A class of hydrazide compounds, preparation method and application thereof

Abstract

The present invention relates to a compound of the structure shown in formula I, which shows excellent antiviral activity against orthopoxviruses and in a pharmacokinetic test in mice, various parameter indicators are improved to varying degrees, especially showing a higher exposure and a significant improvement in bioavailability. The present invention further provides a method for preparing the compound shown in formula I and its use in treating orthopoxvirus-related viruses, such as smallpox virus, monkeypox virus, cowpox virus, camelpox virus, horsepox virus and other related viruses causing related diseases.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a class of hydrazide compounds, a preparation method thereof, and an application thereof in treating poxvirus infection. Background Art

[0002] Poxviruses belong to the Poxviridae family, a family of double-stranded DNA viruses that multiply in large numbers in cells after infection. Under an electron microscope, they appear as brick-shaped or oval structures. Poxviruses are also called ancient viruses because they have been found in insects, reptiles, birds, and mammals. Poxviruses include two subfamilies: the chordopoxvirinae and the entomopoxvirinae. Among them, the chordopoxvirinae includes the genus Orthopoxvirus, whose virus particles are large and brick-shaped (the same is true for the virus particles of Attapoxvirus and Molluscumpoxvirus), with a length ranging from 220-450nM. It mainly includes 12 viruses such as monkeypox, smallpox, cowpox, horsepox, vaccinia virus, and camelpox (Fenner F, Henderson DA, Arita I, et al., Smallpox and its Eradication), all of which can infect humans and spread between humans, causing serious diseases.

[0003] Monkeypox is a zoonotic viral disease caused by infection with the monkeypox virus (MPXV). The main clinical manifestations are fever, rash, and swollen lymph nodes.

[0004] Currently, only two small molecule drugs (Tecovirimat and Brincidofovir) for the treatment of smallpox have been granted Expanded Access Drug Designation (EA-IND) by the US CDC and can be used in monkeypox outbreaks.

[0005] Clearly, new treatments and prophylaxis are needed for diseases caused by orthopoxvirus infections. Summary of the invention

[0006] Problems to be solved by the invention:

[0007] After continuous efforts, the inventors of the present application have discovered a compound represented by the general formula (I) with a completely new structure, and found that compounds of this structure have therapeutic effects on treating diseases related to orthopoxviruses (such as smallpox, monkeypox, and cowpox viruses), and in PO administration, the compound represented by the general formula (I) of the present invention shows higher exposure and more excellent bioavailability characteristics.

[0008] Solutions used to solve the problem:

[0009] In order to solve the above problems, the inventors of the present application conducted intensive research and found that specific hydrazide compounds can achieve the desired purpose, resulting in the completion of the present invention.

[0010] The present invention relates to the following hydrazide compounds.

[0011] The present invention protects the following specific embodiments:

[0012] A compound represented by formula (I), its polymorph, cocrystal, solvate or pharmaceutically acceptable salt:

[0013]

[0014] in,

[0015] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from hydrogen, deuterium or halogen;

[0016] R a Selected from Where X is N, NR 10 or CR 10 ; Y is N, NR 11 or CR 11 ; Z is N, NR 12 or CR 12 ;

[0017] R 9 and R 13 One of them is deuterium and the other is hydrogen, halogen or C 1-6 Alkyl, R 10 , R 12 are each independently selected from hydrogen, halogen or C 1-6 alkyl;

[0018] R 11 is selected from H, deuterium, halogen, nitro, cyano, mesyl, -CHF2, -CF3, -OCF3, -CF2Cl or -CF2Br;

[0019] ------ is a single key or does not exist.

[0020] In some embodiments, R 11 Selected from H, deuterium, halogen, nitro, cyano, -CHF2, -CF3 or -OCF3.

[0021] In some embodiments, R 11Selected from nitro, -CHF2, -CF3 or -OCF3.

[0022] In some embodiments, R 11 Selected from nitro, -CHF2 or -CF3.

[0023] In some embodiments, R 11 Selected from -CF3.

[0024] In some embodiments, the C 1-6 The alkyl group is selected from C 1-4 Alkyl, C 5-6 alkyl.

[0025] In some embodiments, the C 1-6 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0026] In some specific embodiments, Formula I has a structure selected from Formula IB, IC, ID, IE, IX, IY, IZ, IW, IV:

[0027]

[0028] Among them, in formula IB, R 9 , R 10 , R 12 , R 13 As defined in Formula I; in Formula IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 As defined in Formula I.

[0029] In some specific embodiments, in Formula IB, IC, ID, IE, IX, IY, IZ, IW, IV, R 9 and R 13 One of them is deuterium and the other is hydrogen or a halogen, R 10 , R 12 are each independently selected from hydrogen or halogen.

[0030] In some specific embodiments, in Formula IB, IC, ID, IE, IX, IY, IZ, IW, IV, R 9 and R13 One of them is deuterium and the other is hydrogen or a halogen, R 10 , R 12 All are hydrogen.

[0031] In some specific embodiments, in Formula IB, IC, ID, IE, IX, IY, IZ, IW, IV, R 9 and R 13 One of them is deuterium and the other is hydrogen, F, Cl or Br, R 10 , R 12 All are hydrogen.

[0032] In some specific embodiments, in Formula IB, IC, ID, IE, IX, IY, IZ, IW, IV, R 9 is deuterium, R 10 , R 12 , R 13 Both are H.

[0033] In some specific embodiments, in Formula IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Both are H.

[0034] In some specific embodiments, in Formula IB, R 9 and R 13 One of them is deuterium and the other is hydrogen or a halogen, R 10 , R 12 are each independently selected from hydrogen or halogen.

[0035] In some specific embodiments, in Formula IB, R 9 and R 13 One of them is deuterium and the other is hydrogen or a halogen, R 10 , R 12 All are hydrogen.

[0036] In some specific embodiments, in Formula IB, R 9 and R 13 One of them is deuterium and the other is hydrogen, F, Cl or Br, R 10 , R 12 All are hydrogen.

[0037] In some specific embodiments, in Formula IB, R 9 is deuterium, R 10 , R 12 , R 13Both are H.

[0038] In some specific embodiments, in Formula IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Both are H; R 9 , R 10 , R 12 , R 13 As defined in Formula I.

[0039] In some specific embodiments, in Formula IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Both are H; R 9 and R 13 One of them is deuterium and the other is hydrogen or a halogen, R 10 , R 12 are each independently selected from hydrogen or halogen.

[0040] In some specific embodiments, in Formula IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Both are H; R 9 and R 13 One of them is deuterium and the other is hydrogen or a halogen, R 10 , R 12 All are hydrogen.

[0041] In some specific embodiments, in Formula IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Both are H; R 9 and R13 One of them is deuterium and the other is hydrogen, F, Cl or Br, R 10 , R 12 All are hydrogen.

[0042] In some specific embodiments, in Formula IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Both are H; R 9 is deuterium, R 10 , R 12 , R 13 Both are H.

[0043] In some specific embodiments, Formula I has a structure selected from Formula IB, IX, IY, IZ, IW, IV:

[0044]

[0045]

[0046] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 Defined as above.

[0047] In some specific embodiments, Formula I has a structure selected from Formula IB, IY, IW:

[0048]

[0049] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 Defined as above.

[0050] In some specific embodiments, Formula I has a structure selected from Formula IB:

[0051]

[0052] Among them, R 9 , R 10 , R 12 , R 13 Defined as above.

[0053] In the present invention, R 9 and R 13 One of them is deuterium, which should be understood as:

[0054] In one specific case, R 9 or R 13 The corresponding deuterated sites have a deuterium enrichment of not less than 1%.

[0055] In one specific case, R 9 or R 13 The corresponding deuterated sites have a deuterium enrichment of not less than 5%.

[0056] In one specific case, R 9 or R 13 The corresponding deuterium-substituted sites have a deuterium enrichment of not less than 10%.

[0057] In one specific case, R 9 or R 13 The corresponding deuterium-substituted sites have a deuterium enrichment of not less than 20%.

[0058] In one specific case, R 9 or R 13 The corresponding deuterated sites have a deuterium enrichment of not less than 50%.

[0059] In one specific case, R 9 or R 13 The corresponding deuterium-substituted sites have a deuterium enrichment of not less than 60%.

[0060] In one specific case, R 9 or R 13 The corresponding deuterium-substituted sites have a deuterium enrichment of not less than 70%.

[0061] In one specific case, R 9 or R 13 The corresponding deuterated sites have a deuterium enrichment of not less than 80%.

