SILICON PHTHALOCYANINE COMPLEX, PREPARATION METHOD AND MEDICINAL APPLICATION THEREOF

Abstract

The present invention relates to a silicon phthalocyanine complex, the preparation method and the medicinal application thereof. The present invention particularly relates to a silicon phthalocyanine complex of formula (I), the preparation method thereof and a pharmaceutical composition comprising the same, as well as the use thereof as a photosensitizer, in particular the use in the treatment of cancers, wherein each substituent in formula (I) is the same as defined in the description.

Claims

1. A compound of formula (I): ##STR00059## or a tautomer, mesomer, racemate, enantiomer, diastereoisomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L is selected from the group consisting of CH.sub.2CH.sub.2OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2 and CH.sub.2CH.sub.2CH.sub.2, wherein one or more hydrogens are optionally substituted by a group selected from the group consisting of C.sub.1-4 alkyl, haloC.sub.1-4 alkyl, C.sub.1-4 alkoxy, haloC.sub.1-4 alkoxy, halo, amino, nitro, hydroxyl and cyano; R.sub.1 and R.sub.2 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-4 alkyl, C.sub.1-4 alkylene-OC.sub.1-4 alkyl, C.sub.1-4 alkylene OC.sub.1-4 alkylene-OC.sub.1-4 alkyl and C.sub.1-4 alkylene-OC.sub.1-4 alkylene-OC.sub.1-4 alkylene-OC.sub.1-4 alkyl, wherein said C.sub.1-4 alkyl and C.sub.1-4 alkylene are optionally substituted by one or more groups selected from the group consisting of C.sub.1-4 alkyl, haloC.sub.1-4 alkyl, C.sub.1-4 alkoxy, haloC.sub.1-4 alkoxy, halo, amino, nitro, hydroxyl and cyano; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a following group: ##STR00060## said group is optionally substituted by one or more groups selected from the group consisting of C.sub.1-4 alkyl, haloC.sub.1-4 alkyl, C.sub.1-4 alkoxy, haloC.sub.1-4 alkoxy, halogen, amino, nitro, hydroxyl and cyano; R.sub.3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, C.sub.1-4 alkyl, haloC.sub.1-4 alkyl, C.sub.1-4 alkoxy, haloC.sub.1-4 alkoxy, halogen, amino, nitro, hydroxyl and cyano, and p is an integer of 0, 1, 2, 3 or 4; on the condition that when L is CH.sub.2CH.sub.2CH.sub.2, R.sub.1 and R.sub.2 together with the atoms to which they are attached do not form ##STR00061##

2. The compound of formula (I) according to claim 1, wherein R.sub.1 and R.sub.2 are each independently selected from the group consisting of a hydrogen atom, methyl, ethyl, CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 and CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3.

3. The compound of formula (I) according to claim 1, wherein R.sub.3 is a hydrogen atom.

4. The compound of formula (I) according to claim 1, wherein p is 0.

5. The compound of formula (I) according to claim 1, wherein: L is CH.sub.2CH.sub.2OCH.sub.2CH.sub.2; and R.sub.1 and R.sub.2 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-4 alkyl, CH.sub.2CH.sub.2OCH.sub.3 and CH.sub.2CH.sub.2CH.sub.2OCH.sub.3; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a following group: ##STR00062##

6. The compound of formula (I) according to claim 1, wherein: L is CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2; and R.sub.1 and R.sub.2 are each independently selected from the group consisting of the group consisting of a hydrogen atom, C.sub.1-4 alkyl, CH.sub.2CH.sub.2OCH.sub.3 and CH.sub.2CH.sub.2CH.sub.2OCH.sub.3; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a following group: ##STR00063##

7. The compound of formula (I) according to claim 1, wherein: L is CH.sub.2CH.sub.2CH.sub.2; R.sub.1 is a hydrogen atom; and R.sub.2 is selected from the group consisting of CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 and CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3.

8. The compound of formula (I) according to claim 1, wherein the compound is selected from the group consisting of: ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##

9. A process for preparing the compound of formula (I) according to claim 1, comprising a step of: ##STR00072## reacting a compound of formula (II) with a compound of formula (III) in an organic solvent under an alkaline condition to obtain the compound of formula (I); wherein L, R.sub.1-R.sub.3 and p are as defined in claim 1.

10. The method according to claim 9, wherein: the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:1-4, preferably 1:2-3; said organic solvent is selected from the group consisting of toluene, benzene, xylene, hexane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate and acetone, preferably toluene; said alkaline condition are provided by a reagent selected from the group consisting of pyridine, sodium hydride, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate and sodium carbonate, preferably from pyridine or sodium hydride; said reaction is carried out at a temperature of 0-200 C., preferably 20 C.-140 C.

11. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

12. A method for performing photodynamic or photosensitive therapy comprising administering the compound of formula (I) according to claim 1 or a pharmaceutical composition comprising the compound of claim 1 to a subject in need thereof.

13. A method for treating cancer comprising administering the compound of formula (I) according to claim 1 or a pharmaceutical composition comprising the compound of claim 1 to a subject in need thereof.

14. The method of claim 13, wherein said cancers are selected from the group consisting of skin cancer, esophageal cancer, lung cancer, brain tumor, head and neck cancer, eye tumor, inflammatory carcinoma, breast cancer, bladder cancer, rectal cancer, liver cancer, bile duct cancer, stomach cancer and ovarian cancer, preferably skin cancer and esophageal cancer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0078] By reading the following examples, the person skilled in the art will better understand the present invention. It is to be understood that the following examples merely serve to explain the present invention.

[0079] Experimental methods in the examples of the present invention, for which no specific conditions are indicated, will be carried out according to conventional conditions or recommended conditions of the raw materials and the product manufacturer. The experimental reagents for which no specific sources are indicated will be conventional reagents generally purchased from market.

