BENZO[b]SELENOPHENE STING REGULATOR, PREPARATION METHOD AND USE THEREOF

Abstract

A benzo[b]selenophene STING regulator, a preparation method therefore and use thereof are disclosed. The structure of the compound is shown in Formula I. A derivative, salt, stereoisomer, prodrug molecule and pharmaceutical composition of the present invention can serve as an immune regulator to effectively activate an innate immune regulation passageway to kill tumor cells.

##STR00001##

Claims

1. A compound as shown in general formula (I), a stereisomer or a pharmaceutically acceptable salt thereof: ##STR00040## where R.sup.1 is selected from H, halo, cyano, nitro, OR.sup.6, N(R.sup.6).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl substituted with OR.sup.6 or C.sub.1-C.sub.6 alkyl substituted with N(R.sup.6).sub.2; R.sup.2 is selected from H, halo, cyano, nitro, OR.sup.6, SR.sup.6, N(R.sup.6).sub.2, COOR.sup.6, C(O)N(R.sup.6).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl substituted with OR.sup.6, C.sub.1-C.sub.6 alkyl substituted with N(R.sup.6).sub.2, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl(enyl) or C.sub.3-C.sub.6 cycloalkyl; R.sup.3 is selected from H, halo, cyano, nitro, OR.sup.6, SR.sup.6, N(R.sup.6).sub.2, COOR.sup.6, C(O)N(R.sup.6).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl substituted with OR.sup.6, and C.sub.1-C.sub.6 alkyl substituted with N(R.sup.6).sub.2, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl(enyl) or C.sub.3-C.sub.6 cycloalkyl; or R.sup.2 and R.sup.3, together with atoms to which they are attached, can form a 5- or 6-membered heterocycle comprising one to two members selected from O, S or N ring members. R.sup.4 is selected from H, halo, cyano, nitro, OR.sup.6, N(R.sup.6).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl substituted with OR.sup.6 or C.sub.1-C.sub.6 alkyl substituted with N(R.sup.6).sub.2; R.sup.5 is selected from H, halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl and C.sub.3-C.sub.6 cycloalkyl; R.sup.6 on the same atom is identical or different, R.sup.6 on different atoms are identical or different, and each R.sup.6 is independently selected from H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.8 heterocyclyl or C.sub.5-C.sub.10 aryl; X.sup.1 is C(O); X.sup.2 is (C(R.sup.7).sub.2)(1-3); R.sup.7 on the same atom is identical or different, R.sup.7 on different atoms are identical or different, and each R.sup.7 is independently selected from H, halo, CN, OR.sup.6, N(R.sup.6).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl substituted with OR.sup.6 or C.sub.3-C.sub.6 cycloalkyl; or two R.sup.7 on different carbon atoms, together with atoms to which they are attached, can form a 3- to 6-membered ring; or two R.sup.7 on a single carbon atom, together with atoms to which they are attached, can form a 3- to 6-membered ring; and X3 is selected from COOR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, SO.sub.2R.sup.6, S(O)NR.sup.6 or C(CF.sub.3).sub.2OR.sup.6.

2. The compound, the stereisomer or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.1 is selected from H, F, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl, preferably H and F; R.sup.2 is selected from H, halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, OC.sub.1-C.sub.3 alkyl, OC.sub.1-C.sub.3 haloalkyl or OH; R.sup.3 is selected from H, halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, OC.sub.1-C.sub.3 alkyl, OC.sub.1-C.sub.3 haloalkyl or OH; R.sup.4 is selected from H, F, C.sub.1-C.sub.3 haloalkyl; R.sup.5 is selected from H, halo, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl; X.sup.1 is C(O); X2 is CH.sub.2CHR.sup.7; X3 is selected from COOR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, SO.sub.2R.sup.6, S(O)NR.sup.6 or C(CF.sub.3).sub.2OR.sup.6; each R.sup.6 is independently selected from H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.8 heterocyclyl or C.sub.5-C.sub.10 aryl; each R.sup.7 is independently selected from H, F, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6 cycloalkyl or C.sub.1-C.sub.4 alkyl substituted with OC.sub.1-C.sub.3.

3. The compound, the stereisomer or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.1 is selected from H, F, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl; R.sup.2 is selected from H, halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, OC.sub.1-C.sub.3 alkyl, OC.sub.1-C.sub.3 haloalkyl; R.sup.3 is selected from H, halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, OC.sub.1-C.sub.3 alkyl, OC.sub.1-C.sub.3 haloalkyl or OH; R.sup.4 is selected from H, F, C.sub.1-C.sub.3 haloalkyl; R.sup.5 is selected from H, halo, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl; X.sup.1 is C(O); X.sup.2 is CHR.sup.7CHR.sup.7; X3 is selected from COOR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, SO.sub.2R.sup.6, S(O)NR.sup.6 or C(CF.sub.3).sub.2OR.sup.6. each R.sup.6 is independently selected from H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.8 heterocyclyl or C.sub.5-C.sub.10 aryl; each R7 is independently selected from H, F, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6 cycloalkyl or C.sub.1-C.sub.4 alkyl substituted with OC.sub.1-C.sub.3, or two R7, together with atoms to which they are attached, form a 3- to 6-membered ring.

4. A compound as shown in general formula (I-1), a stereisomer or a pharmaceutically acceptable salt thereof: ##STR00041## where X2 is CHR.sup.7CHR.sup.7; R.sup.7 is identical or different, and each R.sup.7 is independently selected from H, halo, CN, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl substituted with OR.sup.6 and C.sub.3-C.sub.6 cycloalkyl; or two R.sup.7 on different carbon atoms, together with atoms to which they are attached, form a 3- to 6-membered ring; and R.sup.6 is independently selected from H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.8 heterocyclyl or C.sub.5-C.sub.10 aryl.