[0062] In one specific case, R 9 or R 13 The corresponding deuterated sites have a deuterium enrichment of not less than 90%.

[0063] In one specific case, R 9 or R 13 The corresponding deuterated sites have a deuterium enrichment of not less than 95%.

[0064] In one specific case, R 9 or R 13 The corresponding deuterated sites have a deuterium enrichment of not less than 98%.

[0065] In some specific embodiments, the compound represented by formula (I) is selected from the following specific compounds:

[0066]

[0067] The present invention provides another specific embodiment:

[0068] A compound represented by formula (I), its polymorph, cocrystal, solvate or pharmaceutically acceptable salt thereof:

[0069]

[0070] in,

[0071] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from hydrogen, deuterium or halogen;

[0072] R a Selected from Where X is N, NR 10 or CR 10 ; Y is N, NR 11 or CR 11 ; Z is N, NR 12 or CR 12 ;

[0073] R 9 , R 10 , R 12 , R 13 are each independently selected from hydrogen, deuterium, halogen or C 1-6 Alkyl; R 11 is selected from H, halogen, nitro, cyano, mesyl, -CHF2, -CF3, -OCF3, -CF2Cl or -CF2Br; and when Y is N or when R 11 When R is H, nitro, cyano, halogen or -CF3, 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 Not at the same time hydrogen;

[0074] ------ is a single key or does not exist.

[0075] In some specific embodiments, in Formula I, ------ is a single bond.

[0076] In some specific embodiments, in Formula I, ------ is absent.

[0077] In some embodiments, when R a Selected from When R 9 , R 10 , R 12 , R 13 are each independently selected from hydrogen, deuterium, halogen or C 1-6 Alkyl; R 11 is selected from H, halogen, nitro, cyano, mesyl, -CHF2, -CF3, -CF2Cl or -CF2Br; and when Y is N or when R 11 When R is H, nitro, cyano, halogen or -CF3, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 Not hydrogen at the same time.

[0078] In some embodiments, when R a Selected from When R 9 , R 10 , R 12 , R 13 are each independently selected from hydrogen, deuterium, halogen or C 1-6 Alkyl; R 11 is selected from H, halogen, nitro, cyano, mesyl, -CHF2, -CF3, -CF2Cl or -CF2Br; and when Y is N or when R 11When R is H, nitro, cyano, halogen, -CHF2, mesyl or -CF3, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 Not hydrogen at the same time.

[0079] In some embodiments, when R a Selected from When Formula I has a structure selected from Formulas IA, IB, IC, ID, IE, IX, IY, IZ, IW, and IV:

[0080]

[0081]

[0082] In the formula IA, IB, IC, ID, IE, IX, IY, IZ, IW, IV, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 As defined in Formula I.

[0083] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of them is deuterium, and the others are independently selected from hydrogen, deuterium or halogen.

[0084] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8At least one of them is deuterium and the rest are H.

[0085] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least two of them are deuterium and the rest are H.

[0086] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At most two of them are deuterium, and the rest are H.

[0087] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 98%.

[0088] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 95%.

[0089] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 90%.

[0090] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 80%.

[0091] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 70%.

[0092] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 60%.

[0093] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 50%.

[0094] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 20%.

[0095] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8At least one of the above independently has a deuterium enrichment of not less than 10%.

[0096] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 5%.

[0097] In some specific embodiments, in Formula IA, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 At least one of the above independently has a deuterium enrichment of not less than 1%.

[0098] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of them is deuterium, and the others are independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl.

[0099] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 Choose one (such as R 9 , R 10 or R 13 ) is deuterium, and the rest are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

[0100] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 Choose any two (such as R 9 and R 10 , R 9 and R 13 , R 10 and R 13 , R 10 and R 12 ) is deuterium, and the rest are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

[0101] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 wherein three (e.g.) are deuterium, and the rest are independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

[0102] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 All are deuterium;

[0103] In some specific embodiments, herein, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or C 5-6 alkyl.

[0104] In some specific embodiments, herein, the C 1-6 The alkyl group is methyl.

[0105] In some specific embodiments, herein, the halogen is F, Cl, Br or I.

[0106] In some specific embodiments, herein, the halogen is F, Cl or Br. In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of them is deuterium, and the rest are hydrogen, methyl, F, Cl or Br.

[0107] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 98%.

[0108] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 95%.

[0109] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 90%.

[0110] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 80%.

[0111] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 70%.

[0112] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 60%.

[0113] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 50%.

[0114] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 20%.

[0115] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 10%.

[0116] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 At least one of the above independently has a deuterium enrichment of not less than 5%.

[0117] In some specific embodiments, in Formula IB, R 9 , R 10 , R 12 , R 13 In some embodiments, in Formulas IA, IB, IC, ID, IE, IX, IY, IZ, IW, and IV, ------ is a single bond.

[0118] In some specific embodiments, in Formula IA, IB, IC, ID, IE, IX, IY, IZ, IW, and IV, ------ is absent.

[0119] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0120] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 98%.

[0121] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0122] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 95%.

[0123] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0124] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 90%.

[0125] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0126] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 80%.

[0127] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0128] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 70%.

[0129] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0130] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 60%.

[0131] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0132] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 50%.

[0133] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0134] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 20%.

[0135] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0136] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 10%.

[0137] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0138] R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 5%.

[0139] In some specific embodiments, when in Formula IC, ID, IE, IX, IY, IZ, IW, IV,

[0140] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 When any one or more of the deuterated sites are deuterated, at least one of the deuterated sites independently has a deuterium enrichment of not less than 1%.

[0141] In some embodiments, Formula I has the structure shown in Formula I":

[0142] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 As defined in Formula I.

[0143] In some embodiments, the compound represented by formula (I) is selected from the following specific compounds:

[0144]

[0145] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 1%.

[0146] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 5%.

[0147] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 10%.

[0148] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 20%.

[0149] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 50%.

[0150] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 60%.

[0151] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 70%.

[0152] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 80%.

[0153] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 90%.

[0154] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 95%.

[0155] In some embodiments, as described above for specific compounds, each of the positions denoted by D has a deuterium enrichment of at least 98%.

[0156] Preparation method:

[0157] The present invention also provides a method for preparing the compound. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered in any way to limit the scope of the present invention. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the method described in the present invention. The product obtained by each step of the reaction is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0158] The compound of the general formula (I) of the present invention can be synthesized according to the following method:

[0159] 1) Raw material Ia and raw material Ib undergo Diels-Alder reaction to obtain intermediate Ic;

[0160] Among them, when R in Formula I 7 , R 8 When the ------ between the carbon atoms connected to each other does not exist, further reduction of the double bond of Ic gives I-c'

[0161] 2) The intermediate Ic / I-c' is condensed with hydrazide Id to obtain product I;

[0162]

[0163] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a Definitions are as described for Formula I.

[0164] Pharmaceutical composition

[0165] The present invention also provides a pharmaceutical composition, which comprises the aforementioned compound, or a pharmaceutically acceptable salt, polymorph, cocrystal, solvate, and a pharmaceutical adjuvant.

[0166] In some embodiments, the pharmaceutical composition may further comprise other drugs for treating and / or preventing diseases related to orthopoxvirus infection.

[0167] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredients are known or will be apparent to those skilled in the art based on the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0168] Medical Uses

[0169] On the other hand, the present invention also provides the use of the compound, or pharmaceutically acceptable salt, polymorph, cocrystal, solvate, or pharmaceutical composition in the preparation of drugs for treating and / or preventing diseases related to orthopoxvirus infection.

[0170] On the other hand, the present invention also provides the use of the compound, or pharmaceutically acceptable salt, polymorph, cocrystal, solvate, or pharmaceutical composition in the treatment and / or prevention of diseases related to orthopoxvirus infection.

[0171] In another aspect, the present invention also provides the compound, or pharmaceutically acceptable salt, polymorph, cocrystal, solvate, or pharmaceutical composition for treating and / or preventing diseases related to orthopoxvirus infection.

[0172] On the other hand, the present invention also provides a method for treating and / or preventing related diseases caused by orthopoxvirus infection, which comprises: administering to a subject / individual in need thereof a therapeutic and / or preventive effective amount of the compound, or a pharmaceutically acceptable salt, polymorph, cocrystal, solvate, or the pharmaceutical composition.

[0173] In some embodiments, the orthopoxviruses described herein include, but are not limited to, smallpox virus, monkeypox virus, camelpox virus, cowpox virus, rabbitpox virus, and mousepox virus.