[0080] Nuclear Magnetic Resonance Spectrometer: Bruker ARX-500 machine and Bruker ARX-400 machine.

[0081] Mass spectrometry: QSTAR Elite tandem quadrupole time-of-flight mass spectrometer.

[0082] MTT detecting instrument: Thermo Scientific Multiskan GO Multiskan Spectrum Microplate Reader

[0083] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR chemical shift () is given in 10.sup.6 (ppm). The solvent for determination is deuterated chloroform (CDCl.sub.3), and the internal standard is tetramethylsilane (TMS). The following abbreviations are used: s for singlet, bs for broad singlet, d for doublet, t for triplet, qdt for quartet, m for multiplet or massive, dd for double of doublet, etc.

[0084] Qingdao GF254 silica gel plate is used for thin layer chromatography (TLC) silica plate, and the dimension of the plates used in TLC is 0.15 mm-0.2 mm, and the dimension of the plates used in product purification is 0.4 mm-0.5 mm.

[0085] For the column chromatography, Yantai Huanghai silica gel of 200-300 mesh silica gel is generally used as a carrier.

[0086] If there is no special instruction in the examples, the reactions are carried out under an argon atmosphere or a nitrogen atmosphere.

[0087] If there is no special instruction in the examples, the reaction solution refers to an aqueous solution.

[0088] If there is no special instruction in the examples, the reaction temperature is room temperature.

[0089] The reaction progress in the examples is monitored by thin layer chromatography (TLC).

Example 1

[0090] ##STR00033##

Step 1

[0091] Compound 1-1 (166 g, 1.57 mol) was dissolved in 500 mL of tetrahydrofuran, potassium hydroxide (32 g, 571 mmol) was added in an ice bath, and then p-toluenesulfonyl chloride 1-2 (100 g, 0.52 mol) was added in batches, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 1200 mL of water, (400 mL) and extracted twice with ethyl acetate. The extract liquid was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by silica gel column chromatography, with an eluent (petroleum ether:ethyl acetate=1:1), to obtain the target product 1-3 (55 g, 65%) as a colorless oil, LC-MS: m/z=261 [M+H].sup.+.

Step 2

[0092] Compound 1-3 (5.1 g, 19.6 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of methylamine hydrochloride 1-4 (13.4 g, 196 mmol), and potassium carbonate (13.8 g, 100 mmol) was added under stirring in batches, followed by stirring the reaction overnight under conditions of 50 C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 1-5 (1.2 g, 52%) as a pale yellow oil, LC-MS: m/z=120[M+H].sup.+.

Step 3

[0093] Compound 1-5 (260 mg, 2.18 mmol), compound 1-6 (445 mg, 0.73 mmol) (purchased from Aldrich Company, Product No. 287768) and 1.2 mL of pyridine were added into a 100 mL reaction flask, then toluene (25 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 1 (60 mg, 10.6%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.66-9.63 (m, 8H), 8.37-8.34 (m, 8H), 1.96-1.92 (m, 4H), 1.75-1.71 (m, 10H), 0.43-0.40 (m, 4H), 1.89-1.90 (m, 4H). HRMS: 799.9205 [M+Na].sup.+.

Example 2

[0094] ##STR00034##

Step 1

[0095] Compound 1-3 (3.5 g, 13.5 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of ethylamine hydrochloride 2-1 (2.2 g, 27 mmol), and carbonate (3.73 g, 27 mmol) was added under stirring potassium in batches, followed by stirring the reaction overnight under at 70 C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 2-2 (1.5 g, 83%) as a pale yellow oil, LC-MS: m/z=134[M+H].sup.+.

Step 2

[0096] Compound 2-2 (201 mg, 1.47 mmol), compound 1-6 (300 mg, 0.49 mmol) and sodium hydride (118 mg, 2.94 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature for 5 hours. The reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 2 (56 mg, 14.2%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.68-9.64 (m, 8H), 8.38-8.34 (m, 8H), 2.17-2.11 (m, 4H), 1.75-1.68 (m, 8H), 0.83-0.80 (m, 6H), 0.41-0.38 (m, 4H), 1.86-1.89 (m, 4H). HRMS: 827.3210 [M+Na].sup.+.

Example 3

[0097] ##STR00035##

Step 1

[0098] Compound 1-3 (5.7 g, 22 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of methoxyethylamine 3-1 (2 g, 27 mmol), and potassium carbonate (3.73 g, 27 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70 C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 3-2 (2.1 g, 58%) as a pale yellow oil, LC-MS: m/z=164[M+H].sup.+.

Step 2

[0099] Compound 3-2 (240 mg, 1.5 mmol), compound 1-6 (445 mg, 0.49 mmol) and 1.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 3 (60 mg, 14.2%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.67-9.65 (m, 8H), 8.37-8.35 (m, 8H), 3.19-3.15 (m, 10H), 2.27-2.25 (m, 4H), 1.72-1.67 (m, 8H), 0.40-0.37 (m, 4H), 1.87-1.89 (m, 4H). HRMS: 887.3420 [M+Na].sup.+.

Example 4

[0100] ##STR00036##

Step 1

[0101] Compound 1-3 (3.5 g, 13.5 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of methoxypropylamine 4-1 (4.81 g, 54 mmol), and potassium carbonate (5.52 g, 40 mmol) was added under stirring in batches, followed by stirring the reaction overnight under at 70 C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 4-2 (1.6 g, 67%) as a pale yellow oil, LC-MS: m/z=178[M+H].sup.+.