5. Compounds as shown in the following general formulas, stereisomers or pharmaceutically acceptable salts thereof: TABLE-US-00005 Code Structural formula I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24

6. A preparation method for the compound according to claim 1, wherein when the compound is a compound as shown in general formula (Ia), a compound of general formula (IV) is prepared from a compound of general formula (II) and compound of general formula (III) under an alkaline condition by means of a substitution reaction, a compound of general formula (VI) is prepared from the compound of general formula (IV) and a compound of general formula (V) by means of a substitution reaction, a compound of general formula (VII) is prepared from the compound of general formula (VI) under an alkaline condition by means of an intramolecular condensation reaction, a compound of general formula (VIII) is prepared from the compound of general formula (VII) by means of a hydrolysis reaction, a compound of general formula (X) is prepared from the compound of general formula (VIII) and a compound of general formula (IX) by means of a condensation reaction, a compound of general formula (XII) is prepared from the compound of general formula (X) and a compound of general formula (XI) by means of a nucleophilic substitution reaction, and a compound of general formula (Ia) is prepared from the compound of general formula (XII) by means of a hydrolytic decarboxylation reaction, a synthetic route of the compound of general formula (Ia) being as follows: ##STR00066## wherein R.sup.2, R.sup.3 and R.sup.7 are in accordance with claim 1, R.sup.8 is selected from CH.sub.3, CH.sub.2CH.sub.3 and C(CH.sub.3).sub.3, R.sup.9 is selected from CH.sub.3 and CH.sub.2CH.sub.3, and X is selected from Cl, Br and I; when the compound is a compound of general formula (Ib), a compound of general formula (XIII) is prepared from the compound of general formula (VIII) by means of a decarboxylic reaction, and a compound of general formula (Ib) is prepared from the compound of general formula (XIII) and a compound of general formula (XIV) by means of a Friedel-Crafts acylation, a synthetic route of the compound of general formula (XIV) being as follows: ##STR00067## wherein R.sup.2 and R.sup.3 are in accordance with claim 1, n representing 1, 2, 3 or 4.

7. A drug composition, wherein the drug composition comprises an active component of an effective dose of drug and a pharmaceutically acceptable accessory; and the active component comprises the compound according to claim 1, a stereisomer or one or more of pharmaceutically acceptable salts thereof.

8. A method comprising activating a cGAS-STING pathway using the compound according to claim 1.

9. A method comprising preparing a drug with the compound according to claim 1, the drug being used for treating diseases related to activity of a STING pathway; preferably, the diseases related to the activity of the STING pathway being one or more of diseases related to autoimmune diseases, infectious diseases, cancer and precancerous syndromes.

10. A method comprising preparing an immune adjuvant with the compound according to claim 1.

Description

DETAILED DESCRIPTION

[0085] To further elaborate on the present invention, a series of embodiments are provided below. These embodiments are entirely illustrative, and are only used for describing the present invention specifically, and should not be understood as a limit of the present invention.

[0086] The raw materials and equipment used in the embodiments of the present invention are known products and obtained by purchasing commercially available products.

ABBREVIATION

[0087] DTT DL-Dithiothreitol [0088] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene [0089] .sup.1H NMR Proton nuclear magnetic resonance spectrum [0090] .sup.13C NMR .sup.13C nuclear magnetic resonance spectrum [0091] HRMS High resolution mass spectrum [0092] DMSO Dimethyl sulfoxide [0093] CDCl.sub.3 Deuterated chloroform [0094] TLC Thin-layer chromatography [0095] DMF N,N-dimethylformamide [0096] CDI N,N-carbonyldiimidazole

Embodiment 1

[0097] ##STR00030##

Step 1: Preparation of 4,5-dimethoxy-2-(methylseleno) benzaldehyde (IV-1)

[0098] 3.14 g of DTT (20.4 mmol), 2.56 g of dimethyldiselane (III, 13.6 mmol) and 50 mL of DMF were added into a 250 mL single mouth flask, and stirred for 1 h at room temperature under nitrogen protection. 5.0 g of 2-Bromo-4,5-dimethoxybenzaldehyde (IT-1) (20.4 mmol) and 7.76 g of DBU (51 mmol) were added into the reaction flask, and stirred overnight at room temperature under nitrogen protection. The reaction was monitored by TLC, and stopped after the reactant II-1 reacted completely. The reaction liquid was poured into 200 mL of ice water, and a solid was precipitated. Suction filtration was carried out, and a filter cake was washed with water and dried to obtain a light yellow solid of 4.46 g with a yield of 84%. .sup.1H NMR (300 MHz, CDCl.sub.3): =10.19 (s, 1H), 7.35 (s, 1H), 7.00 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.32 (s, 3H) ppm. HRMS (ESI.sup.+): C.sub.10H.sub.13O.sub.3Se (M+H).sup.+, 261.0024; found, 261.0021.

Step 2: Preparation of 2-((2-formyl-4,5-dimethoxyphenyl) seleno) ethyl acetate (VI-1)

[0099] 4.0 g of the compound IV-1 (15.4 mmol) and 8.5 mL of ethyl bromoacetate (77 mmol) were added into a 100 mL single mouth flask, and stirred at 170 C. for 4 h. After it was monitored by TLC that the reactant IV-1 reacted completely, the reaction was stopped. Reaction liquid was cooled to room temperature, added with 30 mL of water for dilution, and extracted twice using 50 mL of ethyl acetate. Organic layers were combined, washed with 50 mL of water, washed with 30 mL of a saturated salt solution and dried with sodium sulphate anhydrous, and underwent suction filtration, and a filtrate was vaporized under reduced pressure to remove a solvent to obtain a brown oily substance, which directly entered into the next step of the reaction without additional purification. HRMS (ESI.sup.+): C.sub.13H.sub.17O.sub.5Se (M+H).sup.+, 333.0236; found, 333.0233.

Step 3: Preparation of 5,6-dimethoxybenzo[b]selenophene-2-ethyl formate (VII-1)

[0100] The compound VI-1 obtained in the previous step was added into a 100 mL single mouth flask, and 7.6 g of potassium carbonate (55 mmol) and 25 mL of acetonitrile were added. A reflux reaction was carried out for 6 h. After it was detected by TLC that the raw materials reacted completely, heating was stopped. Reaction liquid underwent suction filtration, was vaporized under reduced pressure to remove a solvent, added with 50 mL of water, and extracted twice using 40 mL of ethyl acetate. Organic layers were combined, washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated. A crude product was purified by column chromatography using silica gel to obtain an earthy yellow solid of 3.2 g with a total yield of 46% in two steps. .sup.1H NMR (300 MHz, CDCl.sub.3): =8.17 (s, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 4.40 (q, J=7.1 Hz. 2H), 3.97 (s, 3H), 3.94 (s, 3H), 1.41 (t, J=7.1 Hz. 3H) ppm. HRMS (ESI.sup.+): calcd for C.sub.13H.sub.14O.sub.4Se (M+H).sup.+315.0130; found, 315.0124.