[0174] In the present invention, "treatment" generally refers to obtaining the desired pharmacological and / or physiological effect. The effect may be preventive, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or side effects caused by a disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) preventing a disease or symptom from occurring in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) inhibiting the symptoms of a disease, i.e., preventing its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0175] In the present invention, "subject" or "individual in need" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal refers to a human.

[0176] In the present invention, "effective amount" refers to an amount that is effective in achieving the desired therapeutic or preventive effect at the required dosage and time. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the substance / molecule to induce a desired response in the individual. The therapeutically effective amount also encompasses the amount in which the therapeutic beneficial effects of the substance / molecule outweigh any toxic or harmful consequences. "Prophylactically effective amount" refers to an amount that is effective in achieving the desired preventive effect at the required dosage and time. Usually, but not necessarily, since the preventive dose is used for the subject before the onset of the disease or in the early stages of the disease, the preventive effective amount will be lower than the therapeutically effective amount.

[0177] Definition of terms:

[0178] According to the practice in this field, The bonds used in the formulae herein to describe the points of attachment of the moiety or substituent to the parent core or structure.

[0179] A dash "-" that does not appear between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CF3 is attached through a carbon atom. As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced by a selection of designated groups, provided that the normal valence of the designated atom is not exceeded.

[0180] The term "one or more H atoms in XXX may be further replaced by 1-3 YYY" means that the H atoms in XXX may be replaced by YYY or not; when substituted, XXX may be replaced by 1 YYY or by multiple YYYs, and each YYY may be the same or different.

[0181] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently, or "C 1-4 Alkyl", or independently disclosed "C 1-3 alkyl".

[0182] The term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. 1-6 "Alkyl" refers to C1, C2, C3, C4, C5 and C6. In addition, for example, "C 1-6"Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0183] The term "cycloalkyl" refers to a cyclized alkyl group, including a monocyclic, bicyclic or polycyclic system. When the cycloalkyl group is bicyclic or polycyclic, each ring should be a saturated carbocyclic ring or a carbocyclic residue. The connection between each two rings of the bicyclic or polycyclic cycloalkyl group may include bridging, fusion or spiro connection. For example, C 3-10 Cycloalkyl refers to C3, C4, C5, C6, C7, C8, C9 and C 10 Cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0184] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0185] The term "carbocycle" refers to any stable 3-, 4-, 5-, 6- or 7-membered monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially saturated, unsaturated or aromatic. Herein, the 4-7 membered carbocycle is particularly 4-7 membered cycloalkyl, including but not limited to cyclobutyl, cyclopentyl, cyclohexyl.

[0186] The term "heterocycle" refers to substituted and unsubstituted 4- to 7-membered monocyclic or bicyclic groups; wherein at least one ring has at least one heteroatom (O, S or N), and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, with the restriction that the total number of heteroatoms in each ring is 4 or less, and further with the restriction that the ring contains at least one carbon atom. In some preferred embodiments, the heteroatom refers only to N or O, and the total number does not exceed 3, preferably only 1-2 heteroatoms. Carbon and sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and when valence permits, ring atoms on the heterocycle may be optionally substituted with =O (oxo). (For example: ). The heterocyclic group may be attached at any available nitrogen or carbon atom. The term "heterocycle" may be aromatic or non-aromatic, saturated, unsaturated or partially unsaturated; in this context, 4-7 membered heterocycles particularly refer to 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl, 4-7 membered heteroaryl, and exemplary 4-7 membered heterocycles include but are not limited to

[0187]

[0188] The term "heterocycloalkyl" refers to a heterocyclic group in which all the ring atoms are fully saturated, as defined above, for example

[0189] The term "heterocycloalkenyl" refers to a heterocyclic group having at least one carbon-carbon double bond in the heterocyclic ring as defined above, for example

[0190] The term "heteroaryl" refers to substituted and unsubstituted aryl groups described above having at least one heteroatom (O, N or S) in at least one ring, including aromatic 5-8-membered monocyclic groups, 8-10-membered bicyclic groups and 10-14-membered tricyclic groups, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, N or S. Each heteroatom-containing ring of the heteroaryl group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, with the proviso that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. Carbon and sulfur atoms may be optionally oxidized and nitrogen atoms may be optionally quaternized. Each ring of a bicyclic or tricyclic heteroaryl group is an aromatic ring.

[0191] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds and compounds useful as pharmaceutically acceptable compounds and / or intermediate compounds useful in preparing pharmaceutically acceptable compounds.

[0192] Effect of the invention:

[0193] The compound represented by formula (I) of the present invention shows excellent antiviral activity in the "inhibitory activity test on HFF-1 cytopathic effect caused by vaccinia virus" and in the pharmacokinetic test in mice, various parameter indicators are improved to varying degrees, especially showing a higher exposure and a significant improvement in bioavailability, with unexpected technical effects. DETAILED DESCRIPTION

[0194] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device and material similar or equivalent to that described herein can be used to implement or test the present invention, preferred methods, devices and materials are now described.

[0195] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured using a Bruker ASCENA-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts at 10 -6 (ppm) is given as the unit.

[0196] Reaction monitoring and MS measurements were performed using a Thermofisher ESQ (ESI) mass spectrometer.

[0197] The HPLC determination was performed using a Thermo Fisher U3000 DAD high pressure liquid chromatograph (GL Sciences ODS-HL HP 3 μm 3.0*100 mm chromatographic column).

[0198] The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15-0.2 mm. The thin layer chromatography separation and purification (Prep-TLC) product uses a high-performance thin layer chromatography preparation plate with a specification of 0.9-1.0 mm. Column chromatography uses Qingdao Ocean 200-300 mesh silica gel as a carrier. The developing solvent system used is A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound. The biotage isera one type preparative liquid phase is used for medium pressure preparative liquid phase purification.

[0199] In the following examples, unless otherwise specified, all reaction raw materials can be purchased from manufacturers such as San Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., and Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0200] In the following examples, unless otherwise specified, concentrated sulfuric acid refers to concentrated sulfuric acid with a mass percentage of 98%.

[0201] Abbreviated description

[0202]

[0203] Example 2

[0204] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2-d

[0205]

[0206] Step 1: Add 2-bromo-4-(trifluoromethyl)benzoic acid (2-a, 2000mg, 7.3mmol), concentrated sulfuric acid (1ml) and solvent methanol (20mL) to a 100ml single-mouth bottle, stir and reflux at 80℃ for 3hr. TLC monitoring shows that no raw material remains. Add saturated sodium bicarbonate to the reaction solution to adjust it to neutrality, extract the aqueous phase with 3*50ml ethyl acetate, combine the organic phases, wash with 1*50ml saturated brine, and dry over anhydrous sodium sulfate. Remove the solvent under reduced pressure to obtain methyl 2-bromo-4-(trifluoromethyl)benzoate (2-b, 2000mg, 7.0mmol, 95% yield).

[0207] Step 2: Into a 25 ml single-mouth bottle, methyl 2-bromo-4-(trifluoromethyl)benzoate (2-b, 100 mg, 0.35 mmol), Pd2(dba)3 (32 mg, 0.04 mmol), tri-tert-butylphosphine (7.1 mg,

[0208] 0.04mmol), sodium deuterated formate (96mg, 1.4mmol) and solvent DMSO (2mL), replaced with nitrogen three times, and stirred at 80℃ for 12hr under nitrogen atmosphere. LCMS monitoring showed that no raw material remained. The reaction solution was cooled to room temperature, filtered, and the filtrate was dried under reduced pressure. The crude product was purified by prep-TLC (EA:PE=1:10) to obtain 4-(trifluoromethyl)benzoic acid methyl ester-2-d (2-c, 60mg, 0.29mmol, 82%yield).

[0209] Step 3: 4-(trifluoromethyl)benzoic acid methyl ester-2-d (2-c, 60 mg, 0.29 mmol), hydrazine hydrate (0.5 ml) and solvent methanol (5 ml) were added to a 50 ml single-mouth bottle in sequence, and the mixture was stirred and refluxed at 80°C for 2 hr. No raw material remained after TLC monitoring. The reaction solution was dried under reduced pressure, 20 ml of DCM was added, and 3*5 ml of saturated brine was washed. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by prep-TLC (DCM: MeOH = 30: 1) to obtain 4-(trifluoromethyl)benzoic acid hydrazide-2-d (2-d, 50 mg, 0.24 mmol, 82% yield). MS Calcd: 205.06; MS Found: 206.08 ([M+H] + ).

