.24, 4.68, 3.84 may be the characteristics peaks of the E-configuration.

EXAMPLE 8

Preparation of (4-(2-aminomethyl-3-fluoroallyloxy)phenyl)-(5-chloroisoindolin-2-yl)-methanone trifluoroacetate (TM71)

[0269] ##STR00044## ##STR00045##

Step I: Preparation of 1,2-di(bromomethyl)-4-chlorobenzene (8-1)

[0270] The compound 4-chloro-1,2-dimethylbenzene (0.2 mL, 1.5 mmol) was dissolved in acetonitrile (26 mL) and then added with NBS (0.55 g, 3.0 mmol) and AIBN (0.14 g, 0.8 mmol), and the mixture was reacted at 75 C. for 2 hours. The reaction was quenched by adding water, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated saline solution, and dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was subjected to column chromatograph to afford the target product (0.20 g, 47%).

Step II: Preparation of 5-chloro-2-p-tosylisoindoline (8-2)

[0271] Sodium hydride (1.60 g, 40.00 mmol) was dissolved in DMF (20 mL) and then dripped with a solution of 4-methylbenzene sulfonamide(2.64 g, 15.40 mmol) in DMF (10 mL), the mixture was reacted at 90 C. for 2 hours. A solution of the compound 8-1 (2.00 g, 6.76 mmol) in DMF (10 mL) was dripped, the resulting mixture was reacted for 4 hours at 90 C. The reaction solution was poured into ice water, the mixture was subjected to stirring and suction filtration. The filter cake was washed with diluted hydrochloric acid and dissolved with ethyl acetate, then washed with 5% sodium carbonate solution. The organic phase was collected and washed with saturated saline solution, and dried over anhydrous sodium sulfate and concentrated in vacuum to afford the target product (1.40 g, 68%).

[0272] MS m/z (ESI): 308 [M+H].sup.+

Step III: Preparation of 5-chloroisoindoline (8-3)

[0273] The compound 8-2 (1 g, 3.26 mmol), phenol (1 g, 10.60 mmol), hydrobromic acid (8 mL) and isopropanol (1.4 mL) were reacted at 126 C. for 4 hours. The reaction was quenched by adding water, the mixture was extracted three times with ethyl acetate. The aqueous phase was regulated to pH=8-9 by diluted sodium hydroxide aqueous solution, and extracted twice with ethyl acetate. The combined organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was added with HCl/1,4-dioxane solution, then subjected to stirring, and followed by concentrated in vacuum to afford the target product (489 mg, 98%).

[0274] MS m/z (ESI): 155[M+H].sup.+

Step IV: Preparation of 4-(5-chloroisoindoline-2-carbonyl)phenyl-4-hydroxybenzoate (8-4)

[0275] Para-hydroxy benzoic acid (270 mg, 1.95 mmol) was dissolved in DMF (6 mL), and in ice bath successively added with DIEA (503 mg, 3.90 mmol) and HATU (1.11 g, 2.93 mmol), the mixture was reacted for 1 hour under the protection of nitrogen gas. Then followed by an addition of the solution of the compound 8-3 (300 mg, 1.95 mmol) in DMF (2 mL), the mixture was reacted for 15 min in ice bath under the protection of nitrogen gas, then warmed to room temperature and reacted overnight. After the completion of the reaction, the mixture was quenched with sodium bicarbonate aqueous solution, the aqueous phase was extracted with ethyl acetate. The organic phase was combined, washed with water, dried and concentrated to afford the crude product (400 mg).

[0276] MS m/z (ESI): 394 [M+H].sup.+

Step V: Preparation of (5-chloroisoindolin-2-yl)(4-hydroxyphenyl)methanone (8-5)

[0277] The compound 8-4 (300 mg, 0.76 mmol) was dissolved in methanol (8 mL) and added with potassium carbonate solids (300 mg, 2.17 mmol) and water (2 mL), the mixture was reacted at room temperature for 4 hours. After the completion of the reaction, the reaction solution was diluted with water and regulated with diluted hydrochloric acid to pH=3-4. The aqueous solution was extracted twice with dichloromethane. The organic phase was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated, then purified with preparative TLC, to afford the target product (94 mg, 45%).

[0278] MS m/z (ESI): 274 [M+H].sup.+

Step VI: Preparation of tert-butyl (2-(4-(5-chloroisoindolin-2-carbonyl) phenoxymethyl)-3-fluoroallyl)carbamate (8-6)

[0279] Except for that the intermediate 8-5 in this step replaced the intermediate 1-1 in step II in Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 90%.

[0280] MS m/z (ESI): 461 [M+H].sup.+

Step VII: Preparation of (4-(2-aminomethyl-3-fluoroallyloxy)phenyl)-(5-chloroisoindolin-2-yl)-methanone trifluoroacetate (TM71)

[0281] Except for that the intermediate 8-6 in this step replaced the intermediate 1-2 in step III in Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of 72%.

[0282] MS m/z (ESI): 361 [M+H].sup.+

[0283] .sup.1HNMR (400 MHz, DMSO-d.sub.6) : 7.79 (br, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.50-7.24 (m, 4H), 7.11-7.06 (m, 2H), 4.85-4.78 (m, 4H), 4.80 (s, 2H)), 4.65 (d, J=3.2 Hz, 2H), 3.64 (s, 2H), 3.55 (s, 2H).

[0284] According to general empirical analyses, it was deduced that the chemical shifts 4.80, 3.55 may be the characteristic peaks of the Z-configuration, and the chemical shifts 4.65, 3.64 may be the characteristics peaks of the E-configuration.

EXAMPLE 9

Preparation of N-phenyl-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM1) and Resolution of the Isomers Thereof

[0285] ##STR00046##

[0286] Except for that in Step I of the example, aniline replaced the 2-naphthylamine in Step I of Example 1, the title compound was prepared according to a similar method to that described in Example 1, with the total yield of 35%.

[0287] Method for resolution cf N-phenyl-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate isomers

[0288] Apparatus: Agilent 1260, Sunfire C18; Mobile phase: A: 0.1% TFA, B: ACN;

[0289] Elution gradient: 0-8 min: 20%-30% B, flow rate: 16 mL/min; 8.1-10 min: 95% B, flow rate: 20 mL/min; 10.1-12 min: 20% B, flow rate: 20 mL/min.

[0290] The eluent liquid having a retention time from 5.6 to 6.7 min was collected and lyophilized to give the TM1-E, and the eluent liquid having a retention time from 7.0 to 8.0 min was collected and lyophilized to give the TM1-Z.

[0291] (Z)-N-phenyl-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate

[0292] (TM1-Z)

[0293] MS m/z (ESI): 301 [M+H].sup.+

[0294] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.97 (d, J=8.8 Hz, 2H), 7.66 (dd, J=7.6 Hz, 2H), 7.37-7.33 (m, 2H), 7.16-7.12 (m, 3H), 7.12 (d, J=80.4 Hz, 1H), 4.90 (d, J=2.0 Hz, 2H), 3.71 (d, J=2.4 Hz, 2H).

[0295] (E)-N-phenyl-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM 1-E).

[0296] MS m/z (ESI): 301[M+H].sup.+

[0297] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.97 (d, J=9.2 Hz, 2H), 7.66 (dd, J=7.6 Hz, 2H), 7.37-7.33 (m, 2H), 7.33-7.11 (m, 4H), 4.70 (d, J=2.8 Hz, 2H), 3.84 (d, J=2.0 Hz, 2H).

EXAMPLE 10

Preparation of (S)-N-(1,2,3,4-tetrahydro-1-naphthyl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM63) and Resolution of the Isomers Thereof

[0298] ##STR00047##

[0299] Except for that in Step I of the example, (S)-1,2,3,4-tetrahydro-1-naphthylamine replaced 2-naphthylamine in Step I of Example 1, the title compound was prepared according to a similar method to that described in Example 1, with the total yield of 46%.

[0300] A method similar to that as described in Example 9 is applied to resolute the isomers, and the retention time of the TM63-E is earlier than that of the TM63-Z. (Z)-(S)-N-(1,2, 3,4-tetrahydro-1-naphthyl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM63-Z).

[0301] MS mlz (ESI): 355 [M+H].sup.+

[0302] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.80 (d, J=8.8 Hz, 2H), 7.30-7.23 (m, 4H), 7.10 (d, J=8.8 hz, 2H), 7.05 (d, J=80.4 Hz, 1 H), 5.20 (t, J=5.6 Hz, 1H), 4.92 (d, J=1.6 Hz, 2H), 3.75 (s, 2H), 2.89-2.72 (m, 2H), 2.14-1.86 (m, 4H).

[0303] (E)-(S)-N-(1,2,3,4-tetrahydro-1-naphthyl)-4-(2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM63-E).

[0304] MS m/z (ESI): 355 [M+H].sup.+

[0305] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.80 (dd, J=22.8 Hz, 8.8 Hz, 2H), 7.30-7.23 (m, 4H), 7.10-7.05 (m, 2H), 5.20 (t, J=6.0 Hz, 1H), 4.70 (d, J=3.2 Hz, 2H), 3.90 (s, 2H), 2.91-2.72 (m, 2H), 2.14-1.84 (m, 4H).

EXAMPLE 11

Preparation of (4-((2-aminomethyl-3-fluoroallyl)oxy)-3-fluorophenyl)-(4-phenylpiperidin-1-yl)methanone trifluoroacetate (TM48)

[0306] ##STR00048##

[0307] Except for that in Step I of the example, 4-phenylpiperidine replaced 2-naphthylamine in Example 1, the title compound was prepared according to a similar method to that described in Example 1, with the total yield of 57%.

[0308] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM48-E is earlier than that of the TM48-Z.

[0309] (Z)-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)-3-fluorophenyl)-(4-phenylpiperidin-1-yl)methanone trifluoroacetate (TM48-Z).

[0310] MS m/z (ESI): 387 [M+H].sup.+

[0311] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.48-7.02 (m, 9H), 4.93 (d, J=2.4 Hz, 2H), 4.78-4.48 (m, 1H), 3.91-3.82 (m, 1H), 3.72 (d, J=2.0 Hz , 2H), 3.29-3.23 (m, 1H), 2.98-2.93 (m, 1H), 2.87-2.83 (m, 1H), 1.93-1.71 (m, 4H).

[0312] (E)-(4-((2-(aminomethyl)-3-fluoroally)oxy)-3-fluorophenyl)-(4-phenyl piperidin-1-yl)methanone trifluoroacetate (TM48-E).

[0313] MS m/z (ESI): 387 [M+H].sup.+

[0314] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.34-7.14 (m, 9H), 4.78-4.73 (m, 1H), 4.73 (d, J=3.2 Hz, 2H), 3.90-3.84 (m, 1H), 3.84 (s, 2H), 3.29-3.23 (m, 1H), 2.98-2.93 (m, 1H), 2.87-2.83 (m, 1H), 1.93-1.71 (m, 4H).

EXAMPLE 12

Preparation of (4-((2-aminomethyl-3-fluoroallyl)oxy)-3-fluorophenyl)-(3,4-tetrahydroisoquinoline-2(1H)-yl)methanone trifluoroacetate (TM72)

[0315] ##STR00049##

[0316] Except for that in Step I of the example, tetrahydroisoquinoline replaced 2-naphthylamine in Step I of Example 1, the title compound was prepared according to a similar method to that described in Example 1, with the total yield of 31%.

[0317] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM72-E is earlier than that of the TM27-Z.

[0318] (Z)-(4-((2-aminomethyl-3-fluoroallyl)oxy)-3-fluorophenyl)-(3,4-tetrahydroiso-quinoline-2(1H)-yl)methanone trifluoroacetate (TM72-Z).

[0319] MS m/z (ESI): 359 [M+H].sup.+

[0320] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.41-6.94 (m, 8H), 4.94 (d, J=2.4 Hz, 2H), 4.85-4.75 (m, 1H), 4.70-4.65 (m, 1H), 3.95-3.93 (m, 1H), 3.72 (s, 2 H), 3.72-3.70 (m, 1H), 2.95-2.93 (m, 2 H).

[0321] (E)-(4-((2-aminomethyl-3-fluoroallyl)oxy)-3-fluorophenyl)-(3,4-tetrahydroiso-quinoline-2(1H)-yl)methanone trifluoroacetate (TM72-E).