Step 4: Preparation of 5,6-dimethoxybenzo[b]selenophene-2-formic acid (VIII-1)

[0101] 3.2 g of the compound VII-1, 35 mL of tetrahydrofuran and 35 mL of methanol were added into a 250 mL reaction flask. A total of 15 mL of a 2 N aqueous sodium hydroxide solution was added into the reaction flask at room temperature, and the mixture underwent a stirred reaction at 60 C. for 3 h. After it was detected by TLC that the reaction was completed, reaction liquid was concentrated, pH was adjusted to 3-4 using 1 N hydrochloric acid, and a solid was precipitated. After suction filtration, a filter cake was washed with water and dried to obtain a light yellow solid of 2.9 g with a yield of 98%. .sup.1H NMR (300 MHz, CDCl.sub.3): =8.28 (s, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H) ppm. HRMS (ESI.sup.): C.sub.11H.sub.9O.sub.4Se (MH).sup., 284.9672; found, 284.9674.

Embodiment 2

[0102] ##STR00031##

Preparation of 3-(5,6-dimethoxybenzo[b]selenophene-2-yl)-3-oxo-propionic acid ethyl ester (X-1)

[0103] 2.9 g of the compound VIII-1 (10.1 mmol), 5.1 g of CDI (31.6 mmol) and 50 mL of anhydrous tetrahydrofuran were added into a 100 mL reaction flask, and stirred for 1 h at room temperature. 5.4 g of ethyl potassium malonate (31.6 mmol) and 3.0 g of magnesium chloride (31.6 mmol) were added into the above reaction liquid and continued to be stirred for 4 h at room temperature. After it was detected by TLC that the reaction was completed, the reaction liquid was added with 50 mL of water for dilution, and extracted twice using 40 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain a yellow solid of 3.0 g with a yield of 84%. .sup.1H NMR (300 MHz, CDCl.sub.3): =8.09 (s, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.98 (s, 5H), 3.94 (s, 3H), 1.30 (t, J=7.1 Hz, 3H) ppm. HRMS (ESI.sup.+): C.sub.15H.sub.17O.sub.5Se (M+H).sup.+, 357.0236; found, 357.0231.

Embodiment 3

[0104] ##STR00032##

Step 1: Preparation of 2-(5,6-dimethoxybenzo[b]selenophene-2-formyl) diethyl succinate (XII-1)

[0105] 0.17 g of the compound X-1 (0.5 mmol), 0.14 g of potassium carbonate (1 mmol) and 5 mL of DMF were added into a 100 mL reaction flask, and stirred for 30 mins at room temperature. 0.13 g of ethyl 2-bromoacetate (0.75 mmol) and 8 mg of potassium iodide (0.05 mmol) were added into the above reaction liquid, and continued to be stirred for 4 h at room temperature. After it was monitored by TLC that the reaction was completed, the reaction liquid was added with 20 mL of water and extracted twice using 20 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a yellow oily substance, which directly entered into the next step of the reaction without additional purification. HRMS (ESI.sup.+): C.sub.19H.sub.23O.sub.7Se (M+H).sup.+, 443.0604; found, 443.0600.

Step 2: Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-4-oxobutanoic acid (I-1)

[0106] The compound XII-1 obtained in the previous step, 2 mL of concentrated hydrochloric acid and 2 mL of acetic acid were added into a 100 mL reaction flask, and the mixture underwent a stirred reaction at 100 C. for 3 h. After it was monitored by TLC that the reactant XII-1 reacted completely, the reaction liquid was cooled to room temperature, added with 20 mL of water for dilution, and extracted twice using 20 mL of ethyl acetate, respectively. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain a white solid of 45 mg with a total yield of 26% in two steps. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =8.42 (s, 1H), 7.70 (s, 1H), 7.53 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.24 (sbr, 2H), 2.57 (sbr, 2H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =193.99, 174.14, 150.77, 148.81, 145.06, 137.15, 135.46, 134.61, 109.36, 108.37, 56.24, 56.01, 32.98, 28.49 ppm. HRMS (ESI.sup.): C.sub.14H.sub.13O.sub.5Se (MH).sup., 340.9934; found, 340.9933.

Embodiment 4

Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-2)

[0107] Referring to the preparation method of Embodiment 3, the compound I-2 was prepared using ethyl 2-bromopropionate instead of ethyl 2-bromoacetate by the same synthetic method. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.19 (s, 1H), 8.43 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.43-3.37 (m, 1H), 3.11-3.03 (m, 1H), 2.92-2.85 (m, 1H), 1.19 (d, J=7.1 Hz, 3H) ppm. .sup.3C NMR (75 MHz, CDCl.sub.3): =192.78, 181.10, 150.67, 148.70, 145.30, 138.00, 135.02, 133.08, 108.21, 107.02, 56.17, 56.03, 41.25, 35.18, 17.10 ppm. HRMS (ESI.sup.): C.sub.15H.sub.15O.sub.5Se (MH).sup., 355.0090; found, 355.0091.

Embodiment 5

[0108] ##STR00033##

Step 1: Preparation of (3R)-2-(5,6-dimethoxybenzo[b]selenophene-2-formoxyl)-3-diethyl methyl succinate (XII-2)

[0109] 0.17 g of the compound X-1 (0.5 mmol), 0.14 g of potassium carbonate (1 mmol) and 5 mL of DMF were added into a 100 mL reaction flask, and stirred for 30 mins at room temperature. 0.14 g of ethyl (S)-2-chloropropionate (1 mmol) was added into the above reaction liquid, and stirred overnight at 55 C. The reaction was monitored by TLC. The reaction liquid was added with 20 mL of water and extracted twice using 20 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a yellow oily substance, which directly entered into the next step of the reaction without additional purification. HRMS (ESI.sup.+): C.sub.20H.sub.25O.sub.7Se (M+H).sup.+, 457.0760; found, 457.0758.