[0210] Step 4: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 55 mg, 0.29 mmol), 4-(trifluoromethyl)benzohydrazide-2-d (2-d, 50 mg, 0.24 mmol), DIPEA (31 mg, 0.24 mmol) and solvent ethanol (10 ml) to a 50 ml single-mouth bottle and stir at 80 ° C for 12 hours. LC-MS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, 3*5 ml of saturated brine is washed, the organic phase is dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product is purified by Prep-TLC (DCM: MeOH = 30: 1) to obtain the title compound: N-

[0211] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropa[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2-d (2, 40 mg, 0.11 mmol, 43% yield). MS Calcd: 377.11; MS Found: 378.10 ([M+H] + ). 1 H NMR(600MHz,DMSO-d6)δ11.37(s,1H),8.10-8.05(m,1H),7.94-7.92(m,2H),5.81-5.7 8(m,2H),3.31–3.21(m,4H),1.21-1.15(m,2H),0.29-0.26(m,1H),0.09-0.06(m,1H).

[0212] Example 3

[0213] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-3-d

[0214]

[0215] Step 1: Add 3-bromo-4-(trifluoromethyl)benzoic acid (3-a, 3000mg, 11.1mmol), concentrated sulfuric acid (1.5ml) and solvent methanol (30mL) to a 100ml single-mouth bottle, stir and reflux at 80℃ for 3hr. TLC monitoring shows that there is no residual raw material. Add saturated sodium bicarbonate to the reaction solution to adjust it to neutrality, extract the aqueous phase with 3*50ml ethyl acetate, combine the organic phases, wash with 1*50ml saturated brine, and dry over anhydrous sodium sulfate. Dry under reduced pressure to obtain 3-bromo-4-(trifluoromethyl)benzoic acid methyl ester (3-b, 2900mg, 10.2mmol, 91% yield).

[0216] Step 2: Add 3-bromo-4-(trifluoromethyl)benzoic acid methyl ester (3-b, 100 mg, 0.35 mmol), Pd2(dba)3 (32 mg, 0..04 mmol), tri-tert-butylphosphine (7.1 mg, 0.04 mmol), sodium deuterated formate (96 mg, 1.4 mmol) and solvent DMSO (2 mL) to a 25 ml single-mouth bottle, replace with nitrogen 3 times, and stir at 80 ° C for 12 hours under nitrogen atmosphere. LCMS monitoring shows that there is no residual raw material. The reaction solution is cooled to room temperature, filtered, and the filtrate is dried under reduced pressure. The crude product is purified by prep-TLC (EA: PE = 1: 10) to obtain 4-(trifluoromethyl)benzoic acid methyl ester-3-d (3-c, 65 mg, 0.31 mmol, 88% yield).

[0217] Step 3: methyl 4-(trifluoromethyl)benzoate-3-d (3-c, 65 mg, 0.31 mmol), hydrazine hydrate (0.5 ml) and methanol (5 ml) were added to a 50 ml single-mouth bottle in sequence, and the mixture was stirred and refluxed at 80°C for 2 hr. No raw material remained after TLC monitoring. The reaction solution was dried under reduced pressure, 20 ml of DCM was added, and 3*5 ml of saturated brine was washed. The organic phase was dried over anhydrous sodium sulfate. The crude product was purified by prep-TLC (DCM: MeOH = 30: 1) to obtain 4-(trifluoromethyl)benzoylhydrazide-3-d (3-d, 50 mg, 0.24 mmol, 76% yield). MS Calcd: 205.06; MS Found: 206.04 ([M+H] + ).

[0218] Step 4: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 55 mg, 0.29 mmol), 4-(trifluoromethyl)benzohydrazide-3-d (3-d, 50 mg, 0.24 mmol), DIPEA (31 mg, 0.24 mmol) and solvent ethanol (10 ml) to a 50 ml single-mouth bottle and stir at 80 ° C for 12 hours. LC-MS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed. The organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure. The crude product is purified by Prep-TLC (DCM: MeOH = 30: 1) to obtain the title compound: N-

[0219] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-3-d (3, 50 mg, 0.13 mmol, 54% yield,). MS Calcd: 377.11; MS Found: 378.09 ([M+H] + ). 1 H NMR (600MHz, DMSO-d6) δ11.25 (s, 1H), 8.09-8.06 (m, 2H), 7.93 (d, J = 8.4Hz, 1H), 5.81-5 .78(m,2H),3.32–3.19(m,4H),1.20-1.14(m,2H),0.29-0.25(m,1H),0.09-0.05(m,1H).

[0220] Example 4

[0221] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxooctahydro-4,6-ethylcyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2-d

[0222]

[0223] Step 1: In a 25 ml single-necked bottle, N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2-d (2, 15 mg, 0.04 mmol), Pd / C (30%) (2 mg) and solvent methanol (5 ml) were added. The gas was replaced with hydrogen three times and stirred at room temperature for 2 hr under a hydrogen atmosphere. The reaction was completed by LC-MS monitoring. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 2*5 ml of methanol. The organic phase was dried under reduced pressure to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxooctahydro-4,6-ethylcyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2-d (4, 12 mg, 0.03 mmol, 79% yield,). MS Calcd: 379.13; MS Found: 380.09 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.33(s,1H),8.12(d,J=8.4Hz,1H),8.00–7.93(m,2H),3.25 -3.19(m,2H),2.40(s,2H),1.50–1.07(m,6H),0.83-0.80(m,1H),0.58–0.49(m,1H).

[0224] Example 5

[0225] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxooctahydro-4,6-ethylcyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-3-d

[0226]

[0227] Step 1: In a 25 ml single-necked bottle, N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-3-d (3, 15 mg, 0.04 mmol), Pd / C (30%) (2 mg) and solvent methanol (5 ml) were added. The atmosphere was replaced with hydrogen three times and stirred at room temperature for 2 hr under a hydrogen atmosphere. The reaction was completed by LC-MS monitoring. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 2*5 ml of methanol. The organic phase was dried under reduced pressure to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxooctahydro-4,6-ethylcyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-3-d (5, 13 mg, 0.03 mmol, 86% yield,). MS Calcd: 379.13; MS Found: 380.09 ([M+H]). 1H NMR (400MHz, DMSO-d6) δ11.34 (s, 1H), 8.13-8.11 (m, 2H), 7.95 (d, J = 8.4Hz, 1H), 3.25 -3.19(m,2H),2.40(s,2H),1.51–1.06(m,6H),0.83-0.80(m,1H),0.56-0.50(m,1H).

[0228] Example 6

[0229] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)2-fluoro-4-(trifluoromethyl)benzamide-6-d

[0230]

[0231] Step 1: Add 2-fluoro-4-(trifluoromethyl)benzoic acid (6-a, 200 mg, 0.96 mmol), bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (III) (28 mg, 0.05 mmol), sodium acetate (86 mg, 1.06 mmol) and solvent heavy water (10 mL) into a 50 ml single-mouth bottle and stir at 90°C for 48 hr. LCMS monitoring showed that no raw material remained. The reaction solution was adjusted to acidity by adding 1 M hydrochloric acid, and the aqueous phase was extracted with 3*30 ml DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 2-fluoro-4-(trifluoromethyl)benzoic acid-6-d (6-b, 190 mg, 0.91 mmol, 94% yield). MS Calcd: 209.02; MS Found: 208.01 ([MH] - ).

[0232] Step 2: Add 2-fluoro-4-(trifluoromethyl)benzoic acid-6-d (6-b, 150 mg, 0.72 mmol) and solvent methanol (10 ml) to a 50 ml single-mouth bottle, slowly add concentrated sulfuric acid (0.5 ml), stir and reflux at 80 ° C for 2 hours. TLC monitoring shows that there is no residual raw material, add hydrazine hydrate (2 ml) to the reaction solution, and continue stirring at 80 ° C for 2 hours. LC-MS monitoring shows that there is no residual raw material. The reaction solution is cooled to room temperature, the reaction solution is dried under reduced pressure, 30 ml DCM is added, and the organic phase is washed with 3*10 ml saturated brine. The organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure to obtain 2-fluoro-4-(trifluoromethyl)benzoylhydrazide-6-d (6-c, 180 mg, 0.58 mmol, 81% yield). MS Calcd: 223.05; MS Found: 224.06 ([M+H] + )..