[0322] MS m/z (ESI): 359 [M+H].sup.+

[0323] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.39-6.94 (m, 8H), 4.85-4.82 (m, 1H), 4.75 (d, J=3.2 Hz, 2H), 4.68-4.65 (m, 1H), 3.95-3.93 (m, 1H), 3.84 (s, 2H), 3.72-3.69 (m, 1H), 2.99-2.93 (m, 2H).

EXAMPLE 13

Preparation of (4-((2-aminomethyl-3-fluoroallyl)oxy)-3-fluorophenyl)-(5-chloro-3,4-dihydroisoquinoline-2(1H)-yl)methanone trifluoroacetate (TM73)

[0324] ##STR00050##

[0325] Except for that in Step I of the example, 5-chlorotetrahydroisoquinoline replaced the 2-naphthylamine in Step I of Example 1, the title compound was prepared according to a similar method to that described in Example 1, with the total yield of 32%.

[0326] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM73-E is earlier than that of the TM73-Z.

[0327] (Z)-(4-((2-aminomethyl-3-fluoroallyl)oxy)-3-fluorophenyl)-(5-chloro-3,4-di-hydroisoquinoline-2(1H)-yl)methanone trifluoroacetate (TM73-Z).

[0328] MS m/z (ESI): 393 [M+H].sup.+

[0329] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.35-7.20 (m, 6H), 7.13 (d, J=80.0 Hz, 1H), 4.95 (d, J=2.4 Hz, 2H), 4.81-4.64 (m, 2H), 4.13-3.79 (m, 2H), 3.73 (d, J=2.0 Hz, 2H), 3.00-2.92 (m, 2H).

[0330] (E)-(4-((2-aminomethyl-3-fluoroallyl)oxy)-3-fluorophenyl)-(5-chloro-3,4-di-hydroisoquinoline-2(1H)-yl)methanone trifluoroacetate (TM73-E).

[0331] MS m/z (ESI): 393 [M+H].sup.+

[0332] .sup.1HNMR (400 MHz, CD30D) : 7.44-7.15 (m, 7H), 4.75 (d, J=3.2 Hz, 2H), 4.85-4.62 (m, 2H), 4.11-3.65 (m, 2H), 3.85 (s, 2H), 3.01-2.89 (m, 2H).

EXAMPLE 14

Preparation of N-(4-fluorophenyl)-4-((2-aminomethyl-3-fluoroallyl) oxy)-3-chloro-benzamide trifluoroacetate (TM65)

[0333] ##STR00051##

[0334] Except for that in Step I of the example, para-fluoroaniline replaced the 2-naphthylamine in Step I of Example 1, and 3-chloro-4-hydroxybenzoic acid replaced the para-hydroxybenzoic acid in Step I of Example 1, the title compound was prepared according to a similar method to that described in Example 1, with the total yield of 8%.

[0335] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM65-E is earlier than that of the TM65-Z.

[0336] (Z)-N-(4-fluorophenyl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-3-chloro-benzamide trifluoroacetate (TM65-Z).

[0337] MS m/z (ESI): 353 [M+H].sup.+

[0338] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.06 (d, J=2.4 Hz, 1H), 7.95 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.15 (d, J=80.8 Hz, 1H), 7.10 (t, J=8.8 Hz, 2H), 4.99 (d, J=2.4 Hz, 2H), 3.76 (d, J=2.4 Hz, 2H).

[0339] (E)-N-(4-fluorophenyl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-3-chloro-benzamide trifluoroacetate (TM65-E).

[0340] MS m/z (ESI): 353 [M+H].sup.+

[0341] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.06 (d, J=2.4 Hz, 1H), 7.94 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.28 (d, J=80.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10 (t, J=8.8 Hz, 2H), 4.78 (d, J=3.2 Hz, 2H), 3.88 (d, J=3.2 Hz, 2H).

EXAMPLE 15

Preparation of (4-((2-aminomethyl-3-fluoroallyl)oxy)phenyl)-(3,4-dihydroisoquinolin-2(1H)-yl)methanone trifluoroacetate (TM45)

[0342] ##STR00052##

[0343] Except for that in Step I of the example, tetrahydroisoquinoline replaced the para-fluoroaniline in Step III of Example 3, the title compound was prepared according to a similar method to that described in Steps III and IV of Example 3, with the total yield of 81%.

[0344] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM45-E is earlier than that of the TM45-Z.

[0345] (Z)-(4-((2-aminomethyl-3-fluoroallyl)oxy)phenyl)-(3,4-dihydroiso-quinoline-2(1H)-yl)methanone trifluoroacetate (TM45Z).

[0346] MS m/z (ESI): 341 [M+H].sup.+

[0347] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.47 (d, J=8.4 Hz, 2H), 7.21-7.11 (m, 6H), 7.11 (d, J=80.8 Hz, 1H, 1H), 4.89 (d, J=2.4 Hz, 2H), 4.83-4.67 (m, 2H), 3.94-3.70 (m, 2H), 3.70 (d, J=2.0 Hz, 2H), 2.93 (s, 2H).

[0348] (E)-(4-((2-aminomethyl-3-fluoroallyl)oxy)phenyl)-(3,4-di hydroisoquinoline-2 (1H)-yl)methanone trifluoroacetate (TM45-E).

[0349] MS m/z (ESI): 341 [M+H].sup.+

[0350] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.46 (d, J=8.8 Hz, 2H), 7.24 (d, J=81.2 Hz, 1H), 7.19-6.92 (m, 6H), 4.82-4.67 (m, 2H), 4.67 (d, J=2.8 Hz, 2H), 3.94 (br, 1H), 3.83 (s, 2H), 3.70 (br, 1H), 2.92 (s, 2H).

EXAMPLE 16

Preparation of (4-((2-aminomethyl-3-fluoroallyl)oxy)phenyl)-(4-phenylpiperidin-1-yl)methanone trifluoroacetate (TM44)

[0351] ##STR00053## ##STR00054##

[0352] Except for that in Step I of the example, 4-phenylpiperidine replaced the para-fluoroaniline in Step III of Example 3, the title compound was prepared according to a similar method to that described in Steps III and IV of Example 3, with the total yield of 42%.

[0353] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM44-E is earlier than that of the TM44-Z.

[0354] (Z)-(4-((2-aminomethyl-3-fluoroallyl)oxy)phenyl)-(4-phenylpiperidine-1-yl) methanone trifluoroacetate (TM44-Z)

[0355] MS m/z (ESI): 369 [M+H].sup.+

[0356] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.46 (d, J=8.8 Hz, 2H), 7.22-7.00 (m, 8H), 4.84 (d, J=2.4 Hz, 2H), 4.81-4.56 (m, 1H), 4.01-3.83 (m, 1H), 3.69 (d, J=2.4 Hz, 2H), 3.23-2.82 (m, 3H), 2.10-1.54 (m, 4H).

[0357] (E)-(4-((2-aminomethyl-3-fluoroallyl)oxy)phenyl)-(4-phenylpiperidine-1-yl) methanone trifluoroacetate (TM44-E)

[0358] MS m/z (ESI): 369 [M+H].sup.+

[0359] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.45 (d, J=8.4 Hz, 2H), 7.34-7.24 (m, 6H), 7.09 (d, J=8.8 Hz, 2H), 4.84-4.70 (m, 1H), 4.66 (d, J=3.2 Hz, 2H), 4.01-3.86 (m, 1H), 3.82 (d, J=2.0 Hz, 2H), 3.27-2.93 (m, 2H), 2.90-2.82 (m, 1H), 2.04-1.55 (m, 4H).

EXAMPLE 17

Preparation of 2-(4-(2-pyrimidyl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM39)

[0360] ##STR00055##

Step I: Preparation of 4-(2-pyrimidyl)phenol (17-1)

[0361] 2-chloropyrimidine (1.0 g, 8.77 mmol), 4-hydroxyphenylboric acid (2.3 g, 10.53 mmol), the saturated sodium bicarbonate aqueous solution (2 mL) and dioxane (8 mL) were placed in a reaction flask and bubbled up with nitrogen gas for 5 min, and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (320 mg, 0.44 mmo!) was added thereto. The mixture was further bubbled up with nitrogen gas for 3 min, and then heated to 100 C. and stirred for 8 hour. The reaction solution was extracted with water and ethyl acetate. The organic phases were combined, washed with water and saturated saline solution, then dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by silica gel column chromatograph to afford the product (150 mg, 9%).

[0362] MS m/z (ESI):173 [M+H].sup.+

Step II: Preparation of 2-(4-(2-pyrimidyl) phenoxymethyl)-3-fluoroallylamine (17-2)

[0363] The compound 17-1 (110 mg, 0.636 mmol), the compound Int-1 (204 mg, 0.763 mmol) and potassium carbonate (132 mg, 0.954 mmol) were dissolved in DMF (10 mL) and reacted at room temperature overnight. The reaction solution was extracted by adding water and ethyl acetate. The organic phases were combined, washed with water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by TLC plate to afford the product (100 mg, 37%).

Step III: Preparation of 2-(4-(2-pyrimidyl) phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM39)

[0364] Except for that the intermediate 17-2 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of about 100%.

[0365] Method of resolution of 2-(4-(2-pyrimidyl) phenoxymethyl)-3-fluoroallylamine trifluoroacetate isomers

[0366] Apparatus: Agilent 1260, Sunfire C18, OBD 5 m, 19*150 mm column; Mobile phase: A: 0.1% TFA, B: ACN;

[0367] Elution gradient: flow rate 16 mL/min; 0-9.6 min: 10%-28% B, 9.7-12 min: 95% B; 12.1-15 min: 10% B.

[0368] The eluent liquid having a retention time from 6.8 to 7.7 min was collected and lyophilized to afford the TM39-E, and the eluent liquid having a retention time from 8.2 to 8.8 min was collected and lyophilized to afford the TM39-Z.

[0369] (Z)-2-(4-(2-pyrim idyl) phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM39-Z)

[0370] MS m/z (ESI): 260 [M+H].sup.+

[0371] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.80 (d, J=4.8Hz, 2H), 8.37 (d, J=8.8 Hz, 2H), 7.31 (t, J=4.8 Hz, 1H), 7.14 (d; J=7.2 Hz, 2H), 7.12 (d, J=80.8 Hz, 1H), 4.90 (d, J=2.4 Hz, 2H), 3.71 (d, J=2.0 Hz, 2H).

[0372] (E)- 2-(4-(2-pyrimidyl) phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM39-E)

[0373] MS m/z (ESI): 260 [M+H].sup.+

[0374] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.80 (d, J=4.8Hz, 2H), 8.37 (d, J=8.8 Hz, 2H), 7.31 (t, J=4.8 Hz, 1H), 7.24 (d, J=81.2 Hz, 1H), 7.14-7.11 (m, 2H), 4.70 (d, J=3.2 Hz, 2H), 3.85 (d, J=1.2 Hz, 2H).

EXAMPLE 18

Preparation of 2-(4-(1H-benzoimidazol-2-yl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM42)

[0375] ##STR00056##

Step I: Preparation of 4-(1H-benzoimidazol-2-yl)phenol (18-1)

[0376] The compound ortho-diphenylamine (300 mg, 2.78 mmol) and para-hydroxybenzaldehyde (430 mg, 3.52 mmol) were dissolved in DMF (10 mL) and then dripped with ice acetic acid (20 drops), the mixture was reacted under reflux at 145 C. for 5 h. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phases were combined, then added with saturated saline solution to precipitate yellow solids, and the solids were filtered and dried to afford the target product (220 mg, 38%).

[0377] MS m/z(ESI): 211 [M+H].sup.+

Step II: Preparation of tert-butyl (2-(4-(1H-benzoimidazol-2-yl) phenoxy-methyl)-3-fluoroallyl)carbamate (18-2)

[0378] Except for that the intermediate 18-1 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, and the crude product is directly used in the next step.

[0379] MS m/z (ESI): 398 [M+H].sup.+

Step III: Preparation of 2-(4-(1H-benzoimidazol-2-yl) phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM42)

[0380] Except for that the intermediate 18-2 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of 90%.

[0381] Method of resolution of 2-(4-(1H-benzoimidazole-2-yl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate isomers

[0382] A separation method similar to that as described in Example 9 is applied, wherein elution gradient: 0-6 min: 10%-28.7% B, flow rate: 16 mL/min; 6.1-9 min: 95% B, flow rate: 16 mL/min; 9.1-12 min: 10% B, flow rate: 16 mL/min. The eluent liquid having a retention time from 5.1 to 5.3 min was collected and lyophilized to afford the TM42-E, and the eluent liquid having a retention time from 5.5 to 5.7 min was collected and lyophilized to afford the TM42-Z.