Step 2: Preparation of R-4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-3)

[0110] The compound XII-2 obtained in the previous step, 2 mL of concentrated hydrochloric acid and 2 mL of acetic acid were added into a 100 mL reaction flask, and the mixture underwent a stirred reaction at 100 C. for 3 h. After it was monitored by TLC that the reactant XII-2 reacted completely, the reaction liquid was cooled to room temperature, added with 20 mL of water for dilution, and extracted twice using 20 mL of ethyl acetate, respectively. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a crude product. The crude product was purified by chiral preparation to obtain a light yellow solid of 15 mg with 95% ee and a total yield of 9% in two steps. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.20 (s, 1H), 8.42 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.43-3.37 (m, 1H), 3.08-3.01 (m, 1H), 2.91-2.84 (m, 1H), 1.18 (d, J=7.1 Hz, 3H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3): =191.59, 180.78, 151.88, 147.46, 145.55, 138.37, 134.62, 132.20, 108.17, 107.76, 56.19, 55.96, 41.19, 34.84 17.06 ppm. HRMS (ESI.sup.): C.sub.15H.sub.15O.sub.5Se (MH).sup., 355.0090; found, 355.0088.

Embodiment 6

Preparation of S-4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-4)

[0111] Referring to the preparation method of Embodiment 5, the compound I-4 of 19 mg was prepared from a raw material of the compound X-1 using ethyl (R)-2-chloropropionate instead of ethyl (S)-2-chloropropionate by the same synthetic method with 95% ee and a total yield of 11% in two steps. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.12 (s, 1H), 8.42 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.43-3.37 (m, 1H), 3.09-3.02 (m, 1H), 2.91-2.85 (m, 1H), 1.19 (t, J=6.9 Hz, 3H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3): =192.30, 181.22, 150.92, 147.69, 145.17, 137.61, 135.08, 133.27, 109.03, 107.21, 56.25, 56.08, 42.67, 34.44, 17.25 ppm. HRMS (ESI.sup.): C.sub.15H.sub.15O.sub.5Se (MH).sup., 355.0090; found, 355.0089.

Embodiment 7

Preparation of 4-(5-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-5)

[0112] Referring to the preparation method of Embodiments 1-3, the target compound I-5 was prepared from a starting raw material of 2-bromo-5-methoxybenzaldehyde instead of 2-bromo-4,5-dimethoxybenzaldehyde, by means of a reactant of ethyl 2-bromopropionate instead of ethyl 2-bromoacetate, and by the same synthetic method. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.22 (s, 1H), 8.51 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.13 (dd, J.sub.1=8.8 Hz, J.sub.2=2.6 Hz, 1H), 3.83 (s, 3H), 3.48-3.39 (m, 1H), 3.15-3.08 (m, 1H), 2.96-2.84 (m, 1H), 1.20 (d, J=7.2 Hz, 3H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =194.52, 175.23, 150.69, 146.38, 144.21, 138.17, 135.45, 133.80, 109.24, 107.26, 56.07, 42.31, 37.16, 17.47 ppm. HRMS (ESI.sup.): C.sub.14H.sub.13O.sub.4Se (MH).sup., 324.9985; found, 324.9981.

Embodiment 8

Preparation of 4-(6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-6)

[0113] Referring to the preparation method of Embodiments 1-3, the target compound I-6 was prepared from a starting raw material of 2-bromo-4-methoxybenzaldehyde instead of 2-bromo-4,5-dimethoxybenzaldehyde, by means of a reactant of ethyl 2-bromopropionate instead of ethyl 2-bromoacetate, and by the same synthetic method. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.19 (s, 1H), 8.50 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.09 (dd, J.sub.1=8.8 Hz, J.sub.2=2.3 Hz, 1H), 3.84 (s, 3H), 3.45-3.33 (m, 1H), 3.12-3.05 (m, 1H), 2.92-2.85 (m, 1H), 1.19 (d, J=7.2 Hz, 3H) ppm. .sup.3C NMR (75 MHz, DMSO-d.sub.6): =193.37, 173.79, 150.51, 146.26, 143.35, 138.01, 135.14, 133.06, 110.20, 106.93, 56.15, 41.29, 35.05, 17.20 ppm. HRMS (ESI.sup.): C.sub.14H.sub.13O.sub.4Se (MH).sup., 324.9985; found, 324.9984.

Embodiment 9

Preparation of 4-(5-hydroxyl-6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-7)

[0114] Referring to the preparation method of Embodiments 1-3, the target compound I-7 was prepared from a starting raw material of 2-bromo-5-hydroxyl-4-methoxybenzaldehyde instead of 2-bromo-4,5-dimethoxybenzaldehyde, by means of a reactant of ethyl 2-bromopropionate instead of ethyl 2-bromoacetate, and by the same synthetic method. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.17 (s, 1H), 9.34 (s, 1H), 8.38 (s, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 3.86 (s, 3H), 3.42-3.36 (m, 1H), 3.10-3.02 (m, 1H), 2.93-2.81 (m, 1H), 1.18 (d, J=7.2 Hz, 3H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =194.42, 174.41, 150.85, 149.87, 147.25, 136.47, 135.91, 133.23, 107.67, 107.05, 56.20, 42.29, 35.83, 18.93 ppm. HRMS (ESI.sup.): C.sub.14H.sub.13O.sub.5Se (MH).sup., 340.9934; found, 340.9932.

Embodiment 10

Preparation of 2-methyl-4-oxo-4-(selenophene[2,3:4,5]benzo[1,2-d][1,3]dioxo-6-yl)butanoic acid (I-8)

[0115] Referring to the preparation method of Embodiments 1-3, the target compound I-8 was prepared from a starting raw material of 6-bromobenzo[1,2-d][1,3]dioxole-5-formaldehyde instead of 2-bromo-4,5-dimethoxybenzaldehyde, by means of a reactant of ethyl 2-bromopropionate instead of ethyl 2-bromoacetate, and by the same synthetic method. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.21 (s, 1H), 8.43 (s, 1H), 7.67 (s, 1H), 7.49 (s, 1H), 6.14 (s, 2H), 3.43-3.36 (m, 1H), 3.10-3.03 (m, 1H), 2.94-2.82 (m, 1H), 1.19 (d, J=7.1 Hz, 3H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =193.66, 178.84, 150.75, 146.34, 144.29, 139.23, 135.11, 132.97, 109.24, 107.14, 100.42, 42.81, 34.38, 16.81 ppm. HRMS (ESI.sup.): C.sub.14H.sub.11O.sub.5Se (MH).sup., 338.9777; found, 338.9775.