[0233] Step 3: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 102 mg, 0.54 mmol), 2-fluoro-4-(trifluoromethyl)benzohydrazide-6-d (6-c, 100 mg, 0.45 mmol), DIPEA (57 mg, 0.45 mmol) and solvent ethanol (15 ml) to a 50 ml single-mouth bottle, and stir at 80 ° C for 12 hours. LC-MS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed, the organic phase is dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH=30:1) to give the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)2-fluoro-4-(trifluoromethyl)benzamide-6-d (6, 80 mg, 0.2 mmol, 43% yield). MS Calcd: 395.10; MS Found: 396.06 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.90(dd,J=10.0,1.6Hz,1H),7.74(d,J=1.6Hz,1H),5. 80-5.76(m,2H),3.31–3.19(m,4H),1.20-1.16(m,2H),0.29-0.24(m,1H),0.08-0.04(m,1H).

[0234] Example 7

[0235] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropano[f]isoindol-2(1H)-yl)4-(trifluoromethoxy)benzamide-2,6-d2

[0236]

[0237] Step 1: Add 4-(trifluoromethoxy)benzoic acid (7-a, 200 mg, 0.97 mmol), di(hexafluoroantimonate)triacetonitrile (pentamethylcyclopentadienyl)rhodium (III) (29 mg, 0.05 mmol), sodium acetate (87 mg, 1.07 mmol) and solvent heavy water (10 mL) into a 50 ml single-mouth bottle and stir at 90°C for 24 hours. LCMS monitoring showed that no raw material remained. The reaction solution was adjusted to acidity by adding 1M hydrochloric acid, and the aqueous phase was extracted with 3*30 ml DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 4-(trifluoromethoxy)benzoic acid-2,6-d2 (7-b, 180 mg, 0.86 mmol, 89% yield) MS Calcd: 208.03; MS Found: 207.00 ([MH] - ).

[0238] Step 2: Add 4-(trifluoromethoxy)benzoic acid-2,6-d2 (7-b, 180 mg, 0.86 mmol) and methanol (15 ml) to a 50 ml single-mouth bottle, slowly add concentrated sulfuric acid (0.5 ml), stir and reflux at 80 ° C for 2 hours. TLC monitoring shows that there is no residual raw material, add hydrazine hydrate (2 ml) to the reaction solution, and continue stirring at 80 ° C for 2 hours. LCMS monitoring shows that there is no residual raw material. The reaction solution is cooled to room temperature, the reaction solution is dried under reduced pressure, 30 ml of DCM is added, and the organic phase is washed with 3*10 ml of saturated brine. The organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure to obtain 4-(trifluoromethoxy)benzoylhydrazide-2,6-d2 (7-c, 150 mg, 0.68 mmol, 78% yield). MS Calcd: 222.06; MS Found: 223.20 ([M+H] + ).

[0239] Step 3: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 102 mg, 0.54 mmol), 4-(trifluoromethoxy)benzohydrazide-2,6-d2 (7-c, 100 mg, 0.45 mmol), DIPEA (57 mg, 0.45 mmol) and solvent ethanol (15 ml) to a 50 ml single-mouth bottle, stir at 80°C for 12 hr. LCMS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed, the organic phase is dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to give the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3,3a, 4,4a, 5,5a, 6,6a-octahydro-4,6-vinylidenecyclopropane [f] isoindole-2 (1H) -yl) 4-(trifluoromethoxy)benzamide-2,6-d2 (7, 110 mg, 0.28 mmol, 62% yield,). MS Calcd: 394.11; MS Found: 395..07 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.54(s,2H),5.84–5.72(m,2H),3.31–3.18(m,4H),1.23-1.18(m,2H),0.29-0.26(m,1H),0.06-0.05(m,1H).

[0240] Example 8

[0241] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-2-methyl-4-(trifluoromethyl)benzamide-6-d

[0242]

[0243] Step 1: Add methyl 2-bromo-4-(trifluoromethyl)benzoate (8-a, 500 mg, 1.7 mmol), methylboronic acid (158 mg, 2.65 mmol), Pd(dppf)Cl2 (129 mg,

[0244] 0.17mmol), potassium carbonate (732mg, 5.3mmol) and solvent dioxane (10mL), water (2ml), stirred and refluxed at 120℃ for 12hr. TLC monitoring showed that no raw material remained. The reaction solution was dried under reduced pressure, 50ml of saturated brine was added, 3*50ml of ethyl acetate was used to extract the aqueous phase, the organic phases were combined, washed with 1*50ml of saturated brine, and dried over anhydrous sodium sulfate. The crude product of 2-methyl-4-(trifluoromethyl)benzoic acid methyl ester (8-b, 350mg) was directly used in the next step reaction.

[0245] Step 2: Add methyl 2-methyl-4-(trifluoromethyl)benzoate (8-b, 350 mg), lithium hydroxide (400 mg, 16 mmol) and solvent methanol (5 mL), tetrahydrofuran (5 ml), water (5 ml) to a 50 ml single-mouth bottle, and stir at room temperature overnight. TLC monitoring shows that no raw material remains. The reaction solution is decompressed to remove the organic solvent, 1M hydrochloric acid is used to adjust the pH to acidic, 3*30 ml EA is used to extract the aqueous phase, the organic phases are combined, dried over anhydrous sodium sulfate, decompressed and dried, and the crude product is purified by rapid column chromatography (EA:PE=0 to 30% in 20 min) to obtain 2-methyl-4-(trifluoromethyl)benzoic acid (8-c, 250 mg, 1.13 mmol, 80% yield).

[0246] Step 3: Add 2-methyl-4-(trifluoromethyl)benzoic acid (8-c, 200 mg, 0.98 mmol), bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III) (29 mg,

[0247] 0.05mmol), sodium acetate (88mg, 1.07mmol) and solvent heavy water (10mL), stirred at 90℃ for 24hr. LC-MS monitoring showed that no raw material remained. The reaction solution was adjusted to acidity by adding 1M hydrochloric acid, and the aqueous phase was extracted with 3*30ml DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 2-methyl-4-(trifluoromethyl)benzoic acid-6-d (8-d, 180mg, 0.88mmol, 89% yield) MS Calcd: 205.05; MS Found: 204.03 ([MH] - ).

[0248] Step 4: Add 2-methyl-4-(trifluoromethyl)benzoic acid-6-d (8-d, 180 mg, 0.29 mmol), concentrated sulfuric acid (0.5 ml) and solvent methanol (5 ml) to a 50 ml single-mouth bottle, stir and reflux at 80°C for 2 hours. Then slowly add hydrazine hydrate (2 ml) to the system, continue to stir and reflux at 80°C for 2 hours. TLC monitoring shows that there is no residual raw material. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed. The organic phase is dried over anhydrous sodium sulfate, and the crude product is purified by prep-TLC (DCM: MeOH = 30: 1) to obtain 2-methyl-4-(trifluoromethyl)benzoylhydrazide-6-d (8-e, 100 mg, 0.46 mmol, 52% yield). MS Calcd: 219.07; MSFound: 220.08 ([M+H] + ).

[0249] Step 5: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 104 mg, 0.55 mmol), 2-methyl-4-(trifluoromethyl)benzohydrazide-6-d (8-e, 100 mg, 0.46 mmol), DIPEA (58 mg, 0.46 mmol) and solvent ethanol (10 ml) to a 50 ml single-mouth bottle, stir at 80°C for 12 hr. LCMS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed, and the organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH=30:1) to give the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-2-methyl-4-(trifluoromethyl)benzamide-6-d (8,70 mg, 0.18 mmol, 39% yield). MS Calcd: 391.37; MS Found: 392.10 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δs(11.09,1H),7.71(s,1H),7.67(s,1H),5.78-5.76(m,2H),3. 31–3.13(m,4H),2.45(s,3H),1.22-1.14(m,2H),0.29-0.24(m,1H),0.08-0.04(m,1H).

[0250] Example 9

[0251] N-(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2,6-d2

[0252]

[0253] Step 1: Add 4-(trifluoromethyl)benzoic acid (9-a, 100 mg, 0.53 mmol), potassium acetate (62 mg, 0.63 mmol), tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium di(hexafluoroantimonate) (16 mg, 0.03 mmol) to heavy water (2 ml), raise the temperature to 90°C, stir for 48 hours, LCMS shows that the raw material reaction is complete, cool to room temperature, add hydrochloric acid (1N) to adjust the pH to 5, extract with DCM (5 ml x 3), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4-(trifluoromethyl)benzoic acid-2,6-d2 (9-b, 91 mg, 0.47 mmol, 89% yield). MS Calcd: 192.04; MS Found: 191.04 ([MH] - ). It was directly used for the next step reaction without purification.