Step 2

[0102] Compound 4-2 (265 mg, 1.5 mmol), compound 1-6 (300 mg, 0.49 mmol) and 1.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 4 (129 mg, 29.5%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.67-9.65 (m, 8H), 8.38-8.35 (m, 8H), 3.23-3.20 (m, 10H), 2.19-2.15 (m, 4H), 1.71-1.69 (m, 8H), 1.46-1.43 (m, 4H), 0.41-0.38 (m, 4H), 1.87-1.90 (m, 4H). HRMS: 893.3913 [M+H].sup.+.

Example 5

[0103] ##STR00037##

Step 1

[0104] Compound 1-3 (3.5 g, 13.5 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 5-1 (1.9 g, 14.2 mmol), and potassium carbonate (3.7 g, 27 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70 C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product as a pale yellow oil 5-2 (1.2 g, 40%), LC-MS: m/z=222[M+H].sup.+.

Step 2

[0105] Compound 5-2 (198 mg, 0.89 mmol), compound 1-6 (182 mg, 0.3 mmol) and 1 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 5 (69 mg, 23.5%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.67-9.65 (m, 8H), 8.38-8.36 (m, 8H), 3.11-3.02 (m, 16H), 2.16-2.12 (m, 8H), 1.75-1.61 (m, 12H), 0.39-0.35 (m, 4H), 1.90-1.92 (m, 4H); HRMS: 1003.4255 [M+Na].sup.+.

Example 6

[0106] ##STR00038##

Step 1

[0107] Compound 6-1 (235 g, 1.57 mol) was dissolved in 500 mL of tetrahydrofuran, then potassium hydroxide (41.2 g, 0.57 mmol, 82% w/w) was added, and then p-toluenesulfonyl chloride 6-2 (100 g, 0.52 mol) was added in batches, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 1200 mL of water, and extracted with ethyl acetate (400 mL*3). The extract liquid was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by silica gel column chromatography, with an eluent (petroleum ether:ethyl acetate=1:1), to obtain the target product 6-3 (118 g, 75%) as a colorless oil. LC-MS: m/z=305[M+H].sup.+.

Step 2

[0108] Compound 6-3 (5.3 g, 17.4 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of compound 1-4 (3.5 g, 52 mmol), and potassium carbonate (4.9 g, 35.8 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 40 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 6-4 (1.2 g, 42%) as a pale yellow oil, LC-MS: m/z=164[M+H].sup.+.

Step 3

[0109] Compound 6-4 (240 mg, 1.5 mmol), compound 1-6 (300 mg, 0.49 mmol) and 1.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 6 (27 mg, 6.4%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.65-9.63 (m, 8H), 8.37-8.34 (m, 8H), 3.60-3.56 (m, 10H), 2.99-2.95 (m, 2H), 2.45-2.41 (m, 6H), 2.12-2.10 (m, 4H), 0.43-0.39 (m, 4H), 1.87-1.91 (m, 4H); HRMS: 865.0365 [M].sup.+.

Example 7

[0110] ##STR00039##

Step 1

[0111] Compound 6-3 (5.3 g, 17.4 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of compound 2-1 (4.24 g, 52 mmol), and potassium carbonate (4.9 g, 35.8 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 40 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 7-1 (1.4 g, 45%) as a pale yellow oil, LC-MS: m/z=178[M+H].sup.+.

Step 2

[0112] Compound 7-1 (250 mg, 1.5 mmol), compound 1-6 (300 mg, 0.49 mmol) and 1.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 7 (65 mg, 14.8%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.67-9.64 (m, 8H), 8.38-8.36 (m, 8H), 2.99-2.97 (m, 4H), 2.41-2.34 (m, 12H), 1.66-1.64 (m, 4H), 0.89-0.86 (m, 6H), 0.45-0.43 (m, 4H), 1.87-1.90 (m, 4H); HRMS: 893.3912 [M+H].sup.+.

Example 8

[0113] ##STR00040##

Step 1

[0114] Compound 6-3 (5.3 g, 17.4 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of compound 3-1 (3.9 g, 52 mmol), and potassium carbonate (4.9 g, 34.8 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 8-1 (1.6 g, 44%) as a pale yellow oil, LC-MS: m/z=208[M+H].sup.+.

Step 2

[0115] Compound 8-1 (310 mg, 1.5 mmol), compound 1-6 (300 mg, 0.49 mmol) and 1.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 8 (82 mg, 17.6%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.65-9.62 (m, 8H), 8.37-8.34 (m, 8H), 3.34-3.30 (m, 4H), 3.23 (s, 6H), 2.97-2.94 (m, 4H), 2.58-2.56 (m, 4H), 2.43-2.41 (m, 8H), 1.67-1.64 (m, 4H), 0.45-0.41 (m, 4H), 1.86-1.89 (m, 4H); HRMS: 975.3945 [M+Na].sup.+.

Example 9

[0116] ##STR00041##

Step 1

[0117] Compound 6-3 (5.3 g, 17.4 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of compound 4-1 (3.9 g, 52 mmol), and potassium carbonate (4.9 g, 34.8 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 9-1 (1.8 g, 46%) as a pale yellow oil, LC-MS: m/z=222[M+H].sup.+.

Step 2

[0118] Compound 9-1 (324 mg, 1.5 mmol), compound 1-6 (300 mg, 0.49 mmol) and 1.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 9 (72 mg, 15%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.66-9.64 (m, 8H), 8.38-8.35 (m, 8H), 3.30-3.27 (m, 4H), 3.21 (s, 6H), 2.97-2.94 (m, 4H), 2.45-2.39 (m, 12H), 1.66-1.63 (m, 4H), 1.60-1.56 (m, 4H), 0.45-0.41 (m, 4H), 1.86-1.89 (m, 4H); HRMS: 975.3945 [M+Na].sup.+.