[0383] (Z)-2-(4-(1H-benzoimidazol-2-yl)phenoxymethyl)-3-ftuoroallylamine trifluoroacetate (TM42-Z)

[0384] MS m/z (ESI): 298 [M+H].sup.+

[0385] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.12 (d, J=8.8 Hz, 2H), 7.77-7.75 (m, 2H), 7.55-7.54 (m, 2H), 7.34 (d, J=9.2 Hz, 2H), 7.16 (d, J=80.4 Hz, 1H), 4.96 (d, J=2.0 Hz, 2H), 3.73 (d, J=2.0 Hz, 2H).

[0386] (E)-2-(4-(1H-benzoimidazol-2-yl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM20-E)

[0387] MS m/z (ESI): 298 [M+H].sup.+

[0388] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.13 (d, J=8.0 Hz, 2H), 7.79-7.77 (m, 2H), 7.59-7.57 (m, 2H), 7.34 (d, J=8.8 Hz, 2H), 7.29 (d, J=80.8 Hz, 1H), 4.77 (d, J=3.2 Hz, 2H), 3.86 (d, J=2.0 Hz, 2H).

EXAMPLE 19

Preparation 2-(4-(6-chloro-benzothiazol-2-yl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM41)

[0389] ##STR00057##

Step I: Preparation of bis(2-amino-5-chlorophenyl)dithioether (19-1)

[0390] 2-amino-6-chloro-benzothiazole (2 g, 5.4 mmol) was dissolved in water (50 mL) and added with potassium hydroxide (10 g, 89 mmol). The mixture was reacted under reflux at 100 C. for 5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature and regulated to pH=6-7 by adding 4N HCl. The mixture added with water andstirred for 1 hour, and then was subjected to suction filtration to afford yellow solids, and after being recrystallized with ethanol/water, yellow solids (710 mg, 32%) were obtained.

Step II: Preparation of 4-(6-chloro-benzothiazole-2-yl)-phenol (19-2)

[0391] The compound 19-1 (710 mg, 2.3 mmol), para-hydroxybenzoaldehyde (280 mg, 4.6 mmol), triphenylphosphine (600 mg, 2.3 mmol) and para-methylbenzene sulfonic acid (90 mg, 0.46 mmol) were mixed and dissolved in toluene (100 mL), and the mixture was heated with stirring to reflux and reacted for 24 hours. After the completion of the reaction, the reaction solution was cooled to room temperature and concentrated, and then dissolved with dichloromethane. The insoluble matter was filtered out. The mother liquor was concentrated and purified by preparative plate to afford white solids (120 mg, 27%).

[0392] MS m/z (ESI): 262[M+H].sup.+

Step III: Preparation of tert-butyl (2-(4-(6-chloro-benzothiazol-2-yl) phenoxymethyl)-3-fluoroallyl)carbamate (19-3)

[0393] Except for that the intermediate 19-2 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 32%.

[0394] MS m/z (ESI): 449[M+H].sup.+

Step IV: Preparation of 2-(4-(6-chloro-benzothiazol-2-yl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM41)

[0395] Except for that the intermediate 19-3 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of 90%.

[0396] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM41-E is earlier than that of the TM41-Z.

[0397] (Z)-2-(4-(6-chloro-benzothiazol-2-yl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM41-Z)

[0398] MS m/z (ESI): 349 [M+H].sup.+

[0399] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.07 (d, J=8.8 Hz, 2H), 8.03 (d, J=2.0 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.51 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.19 (d, J=9.2 Hz, 2H), 7.12 (d, J=80.8 Hz, 1H), 4.91 (d, J=2.4 Hz, 2H), 3.71 (d, J=2.4 Hz, 2H).

[0400] (E)-2-(4-(6-chloro-benzothiazol-2-yl)phenoxymethyl)-3-fluoroallylamine trifluoroacetate (TM41-E)

[0401] MS m/z (ESI): 349 [M+H].sup.+

[0402] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.06 (d, J=8.8 Hz, 2H), 8.03 (d, J=2.0 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.51 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.27 (d, 1H), 7.17 (d, J=8.8 Hz, 2H), 4.71 (d, J=3.2 Hz, 2H), 3.84 (d, J=2.0 Hz, 2H).

EXAMPLE 20

Preparation of 2-(4-(6-chloro-benzothiazol-2-yl)-2-fluorophenoxy-methyl)-3-fluoroallylamine trifluoroacetate trifluoroacetate (TM74)

[0403] ##STR00058##

[0404] Except for that in step II of this example, 3-fluoro-4-hydroxybenzoaldehyde replaced the para-hydroxybenzoaldehyde in Step II of Example 19, the title compound was prepared according to a similar method to that described in Example 19, with the total yield of 9%.

[0405] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM74-E is earlier than that of the TM74-Z.

[0406] (Z)-2-(4-(6-chloro-benzothiazol-2-yl)-2-fluorophenoxymethyl)-3-fluoroallylamine trifluoroacetate trifluoroacetate (TM74-Z)

[0407] MS m/z (ESI): 367 [M+H].sup.+

[0408] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.05 (d, J=2.0 Hz, 1H), 7.97-7.87 (m, 3H), 7.52 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.36 (t, J=8.4 Hz, 1H), 7.15 (d, J=80.4 Hz, 1H), 4.98 (d, J=2.4 Hz, 2H), 3.74 (d, J=2.8 Hz, 2H).

[0409] (E)-2-(4-(6-chloro-benzothiazol-2-yl)-2-fluorophenoxymethyl)-3-fluoroallylamine trifluoroacetate trifluoroacetate (TM74-E)

[0410] MS m/z (ESI): 367 [M+H].sup.+

[0411] .sup.1HNMR (400 MHz, CD.sub.3OD) 5: 8.05 (d, J=2 Hz, 1H), 7.97-7.87 (m, 3H), 7.53 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.28 (d, J=80.8 Hz, 1H), 4.79 (d, J=3.2 Hz, 2H), 3.86 (d, J=2.0 Hz, 2H).

EXAMPLE 21

Preparation of 5-((2-aminomethyl-3-fluoroallyl)oxy)-2-(4-chlorobenzyl)isoindolin-1-one (TM33)

[0412] ##STR00059## ##STR00060##

Step I: Preparation of 2-(4-chlorobenzyl)-5-methoxyisoindolin-1-one (21-1)

[0413] The reactants ethyl 2-bromomethyl-4-methoxybenzoate (500 mg, 1.93 mmol), para-chlorobenzylamine (272 mg, 1.93 mmol) and triethylamine (585 mg, 5.79 mmol) were dissolved in toluene (3 mL), then sealed and heated at 110 C. for 4 hours. After the completion of the reaction, the reaction solution was concentrated, then was extracted with water and ethyl acetate. The organic phases were combined, washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica column chromatograph to afford the product 21-1 (275 mg, 50%).

Step II: Preparation of 2-(4-chlorobenzyl)-5-hydroxyisoindolin-1-one (21-2)

[0414] The compound 21-1 (150 mg, 0.52 mmol) was dissolved in dichloromethane (20 mL), and added with BBr.sub.3 (392 mg, 1.57 mmol) at 78 C., and then the mixture was warmed up to room temperature and reacted for 1 hour. After the reaction was complete, the reaction solution was added to ice water to quench the reaction, and extracted with dichloromethane. The organic phases were combined, washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to afford the product 21-2 (110 mg, 96%).

Step III: Preparation of tert-butyl (2-(2-(4-chlorobenzyl)-1-oxoisoindolin-5-oxymethyl)-3-fluoroallyl)carbamate (21-3)

[0415] The compound 21-2 (80 mg, 0.293 mmol), the compound Int-1 (81 mg, 0.322 mmol) and potassium carbonate (61 mg, 0.439 mmol) were dissolved in DMF (10 mL) and reacted at room temperature overnight. The reaction solution was extracted by adding water and ethyl acetate. The organic phases were combined, washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated to afford the crude product, which was purified by preparative TLC to afford the product 21-3 (80 mg, 48%).

Step IV: Preparation of 5-((2-aminomethyl-3-fluoroallyl)oxy;-2-(4-chlorobenzyl)isoindolin-1-one (TM33)

[0416] Except for that the intermediate 21-3 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of 100%.

[0417] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM33-E is earlier than that of the TM33-Z.

[0418] (Z)-5-((2-aminomethyl-3-fluoroallyl)oxy)-2-(4-chlorobenzyl)isoindolin-1-one (TM33-Z)

[0419] MS m/z (ESI): 361 [M+H].sup.+

[0420] .sup.1HNMR (400 MHz, DMSO-d.sub.6) : 8.08 (br, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.32-7.07(m, 5H), 4.78 (d, J=1.6 Hz, 2H), 4.69 (s, 2H), 4.32 (s, 2H), 3.56 (s, 2H).

[0421] (E)-5-((2-aminomethyl-3-fluoroallyl)oxy)-2-(4-chlorobenzyl)isoindolin-1-one (TM33-E)

[0422] MS m/z (ESI): 361[M+H].sup.+

[0423] .sup.1HNMR (400 MHz, DMSO-d6) : 8.17 (br, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.45-7.24 (m, 5H), 7.18 (d, J=1.6 Hz, 1H), 7.11 (dd, J=8.4 Hz, 2.0 Hz, 1H), 4.69 (s, 2H), 4.67 (s, 2H), 4.32 (s, 2H), 3.64 (s, 2H).

EXAMPLE 22

Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM26)

[0424] ##STR00061##

Step I: Preparation of 6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (22-1)

[0425] 5-hydroxy-1-indone (300 mg, 2.03 mmol) was dissolved in trifluoroacetic acid (10 mL), and slowly added with sodium azide (200 mg, 3.08 mmol), and the mixture was refluxed and reacted at 74 C. for 5 hours. Then, the reaction solution was added with water and subjected to rotary evaporation under vacuum to remove most of trifluoroacetic acid. To the residue was added with sodium bicarbonate to regulate to weak basic, and then extracted with ethyl acetate. The organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the target product (240 mg, 73%).

[0426] MS m/z(ESI): 164 [M+H].sup.+

Step II: Preparation of tert-butyl (2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-oxymethyl)-3-fluoroallyl)carbamate (22-2)

[0427] Except for that the intermediate 22-1 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step 11 of Example 1, with the yield of 58%.

[0428] MS m/z (ESI): 351 [M+H].sup.+

Step III: Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM26)

[0429] Except for that the intermediate 22-2 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of 90%.

[0430] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM26-E is earlier than that of the TM26-Z.

[0431] (Z)-6-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM26-Z)

[0432] MS m/z (ESI): 251 [M+H].sup.+

[0433] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.89 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.11 (d, J=80.8 Hz, 1H), 6.98 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 4.87 (d, J=2.4 Hz, 2H), 3.69 (d, J=2.4 Hz, 2H), 3.48 (t, J=6.8 Hz, 2H), 2.97 (t, J=6.8 Hz, 2H).

[0434] (E)-6-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM26-E)

[0435] MS m/z (ESI): 251 [M+H].sup.+

[0436] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.88 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.23 (d, J=80.8 Hz, 1H), 6.97 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H), 4.67 (d, J=2.4 Hz, 2H), 3.82 (d, J=1.2 Hz, 2H), 3.48 (t, J=6.8 Hz, 2H), 2.96 (t, J=6.8 Hz, 2H).

EXAMPLE 23

Preparation of 6-((2-aminornethyl-3-fluoroallyl)oxy)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM27)

[0437] ##STR00062## ##STR00063##

Step I: Preparation of 6-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene (23-1)

[0438] TiCl.sub.4 (2.2 mL, 0.02 mmol) was dissolved in 20 mL anhydrous dichloromethane and added with Me.sub.2Zn (80 mL, 0.08 mmol) at 40 OC with stirring under the nitrogen protection. The mixture was kept at the temperature and stirred for 30 min, 6-methoxy-1-indone (1.76 g, 0.01 mmol) dissolved with 5 mL dichloromethane was added and the mixture was slowly raised to room temperature and reacted overnight. To the reaction solution, 10 mL anhydrous methanol was slowly dripped to quench the reaction, and then dichloromethane and saturated NH.sub.4Cl solution were added for dilution and extraction. The organic phase was washed with saturated NH.sub.4Cl solution twice, and the aqueous phase was washed twice with dichlormethane. The organic phases were combined, dried and concentrated to afford an oily liquid (2.10 g, 72%).