[0254] Step 2: 4-(Trifluoromethyl)benzoic acid-2,6-d2 (9-b, 91 mg, 0.47 mmol) was added to a methanol solution (2 ml), and then a catalytic amount of concentrated sulfuric acid was added dropwise. The temperature was raised to 80°C and stirred for 2 hours. TLC showed that the reaction of the raw material was complete. Hydrazine hydrate (2 ml) was added to the reaction system, and the temperature was maintained at 80°C and stirred for 2 hours. TLC showed that the reaction of the raw material was complete. Stirring was stopped and the system was concentrated under reduced pressure. The residue was extracted with DCM (3 ml x 3). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column (EA: PE = 3: 1) to obtain 4-(trifluoromethyl)benzohydrazide-2,6-d2 ((9-c, 56 mg, 0.27 mmol, 58% yield). MS Calcd: 206.06; MS Found: 207.06 ([M+H] + ).

[0255] Step 3: 4-(trifluoromethyl)benzoylhydrazide-2,6-d2 (9-c, 56 mg, 0.27 mmol),

[0256] (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 62 mg, 0.32 mmol), DIPEA (104 mg, 0.81 mmol) were added to anhydrous ethanol (2 ml), placed in a microwave reactor, heated to 90°C, stirred for 1 hour, and the reaction was completed, concentrated under reduced pressure, The residue was purified by slurrying with ethyl acetate: petroleum ether (1:1, 4 ml) to obtain the title compound: N-(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2,6-d2 (9, 95 mg, 0.25 mmol, 93% yield). MS Calcd: 378.12; MS Found: 379.12 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),7.93(s,2H),5.82-5.77(m,2H),3.31-3.22(m,4H),1.21-1.15(m,2H),0.29-0.24(m,1H),0.06-0.04(m,1H).

[0257] Example 10

[0258] N-(3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-3-methyl-4-(trifluoromethyl)benzamide-2,6-d2

[0259]

[0260] Step 1: Add methyl 3-bromo-4-(trifluoromethyl)benzoate (3-b, 500 mg, 1.77 mmol), sodium carbonate (562 mg, 5.32 mmol), Pd(dppf)Cl2 (132 mg, 0.18 mmol) and methylboric acid (160 mg, 2.65 mmol) to a mixed solvent of dioxane (10 ml) and water (2 ml), replace with nitrogen for 3 minutes, heat to 100 ° C, stir for 18 hours, stop the reaction, concentrate under reduced pressure, and purify the residue by silica gel column (EA: PE = 1: 4) to obtain methyl 3-methyl-4-(trifluoromethyl)benzoate (10-a, 321 mg, 1.47 mmol, 83% yield).

[0261] Step 2: Add methyl 3-methyl-4-(trifluoromethyl)benzoate (10-a, 321 mg, 1.47 mmol) to methanol solution (10 ml), then add sodium hydroxide aqueous solution (176 mg, 4.41 mmol) dropwise, stir at room temperature for 3 hours, and concentrate under reduced pressure. Adjust the pH of the residue to 5 with HCl (1N), and extract with dichloromethane (5 ml x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate to obtain 3-methyl-4-(trifluoromethyl)benzoic acid (10-b, 260 mg, 1.27 mmol, 87% yield) without purification and directly react in the next step. MS Calcd: 204.04; MS Found: 203.04 ([MH] - ).

[0262] Step 3: Add 3-methyl-4-(trifluoromethyl)benzoic acid (10-b, 100 mg, 0.49 mmol), potassium acetate (62 mg, 0.63 mmol), tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium di(hexafluoroantimonate) (16 mg, 0.03 mmol) to heavy water (2 ml), raise the temperature to 90°C, stir for 48 hours, LCMS shows that the raw material reaction is complete, cool to room temperature, add hydrochloric acid (1N) to adjust the pH to 5, extract with DCM (5 ml x 3), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 3-methyl-4-(trifluoromethyl)benzoic acid-2,6-d2 (10-c, 87 mg, 0.42 mmol, 86% yield). MS Calcd: 206.05; MS Found: 205.05 ([MH] - ). No purification is required and the product can be directly used for the next reaction.

[0263] Step 4: Add 3-methyl-4-(trifluoromethyl)benzoic acid-2,6-d2 (10-c, 87 mg, 0.42 mmol) to a methanol solution (2 ml), then drop a catalytic amount of concentrated sulfuric acid, heat to 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, add hydrazine hydrate (2 ml) to the reaction system, continue to maintain at 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, stop stirring, concentrate under reduced pressure, extract the residue with DCM (3 ml x 3), combine the organic layers, concentrate under reduced pressure, and purify the residue by silica gel column (EA: PE = 3: 1) to obtain 3-methyl-4-(trifluoromethyl)benzoic acid hydrazide-2,6-d2 (10-d, 28 mg, 0.13 mmol, 30% yield). MS Calcd: 220.08; MS Found: 221.08 ([M+H] + ).

[0264] Step 5: 3-methyl-4-(trifluoromethyl)benzohydrazide-2,6-d2 (10-d, 28 mg, 0.13 mmol), (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 30 mg, 0.16 mmol), DIPEA (50 mg, 0.39 mmol) were added to anhydrous ethanol (2 ml), placed in a microwave reactor, and heated to 30 ℃. The mixture was heated to 90°C and stirred for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by slurrying with ethyl acetate: petroleum ether (1:1, 4 ml) to obtain the title compound: N-(3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-3-methyl-4-(trifluoromethyl)benzamide-2,6-d2 (10,44 mg, 0.11 mmol, 86% yield). MS Calcd: 392.13; MS Found: 393.13 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),7.85(s,1H),5.81-5.74(m,2H),3.31-3.22(m,4H),1.20–1.16(m,2H),0.30-0.25(m,1H),0.07-0.05(m,1H).

[0265] Embodiment 11

[0266] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecycloprop[f]isoindol-2(1H)-yl)-4-(methylsulfonyl)benzamide

[0267]

[0268] Step 1: Add the reactants methyl 4-(methylsulfonyl)benzoate (11-a, 500 mg, 2.33 mmol) and MeOH (30 mL) to a 100 mL eggplant-shaped flask, and then add hydrazine hydrate solution (1.5 mL, 46.6 mmol). Stir at 80°C for 14 hours. TLC monitors the completion of the reaction of the raw materials, the reaction solution is concentrated under reduced pressure, and the crude product is purified by flash column chromatography (DCM: MeOH = 40: 1) to obtain 4-(methylsulfonyl)benzohydrazide (11-b, 468 mg, 2.18 mmol, 93.6% yield). MS Calcd: 214.04; MSFound: 215.04 ([M+H] + ).

[0269] Step 2: Compound 4-(methylsulfonyl)benzohydrazide (11-b, 100 mg, 0.47 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 106 mg, 0.56 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85° C. overnight. After the reaction of the raw materials was completed by TLC monitoring, the reaction solution was directly concentrated. The crude product was purified by flash column chromatography (DCM:MeOH=33:1) to give the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(methylsulfonyl)benzamide (11,83 mg, 0.21 mmol, 46.2%). MS Calcd: 386.09; MS Found: 387.30 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),8.09(s,4H),5.89–5.75(m,2H),3.32-3.23(m,4H),1.23-1.12(m,2H),0.30-0.25(m,1H),0.08–0.03(m,1H).

[0270] Embodiment 13

[0271] 3-Bromo-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-fluorobenzamide-2,6-d2

[0272]

[0273] Step 1: Add 3-bromo-4-fluorobenzoic acid (13-a, 100 mg, 0.46 mmol), potassium acetate (54 mg, 0.55 mmol), tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium di(hexafluoroantimonate) (16 mg, 0.03 mmol) to heavy water (2 ml), raise the temperature to 90°C, stir for 48 hours, LCMS shows that the raw material reaction is complete, cool to room temperature, add hydrochloric acid (1N) to adjust the pH to 5, extract with DCM (5 ml x 3), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 3-bromo-4-fluorobenzoic acid-2,6-d2 (13-b, 83 mg, 0.38 mmol, 82% yield). MS Calcd: 219.95; MS Found: 218.95 ([MH] - ). It was directly used for the next step reaction without purification.