Embodiment 11

Preparation of 4-(5-ethoxy-6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-9)

[0116] Referring to the preparation method of Embodiments 1-3, the target compound I-9 was prepared from a starting raw material of 2-bromo-5-ethoxy-4-methoxybenzaldehyde instead of 2-bromo-4,5-dimethoxybenzaldehyde, by means of a reactant of ethyl 2-bromopropionate instead of ethyl 2-bromoacetate, and by the same synthetic method. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.20 (s, 1H), 8.41 (s, 1H), 7.69 (s, 1H), 7.50 (s, 1H), 4.09 (q, J=6.9 Hz, 2H), 3.85 (s, 3H), 3.43-3.37 (m, 1H), 3.10-3.03 (m, 1H), 2.92-2.85 (m, 1H), 1.40 (t, J=6.9 Hz, 3H), 1.19 (d, J=7.2 Hz, 3H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =193.43, 176.68, 150.50, 147.53, 144.77, 136.75, 135.07, 134.41, 109.84, 108.01, 63.82, 55.79, 40.88, 34.85, 17.10, 14.69 ppm. HRMS (ESI.sup.): C.sub.16H.sub.17O.sub.5Se (MH).sup., 369.0247; found, 369.0244.

Embodiment 12

Preparation of 4-(5-isopropoxy-6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butanoic acid (I-10)

[0117] Referring to the preparation method of Embodiments 1-3, the target compound I-10 was prepared from a starting raw material of 2-bromo-5-isopropoxy-4-methoxybenzaldehyde instead of 2-bromo-4,5-dimethoxybenzaldehyde, by means of a reactant of ethyl 2-bromopropionate instead of ethyl 2-bromoacetate, and by the same synthetic method. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.17 (s, 1H), 8.41 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 4.61-4.53 (m, 1H), 3.84 (s, 3H), 3.42-3.34 (m, 1H), 3.10-3.02 (m, 1H), 2.92-2.85 (m, 1H), 1.31 (d, J=6.0 Hz, 6H), 1.19 (d, J=7.2 Hz, 3H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =193.87, 177.07, 151.93, 146.60, 145.18, 137.40, 135.58, 134.86, 113.04, 108.82, 71.01, 56.26, 41.32, 35.29, 22.22, 17.51 ppm. HRMS (ESI.sup.): C.sub.17H.sub.19O.sub.5Se (MH).sup., 383.0403; found, 383.0401.

Embodiment 13

[0118] ##STR00034##

Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-ethyl butyrate (I-11)

[0119] 36 mg of the compound I-2 (0.1 mmol) was dissolved in 10 mL of ethanol, and 24 mg of thionyl chloride (0.2 mmol) was dropwise added into the reaction liquid under an ice bath. The reaction liquid was heated to flux and continued to react for 4 h. After it was detected by TLC that the reaction was completed, the reaction liquid was vaporized under reduced pressure to remove a solvent, added with 10 mL of water for dilution, and extracted twice using 10 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated. A crude product was purified by column chromatography using silica gel to obtain the target compound I-11 of 34 mg with a yield of 89%. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =8.43 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.44-3.38 (m, 1H), 3.19-3.11 (m, 1H), 2.99-2.88 (m, 1H), 1.20-1.13 (m, 6H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =192.97, 176.42, 151.13, 146.92, 145.19, 137.61, 135.09, 133.78, 109.95, 107.10, 62.32, 56.12, 55.81, 42.76, 35.28, 17.27, 16.84 ppm. HRMS (ESI.sup.+): C.sub.17H.sub.21O.sub.5Se (M+H).sup.+, 385.0549; found, 385.0548.

Embodiment 14

[0120] ##STR00035##

Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-N-hydroxyl-2-methyl-4-oxo-butyramide (I-12)

[0121] 177 mg of the compound I-2 (0.5 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, 160 mg of CDI (1 mmol) was added, and the mixture was stirred for 1 h at room temperature. 69 mg of hydroxylamine hydrochloride (1 mmol) was added into the reaction liquid, and continued to be stirred overnight at room temperature. After it was detected by TLC that the reaction was completed, the reaction liquid was added with 10 mL of water for dilution, and extracted twice using 15 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated. A crude product was purified by preparative TLC to obtain the target compound I-12 of 68 mg with a yield of 37%. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =10.38 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.46-3.38 (m, 1H), 3.15-3.06 (m, 1H), 2.97-2.88 (m, 1H), 1.19 (d, J=7.2 Hz, 3H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =193.16, 175.48, 150.63, 149.07, 145.72, 137.40, 136.67, 132.81, 107.77, 107.38, 56.15, 56.01, 43.79, 36.94, 19.22 ppm. HRMS (ESI.sup.): C.sub.15H.sub.18NO.sub.5Se (MH).sup., 370.0199; found, 370.0196.

Embodiment 15

[0122] ##STR00036##

Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-methyl-4-oxo-butyramide (I-13)

[0123] 36 mg of the compound I-2 (0.1 mmol) and 15 mg of N-methylmorpholine (0.15 mmol) were dissolved in 10 mL of tetrahydrofuran, and 21 mg of isobutyl chloroformate (0.15 mmol) was dropwise added into the reaction liquid under an ice bath. After the completion of dropwise adding, the reaction liquid was heated to room temperature and stirred for reacting for 1 h. The reaction liquid was placed into an ice bath again, and 0.1 mL of aqueous ammonia was dropwise added. The reaction liquid reacted for 4 h at room temperature. After it was detected by TLC that the reaction was completed, the reaction liquid was added with 10 mL of water for dilution, and extracted twice using 15 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated. A crude product was purified by silica gel column chromatography to obtain the target compound I-13 of 27 mg with a yield of 76%. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =8.40 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 6.78 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.39-3.31 (m, 1H), 2.95-2.82 (m, 2H), 1.12 (d, J=6.8 Hz, 3H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =193.87, 176.78, 150.33, 148.36, 145.24, 136.76, 135.09, 134.24, 108.28, 107.95, 55.81, 55.59, 41.11, 35.46, 18.20 ppm. HRMS (ESI.sup.+): C.sub.15H.sub.18NO.sub.4Se (M+H).sup.+, 356.0369; found, 356.0366.