Step II: Preparation of 5-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (23-2)

[0439] The compound 23-1 (1.65 g, 9.4 mmol) was dissolved with 20 ml ice acetic acid, and added with CrO.sub.3 that was dissolved with 8 mL ice acetic acid and 7 mL water with stirring at 0 C., and the mixture was slowly raised to room temperature and reacted overnight. The reaction solution was diluted with water and then extracted twice with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution to neutral, and then dried and concentrated to afford a yellow oily liquid (1.50 g, 83%).

Step III: Preparation of 6-methoxy-4,4-dimethyl-3,4-dihydroisoquinolin-1-(2H)-one (23-3)

[0440] The compound 23-2 (1.1 g, 5.8 mmol) and NaN.sub.3 (0.65 g, 10 mmol) were :nixed and placed in a three-mouth flask and added with trifluoroacetic acid (20 mL), and the mixture was reacted for 4 hours at reflux. After the reaction was complete, the reaction solution was cooled to room temperature and then diluted with water. The mixture was regulated to pH=7-8 with saturated sodium bicarbonate, and extracted twice with dichloromethane, the organic phases were combined. The organic phase was dried and concentrated to afford brown solids, which was recrystalized from petroleum ether-ethyl acetate mixed solution (petroleum ether: ethyl acetate=20:1) to afford brown solids (600 mg, 62%).

Step IV: Preparation of 6-hydroxy-4,4-dimethyl-3,4-dihydroisoquinolin-1-(2H)-one (23-4)

[0441] To the compound 23-3 (168 mg, 0.82 mmol), 17% BBr.sub.3 solution in dichloromethane (10 mL) was added and reacted at room temperature overnight. After the reaction was complete, methanol was added to quench the reaction. The reaction solution was concentrated and dissolved with a small amount of dichloromethane, then separated by preparative TLC to afford white solids (82 mg, 52%).

Step V: Preparation of tert-butyl (2-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-one-6-oxymethyl)-3-fluoroallyl)carbamate (23-5)

[0442] Except for that the intermediate 23-4 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 32%.

Step VI: Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM27)

[0443] Except for that the intermediate 23-5 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of about 100%.

[0444] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM27-E is earlier than that of the TM27-Z.

[0445] (Z)-6-((2-aminomethyl-3-fluoroallyl)oxy)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM27-Z)

[0446] MS m/z (ESI): 279 [M+H].sup.+

[0447] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.93 (d, J=8.4 Hz, 1H), 7.22-6.95 (m, 3H), 4.90 (d, J=2.4 Hz, 2H), 3.69 (d, J=2.4 Hz, 2H), 3.27 (s, 2 H), 1.33 (s, 6H).

[0448] (E)-6-((2-aminomethyl-3-fluoroallyl)oxy)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM27-E).

[0449] MS m/z (ESI): 279 [M+H].sup.+

[0450] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.93 (d, J=8.4 Hz, 1H), 7.35-6.96 (m, 3H), 4.69 (d, J=3.6 Hz, 2H), 3.83 (s, 2H), 3.27 (s, 2H), 1.33 (s, 6H).

Example 24: Preparation of 5-((2-aminomethyl-3-fluoroallyl)oxy)isoirdolin-1-one trifluoroacetate (TM77)

[0451] ##STR00064##

[0452] Except for that 5-hydroxyl-isoindol-1-one in this step I replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to method similar to that described in Steps Il and III of Example 1, with the total yield of 63%.

[0453] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM77-E is earlier than that of the TM77-Z

[0454] (Z)-5-((2-aminomethyl-3-fluoroallyl)oxy)isoindol-1-one trifluoroacetate (TM77-Z).

[0455] MS m/z (ESI): 226 [M+H].sup.+

[0456] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.73 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 7.15 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.12 (d, J=80.8 Hz, 1H), 4.90 (d, J=2.4 Hz, 2H), 4.43 (s, 2H), 3.71 (d, J=2.0 Hz, 2H).

[0457] (E)-5-((2-aminomethyl-3-fluoroallyl)oxy)isoindol-1-one trifluoroacetate (TM77-E).

[0458] MS m/z (ESI): 226 [M+H].sup.+

[0459] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.72 (d, J=8.4 Hz, 1H), 7.35-7.12 (m, 3H), 4.70 (d, J=2.8 Hz, 2H), 4.42 (s, 2 H), 3.84 (d, J=2.0 Hz, 2H).

EXAMPLE 25

Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-2,3-dihydro-1-indenone trifluoroacetate (TM7)

[0460] ##STR00065##

Step I: Preparation of 6-hydroxy-2,3-dihydro-1-indenone (25-1)

[0461] The compound 6-methoxy-2,3-dihydro-1-indenone (1.0 g, 6.17 mmol) was placed in a reaction flask and then added with the solvent toluene (20 mL). To the reactor with stirring, aluminum trichloride solids (2.4 g, 18.50mmo1) were added and reacted at 105 C. for 2 hours. After TLC monitored the completion of the reaction, the solvent was removed by concentration, and the reaction solution was added with water and extacted with ethyl acetate. The organic phases were combined, washed with saturated saline solution, dried and concentrated to afford a crude product, which was purified by column chromatography to afford the product 25-1 (420 mg, 46%).

Step II: Preparation of 6-(2-tert-butoxycarbonylaminomethyl-3-fluoroallyloxy)-2,3-dihydro-1-indenone (25-2)

[0462] Except for that the intermediate 25-1 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1.

Step III: Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-2,3-dihydro-1-indenone trifluoroacetate (TM7)

[0463] Except for that the intermediate 25-2 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1.

[0464] The total yield of Step II and Step III is 77%.

[0465] Method of resolution of 6-((2-aminomethyl-3-fluoroallyl)oxy)-2,3-dihydro-1-indenone trifluoroacetate isomers

[0466] A method similar to that as described in Example 9 is applied to resolute the isomers, wherein, elution gradient: 0-9 min: 10%-26.8% B, flow rate: 16 mL/min; 9.1-11 min: 95% B, flow rate: 20 mL/min; 11.1-13 min: 10% B, flow rate: 20 mUmin. The eluent liquid having a retention time from 6.6 to 7.6 min was collected and lyophilized to afford the TM7-E, and the eluent liquid having a retention time from 7.8 to 8.7 min was collected and lyophilized to afford the TM7-Z.

[0467] (Z)-6-((2-aminomethyl-3-fluoroallyl)oxy)-2,3-dihydro-1-indenone trifluoroacetate (TM7-Z)

[0468] MS mlz (ESI): 236 [M+H].sup.+

[0469] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.49 (d, J=8.4 Hz, 1H), 7.35 (dd, J=8.4 Hz, 2.8 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.10 (d, J=80.8 Hz, 1H), 4.85 (d, J=2.4 Hz, 2H), 3.70 (d, J=2.4 Hz, 2H), 3.11-3.09 (m, 2H), 2.73-2.70 (m, 2H).

[0470] (E)-6-((2-aminomethyl-3-fluoroallyl)oxy)-2,3-dihydro-1-indenone trifluoroacetate (TM7-E)

[0471] MS m/z (ESI): 236 [M+H].sup.+

[0472] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.48 (d, J=8.4 Hz, 1H), 7.35-7.32 (m, 1H), 7.25 (s, 1H), 7.23 (d, J=81.2 Hz,1H), 4.65 (d, J=3.6 Hz, 2H), 3.83 (d, J=1.6 Hz, 2H), 3.10-3.18 (m, 2H), 2.72-2.70 (m, 2H).

EXAMPLE 26

Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM38)

[0473] ##STR00066##

Step I: Preparation of 5-methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (26-1)

[0474] The compound 5-methoxy-2,3-dihydro-1-indenone (1.5 g, 9.3 mmol) was dissolved in ether (40 mL), and followed by dripping with iodomethane (2.9 mL, 46.2 mmol) in ice bath. Then in the ice bath, the mixture was added with the solution of potassium tert-butanol (3.4 g, 30.4 mmol) in tert-butanol (20 mL) and reacted at reflux for 6 hours. Water was added to quench the reaction, and the reaction solution was extracted twice with ether. The organic phase was washed with a saturated saline solution. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated by column chromatography to afford the target molecules (1.2 g, 68%).

Step II: Preparation of 6-methoxy-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (26-2)

[0475] Except for that the intermediate 26-1 in this step replaced the intermediate 23-2 in Step III of Example 23, the title compound was prepared according to a similar method to that described in Step III of Example 23, with the yield of 15%.

Step III: Preparation of 6-hydroxyl-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (26-3)

[0476] Except for that the intermediate 26-2 in this step replaced the 6-methoxy-2,3-dihydro-1-indenone in Step I of Example 25, the title compound was prepared according to a similar method to that described in Step I of Example 25.

Step IV: Preparation of 6-(2-tert-butoxycarbonylaminomethyl-3-fluoroallyloxy)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (26-4)

[0477] Except for that the intermediate 26-3 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1.

Step V: Preparation of 6-(2-aminomethyl-3-fluoroallyloxy)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM38)

[0478] Except for that the intermediate 26-4 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1.

[0479] The total yield of Step III to Step V is 46%.

[0480] Method of resolution of 6-((2-aminomethyl-3-fluoroallyl)oxy)- 3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate isomers

[0481] A method similar to that as described in Example 9 is applied to resolute the isomers, wherein elution gradient: 0-7.4 min: 10%-28.5% B, flow rate: 16 mL/min; 7.5-9 min: 95% B, flow rate: 20 mL/min; 9.1-11 min: 10% B, flow rate: 20 mL/min. The eluent liquid having a retention time from 5.6 to 6.2 min was collected and lyophilized to afford the TM38-E, and the eluent liquid having a retention time from 6.4 to 6.9 min was collected and lyophilized to afford the TM38-Z.

[0482] (Z)-6-((2-(methylamino)-3-fluoroallyl)oxy)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM38-Z).

[0483] MS m/z (ESI): 279 [M+H].sup.+

[0484] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.89 (d, J=8.4 Hz, 1H), 7.11 (d, J=80.8 Hz, 1H), 7.01-6.98 (m, 1H), 6.92-6.91 (m, 1H), 4.87 (s, 2H), 3.69 (d, J=2.4 Hz, 2H), 2.92 (s, 2H), 1.29 (s, 6H).

[0485] (E)-6-((2-(methylamino)-3-fluoroallyl)oxy)-3,3-dimethyl-3,4-dihydro-isoquinolin-1(2H)-one trifluoroacetate (TM38-E).

[0486] MS m/z (ESI): 279 [M+H].sup.+

[0487] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.89 (d, J=8.8 Hz, 1H), 7.24 (d, J=81.2 Hz, 1H), 6.98 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.90-6.89 (m, 1H), 4.67 (d, J=2.8 Hz, 2H), 3.82 (s, 2H), 2.92 (s, 2H), 1.29 (s, 6H).

EXAMPLE 27

Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM66)

[0488] ##STR00067##

Step I: Preparation of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (27-1)

[0489] Except for that 5-methoxy-1-indenone in this step replaced the intermediate 23-2 in Step III of Example 23, the title compound was prepared according to a similar method to that described in Step III of Example 23, with the total yield of 48%.

Step II: Preparation of 6-methoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (27-2)

[0490] The compound 27-1 (250 mg, 1.41 mmol) was dissolved in DMF (10 mL), and in ice bath, added with NaH (84 mg, 2.11 mmol, 60%), after reacting for 10 min, the mixture was dripped with iodomethane (300 mg, 2.11 mmol) and warmed slowly to room temperature, then further reacted for 2 hours. LCMS monitored the completion of the reaction, the reaction solution was extracted by adding saturated saline solution and ethyl acetate. The organic phase was washed twice by saturated saline solution. The organic phases were combined, dried and concentrated to dryness, to afford the brown liquid product 27-2 (225 mg, 83%).

Step III: Preparation of 6-hydroxyl-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (27-3)

[0491] Except for that the intermediate 27-2 in this step replaced the 6-methoxy-2,3-dihydro-1-indenone in Step I of Example 25, the title compound was prepared according to a similar method to that described in Step I of Example 25.

