Compound, pharmaceutical composition and application thereof in treating diseases caused by monkey pox virus

Abstract

The invention discloses a compound, a pharmaceutical composition and application of the compound to treatment of diseases caused by monkey pox virus. The compound comprises a structure shown in a formula (I) or a formula (II): # imgabs0 # imgabs1 #. The compound has good anti-monkey pox virus activity, and a new medicine is provided for prevention and treatment of diseases related to monkey pox virus infection.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a compound, a pharmaceutical composition and its application in treating diseases caused by monkeypox virus. Background Art

[0002] Prevention and treatment of monkeypox virus infection include: (1) Vaccines: Since monkeypox virus and smallpox virus belong to the same genus, vaccination with smallpox can provide a certain degree of cross-protection; monkeypox-specific vaccines are currently under development. (2) Antiviral drugs: Cidofovir, Tecovirimat, and other drugs approved for the treatment of smallpox are considered effective in treating monkeypox and have been approved for use in the United States in some cases to treat monkeypox patients. Among them, Tecovirimat is the first choice drug for the treatment of poxvirus (smallpox). It is an envelope phospholipase inhibitor that mainly inhibits the viral protein p37, which is involved in the final step of viral maturation, thereby reducing the production of extracellular virus. Tecovirimat does not inhibit DNA or protein synthesis, nor does it inhibit the formation of mature virus. The mature virus remains in the host cell until the cell lyses. Summary of the Invention

[0003] To overcome the deficiency of the existing technology in the treatment of monkeypox virus, the present application provides a compound, a pharmaceutical composition and its use in treating diseases caused by monkeypox virus.

[0004] This application adopts the following technical solutions:

[0005] The first aspect of the present application discloses a compound or a pharmaceutically acceptable salt thereof, characterized in that the compound comprises a structure represented by formula (I) or formula (II): wherein R1 is selected from: X is selected from: -NH-, -CO-; Y is selected from: -CO-, -SO2-, Z is selected from: -NH-; L is selected from: -(C0-C6 alkylene)-; R2 is selected from: unsubstituted or substituted bridged ring group, unsubstituted or substituted phenyl group.

[0006] In one implementation of the present application, R1 is selected from:

[0007] In one implementation of the present application, R1 is

[0008] In one implementation of the present application, L is selected from: a single bond, -CH2-,

[0009] In one implementation of the present application, L is a single bond, the substituted bridged ring group is selected from one of monosubstituted, disubstituted, and trisubstituted, and the substituted phenyl group is selected from one of monosubstituted, disubstituted, and trisubstituted.

[0010] In one implementation of the present application, the bridge ring group is selected from: adamantyl group.

[0011] In one implementation of the present application, the substituent of the substituted phenyl group is selected from the group consisting of: alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro, and cyano.

[0012] In one implementation of the present application, Y is

[0013] In one implementation of the present application, at least one of the following compounds A1 to A49 is included:

[0014]

[0015] Another aspect of the present application provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0016] Another aspect of the present application provides an application of the above-mentioned compound or its pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases caused by monkeypox virus.

[0017] The beneficial effects of this application are:

[0018] The compound of the present application has good anti-monkeypox virus activity and provides a new drug for the prevention and treatment of diseases related to monkeypox virus infection. DETAILED DESCRIPTION

[0019] The present application is further described in detail below through specific embodiments. In the following embodiments, many detailed descriptions are provided to enable the present application to be better understood. However, those skilled in the art will readily appreciate that some of the features may be omitted under different circumstances, or may be replaced by other materials or methods. In some cases, some operations related to the present application are not shown or described in the specification. This is to avoid overwhelm the core of the present application with excessive descriptions, and for those skilled in the art, it is not necessary to describe these related operations in detail. The related operations can be fully understood based on the description in the specification and the general technical knowledge in the art.

[0020] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate manner to form various embodiments. At the same time, the steps or actions in the method description can also be interchanged or adjusted in a manner that is obvious to those skilled in the art. Therefore, the various orders of the specification are only for the purpose of clearly describing a certain embodiment and are not meant to be a necessary order, unless otherwise specified, in which an order must be followed. Unless otherwise defined, all scientific and technical terms used in this application have the same meaning as those commonly understood by those skilled in the art in the field of technology to which this application relates.

[0021] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain an unsaturated bond, and the hydrocarbon chain radical is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. In this application, C0 alkyl refers to H (hydrogen), i.e., C 0-10 Alkyl (or C0-C 10 Alkyl) includes H and C 1-10 Alkyl (or C1-C 10 alkyl).

[0022] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule, which can be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In this application, a C0 alkylene group refers to a single bond, i.e., C 0-10 Alkylene (or C0-C 10 Alkylene) includes single bonds and C 1-10 Alkylene (or C1-C 10 alkylene).

[0023] The term "halo" refers to a halogen (such as fluorine, chlorine, bromine or iodine) attached to a carbon atom of an organic molecule through a single bond, for example, chloro (-Cl), fluoro (-F), bromo (-Br), iodo (-I).

[0024] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0025] The term "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2-CH2-CF3, -CH2-CH2-CH2-CF3.

[0026] The term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group are replaced by a halogen atom (eg, fluorine, chlorine, bromine, or iodine), for example, -OCHF2, -OCF3, or -CH2-OCF3.

[0027] The term "cyano" refers to a functional group consisting of a carbon atom and a nitrogen atom connected by a triple bond, with the chemical formula -CN.

[0028] The term "nitro" refers to a group consisting of a nitrogen atom covalently bonded to two oxygen atoms, which is in turn single-bonded to the rest of the molecule, with the chemical formula -NO2.

[0029] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0030] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that may be substituted on more than one carbon atom. In this case, all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0031] The term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0032] The term "prodrug" refers to a form of a compound of Formula I that is suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc., and is effective for its intended use, including acetal, ester, and zwitterion forms. The prodrug is transformed in vivo, for example, by hydrolysis in the blood, to yield the parent compound.

[0033] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0034] The term "prevent" or "prevent" refers to treating a disease before it occurs to avoid, minimize, or make the onset or development of the disease more difficult.

[0035] Currently, there are no anti-monkeypox virus drugs in the existing technology. Therefore, it is necessary to develop drugs to treat monkeypox virus infection and establish a strategic drug reserve to respond to emerging infectious diseases more promptly and effectively, and to prevent poxviruses from seriously impacting national public health security. In this application, through structural modification and optimization research on Tecovirimat, a compound with excellent anti-monkeypox virus activity was synthesized, which has excellent application prospects and research value.

[0036] The present invention is further described in detail below by means of specific examples. The following examples are only provided to further illustrate the present invention and should not be construed as limiting the present invention. In the present examples, unless otherwise specified, the reagents and instruments used are all commercially available, and the experimental procedures are all carried out in accordance with the product specifications and conventional experimental specifications.