[0274] Step 2: Add 3-bromo-4-fluorobenzoic acid-2,6-d2 (13-b, 83 mg, 0.38 mmol) to a methanol solution (2 ml), then drop a catalytic amount of concentrated sulfuric acid, heat to 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, add hydrazine hydrate (2 ml) to the reaction system, continue to maintain at 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, stop stirring, concentrate under reduced pressure, extract the residue with DCM (3 ml x 3), combine the organic layers, concentrate under reduced pressure, and purify the residue by silica gel column (EA: PE = 3: 1) to obtain 3-bromo-4-fluorobenzoic acid hydrazide-2,6-d2 (13-c, 27 mg, 0.11 mmol, 30% yield). MS Calcd: 233.98; MS Found: 234.98 ([M+H] + ).

[0275] Step 3: 3-bromo-4-fluorobenzoylhydrazide-2,6-d2 (13-c, 27 mg, 0.11 mmol),

[0276] (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 25 mg, 0.13 mmol), DIPEA (43 mg, 0.33 mmol) were added to anhydrous ethanol (1 ml), placed in a microwave reactor, heated to 90 ° C, stirred for 1 hour, the reaction was completed, and reduced The residue was purified by prep-HPLC to give the title compound: 3-bromo-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-fluorobenzamide-2,6-d2 (13,12 mg, 0.03 mmol, 27% yield). MS Calcd: 406.03; MS Found: 407.03 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),7.57(d,J=8.8Hz,1H),5.81–5.76(m,2H ),3.32-3.22(m,4H),1.24–1.15(m,2H),0.30-0.25(m,1H),0.08-0.04(m,1H).

[0277] Embodiment 14

[0278] 2-Bromo-N-(1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindole-2(1H)-

[0279] 4-(Trifluoromethyl)benzamide-6-d

[0280]

[0281] Step 1: Compound 2-bromo-4-(trifluoromethyl)benzoic acid (2-a, 200 mg, 0.74 mmol), catalyst di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (III) (22.2 mg, 0.04 mmol) and potassium acetate (72.8 mg, 0.89 mmol) were placed in a 10 mL microwave tube, 2 mL of D2O was added thereto, and the reaction was stirred at 90°C for 24 h. LC-MS detected that the reaction of the raw material was complete, and 15 mL of 1M HCl solution was added to the reaction solution. 20 mL of DCM was added, and then the liquids were separated. The aqueous phase was extracted with DCM (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, 2-bromo-4-(trifluoromethyl)benzoic acid-6-d (14-a, 190 mg, 0.70 mmol, 94.7% yield) was obtained. MS Calcd:268.94;MS Found:267.94([MH] - ).

[0282] Step 2: Add compound 2-bromo-4-(trifluoromethyl)benzoic acid-6-d (14-a, 190 mg, 0.7 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.02 mL, 0.46 mmol) dropwise, stir and reflux at 80 ° C for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (1 mL, 24.38 mmol) and continue to reflux for 0.5 hours. The reaction solution was dried under reduced pressure, 50 mL DCM was added, and the organic phase was washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 2-bromo-4-(trifluoromethyl)benzoylhydrazide-6-d (14-b, 190 mg, 0.67 mmol, 95% yield). MS Calcd: 282.97; MS Found: 283.92 ([M+H] + ).

[0283] Step 3: Compound 2-bromo-4-(trifluoromethyl)benzohydrazide-6-d (14-b, 100 mg, 0.35 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 80.3 mg, 0.42 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85° C. overnight. After the reaction of the raw materials was completed by TLC monitoring, the reaction solution was directly concentrated. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to give the title compound: 2-bromo-N-(1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-6-d (14, 98 mg, 0.21 mmol, 61% yield). MS Calcd: 455.02; MS Found: 456.02 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.28(brs,1H),8.16(d,J=2.0Hz,1H),7.92(d,J=2.0Hz,1H),5.81 -5.77(m,2H),3.32-3.25(m,4H),1.22-1.18(m,2H),0.31-0.26(m,1H),0.09–0.06(m,1H).

[0284] Embodiment 15

[0285] 4-(Difluoromethyl)-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-

[0286] Vinylenecyclopropyl[f]isoindol-2(1H)-yl)benzamide-2,6-d2

[0287]

[0288] Step 1: Compound 4-(difluoromethyl)benzoic acid (15-a, 172 mg, 1 mmol), catalyst di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (III) (29.9 mg, 0.05 mmol) and potassium acetate (117.6 mg, 1.2 mmol) were placed in a 10 mL microwave tube, 2 mL D2O was added thereto, and the reaction was stirred at 90°C for 24 h. LC-MS detected that the reaction of the raw material was complete, and 15 mL 1M HCl solution was added to the reaction solution. 20 mL DCM was added, and then the liquids were separated. The aqueous phase was extracted with DCM (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, 4-(difluoromethyl)benzoic acid-2,6-d2 (15-b, 160 mg, 0.92 mmol, 91.9% yield) was obtained. MS Calcd: 174.05; MS Found: 173.01 ([MH] - ).

[0289] Step 2: Add compound 4-(difluoromethyl)benzoic acid-2,6-d2 ((15-b, 160 mg, 0.92 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.02 mL, 0.46 mmol) dropwise therein, stir and reflux at 80 degrees Celsius for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (0.58 mL, 18.38 mmol) thereto, and continue to reflux for 0.5 hours. The reaction solution was dried under reduced pressure, 50 mL DCM was added, and the organic phase was washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the target compound: 4-(difluoromethyl)benzoylhydrazide-2,6-d2 (15-c, 122 mg, 0.65 mmol, 70.5% yield) MS Calcd: 188.07; MS Found: 189.11 ([M+H] + ).

[0290] Step 3: Compound 4-(difluoromethyl)benzoylhydrazide-2,6-d2 (15-c, 122 mg, 0.65 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 148 mg, 0.78 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85°C overnight. TLC monitored the completion of the reaction of the raw materials, and the reaction solution was directly concentrated. The crude product was purified by Prep-TLC (DCM: MeOH = 20: 1) to obtain the title compound: 4-(difluoromethyl)-N-

[0291] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)benzamide-2,6-d2 (15,168 mg, 0.47 mmol, 71.9% yield). MS Calcd: 360.13; MS Found: 361.10 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.26 (brs, 1H), 7.74 (s, 2H), 7.13 (t, J = 56.0Hz, 1H), 5.82-5. 77(m,2H),3.30–3.22(m,4H),1.22-1.15(m,2H),0.30-0.24(m,1H),0.08–0.04(m,1H).

[0292] Example 16

[0293] 4-(Difluoromethyl)-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-

[0294] Vinylenecyclopropyl[f]isoindol-2(1H)-yl)benzamide

[0295]

[0296] Step 1: Add compound 4-(difluoromethyl)benzoic acid (15-a, 172.1 mg, 1 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.03 mL, 0.5 mmol) dropwise, stir and reflux at 80 degrees Celsius for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (0.63 mL, 20 mmol) and continue to reflux for 0.5 hours. The reaction solution is dried under reduced pressure, 50 mL DCM is added, and the organic phase is washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the target compound: 4-(difluoromethyl)benzoylhydrazide (16-a, 160 mg, 0.86 mmol, 85.9% yield) MS Calcd: 186.06; MS Found: 187.07 ([M+H] + ).

[0297] Step 2: Compound 4-(difluoromethyl)benzohydrazide (16-a, 160 mg, 0.86 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 196 mg, 1.03 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85°C overnight. TLC monitored the completion of the reaction of the raw materials, and the reaction solution was directly concentrated. The crude product was purified by Prep-TLC (DCM: MeOH = 20: 1) to obtain the title compound: 4-(difluoromethyl)-N-

[0298] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)benzamide (16,230 mg, 0.64 mmol, 74.7% yield). MS Calcd: 358.11; MS Found: 359.13 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.02(d,J=8.0Hz,2H),7.74(d,J=8.0Hz,2H),7.13(t,J=56Hz, 1H),5.82-5.76(m,4H),3.30-3.22(m,4H),1.20-1.16(m,4H),0.30-0.25(m,1H),0.08-0.04(m,1H).

[0299] Embodiment 17

[0300] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-2-methyl-4-nitrobenzamide-2,6-d2

[0301]

[0302] Step 1: Add 4-nitrobenzoic acid (17-a, 150 mg, 0.90 mmol), di(hexafluoroantimonate)triacetonitrile (pentamethylcyclopentadienyl)rhodium (III) (26.8 mg, 0.04 mmol), sodium acetate (81.0 mg, 0.99 mmol) and solvent heavy water (2 mL) into a 50 ml single-mouth bottle and stir at 90°C for 24 hours. LCMS monitoring showed that no raw material remained. The reaction solution was adjusted to acidity by adding 1M hydrochloric acid, and the aqueous phase was extracted with 3*30 ml DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 4-nitrobenzoic acid-2,6-d2 (17-b, 115 mg, 0.68 mmol, 75.8% yield). MS Calcd: 169.03; MS Found: 167.99 ([MH] - ).