Step IV: Preparation of 6-(2-tert-butoxycarbonylaminomethyl-3-fluoroallyloxy)-2-methyl-3,4-di hydroisoq uinolin-1(2H)-one (27-4)

[0492] Except for that the intermediate 27-3 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1.

Step V: Preparation of 6-((2-aminomethyl-3-fluoroallyl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM66)

[0493] Except for that the intermediate 27-4 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1.

[0494] The total yield of Step III to Step V is 77%.

[0495] Method of resolution of 6-((2-aminomethyl-3-fluoroallyl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2 H)-one trifluoroacetate isomers

[0496] A method similar to that as described in Example 9 is applied to resolute the isomers, wherein elution gradient: 0-7.8 min: 10%-24.6% B, flow rate: 16 mL/min; 7.9-10 min: 95% B, flow rate: 20 mL/min; 10.1-12 min: 10% B, flow rate: 20 mL/min. The eluent liquid having a retention time from 5.6 to 6.2 min was collected and lyophilized to afford the TM66-E, and the eluent liquid having a retention time from 6.8 to 7.3 min was collected and lyophilized to afford the TM66-Z.

[0497] (Z)-6-((2-(methylamino)-3-fluoroallyl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM66-Z)

[0498] MS m/z (ESI): 265 [M+H].sup.+

[0499] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.89 (d, J=8.8 Hz, 1H), 7.10 (d, J=80.8 Hz, 1H), 6.98-6.96 (m, 1H), 6.90 (d, J=2.4 Hz, 1H), 4.86 (d, J=2.4 Hz, 2H), 3.69 (d, J=2.0 Hz, 2H), 3.60 (t, J=6.8 Hz, 2H), 3.12 (s, 3H), 3.01 (t, J=6.8 Hz, 2H).

[0500] (E)-6-((2-(methylamino)-3-fluoroallyl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM66-E)

[0501] MS m/z (ESI): 265 [M+H].sup.+

[0502] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.89 (d, J=8.4 Hz, 1H), 7.24 (d, J=81.2 Hz, 1H), 6.96 (dd, J=8.8 Hz, 2.4 Hz,1H), 6.88 (d, J=2.4 Hz, 1H), 4.66 (d, J=2.8 Hz, 2H), 3.82 (s, 2H), 3.60 (t, J=6.8 Hz, 2H), 3.12 (s, 3H), 3.01 (t, J=6.8 Hz, 2H).

EXAMPLE 28

Preparation of 7-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydro-isoquinolin-1(2H)-one trifluoroacetate (TM75)

[0503] ##STR00068##

Step I: Preparation of 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (28-1)

[0504] Except for that 6-methoxy-1-indanone in this step replaced the intermediate 23-2 in Step III of Example 23, the title compound was prepared according to a similar method to that described in Step III in Example 23, with the total yield of 49%.

Step II: Preparation of 7-hydroxyl-3,4-dihydroisoquinolin-1(2H)-one (28-2)

[0505] Except for that the intermediate 28-1 in this step replaced the 6-methoxy-2,3-dihydro-1-indenone in Step I of Example 25, the title compound was prepared according to a similar method to that described in Step I in Example 25, with the total yield of 67%.

Step III: Preparation tert-butyl (2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-7-oxymethyl)-3-fluoroallyl)carbamate (28-3)

[0506] Except for that in the step, the intermediate 1-1 in Step II of Example 1 was replaced by the intermediate 28-2, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 53%.

Step IV: Preparation of 7-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydro-isoquinolin-1(2H)-one trifluoroacetate (TM75)

[0507] Except for that the intermediate 28-3 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of about 100%.

[0508] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM75-E is earlier than that of the TM75-Z

[0509] (Z)-7-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM75-Z)

[0510] MS m/z (ESI): 251 [M+H].sup.+

[0511] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.07 (d, J=81.2 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.64 (dd, J=8.4 Hz, 2.8 Hz, 1H) 6.53 (d, J=2.8 Hz, 1H), 4.77 (d, J=2.0 Hz, 2H), 3.67 (d, J=2.4 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H).

[0512] (E)-7-((2-aminomethyl-3-fluoroallyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one trifluoroacetate (TM75-E)

[0513] MS m/z (ESI): 251 [M+H].sup.+

[0514] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.18 (d, J=81.8 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.63 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 4.56 (d, J=3.6 Hz, 2H), 3.81 (s, 2H), 2.86 (t, J=7.6 Hz 2H), 2.51 (t, J=7.6 Hz, 2H).

EXAMPLE 29

Preparation of N-(tetrahydro-2H-pyran-4-yl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM76)

[0515] ##STR00069##

Step I: Preparation of 4-((tetrahydro-2H-pyran-4-yl)aminoformyl)phenyl acetate(29-1)

[0516] 4-acetoxybenzoic acid (500 mg, 2.78 mmol) was dissolved in anhydrous dichloromethane (10 mL) and DMF (10 mL), and in ice bath, added with oxalyl chloride (1.06 g, 8.34 mmol), and the mixture was reacted for half an hour. The reaction solution was then concentrated for further use. 4-aminotetrahydro-2H-pyran (336 mg, 3.33 mmol) was dissolved in DMF and added with the above prepared acyl chloride solution, and the mixture was reacted at room temperature. LCMS was used to monitor the reaction. After 5 hours, the reaction solution was added with water and extracted with ethyl acetate. The organic phase was dried and concentrated, then subject to column chromatography separation to afford the title compound, which was a brown liquid (225 mg, 31%).

Step II: Preparation of 4-hydroxyl-N-(tetrahydro-2H-pyran-4-yl)benzamide (29-2)

[0517] The compound 29-1 (225 mg, 0.86 mmol) was dissolved in 10 mL anhydrous methanol and added with 1 ml water and potassium carbonate (354 mg, 2.58 mmol), and the mixture was reacted at room temperature for 1 hour. The reaction solution was then concentrated, added with water, and extracted with ethyl acetate. The organic phase was concentrated to dryness to afford the title compound, which was an oily liquid (125 mg, 66%).

Step III: Preparation of N-(tetrahydro-2H-pyran-4-yl)-4-((2-tert-butoxycarbonyl aminomethyl-3-fluoroallyl)oxy)-benzamide (29-3)

[0518] Except for that the intermediate 29-2 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 42%.

Step IV: Preparation of N-(tetrahydro-2H-pyran-4-yl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM76)

[0519] Except for that the intermediate 29-3 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of 99%.

[0520] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM76-E is earlier than that of the TM76-Z

[0521] (Z)-N-(tetrahydro-2H-pyran-4-yl)-4-((2-aminomethyl-3-fluoroallyl)oxy)-benzamide trifluoroacetate (TM76-Z)

[0522] MS m/z (ESI): 309 [M+H].sup.+

[0523] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.83 (d, J=9.2 Hz, 2H), 7.10 (d, J=80.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 4.86 (d, J=2.4 Hz, 2H), 4.12-4.06 (m, 1H), 3.98 (dd, J=8.0 Hz, 2.4 Hz, 2H), 3.69 (s, 2H), 3.52 (td, J=12.0 Hz, 2.0 Hz, 2H), 1.89-1.86 (m, 2H), 1.71-1.61 (m, 2H).

[0524] (E)-N-(tetrahyd ro-2H-pyran-4-yl)-4-((2-ami nomethyl-3-fluoroal lyl)oxy)-benzamide trifluoroacetate (TM76-E)

[0525] MS m/z (ESI): 309 [M+H].sup.+

[0526] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.83 (d, J=8.8 Hz, 2H), 7.24 (d, J=80.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.66 (d, J=3.6 Hz, 2H), 4.12-4.06 (m, 1H), 3.98 (dd, J=12.0 Hz, 2.4 Hz, 2H), 3.82 (s, 2H), 3.52 (td, 12.0 Hz, 2.0 Hz, 2H), 1.90-1.86 (m, 2H), 1.71-.61 (m, 2H).

EXAMPLE 30

Preparation of 4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(pyridin-2-ylmethyl)benzamide trifluoroacetate (TM112)

[0527] ##STR00070##

Step I: Preparation of 4-((pyrid-2-yl-methyl)aminoformyl)phenyl acetate (30-1)

[0528] The compound 4-acetoxybenzoic acid (2.00 g, 11.1 mmol) was dissolved in dichloromethane (24 mL) and dripped with oxalyl chloride (2.11 g, 16.65 mmol) and DMF (5 drops), the mixture was reacted at room temperature for 3 hours.

[0529] Supplementary Oxalyl chloride (1.50 g, 11.81 mmol) was added, the mixture was reacted at room temperature for 3 hours, and then subjected to dryness by rotary evaporation for further use. The compound 2-aminomethylpyridine (0.5 g, 4.62 mmol) was dissolved in dichloromethane (10 mL) and added with DIPEA (1.79 g, 13.86 mmol) and the above prepared acryl chloride (0.92 g, 4.62 mmol), the mixture was reacted at room temperature for 6 hours. The reaction was quenched by adding water, and the reaction solution was extracted twice with dichloromethane, the organic phase was washed with saturated saline solution. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography. The crude product was directly used in the next step.

Step II: Preparation of 4-hydroxyl-N-(pyridin-2-methyl)benzamide (30-2)

[0530] The crude product of the compound 30-1 was dissolved in methanol (20 mL) and added with water (20 mL) and potassium carbonate (2.50 g, 18.10 mmol), the mixture was reacted at room temperature overnight. The reaction mixture was diluted with water, and regulated with dilute.sub.. hydrochloric acid to pH=about 3. A saturated sodium bicarbonate was further added to regulate the pH=about 8. The resulting mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated saline solution. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated and purified by column chromatography, to afford the target product (0.20 g, the yield of the two steps is 19%).

Step III: Preparation of 4-((2-tert-butoxycarbonylaminomethyl-3-fluoroallyl)oxy)-N-(pyridin-2-ylmethyl)benzamide (30-3)

[0531] Except for that the intermediate 30-2 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 56%.

Step IV: Preparation of 4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(pyridin-2-ylmethyl)benzamide trifluoroacetate (TM112)

[0532] Except for that the intermediate 30-3 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III in Example 1, with the total yield of 99%.

[0533] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM112-E is earlier than that of the TM112-Z

[0534] (Z)-4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(pyridin-2-ylmethyl)benzamide trifluoroacetate (TM112-Z)

[0535] MS m/z (ESI): 316 [M+H].sup.+

[0536] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.72 (d, J=4.8 Hz, 1H), 8.42 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.93-7.91 (m, 3H), 7.85-7.82 (m, 1H), 7.11 (d, J=80.8 Hz, 1H), 7.14-7.12 (m, 2H), 4.88 (d, J=2.4 Hz, 2H), 4,84 (s, 2H), 3.70 (d, J=2.0 Hz, 2H).

[0537] (E)-4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(pyridin-2-ylmethyl)benzamide trifluoroacetate (TM112-E)

[0538] MS m/z (ESI): 316 [M+H].sup.+

[0539] .sup.1HNMR (400 MHz, CD.sub.3OD) : 8.72 (d, J=5.6 Hz, 1H), 8.42 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.93-7.90 (m, 3H), 7.86-7.82 (m, 1H), 7.24 (d, J=80.8 Hz, 1H), 7.13-7.09 (m, 2H), 4.84 (s, 2H), 4.68 (d, J=3.2 Hz, 2H), 3.83 (d, J=1.2 Hz, 2H).

EXAMPLE 31

Preparation of 4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(2,3-dihydrobenzo[b][1,4]dioxa-6-yl)benzamide trifluoroacetate (TM114)

[0540] ##STR00071##

[0541] Except for that 6-amino-1,4-benzodioxane in step I of the example replaced the 2-aminomethylpyridine in Step I of Example 30, the title compound was prepared according to a similar method to that described in Example 30, with the total yield of 9%.

[0542] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM114-E is earlier than that of the TM114-Z

[0543] (Z)-4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(2,3-dihydrobenzo[b][1,4]dioxa-6-yl)benzamide trifluoroacetate (TM114-Z)

[0544] MS m/z (ESI): 359 [M+H].sup.+

[0545] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.92 (d, J=8.8 Hz, 2H), 7.26-7.25 (m, 1H), 7.12 (d, J=8.8 Hz, 2H), 7.11 (d, J=80.8 Hz, 1H), 7.05-7.03 (m, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.88 (s, 2H), 4.25-4.22 (m, 4H), 3.70 (d, J=2.4 Hz, 2H).