[0037] Example 1: (3aR,4R,4aR,5aS,6S,6aS)-2-amino-4,4a,5,5a,6,6a-hexahydro-4,6-cyclopropyl[f]isoindole-1,3(2H,3aH)-dione (H-3)

[0038]

[0039] Cycloheptatriene solution (5.60 g, 54.26 mm), maleic anhydride (6.13 g, 62.40 mm) and xylene (35 mL) were added to a 100 mL single-necked bottle, heated to 140 ° C and refluxed for 12 h under nitrogen protection, then stopped heating, cooled to 0 ° C, and filtered to obtain 6.47 g of compound H-1 (white solid, yield 56%). 1 HNMR(600MHz,Chloroform-d)δ5.90-5.88(m,2H),3.47-3.46(m,2H),3.26-3.25(m,2H),1.13-1.11(m,2H),0.35(q,J=7.3Hz,1H),0.27-0.25(m,1H).

[0040] Compound H-1 (4.0 g, 21.05 mmol), tert-butyl carbazate (3.06 g, 23.16 mmol) and anhydrous ethanol (35 ml) were added to a 100 mL single-necked bottle and heated to 80 ° C. under nitrogen protection and refluxed for 12 h. The heating was stopped, and the reaction solution was concentrated under reduced pressure and filtered to obtain 4.35 g of compound H-2 (white solid, yield 68%), which was directly used in the next reaction. 1HNMR(600MHz,Chloroform-d)δ6.51-6.40(m,1H),5.76-5.75(m,2H),3.40(s,2H), 3.02(s,2H),1.43(s,9H),1.09-1.08(m,2H),0.28-0.24(m,1H),0.21-0.19(m,1H).

[0041] 2.0 g of compound H-2 was dissolved in 15 mL of dioxane hydrochloride solution and stirred at room temperature for 4 hours. The reaction was stopped and the reaction solution was concentrated under reduced pressure and filtered to obtain compound H-3, which was directly used in the next reaction.

[0042] Example 2: N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-thienylcyclopropyl[f]isoindol-2(1H)-yl]-4-(trifluoromethoxy)benzenesulfonamide (A1)

[0043]

[0044] Compound 4-(trifluoromethoxy)benzenesulfonyl chloride (0.3 g, 1.15 mmol) and dichloromethane (2 mL) were added to a 25 mL single-necked bottle. After cooling to 0°C, 80% hydrazine hydrate (70 mg, 1.38 mmol) was slowly added dropwise. After the reaction was completed after 2 h, water was added to the reaction solution to precipitate a solid, which was filtered and dried to obtain 0.22 g of compound H-4 (white solid, yield 75%), which was directly used in the next reaction.

[0045] Compound H-4 (0.22 g, 0.85 mmol), H-1 (0.16 g, 0.85 mmol), and anhydrous ethanol (5 mL) were added to a 25 mL single-necked flask. The mixture was heated to 80°C under reflux for 12 h under nitrogen. The mixture was then cooled to room temperature and the organic solvent was removed by rotary evaporation. Column chromatography afforded 0.20 g of compound A1 (white solid, 56% yield). 1 HNMR (600MHz, CDCl3): δ (ppm) 8.00-7.97 (m, 2H), 7.49-7.33 (m, 3H), 5.76-5.73 (m, 2H), 3.3 9-3.38(m,2H),3.04-3.03(m,2H),1.10-1.09(m,2H),0.31-0.28(m,1H),0.22-0.18(m,1H). 13C NMR (150MHz, CDCl3): δ (ppm) 174.17, 153.07, 136.68, 130.58, 127.84, 120.51, 43.44, 33.38, 9.48, 4.29.

[0046] Example 3: N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-thienylcyclopropyl[f]isoindol-2(1H)-yl]-4-methylbenzenesulfonamide (A2)

[0047]

[0048] According to the method described in Example 2, p-toluenesulfonyl chloride was used as the starting material to synthesize 0.22 g of compound A2 as a white solid, with a total yield of 40% over two steps. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.78 (d, J = 8.2Hz, 2H), 7.30 (d, J = 8.0Hz, 2H), 7.18 (brs, 1H), 5.72 (t, J = 4.4Hz ,2H),3.36(s,2H),3.01(s,2H),2.43(s,3H),1.08-1.01(m,2H),0.26(q,J=7.3Hz,1H),0.20-0.18(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.05, 145.25, 135.22, 129.56, 128.37, 127.81, 43.41, 33.31, 21.75, 9.48, 4.26.

[0049] Example 4: 4-Chloro-N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]benzenesulfonamide (A3)

[0050]

[0051] According to the method described in Example 2, 0.25 g of compound A3 as a white solid was synthesized using p-chlorobenzenesulfonyl chloride as the starting material. The total yield of the two steps was 43%. 1H NMR (600MHz, CDCl3): δ (ppm) 7.85 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.27 (brs, 1H), 5.75-5.73 (m,2H),3.38-3.37(s,2H),3.02(s,2H),1.10-1.09(s,2H),0.26(q,J=7.3Hz,1H),0.21-0.19(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.06, 140.67, 136.90, 129.75, 129.26, 127.84, 43.43, 33.36, 9.48, 4.29.

[0052] Example 5: 4-Cyano-N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]benzenesulfonamide (A4)

[0053]

[0054] According to the method described in Example 2, 0.22 g of compound A4 was synthesized as a white solid using p-cyanobenzenesulfonyl chloride as the starting material. The total yield of the two steps was 41%. 1 H NMR (600MHz, CDCl3): δ (ppm) 8.05 (d, J = 8.5Hz, 2H), 7.82 (d, J = 8.5Hz, 2H), 7.30 (brs, 1H), 5.77-5. 74(m,2H),3.39(s,2H),3.04(s,2H),1.11-1.10(s,2H),0.31(q,J=7.3Hz,1H),0.22-0.20(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 173.99, 142.82, 132.69, 128.81, 127.87, 127.68, 117.55, 117.17, 43.44, 33.40, 9.46, 4.31.

[0055] Example 6: (N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-thienylcyclopropyl[f]isoindol-2(1H)-yl]-4-trifluoromethylbenzenesulfonamide (A5)

[0056]

[0057] According to the method described in Example 2, 0.24 g of compound A5 was synthesized as a white solid using p-trifluoromethylbenzenesulfonyl chloride as the starting material. The total yield of the two steps was 42%. 1 HNMR (600MHz, CDCl3): δ (ppm) 8.07-8.05 (m, 2H), 7.79-7.78 (m, 2H), 7.37 (brs, 1H), 5.75- 5.74(m,2H),3.38(s,2H),3.03(s,2H),1.10(s,2H),0.31-0.25(m,1H),0.22-0.18(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.11, 142.24, 135.30, 128.76, 127.85, 126.07, 126.06, 43.45, 33.39, 9.47, 4.29.