Example 10

[0119] ##STR00042##

Step 1

[0120] Compound 6-3 (5.3 g, 17.4 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of compound 5-1 (4.85 g, 36.5 mmol), and potassium carbonate (4.9 g, 34.8 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 10-1 (2.2 g, 47.7%) as a pale yellow oil, LC-MS: m/z=266[M+H].sup.+.

Step 2

[0121] Compound 10-1 (265 mg, 1 mmol), compound 1-6 (200 mg, 0.33 mmol) and 1 mL of pyridine were added into a 100 mL reaction flask, then toluene (30 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 10 (100 mg, 28.4%) as a deep blue solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.67-9.64 (m, 8H), 8.38-8.36 (m, 8H), 3.30-3.27 (m, 8H), 3.22 (s, 12H), 2.97-2.94 (m, 4H), 2.55-2.52 (m, 6H), 2.44-2.42 (m, 10H), 1.67-1.65 (m, 4H), 0.42-0.39 (m, 4H), 1.87-1.90 (m, 4H); HRMS: 1091.4779 [M+Na].sup.+.

Example 11

[0122] ##STR00043##

Step 1

[0123] Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), followed by addition of diethylamine 11-1 (2.2 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70 C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 11-2 (0.68 g, 42%) as a pale yellow oil, LC-MS: m/z=162[M+H].sup.+.

Step 2

[0124] Compound 11-2 (140 mg, 0.87 mmol), compound 1-6 (265 mg, 0.43 mmol) and sodium hydride (70 mg, 1.75 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 11 (70 mg, 18.9%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.61 (m, 8H), 8.34-8.32 (m, 8H), 1.91-1.88 (m, 8H), 1.63 (t, J=5 Hz, 4H), 1.47 (t, J=5 Hz, 4H), 0.57 (t, J=5 Hz, 12H), 0.35-0.33 (m, 4H), 1.91-1.94 (m, 4H); HRMS: 883.3833 [M+Na].sup.+.

Example 12

[0125] ##STR00044##

Step 1

[0126] Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), followed by addition of tetrahydropyrrole 12-1 (2.14 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70 C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 12-2 (0.71 g, 45%) as a pale yellow oil, LC-MS: m/z=160[M+H].sup.+.

Step 2

[0127] Compound 12-2 (100 mg, 0.63 mmol), compound 1-6 (192 mg, 0.315 mmol) and sodium hydride (50 mg, 1.26 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 12 (30 mg, 11.2%) as a deep blue solid.

TABLE-US-00002 Target Reaction Compound Compound product batch 12-2 1-6 12 Yield 1 100 mg 192 mg 30 mg 11.2% 2 100 mg 192 mg 28 mg 10.4%

[0128] .sup.1H NMR (500 MHz, CDCl.sub.3): 9.64-9.61 (m, 8H), 8.34-8.32 (m, 8H), 1.82-1.76 (m, 8H), 1.65-1.62 (m, 4H), 1.48-1.44 (m, 12H), 0.36 (t, J=5 Hz, 4H), 1.92 (t, 4H, J=7.5 Hz). HRMS: 879.3520 [M+Na].sup.+.

Example 13

[0129] ##STR00045##

Step 1

[0130] Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), followed by addition of piperidine 13-1 (2.52 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70 C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 13-2 (0.73 g, 42%) as a pale yellow oil, LC-MS: m/z=174[M+H].sup.+.

Step 2

[0131] Compound 13-2 (150 mg, 0.867 mmol), compound 1-6 (265 mg, 0.433 mmol) and sodium hydride (70 mg, 1.74 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (25 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 13 (58 mg, 15.1%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.62 (m, 8H), 8.34-8.32 (m, 8H), 1.72-1.66 (m, 8H), 1.63 (t, J=7.5 Hz, 4H), 1.34 (t, J=5 Hz, 4H), 1.25-1.23 (m, 12H), 0.34 (t, J=5 Hz, 4H), 1.93 (t, J=7.5 Hz, 4H). HRMS: 907.3834 [M+Na].sup.+.

Example 14

[0132] ##STR00046##

Step 1

[0133] Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of morpholine 14-1 (2.61 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70 C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 14-2 (1 g, 57.1%) as a pale yellow oil, LC-MS: m/z=176[M+H].sup.+.

Step 2

[0134] Compound 14-2 (150 mg, 0.856 mmol), compound 1-6 (262 mg, 0.428 mmol) and sodium hydride (68 mg, 1.7 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (25 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 14 (52 mg, 13.6%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.64-9.62 (m, 8H), 8.35-8.34 (m, 8H), 3.38-3.32 (m, 8H), 1.73-1.68 (m, 8H), 1.35-1.33 (m, 8H), 0.38 (t, J=5 Hz, 4H), 1.93 (t, J=5 Hz, 4H). HRMS: 911.3417 [M+Na].sup.+.

Example 15

[0135] ##STR00047##

Step 1

[0136] Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of N-methylpiperazine 15-1 (3 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70 C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 15-2 (1.45 g, 77.1%) as a pale yellow oil, LC-MS: m/z=189[M+H].sup.+.

Step 2

[0137] Compound 15-2 (100 mg, 0.53 mmol), compound 1-6 (163 mg, 0.265 mmol) and sodium hydride (84 mg, 2.1 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (15 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 15 (102 mg, 42.1%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.61 (m, 8H), 8.34-8.32 (m, 8H), 2.15 (s, 6H), 1.82-1.78 (m, 8H), 1.59-1.55 (m, 12H), 1.38 (t, J=5 Hz, 4H), 0.36 (t, J=5 Hz, 4H), 1.93 (t, J=5 Hz, 4H); HRMS: 937.4049 [M+Na].sup.+.