[0546] (E)-4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(2,3-dihydrobenzo[b][1,4]dioxa-6-yl)benzamide trifluoroacetate (TM114-E)

[0547] MS m/z (ESI): 359 [M+H].sup.+

[0548] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.91 (d, J=8.8 Hz, 2H), 7.25 (d, J=80.8 Hz, 1H), 7.26-7.25 (m, 1H), 7.10 (d, J=8.8 Hz, 2H), 7.04 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 4.68 (d, J=3.2 Hz, 2H), 4.25-4.22 (m, 4H), 3.83 (s, 2H).

EXAMPLE 32

Preparation of 4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(3-(2-methoxyethoxy)phenyl)benzamide trifluoroacetate (TM106)

[0549] ##STR00072##

Step I: Preparation of N-tert-butoxycarbonyl-3-aminophenol (32-1)

[0550] The compound 3-aminophenol (10.0 g, 91.7 mmol) was placed in a reaction flask, and successively added with DCM (100 mL), TEA (27.8 g, 275.1 mmol) and Boc.sub.2O (21.8 g, 100.0 mmol), the resulting mixture was reacted at room temperature for 3 hours. The mixture was concentrated at low temperature, then added with water, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated saline solution, dried and concentrated to afford a crude product, which was purified by column chromatography to afford the title compound (3.8 g, 20%).

Step II: Preparation of N-tert-butoxycarbonyl-3-(2-methoxyethoxy)aniline (32-2)

[0551] The compound 32-1 (3.8 g, 18.2 mmol) was dissolved DMF (10 mL), and added with K.sub.2CO.sub.3 (7.5 g, 54.6 mmol) and 2-bromoethylmethylether (2.8 g, 20.0 mmol), and the mixture was reacted at room temperature for 10 hours. After the reaction solution was diluted by adding water, it was extracted with ethyl acetate. After the organic phase was washed with water, it was washed with a saturated saline solution three times, and then it was dried over sodium sulfate and concentrated by filtration. The crude product was purified by a column chromatograph to afford the title compound (2.9 g, 60%).

Step III: Preparation of 3-(2-methoxyethoxy)aniline (32-3)

[0552] The compound 32-2 (2.9 g, 10.8 mmol) was dissolved in DCM (10 mL), and at low temperature, added with TFA (3 mL), the mixture was reacted at room temperature for 1 hour. After TLC monitored the completion of the reaction, the reaction solution was concentrated at low temperature. The crude product was dissolved with water, then alkalized with saturated sodium carbonate, and extracted with ethyl acetate. The organic phases were combined, washed with saturated saline solution three times, dried over sodium sulfate and concentrated by filtration, to afford the title compound. The title compound was directly used in the text step without any further purification.

Step IV: Preparation of 4-((3-(2-methoxyethoxy)phenyl)carbamoyl)phenyl acetate (32-4)

[0553] Except for that the intermediate 32-3 in this step replaced the 2-aminomethylpyridine in Step I of Example 30, the title compound was prepared according to a similar method to that described in Step I in Example 30, with the total yield of 49%.

Step V: Preparation of 4-hydroxyl-N-(3-(2-methoxyethoxy)phenyl)benzamide (32-5)

[0554] Except for that the intermediate 32-4 in this step replaced the intermediate 30-1 in Step II of Example 30, the title compound was prepared according to a similar method to that described in Step II of Example 30, with the yield of 91%.

Step VI: Preparation of 4-((2-tert-butoxycarbonylaminomethyl-3-fluoroallyl) oxy)-N-(3-(2-methoxyethoxy)phenyl)benzamide (32-6)

[0555] Except for that the intermediate 32-5 in this step replaced the intermediate 1-1 in Step II of Example 1, the title compound was prepared according to a similar method to that described in Step II of Example 1, with the yield of 37%.

Step VII: Preparation of 4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(3-(2-thoxyethoxy)phenyl)benzamide trifluoroacetate (TM106)

[0556] Except for that the intermediate 32-6 in this step replaced the intermediate 1-2 in Step III of Example 1, the title compound was prepared according to a similar method to that described in Step III of Example 1, with the yield of 99%.

[0557] A method similar to that as described in Example 9 is applied to resolute the isomers, the retention time of the TM106-E is earlier than that of the TM106-Z.

[0558] (Z)-4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(3-(2-methoxyethoxy)phenyl) benzamide trifluoroacetate (TM106-Z)

[0559] MS m/z (ESI): 375 [M+H].sup.+

[0560] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.94 (d, J=8.8 Hz, 2H), 7.40 (s, 1H), 7.25-7.23 (m, 2H), 7.12 (d, J=8.8 Hz, 2H), 7.11 (d, J=80.8 Hz, 1H), 6.75-6.72 (m, 1H), 4.89 (s, 2H), 4.13-4.11 (m, 2H), 3.76-3.74 (m, 2H), 3.70 (d, J=2.0 Hz, 2H), 3.43 (s, 3H).

[0561] (E)-4-((2-aminomethyl-3-fluoroallyl)oxy)-N-(3-(2-methoxyethoxy)phenyl) benzamide trifluoroacetate (TM106-E)

[0562] MS m/z (ESI): 375 [M+H].sup.+

[0563] .sup.1HNMR (400 MHz, CD.sub.3OD) 5: 7.93 (d, J=8.8 Hz, 2H), 7.40 (s, 1H), 7.23 (d, J=81.2 Hz, 1H), 7.25-7.23 (m, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.75-6.72 (m, 1H), 4.68 (d, J=3.6 Hz, 2H), 4.13-4.11 (m, 2H), 3.83 (s, 2H), 3.76-3.74 (m, 2H), 3.43 (s, 3H).

EXAMPLE 33

Preparation of (E)-6-((2-(aminomethyl)-3-fluoroallyl)oxy)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one hydrochloride (HC38-E)

[0564] ##STR00073##

[0565] The collected solution of the compound TM-38-E (1.74 g, 5.8 mmol) after isomer resolution was added with 2 mol/L sodium hydroxide solution to pH=9-10 and extracted with DCM twice, and then the organic phases were combined. The organic hase was washed with a saturated saline solution and dried. Then the organic phase was added with 10 mL of 2 mol/L hydrogen chloride solution in ethyl acetate and concentrated to afford the title compound (1.44 g, 98%).

[0566] (E)-6-((2-aminomethyl-3-fluoroallyl)oxy)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one hydrochloride (HC38-E)

[0567] MS m/z (ESI): 279 [M+H].sup.+

[0568] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.88 (d, J=8.4 Hz, 1H), 7.24 (d, J=81.2 Hz, 1H), 6.97 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.91-6.90 (m, 1H), 4.68 (d, J=2.8 Hz, 2H), 3.83 (d, J=2.0 Hz, 2H), 2.92 (s, 2H), 1.29 (s, 6H).

EXAMPLE 34

Preparation of (E)-6-((2-aminomethyl-3-fluoroallyl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one hydrochloride (HC66-E)

[0569] ##STR00074##

[0570] The collected solution of the compound TM-66-E (4.2 g, 11.6 mmol) after isomer resolution was added with 2 mol/L sodium hydroxide solution to pH=9-10, and extracted with DCM twice, and then the organic phases were combined. The organic phase was washed with saturated saline solution and dried. The organic phase was added with 30 mL of a 2 mollL hydrogen chloride solution in ethyl acetate and concentrated to afford the title compound (2.8 g, 80%).

[0571] (E)-6-((2-aminomethyl-3-fluoroallyl)oxy)-2-methyl-3,4-dihydroisoqunolin-1(2H)-one hydrochloride (HC66-E)

[0572] MS m/z (ESI): 265 [M+H].sup.+

[0573] .sup.1HNMR (400 MHz, CD.sub.3OD) : 7.88 (d, J=8.4 Hz, 1H), 7.24 (d, J=81.2 Hz, 1H), 6.97 (dd, J=8.4 Hz, 2.4 Hz,1H), 6.90 (s, 1H), 4.67 (s, 2H), 3.82 (s, 2H), 3.60 (t, J=6.8 Hz, 2H), 3.12 (s, 3H), 3.00 (t, J=6.8 Hz, 2H).

EXPERIMENTAL EXAMPLE 1

Inhibition Experiment Against the Enzymatic Activity of VAP-1(Vascular Adhesion Protein 1) in vitro

[0574] Reagent:

[0575] Test kit: Amplex Red Monoamine Oxidase Assay, Manufacturer: ThermoFisher

[0576] Reaction buffer solution: 50 mM PBS, pH 7.4

[0577] Enzyme: VAP-1, Manufacturer: R&D Systems

[0578] VAP-1 protein (about 20 nM) and different concentrations of the test compound were pre-incubated at room temperature for 10 minutes, followed by an addition of 500 pM benzylamine hydrochloride, 1 U/mL HRP and 200 M Amplex Red reagent according to the specification of the test kit to start the reaction. The reaction plate was placed in the enzyme marker, and in kinetic mode, fluorescence signals were measured at Ex/Em=540/590 nm. The relative inhibition activity of each concentration group was calculated, wherein the ratio (slope) of fluorescence signal to reaction time in the linear range is the reaction rate, the vehicle group (DMSO) is the negative control, and the reaction buffer solution group (without enzymes and the compounds) is the blank control. The half inhibition concentration (IC50) of the compound was calculated according to four-parameter model fitting curve.

[0579] Experimental Results

[0580] According to the above method, the inhibition of the compound against the activity of VAP-1 was measured, and the results were shown in Table 1:

TABLE-US-00002 TABLE 1 Results of inhibition against the enzymatic activity of VAP-1 Compound No. IC.sub.50 (nM) TM70 0.2 0.0 TM1 0.5 0.0 TM68 9.9 1.8 TM67 11.5 1.3 TM8 2.2 0.1 TM62 1.8 0.2 TM26 5.8 1.0 TM42 1.6 0.2 TM41 4.8 0.7 TM39 1.0 0.1 TM33 3.3 0.2 TM48 6.5 0.5 TM61 0.5 0.0 TM72 3.4 0.5 TM71 2.4 0.2 TM44 3.4 0.4 TM45 0.9 0.1 TM69 10.4 1.4 TM45-Z 1.1 0.1 TM45-E 2.4 0.7 TM33-Z 6.3 1.2 TM33-E 4.9 0.5 TM41-Z 3.5 0.4 TM41-E 3.1 0.5 TM48-Z 10.6 1.4 TM48-E 9.2 1.1 TM63-Z 4.4 0.8 TM63-E 5.7 0.8 TM65-Z 1.7 0.3 TM65-E 4.1 0.7 TM73-Z 3.7 0.3 TM73-E 4.2 0.3 TM1-Z 0.7 0.1 TM1-E 1.6 0.2 TM42-Z 1.5 0.1 TM42-E 2.0 0.3 TM26-Z 3.7 0.8 TM26-E 9.9 1.2 TM44-Z 9.7 0.9 TM44-E 12.9 4.4 TM74-Z 5.3 0.2 TM74-E 3.2 0.2 TM39-Z 0.7 0.1 TM39-E 1.2 0.2 TM7-Z 3.8 0.4 TM7-E 3.0 0.7 TM38-Z 2.9 0.3 TM38-E 4.7 1.1 TM66-Z 1.6 0.2 TM66-E 2.0 0.4 TM75-Z 1.3 0.2 TM75-E 23.4 2.2 TM76-Z 1.8 0.2 TM76-E 4.3 0.6 TM112-Z 6.5 1.8 TM112-E 3.2 0.4 TM114-Z 0.8 0.1 TM114-E 1.1 0.2 HC38-E 2.85 0.30

[0581] The results show that the compounds of the invention exhibit a strong inhibition against the activity of VAP-1.

EXPERIMENTAL EXAMPLE 2

Inhibition Experiment Against the Enzymatic Activity (ex-vivo)

[0582] Reagent:

[0583] Tissue homogenate buffer solution (20 mM HEPES, pH 7.2, 1 mM EDTA, 250 mM sucrose, PMSF 0.2 mM)

[0584] Reaction buffer solution: 50 mM PBS, pH 7.4

[0585] Test kit: Amplex Red Monoamine Oxidase Assay, Manufacturer: ThermoFisher

[0586] Experimental Method

[0587] 1. Sample Collection and Treatment

[0588] BALBc mice were administrated orally with different doses of the test compound, and the vehicle group was used as the control group. After six hours, abdominal fat was collected and homogenized at 1:20 (w/v) with the pre-cooled homogenate buffer solution, and thereafter, the homogenate was centrifuged at 10,000 g and 4 C. or 10 minutes, the supernatant was collected and stored at -80 C. for further use.