[0058] Example 7: N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]-4-fluorobenzenesulfonamide (A6)

[0059]

[0060] According to the method described in Example 2, 0.18 g of compound A6 was synthesized as a white solid using p-fluorobenzenesulfonyl chloride as the starting material. The total yield of the two steps was 38%. 1 HNMR (600MHz, CDCl3): δ (ppm) 7.96-7.93 (m, 2H), 7.20 (t, J=8.5Hz, 2H), 7.06 (brs, 1H), 5.74 (t, J= 8.5Hz,2H),3.38(s,2H),3.02(s,2H),1.10-1.09(s,2H),0.29(q,J=5.9Hz,1H),0.22-0.19(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 173.96, 131.29, 131.23, 127.85, 116.37, 43.43, 33.35, 9.48, 4.30.

[0061] Example 8: 3-Chloro-N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]-4-fluorobenzenesulfonamide (A7)

[0062]

[0063] According to the method described in Example 2, 0.18 g of compound A7 was synthesized as a white solid using 3-chloro-4-fluorobenzenesulfonyl chloride as starting material. The total yield for the two steps was 38%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.99-7.98 (m, 1H), 7.86-7.83 (m, 1H), 7.31-7.26 (m, 1H), 7.23 (brs, 1H), 5.79- 5.77m,2H),3.40-3.39(m,2H),3.04-3.02(m,2H),1.11-1.10(m,2H),0.32-0.28(m,1H),0.23-0.21(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.00, 135.37, 135.34, 131.42, 128.94, 128.88, 127.85, 122.25, 122.13, 117.47, 117.32, 43.46, 33.39, 9.49, 4.31.

[0064] Example 9: N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]-3,4,5-trifluorobenzenesulfonamide (A8)

[0065]

[0066] According to the method described in Example 2, 0.12 g of compound A8 was synthesized as a white solid using 3,4,5-trifluorobenzenesulfonyl chloride as the starting material, with a total yield of 28% over two steps. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.60 (t, J = 6.2Hz, 2H), 7.46 (brs, 1H), 5.80-5.78 (m, 2H), 3.40- 3.39(m,2H),3.06-3.05(m,2H),1.12-1.11(m,2H),0.31(q,J=7.4Hz,1H),0.23-0.21(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.15, 151.79, 150.09, 144.42, 142.68, 134.57, 113.70, 43.49, 33.43, 9.49, 4.31.

[0067] Example 10: N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]-3,4-difluorobenzenesulfonamide (A9)

[0068]

[0069] According to the method described in Example 2, 0.15 g of compound A9 was synthesized as a white solid using 3,4-difluorobenzenesulfonyl chloride as the starting material, with a total yield of 30% over two steps. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.79-7.76 (m, 1H), 7.74-7.71 (m, 1H), 5.78-5.76 (m, 2H), 3.40 -3.39(m,2H),3.04-3.03(m,2H),1.12-1.09(m,2H),0.32-0.29(m,1H),0.23-0.20(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 173.96, 154.88, 153.16, 127.87, 125.62, 118.19, 118.07, 43.45, 33.38, 9.48, 4.32.

[0070] Example 11: 3,4-dichloro-N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]benzenesulfonamide (A10)

[0071]

[0072] According to the method described in Example 2, 0.18 g of compound A10 as a white solid was synthesized using 3,4-dichlorobenzenesulfonyl chloride as the starting material, with a total yield of 31% over two steps. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.98-7.97 (m, 1H), 7.78-7.76 (m, 1H), 5.79-5.77 (m, 2H), 3.39 -3.38(m,2H),3.04-3.03(m,2H),1.11-1.10(m,2H),0.31-0.28(m,1H),0.23-0.20(m,1H). 13C NMR (150MHz, CDCl3): δ (ppm) 174.25, 138.66, 138.25, 133.37, 131.09, 130.23, 127.83, 127.29, 43.48, 33.41, 9.50, 4.29.

[0073] Example 12: N-[(3Ar,4R4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl)-4-nitrobenzenesulfonamide (A11)

[0074]

[0075] According to the method described in Example 2, 0.12 g of compound A11 as a white solid was synthesized using p-nitrobenzenesulfonyl chloride as the starting material. The total yield for the two steps was 24%. 1 H NMR (600MHz, CDCl3): δ (ppm) 8.38-8.36 (m, 1H), 8.13-8.11 (m, 1H), 7.38 (brs, 1H), 5.78-5.76 (m, 2 H),3.40-3.39(m,2H),3.05-3.04(m,2H),1.11-1.10(m,2H),0.33-0.29(m,1H),0.23-0.21(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.01, 150.73, 144.41, 129.54, 127.88, 124.12, 43.45, 33.41, 9.46, 4.32.

[0076] Example 13: N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]-cyclohexanesulfonamide (A12)

[0077]

[0078] According to the method described in Example 2, 80 mg of compound A12 was synthesized as a white solid using cyclohexanesulfonyl chloride as the starting material. The total yield of the two steps was 10%. 1H NMR (600MHz, CDCl3): δ (ppm) 6.48 (brs, 1H), 5.79-5.76 (m, 2H), 3.43-3.44 (m, 2H), 3.07-3.06 (m, 2H), 2.32-2.30 (m, 2H), 1.92- 1.89(m,2H),1.72-1.71(m,1H),1.60-1.53(m,2H),1.35-1.17(m,4H),1.12-1.11(m,2H),0.32-0.28(m,1H),0.24-0.22(m,1H). 13 CNMR (150MHz, CDCl3): δ (ppm) 174.58, 127.80, 63.29, 43.49, 33.41, 25.89, 25.09, 25.05, 9.54, 4.32.

[0079] Example 14: N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]pyridine-3-sulfonamide (A13)

[0080]

[0081] According to the method described in Example 2, 90 mg of compound A13 as a white solid was synthesized using pyridine-3-sulfonyl chloride as starting material. The total yield for the two steps was 13%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 11.11 (brs, 1H), 8.91-8.90 (m, 1H), 8.84-8.83 (m, 1H), 8.16-8.15 (m, 1H) ,7.64-7.62(m,1H),5.70-5.69(m,2H),3.16(s,2H),3.06(s,2H),0.23-0.20(m,1H),0.01-0.00(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 174.78, 154.15, 148.24, 136.95, 135.92, 127.93, 124.46, 43.20, 33.31, 9.50, 4.26.

[0082] Example 15: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-4-fluoro-3-(trifluoromethyl)benzenesulfonamide (A14)

[0083]

[0084] According to the method described in Example 2, 101 mg of compound A14 as a white solid was synthesized using 4-fluoro-3-(trifluoromethyl)benzenesulfonyl chloride as the starting material. The total yield for the two steps was 18%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 11.48 (brs, 1H), 8.16-8.10 (m, 2H), 7.78 (t, J = 9.6Hz, 1H), 5.69 -5.68(m,2H),3.16(s,2H),3.06(s,2H),1.11(s,2H),0.23-0.20(m,1H),0.008-0.005(m,1H).