Embodiment 16

Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-ethyl-4-oxo-butanoic acid (I-14)

[0124] Referring to the preparation method of Embodiment 3, the compound I-14 was prepared from a raw material of the compound X-1 by the same synthetic method, except that ethyl 2-bromoacetate was replaced by ethyl 2-bromobutyrate. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.19 (s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.43-3.37 (m, 1H), 3.11-3.04 (m, 1H), 2.82-2.73 (m, 1H), 1.66-1.56 (m, 2H), 0.95 (t, J=7.4 Hz, 3H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3): =192.94, 180.36, 150.71, 148.75, 145.37, 138.04, 135.06, 133.04, 108.27, 107.07, 56.19, 56.05, 41.79, 39.20, 24.95, 11.50 ppm. HRMS (ESI.sup.): C.sub.16H.sub.17O.sub.5Se (MH).sup., 369.0247; found, 369.0246.

Embodiment 17

Preparation of R-4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-ethyl-4-oxo-butanoic acid (I-15)

[0125] Referring to the preparation method of Embodiment 5, the target compound I-15 with 95% ee was prepared from a raw material of the compound X-1 by the same synthetic method, except that ethyl (S)-2-chloropropionate was replaced by ethyl (S)-2-chlorobutyrate as a reactant. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.20 (s, 1H), 8.43 (s, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 3.4 (s, 3H), 3.83 (s, 3H), 3.42-3.36 (m, 1H), 3.10-3.04 (m, 1H), 2.83-2.74 (m, 1H), 1.67-1.56 (m, 2H), 0.97 (t, J=7.5 Hz, 3H) ppm. .sup.3C NMR (75 MHz, CDCl.sub.3): =193.34, 180.67, 151.50, 149.27, 144.99, 138.72, 135.18, 132.03, 108.60, 107.63, 57.23, 56.11, 41.59, 38.81, 25.39, 11.05 ppm. HRMS (ESI.sup.): C.sub.16H.sub.17O.sub.5Se (MH).sup., 369.0247; found, 369.0244.

Embodiment 18

Preparation of S-4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-ethyl-4-oxo-butanoic acid (I-16)

[0126] Referring to the preparation method of Embodiment 5, the target compound I-16 with 95% ee was prepared from a raw material of the compound X-1 by the same synthetic method, except that ethyl (S)-2-chloropropionate was replaced by ethyl (R)-2-chlorobutyrate as a reactant. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.19 (s, 1H), 8.44 (s, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.43-3.35 (m, 1H), 3.13-3.02 (m, 1H), 2.83-2.75 (m, 1H), 1.66-1.55 (m, 2H), 0.95 (t, J=7.4 Hz, 3H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3): =192.24, 181.62, 151.74, 148.57, 144.55, 137.85, 136.49, 133.13, 109.40, 107.23, 56.17, 55.99, 42.28, 39.79, 25.01, 11.84 ppm. HRMS (ESI.sup.): C.sub.16H.sub.17O.sub.5Se (MH).sup., 369.0247; found, 369.0246.

Embodiment 19

Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-isopropyl-4-oxo-butanoic acid (I-17)

[0127] Referring to the preparation method of Embodiment 3, the compound I-17 with 95% ee was prepared from a raw material of the compound X-1 by the same synthetic method, except that ethyl 2-bromoacetate was replaced by ethyl 2-bromopropionate as a reactant. .sup.1H NMR (300 MHz, CDCl.sub.3): =8.13 (s, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.52-3.43 (m, 1H), 3.06-3.00 (m, 2H), 2.17-2.11 (m, 1H), 1.05 (dd, J.sub.1=6.8 Hz, J.sub.2=2.6 Hz, 6H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =192.98, 180.89, 150.86, 149.61, 145.85, 138.32, 134.69, 132.20, 108.11, 106.90, 56.25, 56.07, 48.72, 40.68, 25.81, 22.57 ppm. HRMS (ESI.sup.): C.sub.17H.sub.19O.sub.5Se (MH).sup., 383.0403; found, 383.0401.

Embodiment 20

Preparation of 2-cyclopropyl-4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-4-oxo-butanoic acid (I-18)

[0128] Referring to the preparation method of Embodiment 3, the compound I-18 was prepared from a raw material of the compound X-1 by the same synthetic method, except that ethyl 2-bromoacetate was replaced by ethyl 2-bromo-2-cyclopropylacetate. .sup.1H NMR (300 MHz, CDCl.sub.3): =8.28 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.50-3.41 (m, 1H), 3.10-3.02 (m, 2H), 1.12-1.04 (m, 1H), 0.57-0.49 (m, 2H), 0.21-0.14 (m, 2H) ppm. .sup.3C NMR (75 MHz, DMSO-d.sub.6): =194.07, 176.11, 149.78, 147.75 146.69, 138.73, 135.03, 133.12, 107.38, 107.55, 56.10, 55.74, 47.71, 40.95, 5.10 ppm. HRMS (ESI.sup.): C.sub.17H.sub.17O.sub.5Se (M H).sup., 381.0247; found, 381.0245.

Embodiment 21

Preparation of 4-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-(methoxymethyl)-4-oxo-butanoic acid (I-19)

[0129] Referring to the preparation method of Embodiment 3, the compound I-19 was prepared from a raw material of the compound X-1 by the same synthetic method, except that ethyl 2-bromoacetate was replaced by methyl 2-bromo-3-methoxypropionate. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.34 (s, 1H), 8.44 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.60-3.56 (m, 2H), 3.46-3.37 (m, 1H), 3.25 (s, 3H), 3.14-3.07 (m, 2H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =192.87, 179.61, 150.43, 149.39, 144.87, 138.76, 134.66, 134.09, 108.16, 107.55, 80.16, 60.98, 56.30, 56.08, 39.62, 39.04 ppm. HRMS (ESI.sup.): C.sub.16H.sub.17O.sub.6Se (M H).sup., 385.0196; found, 385.0195.