Example 16

[0138] ##STR00048##

Step 1

[0139] Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 16-1 (1 g, 10 mmol), and potassium carbonate (1.38 g, 10 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70 C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 16-2 (0.76 g, 40.4%) as a pale yellow oil, LC-MS: m/z=189[M+H].sup.+.

Step 2

[0140] Compound 16-2 (100 mg, 0.532 mmol), compound 1-6 (163 mg, 0.266 mmol) and 0.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 16 (55 mg, 22.6%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.64-9.63 (m, 8H), 8.36-8.34 (m, 8H), 5.56-5.51 (m, 2H), 2.59-2.54 (m, 4H), 1.83 (t, J=5 Hz, 4H), 1.56-1.53 (m, 8H), 1.40 (t, J=5 Hz, 4H), 0.41 (t, J=5 Hz, 4H), 1.99 (t, J=5 Hz, 4H); HRMS: 937.3323 [M+Na].sup.+.

Example 17

[0141] ##STR00049##

Step 1

[0142] Compound 6-3 (3.1 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 11-1 (2.2 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight at 40 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 17-1 (1 g, 48.8%) as a pale yellow oil, LC-MS: m/z=206[M+H].sup.+.

Step 2

[0143] Compound 17-1 (200 mg, 1 mmol), compound 1-6 (305 mg, 0.5 mmol) and sodium hydride (80 mg, 2 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (25 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 17 (88 mg, 18.6%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.67-9.64 (m, 8H), 8.34-8.30 (m, 8H), 2.90 (t, J=7.5 Hz, 4H), 2.39 (t, J=7.5 Hz, 4H), 2.31-2.27 (m, 8H), 2.20 (t, J=5 Hz, 4H), 1.64-1.60 (m, 4H), 0.81 (t, J=7.5 Hz, 12H), 0.37 (t, J=5 Hz, 4H,), 1.92 (t, J=5 Hz, 4H); HRMS: 949.4538 [M+H].sup.+.

Example 18

[0144] ##STR00050##

Step 1

[0145] Compound 6-3 (3.04 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 12-1 (2.14 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight at 40 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 18-1 (0.92 g, 45.3%) as a pale yellow oil, LC-MS: m/z=204[M+H].sup.+.

Step 2

[0146] Compound 18-1 (203 mg, 1 mmol), compound 1-6 (305 mg, 0.5 mmol) and sodium hydride (80 mg, 2 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (25 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 18 (62 mg, 13.1%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.61 (m, 8H), 8.34-8.32 (m, 8H), 2.94 (t, J=5 Hz, 4H), 2.41 (t, J=5 Hz, 4H), 2.26-2.23 (m, 8H), 1.65-1.62 (m, 16H), 0.38 (t, J=7.5 Hz, 4H), 1.99 (t, J=7.5 Hz, 4H). HRMS: 945.4230 [M+H].sup.+.

Example 19

[0147] ##STR00051##

Step 1

[0148] Compound 6-3 (3.04 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 13-1 (2.52 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight at 40 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 19-1 (0.72 g, 33.2%) as a pale yellow oil, LC-MS: m/z=218[M+H].sup.+.

Step 2

[0149] Compound 19-1 (150 mg, 0.69 mmol), compound 1-6 (214 mg, 0.35 mmol) and sodium hydride (55 mg, 1.38 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 19 (115 mg, 33.8%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.61 (m, 8H), 8.34-8.32 (m, 8H), 2.94 (t, J=5 Hz, 4H), 2.39 (t, J=5 Hz, 4H), 2.12-2.09 (m, 8H), 1.63-1.61 (m, 8H), 1.42-1.38 (m, 12H), 0.39 (t, J=7.5 Hz, 4H), 1.90 (t, J=7.5 Hz, 4H); HRMS: 973.4539 [M+H].sup.+.

Example 20

[0150] ##STR00052##

Step 1

[0151] Compound 6-3 (3.04 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 14-1 (2.6 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight at 40 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 20-1 (0.75 g, 34.2%) as a pale yellow oil, LC-MS: m/z=220[M+H].sup.+.

Step 2

[0152] Compound 20-1 (150 mg, 0.68 mmol), compound 1-6 (209 mg, 0.34 mmol) and sodium hydride (55 mg, 1.36 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 20 (57 mg, 15.7%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.62 (m, 8H), 8.35-8.32 (m, 8H), 3.51 (t, J=5 Hz, 8H), 2.90 (t, J=5 Hz, 4H), 2.40 (t, J=5 Hz, 4H), 2.19-2.12 (m, 12H), 1.64 (t, J=5 Hz, 4H), 0.39 (t, J=7.5 Hz, 4H), 1.92 (t, J=7.5 Hz, 4H); HRMS: 999.3946 [M+Na].sup.+.

Example 21

[0153] ##STR00053##

Step 1

[0154] Compound 6-3 (3.04 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 15-1 (3 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight at 40 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 21-1 (1.45 g, 62.5%) as a pale yellow oil, LC-MS: m/z=233[M+H].sup.+.

Step 2

[0155] Compound 21-1 (200 mg, 0.86 mmol), compound 1-6 (263 mg, 0.43 mmol) and sodium hydride (69 mg, 1.72 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 21 (81 mg, 18.8%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.62 (m, 8H), 8.34-8.33 (m, 8H), 2.91 (t, J=5 Hz, 4H), 2.39 (t, J=5 Hz, 4H), 2.28-2.20 (m, 14H), 2.14 (t, J=5 Hz, 4H), 1.68-1.60 (m, 12H), 0.39 (t, J=7.5 Hz, 4H), 1.92 (t, 4H, J=7.5 Hz); HRMS: 1003.4758 [M+H].sup.+.