[0085] Example 16: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-3-(trifluoromethyl)benzenesulfonamide (A15)

[0086]

[0087] According to the method described in Example 2, 105 mg of compound A15 as a white solid was synthesized using 3-(trifluoromethyl)benzenesulfonyl chloride as the starting material. The total yield for the two steps was 19%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 11.10 (brs, 1H), 8.09-8.08 (m, 3H), 7.86-7.83 (m, 1H), 5. 69(m,2H),3.16(s,2H),3.06(s,2H),1.11(s,2H),0.26-0.21(m,1H),0.05--0.00(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 174.78, 141.76, 131.96, 131.02, 130.50, 130.48, 127.78, 124.53, 124.50, 43.18, 33.31, 26.80, 9.48, 4.23.

[0088] Example 17: 1-[(3S,5S,7S)-adamantan-1-yl]-3-[(3aR,4R,4aR,5As,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]urea (A16)

[0089]

[0090] Compound H-3 (0.2 g, 0.98 mmol), DIPEA (0.19 g, 1.47 mmol) and tetrahydrofuran (5 mL) were added to a 25 mL single-necked flask, and a 2 mL tetrahydrofuran solution of N,N'-carbonyldiimidazole (0.19 g, 1.17 mmol) was slowly added dropwise at room temperature. The reaction was complete after 2 h and the mixture was directly used for the next reaction.

[0091] Triethylamine (0.15 g, 1.47 mmol) and adamantane-1-amine (0.15 g, 0.98 mmol) were added to the reaction mixture in the previous step, and the mixture was heated to 80°C and refluxed for 12 h. The heating was stopped, and the mixture was cooled to room temperature. The organic solvent was removed by rotary evaporation, and 145 mg of compound A16 was obtained by column chromatography (white solid, 35% yield). 1 HNMR (600MHz, DMSO-d6): δ (ppm) 8.02 (brs, 1H), 5.87 (brs, 1H), 5.75-5.70 (m, 2H), 3.22 (s, 2H), 3.06 (s, 2H), 1.99(s,3H),1.84-1.83(s,6H),1.62-1.57(m,6H),1.14-1.13(m,2H),0.24-0.22(m,1H),0.03-0.01(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 174.58, 127.80, 63.29, 43.49, 33.41, 25.89, 25.09, 25.05, 9.54, 4.32.

[0092] Example 18: (3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-N-[4-(trifluoromethoxy)phenyl]-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindole-2(1H)-carboxamide (A17)

[0093]

[0094] Compound H-1 (0.2 g, 1.05 mmol), 1-[4-(trifluoromethoxy)phenyl]urea (0.23 g, 1.05 mmol) and anhydrous ethanol (5 mL) were added to a 25 mL single-necked bottle, heated to 80 ° C and refluxed for 12 h under nitrogen protection. The heating was stopped and the organic solvent was removed by rotary evaporation. 53 mg of compound A17 (white solid, yield 13%) was obtained by column chromatography. 1HNMR (600MHz, CDCl3): δ (ppm) 7.28-7.23 (m, 1H), 5.87-5.84 (m, 2H), 3.50-3.49 (m ,2H),3.16-3.14(m,2H),1.16-1.15(m,2H),0.35-0.32(m,1H),0.29-0.27(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.38, 148.70, 130.26, 127.93, 127.85, 121.54, 45.32, 33.85, 9.88, 4.70.

[0095] Example 19: (3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-N-[4-(trifluoromethyl)phenyl]-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindole-2(1H)-carboxamide (A18)

[0096]

[0097] According to the method described in Example 18, 47 mg of compound A18 as a white solid was synthesized using 1-[4-(trifluoromethyl)phenyl]urea as starting material, with a yield of 12%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.69 (d, J = 8.5Hz, 2H), 7.35 (d, J = 8.4Hz, 2H), 5.87-5.86 (m, 2H), 3 .51-3.40(m,2H),3.17-3.16(m,2H),1.17-1.16(m,2H),0.36-0.33(m,1H),0.30-0.28(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 177.17, 134.93, 130.32, 127.87, 126.73, 126.16, 126.13, 45.37, 33.87, 9.88, 4.73.

[0098] Example 20: (3aR,4R,4aR,5aS,6S,6aS)-N-(4-chlorophenyl)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindole-2(1H)-carboxamide (A19)

[0099]

[0100] According to the method described in Example 18, 47 mg of compound N106 as a white solid was synthesized using 1-[4-chlorophenyl]urea as starting material, with a yield of 11%. 1 HNMR (600MHz, CDCl3): δ (ppm) 7.39 (d, J = 8.2Hz, 2H), 7.13 (d, J = 8.3Hz, 2H), 5.85 (s, 2H ),3.49(s,2H),3.14(s,2H),1.50-1.49(m,2H),0.35-0.31(m,1H),0.28-0.27(m,1H). 13 C NMR (150MHz, CDCl3): δ (ppm) 177.40, 134.32, 130.29, 129.26, 129.12, 127.83, 127.74, 116.25, 45.32, 33.83, 9.89, 4.70.

[0101] Example 21: 1-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-thienylcyclopropyl[f]isoindol-2(1H)-yl]-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea (A20)

[0102]

[0103] According to the method described in Example 17, 115 mg of compound A20 was synthesized as a white solid using 3-fluoro-4-trifluoromethoxyaniline as starting material. The total yield for the two steps was 31%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 9.40 (brs, 1H), 9.23 (brs, 1H), 7.59-7.57 (m, 1H), 7.44-7.41 (m, 1H), 7.24-7.22 (m,1H),5.71-5.70(m,2H),3.23(s,2H),3.12(s,2H),1.14-1.13(m,2H),0.23-0.20(m,1H),0.02-0.01(m,1H).

[0104] Example 22: 1-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)urea (A21)

[0105]

[0106] According to the method described in Example 17, 125 mg of compound A21 was synthesized as a white solid using 3-fluoro-4-(trifluoromethyl)aniline as starting material. The total yield for two steps was 30%. 1 HNMR (600MHz, DMSO-d6): δ (ppm) 9.73 (brs, 1H), 9.41-8.87 (m, 1H), 7.66 (t, J = 8.6Hz, 1H), 7.63-7.60 (m, 1H), 7.37-7. 36(m,1H),5.74(t,J=3.9Hz,2H),3.27(s,2H),3.17(s,2H),1.18-1.16(m,2H),0.27-0.24(m,1H),0.06-0.05(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 175.83, 160.56, 158.90, 145.78, 128.20, 127.19, 124.27, 122.47, 60.21, 43.42, 33.31, 9.63, 4.41.