Embodiment 22

Preparation of 2-(2-(5,6-dimethoxybenzo[b]selenophene-2-yl)-2-oxo-ethyl) hexanoic acid (I-20)

[0130] Referring to the preparation method of Embodiment 3, the compound I-20 was prepared from a raw material of the compound X-1 by the same synthetic method, except that ethyl 2-bromoacetate was replaced by ethyl 2-bromohexanoate. .sup.1H NMR (300 MHz, CDCl.sub.3): =8.10 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.49-3.39 (m, 1H), 3.13-3.07 (m, 2H), 1.80-1.57 (m, 2H), 1.37-1.32 (m, 4H), 0.93 (t, J=6.7 Hz, 3H) ppm. .sup.3C NMR (75 MHz, DMSO-d.sub.6): =193.85, 179.54, 150.62, 147.88, 145.47, 138.62, 136.00, 132.97, 108.83, 107.06, 56.24, 56.05, 43.93, 42.73, 35.03, 30.10, 24.75, 14.48 ppm. HRMS (ESI.sup.): C.sub.18H.sub.21O.sub.5Se (MH).sup., 397.0560; found, 397.0558.

Embodiment 23

[0131] ##STR00037##

Step 1: Preparation of 2-(5,6-dimethoxybenzo[b]selenophene-2-formyl) diethyl glutarate (XII-3)

[0132] 0.17 g of the compound X-1 (0.5 mmol), 0.14 g of potassium carbonate (1 mmol) and 5 mL of DMF were added into a 100 mL reaction flask, and stirred for 30 mins at room temperature. 0.14 g of ethyl 3-bromopropionate (0.75 mmol) and 8 mg of potassium iodide (0.05 mmol) were added into the above reaction liquid, and the mixture underwent a stirred reaction at 55 C. for 8 h. After it was monitored by TLC that the reaction was completed, the reaction liquid was added with 20 mL of water and extracted twice using 20 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a yellow oily substance, which directly entered into the next step of the reaction without additional purification. HRMS (ESI.sup.+): C.sub.20H.sub.25O.sub.7Se (M+H).sup.+, 457.0760; found, 457.0757

Step 2: Preparation of 5-(5,6-dimethoxybenzo[b]selenophene-2-yl)-5-oxo-pentanoic acid (I-21)

[0133] The compound XII-3 obtained in the previous step, 2 mL of concentrated hydrochloric acid and 2 mL of acetic acid were added into a 100 mL reaction flask, and the mixture was stirred for reacting at 100 C. for 3 h. After it was monitored by TLC that the reactant XII-3 reacted completely, the reaction liquid was cooled to room temperature, added with 20 mL of water for dilution, and extracted twice using 20 mL of ethyl acetate, respectively. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain a white solid of 65 mg with a total yield of 37% in two steps. H NMR (300 MHz, DMSO-d.sub.6): =12.01 (s, 1H), 8.38 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.07 (t, J=7.4 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.88 (t, J=7.1 Hz, 2H) ppm. .sup.13C NMR (75 MHz, DMSO-d.sub.6): =193.29, 178.96, 150.56, 148.61, 146.46, 137.80, 136.19, 134.02, 109.54, 108.49, 56.25, 55.98, 42.97, 31.17, 18.41 ppm. HRMS (ESI.sup.): C.sub.15H.sub.15O.sub.5Se (MH).sup., 355.0090; found, 355.0088.

Embodiment 24

[0134] ##STR00038##

Preparation of 5,6-dimethoxybenzo[b]selenopheneformic acid (XIII-1)

[0135] 0.86 g of the compound VIII-1 (3 mmol), 0.96 g of 200-mesh copper powder (15 mmol) and 12 mL of quinoline were added into a 100 mL reaction flask, and underwent a reflux reaction for 4 h. After it was monitored by TLC that the reaction was completed, suction filtration was carried out, a filtrate was taken to be added with 20 mL of 6 N hydrochloric acid, stirred for 10 mins at room temperature, and extracted twice using 30 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain the compound, i.e. a white solid of 0.59 g, the yield being 81%. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =7.54 (s, 1H), 7.52 (d, J=5.3 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J=5.3 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H) ppm.

Embodiment 25

[0136] ##STR00039##

Preparation of 2-(5,6-dimethoxybenzo[b]selenophene-2-formyl)) cyclopropane-1-formic acid (I-22)

[0137] 0.24 g of the compound (1 mmol), 0.28 g of 3-oxabicyclo[3.1.0]hexane-2,4-dione (2.5 mmol) and 5 mL of dichloromethane were added into a 100 mL reaction flask, and stirred at 0 C. for 1 h. 0.2 g of aluminum trichloride (1.5 mmol) was added into the reaction liquid, and stirred overnight at room temperature. After it was monitored by TLC that the reaction was completed, the reaction liquid was added with 10 mL of 1 N hydrochloric acid and extracted twice using 20 mL of ethyl acetate. After being combined, organic layers were washed with water, washed with a saturated salt solution and dried with sodium sulphate anhydrous, underwent suction filtration, and were concentrated to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain the compound I-22, i.e. a light yellow solid of 102 mg, the yield being 29%. 1H NMR (300 MHz, DMSO-d.sub.6): =12.24 (s, 1H), 8.45 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.07 (q, J=8.4 Hz, 1H), 2.30 (q, J=8.0 Hz, 1H), 2.17-2.01 (m, 1H), 1.56-1.50 (m, 1H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3): =194.01, 176.93, 150.61, 147.58, 145.89, 138.82, 135.66, 131.91, 108.20, 107.44, 56.30, 56.11, 27.92, 19.82, 11.53 ppm. HRMS (ESI.sup.): C.sub.15H.sub.13O.sub.5Se (MH).sup., 352.9934; found, 352.9931.