Example 22

[0156] ##STR00054##

Step 1

[0157] Compound 6-3 (3.04 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 16-1 (1 g, 10 mmol), and under stirring potassium carbonate (1.4 g, 10 mmol) was added, followed by stirring the reaction overnight at 70 C., TLC monitoring showed that the starting material 6-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 22-1 (1.1 g, 47.4%) as a pale yellow oil, LC-MS: m/z=233[M+H].sup.+.

Step 2

[0158] Compound 22-1 (100 mg, 0.43 mmol), compound 1-6 (128 mg, 0.21 mmol) and 0.5 mL of pyridine were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball, the temperature was heated to 120 C., and the reaction was performed at 120 C. for 4 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 22 (52 mg, 24.7%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.63-9.62 (m, 8H), 8.35-8.34 (m, 8H), 6.82-6.78 (m, 2H), 3.01-2.87 (m, 12H), 2.40 (t, J=5 Hz, 4H), 2.31 (t, J=5 Hz, 4H), 2.18 (t, J=5 Hz, 4H), 1.66 (t, J=5 Hz, 4H), 0.39 (t, J=7.5 Hz, 4H), 1.93 (t, J=7.5 Hz, 4H); HRMS: 1025.3847 [M+Na].sup.+.

Example 23

[0159] ##STR00055##

Step 1

[0160] Compound 1-3 (3.12 g, 12 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 23-1 (1 g, 10 mmol), and under stirring potassium carbonate (1.65 g, 12 mmol) was added, followed by stirring the reaction overnight at 70 C., TLC monitoring showed the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 23-2 (1.2 g, 62.8%) as a pale yellow oil, LC-MS: m/z=192[M+H].sup.+.

Step 2

[0161] Compound 23-2 (100 mg, 0.52 mmol), compound 1-6 (160 mg, 0.26 mmol) and sodium hydride (42 mg, 1.04 mmol, 60% w/w) were added into a 100 mL reaction flask, then toluene (20 mL) was added to the reaction system. The atmosphere of the reaction system was changed to a nitrogen atmosphere using nitrogen ball and the reaction was performed at room temperature and monitored by TLC. After TLC showed that compound 1-6 was completely conversed, the reaction system was concentrated under reduced pressure, then 10 mL of water was added to the reaction system, and the resulting mixture was extracted three times with ethyl acetate (10 mL). The extract liquid was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain the target product 23 (140 mg, 59%) as a deep blue solid. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.64-9.62 (m, 8H), 8.36-8.34 (m, 8H), 2.32-2.29 (m, 8H), 1.99-1.97 (m, 8H), 1.54 (t, J=5 Hz, 4H), 1.38 (t, J=7.5 Hz, 4H), 0.38 (t, J=5 Hz, 4H), 1.93 (t, J=5 Hz, 4H); HRMS: 943.2963 [M+Na].sup.+.

Example 24

[0162] ##STR00056##

Step 1

[0163] 7.6 g (0.1 mol) of ethylene glycol monomethyl ether 24-1 was dissolved in 150 mL of anhydrous dichloromethane, 20 g of triethylamine was added, 0.1 M of a solution of methanesulfonyl chloride (0.11 mol) in dichloromethane was added dropwise at 0 C. After the addition was complete, the mixture was reacted at room temperature overnight, washed with water, dried and concentrated to obtain 14.9 g of ethylene glycol monomethyl ether protected with Ms 24-2, yield 97%.

Step 2

[0164] 1.54 g of ethylene glycol monomethyl ether protected with Ms 24-2 (0.01 mol) and 7.5 g of amino-n-propanol 24-3 (0.1 mol) was dissolved in 30 mL of anhydrous tetrahydrofuran, and the mixture was reacted under refluxing for 8 hours. The reaction solution was washed with water and concentrated to obtain the crude target product 24-4. The crude product was dissolved in dichloromethane (30 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent solution (dichloromethane:methanol=20/1-5/1) to obtain 0.63 g of the target product 24-4 as a pale yellow liquid, yield 47%. LC-MS: m/z=134[M+H]+.

Step 3

[0165] 122 mg of silicon phthalocyanine dichloride 1-6 (0.02 mmol) and 266 mg of compound 24-4 (2 mmol) was dissolved in 15 mL of anhydrous toluene and 0.5 mL of pyridine, and the mixture was reacted under refluxing away from light under N2 for 6 hours. The reaction solution was washed with water (100 mL) three times, dried, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain 57 mg of the target product 24, yield 33%. .sup.1H NMR: 9.63 (m, 8H, ArH), 8.34 (m, 8H, ArH), 2.98 (s, s, 6H, CH.sub.3), 2.64 (m, 4H, CH.sub.2), 1.50 (m, 4H, CH.sub.2), 0.10 (m, 4H, CH.sub.2), 1.34 (m, 4H, CH.sub.2), 2.05 (m, 4H, CH.sub.2). HRMS: [M+2H].sup.2+: 806.3462.

Example 25

[0166] ##STR00057##

Step 1

[0167] 12.0 g (0.1 mol) of diethylene glycol monomethyl ether 25-1 was dissolved in 150 mL of anhydrous dichloromethane, 20 g of triethylamine was added, 0.1 M of a solution of methanesulfonyl chloride (0.11 mol) in dichloromethane was added dropwise at 0 C. After the addition was complete, the mixture was reacted at room temperature overnight, washed with water, dried and concentrated to obtain 18.3 g of diethylene glycol monomethyl ether protected with Ms 25-2, yield 92%.