[0107] Example 23: 1-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-thienylcyclopropyl[f]isoindol-2(1H)-yl]-3-(2,4,5-trifluorobenzyl)urea (A22)

[0108]

[0109] According to the method described in Example 17, (2,4,5-trifluorophenyl)methanamine was used as starting material to synthesize compound A22 as a white solid (145 mg). The total yield for the two steps was 38%. 1 HNMR (600MHz, DMSO-d6): δ (ppm) 8.83 (brs, 1H), 7.64-7.60 (m, 2H), 7.26-7.25 (m, 1H), 5.70 (s, 2H), 4 .21-4.20(m,2H),3.24(s,2H),3.09(s,2H),1.19-1.16(m,2H),0.25-0.22(m,1H),0.04-0.02(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 176.24, 132.54, 131.98, 131.92, 129.17, 129.19, 127.89, 106.25, 43.45, 33.31, 9.60, 4.34.

[0110] Example 24: 1-(4-cyanobenzyl)-3-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]urea (A23)

[0111]

[0112] According to the method described in Example 17, 127 mg of compound A23 was synthesized as a white solid using 4-(aminomethyl)benzonitrile as starting material. The total yield for the two steps was 36%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 8.79 (brs, 1H), 7.78 (d, J = 8.2Hz, 2H), 7.40 (d, J = 8.2Hz, 2H), 7.27 (brs, 1H), 5.69 ( s,2H),4.28(d,J=5.9Hz,2H),3.23(s,2H),3.08(s,2H),1.18-1.15(m,2H),0.24-0.21(m,1H),0.03-0.01(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 176.22, 146.65, 132.64, 128.09, 127.89, 119.40, 109.88, 43.45, 32.30, 9.61, 4.34.

[0113] Example 25: 1-{1-[(3R,5R,7R)-adamantan-1-yl]ethyl}-3-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]urea (A24)

[0114]

[0115] According to the method described in Example 17, 136 mg of compound A24 was synthesized as a white solid using 1-[(3r,5r,7r)-adamantan-1-yl]ethan-1-amine as starting material. The total yield for two steps was 34%. 1HNMR(600MHz,DMSO-d6): δ(ppm)8.06(brs,1H),6.00(brs,1H),5.66(s,1H),3.19(s,2H),3.05(s,2H),1.96-1.90(m,3H),1.64-1.62(m ,3H),1.55-1.53(m,3H),1.46-1.44(m,3H),1.38-1.36(m,3H),1.15-1.1.11(m,3H),0.90-0.89(m,3H),0.21-0.19(m,1H),0.01(s,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 176.74, 176.66, 128.43, 60.76, 54.29, 43.84, 38.84, 37.67, 36.73, 33.84, 28.78, 21.76, 15.81, 15.10, 10.17, 4.94.

[0116] Example 26: 1-(3,4-dichlorophenyl)-3-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-cyclopropyl[f]isoindol-2(1H)-yl]urea (A25)

[0117]

[0118] According to the method described in Example 18, (3,4-dichlorophenyl)methanamine was used as starting material to synthesize compound A25 as a white solid (143 mg). The total yield for the two steps was 36%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 8.79 (brs, 1H), 7.58-7.56 (m, 1H), 7.45 (s, 1H), 7.22-7.20 (m, 2H), 5.69 (s, 2H) ), 4.19 (d, J = 6.0Hz, 2H), 3.23 (s, 2H), 3.08 (s, 2H), 1.18-1.16 (m, 2H), 0.24-0.21 (m, 1H), 0.03-0.01 (m, 1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 176.20, 142.01, 131.31, 130.82, 129.54, 129.04, 127.89, 127.66, 60.22, 43.44, 33.30, 21.23, 14.56, 9.61, 4.34.

[0119] Example 27: 1-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-3-(4-(trifluoromethyl)phenyl)urea (A26)

[0120]

[0121] According to the method described in Example 17, 135 mg of compound A26 was synthesized as a white solid using 4-(trifluoromethyl)aniline as starting material. The total yield for the two steps was 34%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 9.43 (brs, 1H), 9.20-8.70 (m, 1H), 7.63 (s, 4H), 5. 74(s,2H),3.26(s,1H),3.15(s,2H),1.16(s,2H),0.25-0.24(m,1H),0.05(s,1H).

[0122] Example 28: 1-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-3-(3-(trifluoromethyl)phenyl)urea (A27)

[0123]

[0124] According to the method described in Example 17, 145 mg of compound A27 was synthesized as a white solid using 3-(trifluoromethyl)aniline as starting material. The total yield for the two steps was 35%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 9.36 (brs, 1H), 9.22-8.69 (m, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.51-7.48 (m, 1H) ,7.33-7.31(m,1H),5.74-5.73(m,2H),3.26(s,2H),3.15(s,2H),1.16(s,2H),0.26-0.22(m,1H),0.05(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 175.93, 140.48, 130.35, 127.85, 125.50, 123.70, 119.09, 43.42, 33.32, 9.64, 4.42.

[0125] Example 29: 1-(3,5-bis(trifluoromethyl)phenyl)-3-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)urea (A28)

[0126]

[0127] According to the method described in Example 17, 175 mg of compound A28 was synthesized as a white solid using 3,5-bis(trifluoromethyl)aniline as starting material. The total yield for two steps was 38%. 1 HNMR (600MHz, DMSO-d6): δ (ppm) 9.84 (brs, 1H), 9.07-9.02 (m, 1H), 8.14 (s, 2H), 7.67 (s, 1H), 5 .76-5.75(m,2H),3.27(s,2H),3.18(s,2H),1.19-1.16(m,2H),0.27-0.24(m,1H),0.06(m,1H).

[0128] Example 30: 1-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-3-(4-(trifluoromethoxy)phenyl)urea (A29)

[0129]

[0130] According to the method described in Example 17, 125 mg of compound A29 was synthesized as a white solid using 4-(trifluoromethoxy)aniline as starting material. The total yield for the two steps was 32%. 1 HNMR (600MHz, DMSO-d6): δ (ppm) 9.17 (brs, 1H), 9.08-8.60 (m, 1H), 7.52-7.50 (m, 2H), 7.28-7. 26(m,2H),5.73(s,2H),3.26(s,2H),3.14(s,2H),1.16(s,2H),0.26-0.23(m,1H),0.05(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 175.96, 143.44, 138.84, 127.80, 123.16, 122.06, 121.46, 120.59, 119.77, 43.42, 33.31, 9.64, 4.40.

[0131] Example 31: 1-(3,4-difluorophenyl)-3-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)thiourea (A30)

[0132]

[0133] Compound H-3 (0.2 g, 0.98 mmol), TEA (0.15 g, 1.47 mmol) and DCM (5 mL) were added to a 25 mL single-necked bottle, and a 2 mL DCM solution of 3,4-difluorophenylisothiocyanate (0.17 g, 1.0 mmol) was slowly added dropwise at room temperature. The reaction was completed after 2 h, and 117 mg of compound A30 (white solid, yield 32%) was obtained by column chromatography. 1 HNMR(600MHz,DMSO-d6): δ(ppm)10.34(brs,1H),9.88(brs,1H),7.52(s,1H),7.45-7.40(m,1H),7.1 3(s,1H),5.72(s,2H),3.26(s,2H),3.14(s,2H),1.18(s,2H),0.25-0.24(m,1H),0.04-0.03(m,1H).