[0589] 2. Enzymatic Activity Measurement

[0590] A test sample was diluted with the reaction buffer solution and successively added with the inhibition solution A: 1 M Clorgyline+1 M pargylin, to inhibit the activities of MAO-A and MAO-B, and the inhibition solution B: 1 M Clorgyline+1 M Pargylin+1 M Mofegiline as the blank control, and after being incubated at room temperature for 20 min, 500 M benzylamine hydrochloride, 1 U/mL HRP and 200 M Amplex Red reagent were added to start the reaction. By referring to the method in Experiment of inhibiting the enzymatic activity of VAP-1, relative activity of each dose group was calculated, wherein the ratio of the fluorescent signal to reaction time in the linear range is the reaction rate, and the vehicle group is the positive control, thereby to study the inhibition of the compound against the enzymatic activity of VAP-1 in abdominal fat of mice.

[0591] Experimental Results

[0592] According to the above method, the inhibition of the compound against the enzymatic activity of VAP-1 in abdominal fats of mouse was measured, as shown in Tables 2 and 3.

TABLE-US-00003 TABLE 2 Results of inhibition against the enzymatic activity of VAP-1 (ex-vivo) Inhibition rate (%) Compound No. 2 mg/kg TM26 112.3 7.1 TM42 106.2 8.4 TM41 96.1 17.4 TM33 105.1 9.1 TM61 99.7 8.7 TM44 95.8 6.2 TM45 91.9 6.4

TABLE-US-00004 TABLE 3 Results of inhibition against the enzymatic activity of VAP-1 (ex-vivo) Inhibition rate (%) Compound No. 0.5 mg/kg TM1-Z 93.3 5.4 TM1-E 96.7 2.2 TM26-Z 86.6 5.5 TM39-Z 93.2 3.9 TM39-E 93.0 2.7 TM38-E 92.7 3.0 TM66-E 92.3 1.9

[0593] The results show that VAP-1 was completely inhibited in vivo six hours after being orally administrated with the compounds TM26, TM33, and TM42 of the invention at a dose of 2 mg/kg. The other compounds of the invention can totally or strong inhibit VAP-1 in vivo at the dose of 2 mg/kg. The compound of the invention exhibits strong inhibitory effect against VAP-1 in vivo even at a low administration dose of 0.5 mg/kg.

[0594] Thus, the compound of the invention exhibits strong inhibition against VAP-1 in vivo.

EXPERIMENTAL EXAMPLE 3

Inhibition Experiment Against the Enzymatic Activity of MAO-A (Monoamine Oxidase Type A)

[0595] 1. Test kit: Amplex Red Monoamine Oxidase Assay, Manufacturer: ThermoFisher

[0596] 2. Reaction Buffer Solution: 50 mM PBS, pH 7.4

[0597] Protein: MAO-A, manufacturer: Sigma Aldrich

[0598] 3. Test Method of Inhibition Against the Enzymatic Activity of MAO-A

[0599] According to the method as described in the specification of the kit, MAO-A protein (15 g/ml) and different concentrations of the test compound were pre-incubated at room temperature for 30 minutes, and then 200 M p-tyramine hydrochloride, 1 U/mL HRP and 200 82 M Amplex Red reagent were added to start the reaction. In kinetic mode, fluorescence signals were measured at Ex/Em=540/590 nm. The inhibition rate of each concentration group was calculated, wherein the ratio of fluorescence signal to reaction time ratio is the reaction rate, the vehicle group (DMSO) is the negative control, and the reaction buffer solution group (without enzymes and the compounds) is the blank control.

[0600] Percent inhibition rate (%)=(1-(reaction rate of each compound concentration groupreaction rate of the blank group)/(reaction rate of vehicle groupreaction rate of the blank group))*100.

[0601] 3. Experimental Results

[0602] According to the above method, the inhibition of the compound against the enzymatic activity of MAO-A was measured, and the range of IC.sub.50 was obtained according to the inhibition rates at 100 M and 10 M. The results are shown in Table 4:

TABLE-US-00005 TABLE 4 Results of inhibition against the enzymatic activity of MAO-A Compound No. IC.sub.50 (M) TM26-Z >100 TM39-E >10 TM77-Z >100 TM7-E >100 TM38-E >100 TM66-E >10 TM75-Z >100 TM76-Z >100 TM76-E >100 TM112-Z >100 TM112-E >100 TM114-Z >10 TM114-E >10

[0603] The results show that the inhibition of the compound of the invention against the activity of MAO-A is weaker than that of VAP-1.

EXPERIMENTAL EXAMPLE 4

Inhibition Experiment Against the Enzymatic Activity of MAO-B (Monoamine Oxidase Type B)

[0604] 1. Test kit: Amplex Red Monoamine Oxidase Assay, Manufacturer: ThermoFisher

[0605] Protein: MAO-B, manufacturer: Sigma Aldrich

[0606] 2. Test Method of the Inhibition Against the Enzymatic Activity of MAO-B

[0607] According to the method as described in the specification of the test kit, MAO-B protein (5 g/ml) and different concentrations of the test compound were pre-incubated at room temperature for 10 minutes, and then 150 M benzylamine hydrochloride, 1 U/mL HRP and 200 M Amplex Red reagent were added to start the reaction. The relative inhibition rate of each concentration group were calculated according to the experimental method of MAO-A.

[0608] 3. Experimental Results

[0609] According to the above method, the inhibition of the compound against the activity of the MAO-B was measured, and the range of IC50 was obtained according to the inhibition rates at 10 M, 1 M and 0.1 M. The results are shown in Table 5:

TABLE-US-00006 TABLE 5 Results of inhibition against the enzymatic activity of MAO-B Compound No. IC.sub.50 (M) TM26-Z >1 TM7-Z >10 TM7-E >10 TM38-Z >10 TM38-E >10 TM66-Z >10 TM66-E >10 TM75-Z >10 TM76-Z >0.1 TM76-E >1 TM112-Z >0.1 TM112-E >0.1

[0610] The results show that the inhibition of the compound of the invention against the enzymatic activity of MAO-B is weaker than that of VAP-1.

EXPERIMENTAL EXAMPLE 5

Inhibition Experiment Against the Enzymatic Activity of DAO (Diamine Oxidase)

[0611] 1. Test kit: Amplex Red Monoamine Oxidase Assay, Manufacturer: ThermoFisher

[0612] Protein: DAO, manufacturer: R&D Systems

[0613] 2. Test Method of Inhibition Against the Enzymatic Activity of DAO

[0614] DAO protein (15 g/ml) and different concentrations of the test compound were pre-incubated at room temperature for 20 minutes, and then 100 M Histamine-dihydrochloride, 1 U/mL HRP and 200 M Amplex Red reagent were added to start the reaction. The inhibition rate of each concentration groups were calculated according to the experimental method of MAO-A.

[0615] 3. Experimental Results

[0616] According to the above method, the inhibition of the compound against the activity of DAO was measured, and the results are shown in Table 6:

TABLE-US-00007 TABLE 6 Results of inhibition against the enzymatic activity of DAO Compound No. IC.sub.50 (M) TM1-E >0.1 TM7-Z >0.1 TM7-E >1 TM38-Z >0.1 TM38-E >1 TM66-E >0.1 TM76-E >0.1 TM112-Z >0.1

[0617] The results show that the inhibition of the compound of the invention against the activity of DAO is weaker than that of VAP-1.

EXPERIMENTAL EXAMPLE 6

hERG (Ether-a-go-go-related Gene Potassium Channel) Inhibition Experiment

[0618] Reagent: Predictor hERG Fluorescence Polarization Assay Kit, Manufacturer: ThermoFisher

[0619] Experimental Method

[0620] The above test kit was used to evaluate the potential of the compound for inducing heart QT prolongation. According to the method as indicated in the specification of the test kit, the test compound, the positive control (E4031) and negative control (Experimental buffer solution) in the kit were added to a microwell plate containing hERG cell membrane, and then a tracer having high affinity to hERG was added. The microwell plate was then incubated at 25 C. for 2 hours, a BMG PHAREStar polyfunctional enzyme marker was used to test the variations in the fluorescent polarization value. By calculating the percent inhibition rates (%) at different concentrations, the range of the half inhibition concentration (IC.sub.50) was determined:

[0621] Percent inhibition rate (%)=(1-(mP of the test compound-mP of 30 M E4031)/(mP of experimental buffer solution-mP of 30 M E4031))*100.

[0622] Experimental Results

[0623] According to the above method, the inhibition of the test compound against the activity of the hERG was measured, and the results are shown in Table 7:

TABLE-US-00008 TABLE 7 Experimental results of inhibition against hERG Compound No. hERG (M) TM70 >30 TM1 >10 TM67 >30 TM62 >30 TM26 >30 TM42 >10 TM39 >30 TM61 >10 TM44 >10 TM45 >10 TM45-Z >10 TM45-E >10 TM33-E >10 TM63-Z >10 TM63-E >10 TM1-Z >10 TM1-E >10 TM42-Z >10 TM42-E >10 TM26-Z >10 TM26-E >10 TM39-Z >10 TM39-E >10 TM77-Z >10 TM7-E >10 TM38-E >10 TM66-E >10 TM76-E >10 TM112-Z >10

[0624] The results show that the compound of the invention has a low affinity to hERG. IC.sub.50 of the test compounds competitively binding to hERG, in relative to the affinitive tracer, are all greater than 10 M.

EXPERIMENTAL EXAMPLE 7

Inhibition Experiment Against the Enzymatic Activity at Different Does and Time Conditions (ex-vivo)

[0625] Reagent:

[0626] Tissue homogenate buffer solution (20 mM HEPES, pH 7.2, 1 mM EDTA, 250 mM sucrose, PMSF 0.2 mM)

[0627] Reaction buffer solution: 50 mM PBS, pH 7.4

[0628] Test kit: Amplex Red Monoamine Oxidase Assay, Manufacturer: ThermoFisher

[0629] Experimental Method

[0630] 1. Sample Collections and Treatments

[0631] BALBc mice were orally administrated with different doses (0.5 mg/kg, 3 mg/kg) of the test compound, and the vehicle group was used as the control group. Abdominal fat was collected at 6 hrs, 10 hrs, 24 hrs respectively, and homogenized with a pre-cooled homogenate buffer solution, and thereafter, the supernatant was collected and stored for use.

[0632] 2. Enzymatic Activity Measurement

[0633] A test sample was diluted with the reaction buffer solution, and respectively added with the inhibition solution A 1 M Clorgyline+1 M pargylin, to inhibit the activities of MAO-A and MAO-B, and the inhibition solution B: 1 M Clorgyline+1 M Pargylin+1 M Mofegiline as the Wank control, and after being incubated at room temperature, 500 M benzylamine hydrochloride, 1 U/mL HRP and 200 M Amplex Red reagent were added to start the reaction. By referring to the method in Experiment of inhibiting the enzymatic activity of VAP-1, the relative activities of each dose groups were calculated, wherein ratio of the fluorescent signal to reaction time in the linear range is the reaction rate, and the vehicle group is the positive control, thereby to study the inhibition of the compound against the enzymatic activity of VAP-1 in abdominal fat of mice.

[0634] Experimental Results

[0635] According to the above method, the inhibition of the compound on the enzymatic activity of VAP-1 in abdominal fat of mice was measured, as shown in Table 8:

TABLE-US-00009 TABLE 8 Inhibition rate of the compound HC38-E against the enzymatic activity of VAP-1 in abdominal fat of mice at different time and dose conditions dose/time 6 hours 10 hours 24 hours 0.5 mg/kg 95.8 3.6% 90.3 3.2% 68.1 7.4% 3.0 mg/kg 96.4 5.6% 95.3 1.9% 78.0 9.3%

[0636] The results show that the inhibition rate of the compound HC38-E against the activity of VAP-1 in abdominal fat is up to 95% 6 hours after administration at the dose of 0.5 mg/kg, the inhibition is still significant 24 hours after administration. The inhibition rate of the compound HC38-E against the activity of VAP-1 in abdominal fat is still up to 95% 10 hours after administrate at the dose of 3.0 mg/kg, and the inhibition is still significant 24 hours after administration.