Step 2

[0168] 1.98 g of diethylene glycol monomethyl ether protected with Ms 25-2 (0.01 mol) and 7.5 g of amino-n-propanol 24-3 (0.1 mol) was dissolved in 30 mL of anhydrous tetrahydrofuran, and the mixture was reacted under refluxing for 6 hours. The reaction solution was washed with water and concentrated to obtain the crude target product 25-3. The crude product was dissolved in dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent solution (dichloromethane:methanol=20/1-5/1) to obtain 1.23 g of the target product 25-3 as a pale yellow liquid, yield 70%. LC-MS: m/z=178[M+H].sup.+.

Step 3

[0169] 61 mg of silicon phthalocyanine dichloride 1-6 (0.01 mmol) and 177 mg of the compound 25-3 (1 mmol) was dissolved in 12 mL of anhydrous toluene and 0.5 mL of pyridine, and the mixture was reacted under refluxing away from light under N2 for 6 hours. The reaction solution was washed with water (100 mL) three times, dried, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain 51 mg of the target product 25, yield 57%. .sup.1H NMR: 9.72 (m, 8H, ArH), 8.49 (m, 8H, ArH), 3.23 (m, 4H, CH.sub.2), 3.18 (m, 4H, CH.sub.2), 3.11 (s, 6H, CH.sub.3), 2.70 (m, 4H, CH.sub.2), 1.51 (m, 4H, CH.sub.2), 0.15 (m, 4H, CH.sub.2), 1.36 (m, 4H, CH.sub.2), 1.98 (m, 4H, CH.sub.2). HRMS: [M+H].sup.+: 893.3920.

Example 26

[0170] ##STR00058##

Step 1

[0171] 16.4 g (0.1 mol) of triethylene glycol monomethyl ether 26-1 was dissolved in 150 mL of anhydrous dichloromethane, 20 g of triethylamine was added, 0.1 M of a solution of methanesulfonyl chloride (0.11 mol) in dichloromethane was added dropwise at 0 C. After the addition was complete, the mixture was reacted at room temperature overnight, washed with water, dried and concentrated to obtain 21.9 g of triethylene glycol monomethyl ether protected with Ms 26-2, yield 91%.

Step 2

[0172] 2.44 g of triethylene glycol monomethyl ether protected with Ms 26-2 (0.01 mol) and 7.5 g of amino-n-propanol 24-3 (0.1 mol) was dissolved in 30 mL of anhydrous tetrahydrofuran, and the mixture was reacted under refluxing for 6 hours. The reaction solution was washed with water and concentrated to obtain the crude target product 26-3. The crude product was dissolved in dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent solution (dichloromethane:methanol=20/1-5/1) to obtain 1.45 g of the target product 26-3 as a pale yellow liquid, yield 66%. LC-MS: m/z=222 [M+H].sup.+.

Step 3

[0173] 61 mg of silicon phthalocyanine dichloride 1-6 (0.01 mmol) and 221 mg of the compound 26-3 (1 mmol) was dissolved in 12 mL of anhydrous toluene and 0.5 mL of pyridine, and the mixture was reacted under refluxing away from light under N2 for 6 hours. The reaction solution was washed with water (100 mL) three times, dried, concentrated, and purified by silica gel column chromatography, with an eluent of ammoniated dichloromethane:methanol=100/3-50/1, to obtain 61 mg of the target product 26, yield 62%. The purity was more than 95%. .sup.1H NMR: 9.66 (m, 8H, ArH), 8.41 (m, 8H, ArH), 3.03 (m, 4H, CH.sub.2), 3.02 (m, 4H, CH.sub.2), 2.99 (m, 4H, CH.sub.2), 2.98 (m, 4H, CH.sub.2), 2.97 (m, 4H, CH.sub.2), 2.79 (s, s, 6H, CH.sub.3), 0.88 (m, 4H, CH.sub.2), 0.19 (m, 4H, CH.sub.2), 0.87 (m, 4H, CH.sub.2), 2.02 (m, 4H, CH.sub.2). HRMS: [M+H].sup.+: 981.4451.

Test Example

In Vitro Tumor Experiment

[0174] Test samples: compounds 1-26 of the present invention

[0175] Positive Control: hematoporphyrin injection (trade name: Hiporfin, Chongqing Huading modern biopharmaceutical Ltd. Co.).

[0176] Main Reagent

[0177] DMSO was purchased from the MP Company (U.S.A.); polyoxyethylene castor oil was purchased from the Sigma Company.

[0178] Dose Design and Group

[0179] 26 test samples were designed and divided into 5-10 doses, with each dose concentration being distributed between 5000-0.025 ng/mL (final concentration of the sample after being added into cell well); at the same time the negative control group (a solvent containing no test sample) was given, a blank well without cell suspension only with complete culture medium was also given. Each 96-well plate does not have the positive control group. Positive drug (Hiporfin) was treated according to the test samples (at a dose of 10, 5, 2.5, 1.25, 0.625 g/mL).

[0180] Experimental Method

[0181] 1. Preparation Method of Main Reagent

[0182] 1.1. RPMI-1640 complete culture medium: to 500 mL RPMI-1640 liquid medium (GIBCO Company), 100,000 units of penicillin/streptomycin and 56 mL of fetal bovine serum were added and mixed uniformly.

[0183] 1.2. DMEM complete culture medium: to 500 mL DMEM liquid medium (GIBCO Company), 100,000 units of penicillin/streptomycin and 56 mL of fetal bovine serum were added and mixed uniformly.

[0184] 1.3. MTT solution (MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, purchased from the MP Company (U.S.A.)): the powdered MTT was dissolved into a PBS solution at a concentration of 5 mg/mL, filtered and sterilized, and it was formulated when used.