[0134] Example 32: 1-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (A31)

[0135]

[0136] According to the method described in Example 31, 139 mg of compound A31 as a white solid was synthesized using 4-(trifluoromethyl)phenylisothiocyanate as the starting material, with an overall yield of 35%. 1 H NMR(600MHz,DMSO-d6): δ(ppm)10.43(brs,1H),9.98(brs,1H),7.72-7.62(m,4H),5.7 3(s,2H),3.27(s,2H),3.16(s,2H),1.19-1.17(m,2H),0.26-0.23(m,1H),0.04(m,1H).

[0137] Example 33: 1-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylcyclopropane[f]isoindol-2(1H)-yl)-3-(4-fluorophenyl)urea (A32)

[0138]

[0139] According to the method described in Example 17, 135 mg of compound A32 was synthesized as a white solid using 4-fluoroaniline as starting material. The total yield for two steps was 33%. 1 H NMR(600MHz,DMSO-d6): δ(ppm)8.97(brs,1H),8.51(brs,1H),7.42-7.40(m,2H),7.11-7.08 (m,2H),5.72(s,2H),3.25(s,2H),3.13(s,2H),1.16(s,2H),0.26-0.22(m,1H),0.05(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 176.02, 158.88, 157.30, 135.83, 127.84, 121.27, 115.74, 115.59, 43.42, 33.31, 9.64, 4.41.

[0140] Example 34: (1R,2S,3R,4S)-3-[2-(4-fluorobenzoyl)hydrazine-1-carbonyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (A33)

[0141]

[0142] Compound nadic anhydride (0.2 g, 1.22 mmol), 4-fluorobenzohydrazide (0.18 g, 1.22 mmol) and anhydrous ethanol (5 mL) were added to a 25 mL single-necked bottle and heated to 80 ° C. under nitrogen protection and refluxed for 12 h. Heating was stopped and the organic solvent was removed by rotary evaporation. 147 mg of compound A33 was obtained by column chromatography (white solid, yield 38%). 1HNMR (600MHz, DMSO-d6): δ (ppm) 11.64 (brs, 1H), 10.36 (s, 1H), 9.92 (s, 1H), 7.93-7.89 (m, 2H), 7.30-7.26 (m, 2H), 6.24-6.19(m,2H),2.93-2.76(m,2H),2.59-2.56(m,1H),2.29-2.27(m,1H),2.12-2.10(m,1H),1.23-1.21(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 174.57, 172.39, 164.75, 138.75, 138.23, 13 0.68,130.59,129.48,115.96,115.75,47.86,46.59,45.53,45.21,44.21.

[0143] Example 35: (1R,2S,3R,4S)-3-[2-(4-cyanobenzoyl)hydrazine-1-carbonyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (A34)

[0144]

[0145] According to the method described in Example 34, 142 mg of compound A34 as a white solid was synthesized using 4-cyanophenylhydrazide as the starting material, with a yield of 36%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 11.83 (brs, 1H), 10.66 (s, 1H), 10.08 (s, 1H), 8.06-7.96 (m, 4H), 6.29-6.2 4(m,2H),2.98-2.71(m,2H),2.64-2.61(m,1H),2.35-2.33(m,1H),2.16-2.14(m,1H),1.28-1.26(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 174.53, 172.29, 164.44, 138.78, 138.21, 13 7.00,133.01,128.77,118.71,114.58,47.83,46.64,45.51,45.22,44.22.

[0146] Example 36: (1R,2S,3R,4S)-3-[2-(4-(trifluoromethyl)benzoyl)hydrazine-1-carbonyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (A35)

[0147]

[0148] According to the method described in Example 34, 4-(trifluoromethyl)benzohydrazide was used as the starting material to synthesize compound A35 as a white solid (143 mg) with a yield of 32%. 1 HNMR (600MHz, DMSO-d6): δ (ppm) 11.83 (brs, 1H), 10.63 (s, 1H), 10.07 (s, 1H), 8.08-8.06 (m, 2H), 7.88-7.77 (m, 2H) ,6.28-6.24(m,2H),2.98-2.91(m,2H),2.64-2.62(m,1H),2.34-2.33(m,1H),2.16-2.15(m,1H),1.27-1.26(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 174.55, 172.30, 164.68, 138.77, 138.22, 136.84, 128.88, 125.93, 125.91, 47.84, 46.64, 45.53, 45.23, 44.22.

[0149] Example 37: N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-4-(trifluoromethoxy)benzamide (A36)

[0150]

[0151] According to the method described in Example 34, 4-(trifluoromethoxy)benzohydrazide was used as the starting material to synthesize compound A36 as a white solid (138 mg) with a yield of 31%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 11.30 (s, 1H), 8.06-8.03 (m, 2H), 7.58-7.56 (m, 2H), 6. 36(s,2H),3.21-3.19(m,2H),2.91-2.84(m,2H),2.03-2.02(m,1H),1.40-1.38(m,1H). 13 C NMR (150MHz, DMSO-d6): δ (ppm) 175.28, 164.35, 151.70, 137.96, 130.70, 130.35, 121.45, 45.69, 45.47, 45.31, 45.16, 43.02.

[0152] Example 38: (1R,2S,3R,4S)-3-[2-(4-chlorobenzoyl)hydrazine-1-carbonyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (A37)

[0153]

[0154] According to the method described in Example 34, 167 mg of compound A37 as a white solid was synthesized using 4-chlorobenzohydrazide as the starting material, with a yield of 41%. 1 HNMR (600MHz, DMSO-d6): δ (ppm) 11.26 (s, 1H), 7.94-7.91 (m, 2H), 7.67-7.65 (m, 2H), 6. 36(s,2H),3.21-3.18(m,2H),2.90-2.84(m,2H),2.02-2.01(m,1H),1.39-1.37(m,1H).

[0155] Example 39: 2-Chloro-N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]benzamide (A38)

[0156]

[0157] According to the method described in Example 34, 147 mg of compound A38 as a white solid was synthesized using 2-chlorobenzoylhydrazide as the starting material, with a yield of 36%. 1 H NMR (600MHz, CDCl3): δ (ppm) 8.27 (brs, 1H), 7.63-7.62 (m, 1H), 7.56-7.54 (m, 1H), 7.4 6-7.42(m,1H),7.29-7.27(m,1H),6.34(s,2H),3.39(s,2H),2.78(s,2H),1.59(m,2H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.74, 137.76, 130.64, 130.58, 123.15, 120.18, 120.03, 115.20, 115.04, 45.89, 45.50, 43.09.