Embodiment 26

Preparation of 2-(5,6-dimethoxybenzo[b]selenophene-2-formyl) cyclopropane-1-formic acid (I-23)

[0138] Referring to the preparation method of Embodiment 25, the target compound I-23, i.e. a light yellow solid of 58 mg, was prepared from a raw material of the compound XIII-1 by the same synthetic method, except that 3-oxabicyclo[3.1.0]hexane-2,4-dione was replaced by cyclobutane-1,4-dicarboxylic anhydride as a reactant, the yield being 32%. .sup.1H NMR (300 MHz, CDCl.sub.3): =7.92 (s, 1H), 7.31 (s, 1H), 4.32-4.24 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.58-3.50 (m, 1H), 2.54-2.44 (m, 2H), 2.41-2.26 (m, 2H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3): =193.91, 177.88, 150.59, 148.67, 144.65, 138.01, 135.06, 132.57, 108.26, 107.07, 56.19, 56.04, 44.40, 40.79, 23.13, 22.27 ppm. HRMS (ESI.sup.): C.sub.16H.sub.15O.sub.5Se (MH).sup., 367.0090; found, 367.0089.

Embodiment 27

Preparation of 2-(5,6-dimethoxybenzo[b]selenophene-2-formyl) cyclopropane-1-formic acid (I-24)

[0139] Referring to the preparation method of Embodiment 25, the target compound I-24, i.e. a light yellow solid of 37 mg, was prepared from a raw material of the compound XIII-1 by the same synthetic method, except that 3-oxabicyclo[3.1.0]hexane-2,4-dione was replaced by 1,2-cyclohexanedicarboxylic anhydride as a reactant, the yield being 19%. .sup.1H NMR (300 MHz, DMSO-d.sub.6): =12.20 (s, 1H), 8.44 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 2.66-2.60 (m, 1H), 2.58-2.53 (m, 1H), 1.85-1.56 (m, 4H), 1.49-1.30 (m, 4H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3): =193.76, 176.12, 150.56, 148.95, 145.01, 137.94, 135.13, 132.29, 109.16, 107.13, 56.24, 56.06, 48.22, 42.50, 26.26, 26.07, 25.87, 23.71 ppm.

[0140] HRMS (ESI.sup.): C.sub.18H.sub.19O.sub.5Se (MH).sup., 395.0403; found, 395.0400.

[0141] Embodiment 28 Luciferase assay based on THP1-Lucia and RAW-Lucia THP1-dual (Invivogen: thpd-nfis) cells or RAW-Lucia (Invivogen: rawl-isg) cells were diluted using a culture medium, and 180 L of cell suspension was sucked and inoculated in a 96-well plate, such that each well contain 110.sup.5 cells. 20 L of a compound to be tested was added into the 96-well plate (the final concentration of said compound was 10 L, and the final volume of each well was 200 L) and cultured at 37 C. for 24 h. 10 L of supernatant was sucked into a new 96-well white plate, and 50 L of a QUANT-Luc reagent was added. After full and even mixing, a microplate reader was used immediately for determination. There were three repeated wells set in the assay. The test result was represented as agitation fold and calculated by (test wellblank well)/(negative wellblank well). The test result was in the following tablet, with 2,3-cGAMP as a positive control, where *** represented an agitation fold of 20 or more, ** represented an agitation fold of 10 to 20, and * represented an agitation fold of 1 to 10.

TABLE-US-00002 TABLE 1 Agitation activity of representative compounds of present invention in luciferase assay Code THP1-dual RAW-Lucia I-1 *** *** I-2 *** *** I-3 *** *** I-4 *** *** I-5 * * I-6 * * I-7 ** * I-8 * * I-9 ** ** I-10 ** ** I-11 * ** I-12 * * I-13 * * I-14 *** *** I-15 *** *** I-16 *** *** I-17 *** ** I-18 *** ** I-19 ** ** I-20 ** ** I-21 * * I-22 ** ** I-23 *** *** I-24 ** **

[0142] As can be seen from Table 1, the compounds of the present invention have good agitation activity on a cGAS-STING pathway.

Embodiment 29 Interferon Induction Assay Based on THP1 Cells

[0143] Secreted cytokine IFN was determined by ELISA. THP1 cells were inoculated in a 96-well plate (there was no serum contained in an RPMI 1640 medium), such that the number of cells in each well ranged from 510.sup.5 to 710.sup.5. A DMSO stock solution of 10 mM was prepared from a compound to be tested, diluted with a culture medium to a target concentration to be added into the 96-well plate containing cells (the final concentration of said compound was 20 M, and the final volume of each well was 200 L), and cultured at 37 C. in 5% CO.sub.2 for 3.5 h. The cells were collected at 4 C. and centrifuged at 1,000 rpm for 20 mins, and supernate was collected for ELISA determination. There were three repeated wells set in the assay. The result was shown in the following tablet, with 2,3-cGAMP as a positive control, where the test result was represented as a percentage of activity relative to 2,3-cGAMP at a concentration of 20 M.

TABLE-US-00003 TABLE 2 Secretion of IFN in THP1 cells induced by part of compounds of present invention Effect relative to Code 2,3-cGAMP at 20 M (%) I-1 259 I-2 245 I-3 234 I-4 201 I-5 59 I-6 15 I-7 75 I-8 20 I-9 96 I-10 91 I-11 9 I-12 11 I-13 6 I-14 260 I-15 2 I-16 281 I-17 293 I-18 277 I-19 107 I-20 132 I-21 12 I-22 115 I-23 273 I-24 142

[0144] As can be seen from Table 2, part of the compounds of the present invention have good activity on inducing THP1 to secrete IFN.

Embodiment 30 Evaluation on ADMET Properties of Part of Compounds of Present Invention

[0145] The ADMET properties of part of preferable compounds were evaluated in this embodiment, and included water solubility, LogP, stability of rat liver microsome within 2 h, stability of human plasma within 24 h, THP1 cell growth inhibition activity and prediction of membrane permeation. The test result was shown in the following table, with MSA2 (Science. 2020, 369, eaba6098) as a reference compound.

TABLE-US-00004 TABLE 3 ADMET properties of part of compounds of present invention water solubility RLM hPlasma THP1 Predict Water PBS @ 2 h @ 24 h IC.sub.50 Mem. Perm. Code (ug/mL) (mg/mL) LogP (%) (%) (uM) (10.sup.6) I-1 36 1.9 2.5 >90 >90 >100 6.8 I-2 30 1.0 2.4 >90 >90 >100 5.9 I-14 28 0.7 2.7 >90 >90 >100 5.3 MSA2 6 0.4 1.5 >90 >90 >100 5.0

[0146] As can be seen from Table 3, the representative compounds of the present invention have good ADMET properties.