EXPERIMENTAL EXAMPLE 8

Experiment of Carbon Tetrachloride-Induced Liver Injury of Mice

[0637] Regent

[0638] Olive oil: Sinapharm Chemical Reagent Co., Ltd

[0639] Carbon tetrachloride: Sinapharm Chemical Reagent Co., Ltd

[0640] Experimental Method

[0641] 1. Model Establishment Method

[0642] Female BALB/c mice received an intraperitoneal injection of a 25% carbon tetrachloride solution (carbon tetrachloride: olive oil=1: 4, volume rate) in an injection volume of 4 ml/kg twice a week for six weeks.

[0643] 2. Grouping and Administration

[0644] Mice, according to body weights, were randomly divided into a model group (0.5% methylcellulose), a group administrated with 3 mg/kg of the compound HC38-E, and a group administrated with 10 mg/kg of the compound HC38-E, each group including ten animals.

[0645] Whilst establishing the models, the administration started with the administration volume of 10 mL/kg, and the models were intragastrically administrated once a day for six weeks.

[0646] 3. Fibrosis Quantitative Analysis

[0647] After the administration, liver tissue was taken from euthanized animals and fixed with 10% formalin. Thereafter, liver tissue slices were prepared and stained with Sirius red. The slices were subjected to calculate the fibrosis areas by using semi-automatic digital image analysis system, measuring software (Osteo Metrics, Inc., Atlanta, Ga.) and Olympus optical microscope.

[0648] Experimental Results

[0649] According to the above method, the impacts of the compound on the liver fibrosis of the mice are measured, as shown in the following Table 9:

TABLE-US-00010 TABLE 9 Impacts of the compound HC38-E on the fibrosis areas of mice induced by carbon tetrachloride Dose Fibrosis area Solvent group 1.05 0.27% 10 mg/kg 0.56 0.23% 3 mg/kg 0.73 0.21%

[0650] The results show that after a six-week administration, the compound HC38-E can reduce the degree of the liver fibrosis at the doses of 10mg/kg and 3mg/kg, especially, the compound have apparent antifibrosis at the dose of 10 mg/kg.

EXPERIMENTAL EXAMPLE 9

Inhibition Experiment Against Cytochrome P450 Isoenzyme (CYP)

[0651] Reagent:

[0652] P450-Glo CYP1A2 Screening System, manufacturer: Promega

[0653] P450-Glo CYP2D6 Screening System, manufacturer: Promega

[0654] P450-Glo CYP3A4 Screening System, manufacturer: Promega

[0655] Experimental Method:

[0656] According to the specification of the test kit, 10 nM CYP1A2, 5 nMCYP2D6, and 1 nM CYP3A4 proteins and corresponding substrates (100 M, 30 M, 3 M) as well as the compound were pre-incubating respectively for 10 min, G6PDH-G6P-NADP regeneration system was added to start the reaction, a test reagent was added later, after 20 min, the chemical luminescent signals were detectted. The inhibition rate was calculated with vehicle group (DMSO) as the negative control and Membrance (inactive enzymes) as the blank control:

[0657] Percent inhibition rate (%)=(1-(signal of each compound concentration group-signal of the blank group)/(signal of the negative control-signal of the blank group))*100.

[0658] According to the inhibition rates of the compound at different concentrations against P450 enzyme, the half inhibition concentration (IC5o) or range was estimated.

[0659] IC.sub.50=X*(1-percent inhibition rate (%))/percent inhibition rate (%), wherein, X is the test concentration of the compound.

[0660] Experimental Results

[0661] According to the above method, the inhibition of the compound at the concentrations 10 M, and 1 M, against three CYPs were measured, and the results were shown in the following Tables 10-12:

TABLE-US-00011 TABLE 10 Results of inhibition against CYP1A2 Compound No. IC.sub.50 (M) TM38-E 6.73 0.39

TABLE-US-00012 TABLE 11 Results of inhibition against CYP2D6 Compound No. IC.sub.50 (M) TM38-E >10 TM66-E >10

TABLE-US-00013 TABLE 12 Results of inhibition against CYP3A4 Compound No. IC.sub.50 (M) TM38-E >10 TM66-E >10

[0662] The above results show that the compound of the invention (for example, the compounds TM38-E, TM66-E) do not have significant inhibitions against three primary CYP-subtypes, which shows that the compound has low possibility of potential drug interactions, and thus has good drug-forming property.

EXPERIMENTAL EXAMPLE 10

Stability of Liver Microsomes

[0663] Reagents:

[0664] Formulation of a compound reservation solution: the test compound, diclofenac acid, testosterone and propafenone were weighted in appropriate amounts, and calibrated by adding about 1 mL of DMSO to provide a 10 mM reservation solution, then stored in a 4 C. refrigerator;

[0665] Formulation of a compound working solution: 10 L of the reservation solution were added to 990 L acetonitrile-water (1:1) to provide a middle solution having a concentration of 100 M, and 120 L of the middle solution is further diluted with 2880 L PBS to provide a 4 M working solution;

[0666] Formulation of a NADPH working solution: the NADPH was weighted in an appreciate amount and calibrated with 33 mM MgCl.sub.2 to provide a 4 mM NADPH working solution;

[0667] Formulation of a liver microsome working solution: 100 L of liver microsomes of human, monkey, dog, rat and mouse were taken respectively and diluted with 1900 L PBS to prepare a 1 mg/mL liver microsome working solution.

[0668] Experimental Method:

[0669] According to the experimental conditions as shown in the following Table 13, the reaction solution of the test compound was formulated:

TABLE-US-00014 TABLE 13 Experimental conditions Incubation time Incubation conditions (min) 50 L the test sample + 50 L 0, 30, 60, 120 NADPH + 100 L microsome

[0670] After being incubated for a certain period of time, an equivalent volume of cooled acetonitrile (4 C.) was added to terminate the reaction, and LC-MS/MS was used to determine the concentrations of the compound after being incubated in various liver microsomes for different time periods. With the incubation time as the horizontal ordinate and the natural logarithm of the percentages of the remained compound at each time point as the longitudinal coordinate, a diagram was plotted, wherein the slope was the velocity constant (Ke), and the half-life (T.sub.1/2) and clearance rate (CL.sub.liver) of the compound were calculated according to the following equation to evaluate the staiblity of the compound in the liver microsomes.

[0671] T.sub.1/2=In(2)/Ke

[0672] Liver clearance rate (CL.sub.liver)=Ke/protein quantity of microsomes contained in per milter of reaction solution (mg)xprotein quantity of microsomes contained in per gram of liver (mg)liver weight correspondent to body weight per kilogram (g).

[0673] Experimental Results

[0674] The stability test results of the compound in liver microsomes of different animals are shown in the following Table 14.

TABLE-US-00015 TABLE 14 Results of the stability in liver microsomes Compound No. Parameters Unit human Monkey Dog Rat Mouse HC38-E T.sub.1/2 min 2677 1249 7081 855 829 CL.sub.liver L/min/mg 0.48 1.11 0.29 1.08 2.78

[0675] The above results show that the compound of the invention (for example, the compound HC38-E) has long half-life (T.sub.1/2) and low clearance rate in vivo in liver microsomes of human, monkey, dog, rate, and mouse, indicating its good staiblity.

EXPERIMENTAL EXAMPLE 11

Caco-2 Permeation Experiment

[0676] Reagents:

[0677] Culture medium: 10%FBS+1% unnecessary amino acid+90%DMEM (high glucose)

[0678] Permeation solution (pH 7.4): HBSS (Ca.sup.+, Mg.sup.+)+10 mM Hepes

[0679] Compound reservation solution: an amount of the test compound was weighted and added with a certain amount of DMSO to formulate a 10 mM reservation solution.

[0680] Experimental Method:

[0681] Cells were inoculated to Transwell cells in a quantity of 6*10.sup.4/cm.sup.2, and at the A side (top side), were added with 200 L of the culture medium, and at the B side (base side), were added with 1000 L of the culture medium. After the inoculation, the solution was replaced once every 2 days, and the culture was conducted for 21 to 28 day.

[0682] After 21 to 28 days since the inoculation of Caco-2 cells, the transmembrane resistance was measured.

[0683] Permeation experiment: after the transepithelial electrical resistance was measured, the buffer solution at the two sides was removed by suction, then added thereto the solution according to the following system.

[0684] According to the experimental conditions as shown in the following Table 15, the reaction solution in each experimental group was formulated:

TABLE-US-00016 TABLE 15 Experimental conditions and grouping Top side A Base side B Concentration (200 L (1000 L permeation System (M) permeation solution) solution) Experimental 2 2 M test compound, group (A.fwdarw.B) 10 g/ml Fluorescein Experimental 2 2 M test compound, group (B.fwdarw.A) 10 g/ml Fluorescein Incubation 120 min time/min wherein, the symbol represents none.

[0685] Fluorescein: after 2-hours incubation, 100 L of the permeation solution were taken from each side of side A and side B, and the fluorescent value at Ex=485nm, Em=530nm were measured by an enzyme marker, and the permeation quantity was calculated (less than 1%).

[0686] Sample treatment: after 2-hours incubation, 50 L of the permeation solution were sucked up from each side of side A and side B, and equivalent volume of cold acetonitrile was added to terminate the reaction, and the concentrations of the compound at the A and B sides were measured by LC-MS/MS. The apparent permeation (Papp) and the Efflux Ratio were calculated according to the following equations:

Papp=(dCr/dt)Vr/(AC.sub.0)

Efflux Ratio=Papp(BA)/Papp (AB)

[0687] wherein, dCr/dt is the integration of the concentration of the compound at the base side realted to time, Vr is the reaction volume at the base side, A is the area of a single layer of cells, being 0.33 cm.sup.2, and C.sub.0 is the concentration of the compound at the top side.

[0688] Experimental Results

[0689] The experimental results of the permeability of the compound to Caco-2 cells are shown in the following Table 16:

TABLE-US-00017 TABLE 16 Results of Caco-2 permeability Average apparent Compound permeability (10.sup.6 cm/s) Efflux No. Concentration A to B B to A ratio HC38-E 2 M 2.60 3.26 1.26

[0690] The above results show that the compounds of the invention (for example HC38-E) have a high permeability, and a low possibility of active efflux.

EXPERIMENTAL EXAMPLE 12

Rat PK Experiment

[0691] Formulation of the test samples:

[0692] The test compounds were formulated according to the method as shown in Table 17:

TABLE-US-00018 TABLE 17 Formulating table of the tested compounds Concen- Administration Group tration volume Subject No. (mg/mL) (mL/kg) Solvent (v/v) HC38-E iv 0.6 5 5% DMSO + po 0.6 5 5% solutol + 90% saline 0.5% MC

[0693] Method:

[0694] Male rats were intravenously (iv) and intragastrically (po) administered the test compounds respectively, and LC-MS/MS was used to measure the blood plasma concentration of the compound in the bodies of the rat. The main pharmacokinetic parameters were calculated by utilizing WinNonlin 6.3 software.

[0695] The grouping of the experimental designs was shown in the following table 18:

TABLE-US-00019 TABLE 18 Grouping Table of experimental design Administration Animal Time point of collecting subject route Quantity species blood or tissue HC38-E i.v n = 3 Rat i.v: 0, 0.083, 0.25, 0.5, p.o n = 3 Rat 1, 2,4, 6, 8 and 24 h p.o: 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h

[0696] Results

[0697] The PK test results of the test compounds in rat blood plasma were shown in the following Table 19:

TABLE-US-00020 TABLE 19 PK data of the test compounds in rats blood plasma Compound No. Administration route iv po HC38-E Dose (mg/kg) 3 3 AUC(0-) 1161 120 1042 129 hr*ng/mL C.sub.max 1041 181 343 24 ng/mL t.sub.1/2 1.43 0.15 1.37 0.01 hr F % / 89.9 11.1 Symbol / represents none.

[0698] The results show that the compound of the invention have good pharmacokinetic parameters both administered intravenously (iv) and intragastrically (po), and the compound of the invention (for example, the average bioavailability (F %) of the compound HC38-E can reach 89.9%) have good oral bioavailability.

[0699] The above examples will nct restrict the invention in any way. Although the specific embodiments in the invention have been illustrated in detail, according to all the disclosed teachings, a person skilled in the art can make various amendments and replacements to the details of the technical solution of the invention, and these changes all fall within the protection scope of the invention. All the scope of the invention will be provided by the appended claims and any equivalent thereof.