[0158] Example 40: 3,5-Dichloro-N-((3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-methylindol-2-yl)benzamide (A39)

[0159]

[0160] According to the method described in Example 34, 139 mg of compound A39 as a white solid was synthesized using 4-(trifluoromethyl)benzohydrazide as the starting material, with a yield of 31%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 11.44 (brs, 1H), 7.97-7.90 (m, 3H), 6.35 (s, 2H) ),3.21-3.18(m,2H),2.95-2.85(s,2H),1.98-1.96(m,1H),1.39-1.38(m,1H). 13 CNMR (150MHz, DMSO-d6): δ (ppm) 174.04, 145.10, 137.75, 135.57, 129.69, 128.19, 45.53, 45.46, 42.94, 21.74.

[0161] Example 41: N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-4-methylbenzenesulfonamide (A40)

[0162]

[0163] Compound 4-methylbenzenesulfonyl chloride (0.2 g, 1.05 mmol) and dichloromethane (2 mL) were added to a 25 mL single-necked bottle. After cooling to 0°C, 80% hydrazine hydrate (63 mg, 1.26 mmol) was slowly added dropwise. After 2 h of reaction, water was added to the reaction solution to precipitate a solid, which was filtered and dried to obtain 0.16 g of compound H-5 (white solid, yield 80%), which was directly used in the next step.

[0164] Compound H-5 (0.16 g, 0.85 mmol), nadic anhydride (0.14 g, 0.85 mmol), and anhydrous ethanol (5 mL) were added to a 25 mL single-necked flask. The mixture was heated to 80°C under nitrogen for 12 h. The mixture was then cooled to room temperature and the organic solvent was removed by rotary evaporation. Column chromatography afforded 127 mg of compound A40 (white solid, 45% yield). 1 H NMR (600MHz, CDCl3): δ (ppm) 7.84-7.83 (m, 2H), 7.33-7.27 (m, 3H), 6.29 (s, 2H), 3.31 (s, 2H), 2.69 (s, 2H), 2.44 (s, 3H), 1.54 (s, 2H). 13C NMR (150MHz, CDCl3): δ (ppm) 174.04, 145.10, 138.09, 137.75, 135.57, 129.69, 128.19, 45.53, 45.46, 42.94, 21.74.

[0165] Example 42: 4-Chloro-N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]benzenesulfonamide (A41)

[0166]

[0167] According to the method described in Example 41, 145 mg of compound A41 as a white solid was synthesized using 4-chlorobenzenesulfonyl chloride as starting material with a yield of 30%. 1 HNMR (600MHz, CDCl3): δ (ppm) 7.91-7.90 (m, 2H), 7.52-7.51 (m, 2H), 6.31 (s, 2H), 3.33 (s, 2H), 2.70-2.69 (s, 2H), 1.57-1.52 (s, 2H). 13 C NMR (150MHz, CDCl3): δ (ppm) 173.94, 140.76, 137.76, 137.16, 129.70, 129.62, 129.57, 129.40, 45.56, 45.50, 42.93.

[0168] Example 43: N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-4-fluorobenzenesulfonamide (A42)

[0169]

[0170] According to the method described in Example 41, 145 mg of compound A42 as a white solid was synthesized using 4-fluorobenzenesulfonyl chloride as starting material, with a yield of 31%. 1 H NMR (600MHz, CDCl3): δ (ppm) 8.00-7.98 (m, 2H), 7.48 (brs, 2H), 7.22-7.19 (m, 2H), 6.30 (s, 2H), 3.31 (s, 2H), 2.70 (s, 2H), 1.55-1.51 (m, 2H). 13C NMR (150MHz, CDCl3): δ (ppm) 174.14, 166.77, 165.07, 137.74, 134.69, 134.67, 131.11, 131.04, 116.46, 116.31, 45.56, 45.47, 42.92.

[0171] Example 44: N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-3-fluoro-4-methoxybenzenesulfonamide (A43)

[0172]

[0173] According to the method described in Example 41, 165 mg of compound A43 as a white solid was synthesized using 3-fluoro-4-methoxybenzenesulfonyl chloride as the starting material, with a yield of 33%. 1 HNMR (600MHz, CDCl3): δ (ppm) 7.96-7.95 (m, 1H), 7.86-7.84 (m, 2H), 7.09-7.02 (m,2H),6.31(s,2H),3.99(s,3H),3.34(s,2H),2.70(s,2H),1.57-1.52(m,2H). 13 CNMR (150MHz, CDCl3): δ (ppm) 173.80, 159.46, 137.76, 130.32, 128.75, 123.31, 111.59, 56.60, 45.56, 45.49, 42.91, 39.98.

[0174] Example 45: N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-4-methoxybenzenesulfonamide (A44)

[0175]

[0176] According to the method described in Example 41, 175 mg of compound A44 as a white solid was synthesized using 4-methoxybenzenesulfonyl chloride as the starting material with a yield of 35%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.89-7.88 (m, 2H), 7.22 (brs, 2H), 7.00-6.98 (m ,2H),6.30-6.29(m,2H),3.83(s,3H),3.31(s,2H),2.69(s,2H),1.53(m,2H). 13CNMR (150MHz, CDCl3): δ (ppm) 174.00, 164.02, 137.42, 130.52, 129.71, 114.26, 55.69, 45.54, 45.45, 42.93.

[0177] Example 46: N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-3,4-difluorobenzenesulfonamide (A45)

[0178]

[0179] According to the method described in Example 41, 135 mg of compound A45 as a white solid was synthesized using 3,4-difluorobenzenesulfonyl chloride as the starting material, with a yield of 29%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.86-7.83 (m, 1H), 7.78-7.70 (m, 2H), 7.34-7.31 (m, 1H), 6.31 (m, 2H), 3.33 (s, 2H), 2.72 (s, 2H), 1.57-1.52 (m, 2H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.25, 154.85, 153.05, 150.90, 149.12, 137.75, 125.43, 118.21, 118.09, 45.57, 45.49, 42.91.

[0180] Example 47: 3,4-Dichloro-N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]benzenesulfonamide (A46)

[0181]

[0182] According to the method described in Example 41, 145 mg of compound A46 as a white solid was synthesized using 3,4-dichlorobenzenesulfonyl chloride as the starting material, with a yield of 28%. 1 H NMR (600MHz, CDCl3): δ (ppm) 8.06-8.05 (m, 1H), 7.81-7.80 (m, 1H), 7.63-7.62 (m,1H),6.32-6.31(m,2H),3.34(s,2H),2.72-2.71(m,2H),1.58-1.52(m,2H). 13CNMR (150MHz, CDCl3): δ (ppm) 174.08, 138.98, 138.51, 137.76, 133.65, 131.15, 130.10, 127.10, 45.57, 45.51, 42.91.