[0185] 2. Preparation Method of Test Sample:

[0186] The test sample was formulated into a mother liquor at a concentration of 1 mM with DMSO; 100 L of 1 mg/mL of the mother liquor was taken in the experiment, 1.15 mL 0.5% (w/w) polyoxyethylenated castor oil in pH 7.4 PBS buffer was added to prepare a 80 g/mL drug liquid, which was diluted into different concentrations with a culture medium. For each test sample and the negative control group, the final concentration of DMSO was 1%. A 5 mL liquid solution containing 25 mg of Hiporfin was formulated, and the concentration was 5 mg/mL. 100 L of 5 mg/mL of the Hiporfin preparation was taken, 4.90 mL of the pH 7.4 PBS buffer was added to prepare a 100 g/mL drug liquid, which was diluted into different concentrations with a culture medium.

[0187] 3. Cell culture: human melanoma cell A375 (Cell bank of Yat-sen University) and human esophageal cancer cell Te-1 (Cell Bank of the Chinese academy of sciences, Shanghai) were each cultured in 10% FBS-containing DMEM medium in a incubator with 37 C., 5% CO.sub.2, and passaged after digestion with 0.25% trypsin. Cells in logarithmic growth phase were collected for experiments.

[0188] 4. MTT Experimental Method:

[0189] Adherent tumor cells in logarithmic growth phase were selected and digested with trypsin, then formulated into a suitable concentration of cell suspensions with a RPMI 1640 or DMEM medium containing 10% fetal bovine serums and inoculated in a 96-well culture plate. Each well was inoculated with 100 L, after the addition was completed in each row, cell suspension was shaken. After the addition of cells was complete, the culture plate was rotated lightly and horizontally such that the cells were uniformly dispersed on the surface of the plate wells, a circle of wells around the 96-hole plate was added with a sterile PBS, and incubated under conditions of 37 C., 5% CO.sub.2 for 24 h. Then, 100 L of different concentrations of test drugs, positive drugs, solvents and culture mediums were added respectively, with three parallel wells in each group. After mixing uniformly, they were divided into two groups, a light group and a dark group, and both were administered with drugs and co-cultured for 2 h, then the medium was discarded and the DMEM complete medium containing no test sample was re-added. The plate was placed under conditions of 37 C., 5% CO.sub.2 for another 24 h. After 24 h, each well was added with 5 mg/mL MTT, 20 L, and incubated under conditions of 37 C., 5% CO.sub.2 for 4 h, the supernatant was carefully sucked and discarded; each well was added with 200 L DMSO, shaken for 10 min, so that the formazan particles formed were fully dissolved, then the absorbance value was determined by a microplate reader, with the detection wavelength of 570 nm, and the reference wavelength of 630 nm. The above experiment was repeated 3 times, the average IC.sub.50 value of the 3 experiments was obtained as the final index. The light source was provided by a 200 watt halogen lamp connected to an insulated water tank plus a filter of more than 610 nm, and the light dose was 48 J cm.sup.2.

[0190] Calculation Method of Growth Inhibition Rate of Drug on Tumor Cell:

[0191] Tumor cell growth inhibition rate (%)=[(OD mean value of the negative control groupOD mean value of the drug group)/OD mean value of the negative control group]100%. The calculation of half inhibitory concentration IC.sub.50 was determined by logit regression method.

[0192] Experimental Results:

TABLE-US-00003 Skin skin Esophagus Esophagus cancer cancer carcinomas carcinomas A375 A375 Te-1 Te-1 Light Dark Light Dark Compound IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 No. ng/mL ng/mL ng/mL ng/mL 1 11 >250 1.8 >5000 2 2 >250 0.07 4000 3 1.8 >250 <0.025 5000 4 2.4 >250 <0.025 3750 5 1.6 >250 <0.025 >5000 6 9 >250 10 >5000 7 9 >250 17 >5000 8 1.9 >250 <0.025 >5000 9 12 >250 4 >5000 10 1.7 >250 <0.025 >5000 11 1 >250 0.03 3150 12 1.8 >250 2.5 >5000 13 13 >5000 1.5 >5000 14 8 >5000 <0.025 >5000 15 1.7 4500 <0.025 >5000 16 1.6 >5000 <0.025 >5000 17 0.8 1560 <0.025 1530 18 0.2 1890 <0.025 2052 19 0.1 >5000 <0.025 >5000 20 0.1 >5000 <0.025 >5000 21 1.2 3025 <0.025 >5000 22 12 >5000 18 >5000 23 1.8 >5000 2.1 >5000 24 1.5 >5000 11 >5000 25 16 >5000 12.7 >5000 26 12.4 >5000 14.6 >5000 Hiporfin 2000 >10000 5000 >10000

[0193] It can be seen from the above test results that China's only marketed anticancer photosensitizer Hiporfin had an IC.sub.50 value of 2000 ng/mL with respect to skin cancer A375 cancer cells under light illumination and an IC.sub.50 value of 5000 ng/mL with respect to the esophageal cancer Te-1 cancer cells under light illumination. The optical activity of the compounds 1-26 disclosed in the present invention is much higher than that of the marketed control drug Hiporfin: for skin cancer A375 cells and esophageal cancer Te-1 cancer cells under the same light illumination conditions, in both cases the IC.sub.50 values were less than 18 ng/mL, the IC.sub.50 values of some of the compounds were even less than 0.025 ng/mL, and the in vitro photodynamic activity thereof was as 200000 times as that of the drug already marketed. It is also noted that the IC.sub.50 values of these compounds, under dark condition, are more than 5000 ng/mL, and the IC.sub.50 values thereof on tumor cells under dark condition is as 200000 times as the IC.sub.50 values under light illumination condition, indicating that theses compounds have very low dark toxicity and a very wide safety window. In summary, the series of compounds disclosed in the present invention have very low dark toxicity and very high photodynamic activity, is a potential second-generation of photosensitive drug having high efficiency and low toxicity.