[0183] Example 48: 3-Chloro-N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-4-fluorobenzenesulfonamide (A47)

[0184]

[0185] According to the method described in Example 41, 135 mg of compound A47 as a white solid was synthesized using 3-chloro-4-fluorobenzenesulfonyl chloride as starting material with a yield of 24%. 1 H NMR (600MHz, CDCl3): δ (ppm) 8.05-8.04 (m, 1H), 7.90-7.87 (m, 1H), 7.76 (brs, 1H), 6.31 (s, 2H), 3.31 (s, 2H), 2.71 (s, 2H), 1.56-1.51 (m, 2H). 13 C NMR (150MHz, CDCl3): δ (ppm) 174.32, 162.21, 160.50, 137.75, 131.16, 128.80, 122.37, 117.34, 45.97, 45.57, 45.48, 42.89, 40.00.

[0186] Example 49: N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-3,4,5-trifluorobenzenesulfonamide (A48)

[0187]

[0188] According to the method described in Example 41, 115 mg of compound A48 as a white solid was synthesized using 3,4,5-trifluorobenzenesulfonyl chloride as starting material with a yield of 20%. 1 H NMR (600MHz, CDCl3): δ (ppm) 7.68-7.66 (m, 1H), 7.43 (brs, 1H), 6.32 (s, 2H), 3.35 (s, 2H), 2.75-2.71 (m, 2H), 1.59-1.50 (m, 2H). 13C NMR (150MHz, CDCl3): δ (ppm) 173.97, 137.77, 113.57, 113.53, 113.44, 46.98, 45.58, 45.53, 42.91, 40.03.

[0189] Example 50: 3-Chloro-N-[(3aR,4S,7R,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-formylisoindol-2-yl]-4-methoxybenzenesulfonamide (A49)

[0190]

[0191] According to the method described in Example 41, 145 mg of compound A49 as a white solid was synthesized using 3-chloro-4-methoxybenzenesulfonyl chloride as starting material with a yield of 27%. 1 H NMR (600MHz, DMSO-d6): δ (ppm) 10.87 (brs, 1H), 7.65-7.62 (m, 2H), 7.37-7.34 ( m,1H),6.31(s,2H),3.90(s,3H),3.10(s,2H),2.68(s,2H),1.39-1.32(s,2H). 13 CNMR (150MHz, DMSO-d6): δ (ppm) 174.84, 151.77, 150.18, 137.95, 125.55, 115.58, 114.03, 57.00, 45.29, 45.21, 42.71.

[0192] Example 51: Determination of the inhibitory activity of the compounds of each example against monkeypox virus

[0193] 1.0×10 5Vero cells were added to each well of a 24-well plate. Twelve hours after cell seeding, the cells were infected with MPXV (MOI = 0.1). Simultaneously, the cells were treated with different concentrations of drugs (10 μM and 1 μM) according to the table below. Forty-eight hours after viral infection, the inhibitory activity of the compounds against MPXV was tested using a nucleic acid extraction kit (Daan Gene, #DA0620). The results are shown in Table 1. As can be seen from Table 1, Cidofovir has no inhibitory activity against monkeypox virus at the 10uM level, while the compounds of the present invention all have inhibitory activity against monkeypox virus at the 10uM level, and most of the compounds have inhibitory activity against monkeypox virus at the 1uM level; in addition, compared with ST-246 (Tecovirimat), the compounds of the present invention and ST-246 have similar 10uM inhibition rates, among which compounds A13, A14, A15, A21, A30, A31 and A32 exhibit better monkeypox virus inhibition than ST-246 at the 10uM level and the 1uM level.

[0194] Table 1 Inhibitory activity of the compounds of the present invention against monkeypox virus at 10uM and 1uM levels

[0195] Compound number 10uM inhibition rate% 1uM inhibition rate% Compound number 10uM inhibition rate% 1uM inhibition rate% A1 89.65±0.015 40.89±0.043 A27 97.28±0.001 55.26±0.036 A2 92.76±0.008 30.55±0.113 A28 96.95±0.004 47.58±0.028 A3 89.72±0.018 7.18±0.045 A29 97.12±0.001 48.38±0.028 A4 90.35±0.023 26.40±0.032 A30 84.09±0.037 90.00±0.023 A5 88.81±0.006 - A31 95.64±0.015 88.90±0.018 A6 78.89±0.052 - A32 96.30±0.004 86.79±0.015 A7 94.30±0.005 - A33 92.78±0.013 23.27±0.214 A8 90.29±0.010 - A34 95.11±0.010 46.03±0.148 A9 67.44±0.028 26.47±0.094 A35 89.31±0.009 33.37±0.0.127 A10 91.43±0.09 - A36 86.78±0.006 24.23±0.100 A11 89.00±0.022 - A37 89.43±0.021 - A12 93.27±0.011 - A38 91.72±0.021 - A13 99.62±0.001 61.31±0.239 A39 93.85±0.015 - A14 90.04±0.007 59.45±0.027 A40 65.83±0.010 - A15 92.69±0.008 88.30±0.015 A41 64.67±0.072 - A16 99.36±0.010 - A42 83.17±0.030 3.54±0.124 A17 94.16±0.007 51.29±0.157 A43 82.71±0.014 - A18 99.66±0.001 42.02±0.081 A44 79.84±0.044 - A19 94.12±0.010 - A45 77.47±0.045 - A20 93.52±0.015 0.35±0.171 A46 96.28±0.005 - A21 96.13±0.002 57.59±0.100 A47 94.48±0.005 14.20±0.070 A22 70.09±0.072 - A48 88.71±0.005 - A23 83.62±0.007 - A49 65.69±0.206 - A24 94.26±0.002 - ST-246 89.13±0.011 56.34±0.137 A25 81.74±0.056 - Cidofovir - - A26 95.78±0.004 42.90±0.020

[0196] Note: - represents no activity

[0197] The above content is a further detailed description of the present application in conjunction with specific implementation methods, and the specific implementation of the present application cannot be considered to be limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound includes a structure represented by formula (I) or formula (II): wherein R1 is selected from: X is selected from: -NH-, -CO-; Y is selected from: -CO-, -SO2-, Z is selected from: -NH-; L is selected from: -(C0-C6 alkylene)-; R2 is selected from: an unsubstituted or substituted bridged ring group, an unsubstituted or substituted phenyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from: Preferably, R1 is 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that L is selected from: single bond, -CH2-, Preferably, L is a single bond.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The substituted bridged ring group is selected from one of mono-substituted, di-substituted and tri-substituted groups, and the substituted phenyl group is selected from one of mono-substituted, di-substituted and tri-substituted groups.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The bridged ring group is selected from: adamantyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The substituent of the substituted phenyl group is selected from the group consisting of an alkyl group, a halogen group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a nitro group, and a cyano group.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that Y is 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein Including at least one of the following compounds A1 to A49:

9. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for preventing and / or treating a disease caused by monkeypox virus.

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