[0303] Step 2: Add 4-nitrobenzoic acid-2,6-d2 (17-b, 115 mg, 0.68 mmol), concentrated sulfuric acid (0.4 ml) and solvent methanol (8 ml) to a 50 ml single-mouth bottle, stir and reflux at 80°C for 2 hours. Then slowly add hydrazine hydrate (1.55 ml) to the system, continue stirring and reflux at 80°C for 2 hours. TLC monitoring shows that there is no residual raw material. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and washed with 3*5 ml of saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain 4-nitrobenzohydrazide-2,6-d2 (17-c, 104 mg, 0.57 mmol, 83.5% yield). MS Calcd: 183.06; MS Found: 182.07 ([MH] - ).

[0304] Step 3: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 130 mg, 0.68 mmol), 4-nitrobenzohydrazide-2,6-d2 (17-c, 104 mg, 0.57 mmol) and solvent ethanol (6 ml) to a 50 ml single-mouth bottle, and stir at 70 ° C for 12 hours. LC-MS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and washed with 3*5 ml of saturated brine. The organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure. The crude product is purified by medium pressure column (DCM = 98%, CH3OH = 2%) and thin layer chromatography to obtain the title compound: N-

[0305] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-2-methyl-4-nitrobenzamide-2,6-d2 (17, 20 mg, 0.06 mmol, 10% yield). MS Calcd: 355.11; MS Found: 354.15 ([MH]) - . 1 H NMR (600MHz, DMSO-d6) δ11.43(s,1H),8.37(s,2H),5.82-5.78(m,2H),3.30–3.23(m,4H),1.20-1.15(m,2H),0.29-0.25(m,1H),0.08-0.04(m,1H).

[0306] Embodiment 18

[0307] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)3-bromo-4-(trifluoromethyl)benzamide-2,6-d2

[0308]

[0309] Step 1: Add 3-bromo-4-(trifluoromethyl)benzoic acid (3-a, 400 mg, 1.49 mmol), bis(hexafluoroantimonate)triacetonitrile (pentamethylcyclopentadienyl)rhodium (III) (44 mg, 0.07 mmol), sodium acetate (134 mg, 1.61 mmol) and solvent heavy water (10 mL) into a 50 ml single-mouth bottle and stir at 90°C for 48 hours. LC-MS monitoring showed that no raw material remained. The reaction solution was adjusted to acidity by adding 1M hydrochloric acid, and the aqueous phase was extracted with 3*30 ml DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the target compound 3-bromo-4-(trifluoromethyl)benzoic acid-2,6-d2 (18-a, 350 mg, 1.29 mmol, 86.8% yield) MS Calcd: 269.95; MSFound: 268.91 ([MH] - ).

[0310] Step 2: 3-bromo-4-(trifluoromethyl)benzoic acid-2,6-d2 (18-a, 100 mg, 0.36 mmol) and solvent methanol (10 ml) were added to a 50 ml single-mouth bottle in sequence, and concentrated sulfuric acid (0.5 ml) was slowly added dropwise, and stirred at 80°C for 2 hours. TLC monitoring showed that there was no residual raw material, and hydrazine hydrate (2 ml) was added to the reaction solution, and stirring was continued at 80°C for 2 hours. LCMS monitoring showed that there was no residual raw material. The reaction solution was cooled to room temperature, the reaction solution was dried under reduced pressure, 30 ml of DCM was added, and the organic phase was washed with 3*10 ml of saturated brine, and the organic phase was dried over anhydrous sodium sulfate, and the target compound 3-bromo-4-(trifluoromethyl)benzohydrazide-2,6-d2 (18-b, 80 mg, 0.28 mmol, 80% yield) was obtained by drying under reduced pressure. MS Calcd: 283.97; MS Found: 285.20 ([M+H] + ).

[0311] Step 3: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 40 mg, 0.21 mmol), 3-bromo-4-(trifluoromethyl)benzohydrazide-2,6-d2 (18-b, 50 mg, 0.18 mmol), DIPEA (45 mg, 0.35 mmol) and solvent ethanol (15 ml) to a 50 ml single-mouth bottle, and stir at 80 ° C for 12 hr. LC-MS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed, the organic phase is dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by Prep-TLC (DCM:MeOH=30:1) to give the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)3-bromo-4-(trifluoromethyl)benzamide-2,6-d2 (18, 0.04 mg, 0.2 mmol, 25% yield). MS Calcd: 456.03; MS Found: 457.18 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.41(brs,1H),8.04(s,1H),5.82-5.77(m,2H),3 .30–3.24(m,4H),1.20–1.17(m,2H),0.30-0.25(m,1H),0.08-0.04(m,1H).

[0312] Embodiment 19

[0313] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2,3,6-d3

[0314]

[0315] Step 1: Add 3-bromo-4-(trifluoromethyl)benzoic acid-2,6-d2 (18-a, 300 mg, concentrated sulfuric acid (0.5 ml) and solvent methanol (10 mL) into a 50 ml single-mouth bottle and stir at 90°C for 4 hours. LCMS monitoring showed that no raw material remained. The reaction solution was added with saturated sodium bicarbonate aqueous solution to adjust the pH to neutral, 3*30 ml EA was used to extract the aqueous phase, the organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 3-bromo-4-(trifluoromethyl)benzoic acid methyl ester-2,6-d2 (19-a, 280 mg, 0.98 mmol, 88% yield).

[0316] Step 2: Add 3-bromo-4-(trifluoromethyl)benzoic acid methyl ester-2,6-d2 (19-a, 250 mg, 0.88 mmol), Pd2(dba)3 (80 mg, 0..09 mmol), tri-tert-butylphosphine (17 mg, 0.09 mmol), sodium deuterated formate (242 mg, 3.5 mmol) and solvent DMSO (4 mL) to a 25 ml single-mouth bottle, replace with nitrogen three times, and stir at 80 ° C for 12 hours under nitrogen atmosphere. LCMS monitoring shows that there is no residual raw material. The reaction solution is cooled to room temperature, filtered, and the filtrate is dried under reduced pressure. The crude product is purified by prep-TLC (EA: PE = 1: 10) to obtain 4-(trifluoromethyl)benzoic acid methyl ester-2,3,6-d3 (19-b, 150 mg, 0.72 mmol, 82% yield).

[0317] Step 3: Add 4-(trifluoromethyl)benzoic acid methyl ester-2,3,6-d3 (19-b, 200 mg, 0.97 mmol) and solvent methanol (10 ml) to a 50 ml single-mouth bottle, add hydrazine hydrate (2 ml) to the reaction solution, and stir at 80°C for 2 hr. LCMS monitoring shows that no raw material remains. The reaction solution is cooled to room temperature, the reaction solution is dried under reduced pressure, 30 ml of DCM is added, and the organic phase is washed with 3*10 ml of saturated brine. The organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure to obtain 4-(trifluoromethyl)benzohydrazide-2,3,6-d3 (19-c, 170 mg, 0.82 mmol, 85% yield). MS Calcd: 207.07; MS Found: 207.88 ([M+H] + ).

[0318] Step 3: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 88 mg, 0.46 mmol), 4-(trifluoromethyl)benzohydrazide-2,3,6-d3 (19-c, 80 mg, 0.39 mmol), DIPEA (99 mg, 0.77 mmol) and solvent ethanol (15 ml) to a 50 ml single-mouth bottle, stir at 80°C for 12 hr. LCMS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed, the organic phase is dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to give the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3,3a, 4,4a, 5,5a, 6,6a-octahydro-4,6-vinylidenecyclopropane [f] isoindole-2 (1H) -yl)-4-(trifluoromethyl)benzamide-2,3,6-d3 (19, 38 mg, 0.1 mmol, 26% yield). MS Calcd: 379.12; MS Found: 380.05 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),7.95(s,1H),5.82-5.78(m,2H),3.31–3.25(m,4H),1.21–1.18(m,2H),0.32-0.27(m,1H),0.09-0.04(m,1H).

[0319] Embodiment 20

[0320] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(difluoromethyl)benzamide-3-d

[0321]

[0322] Step 1: Add 3-bromo-4-(difluoromethyl)benzoic acid (20-a, 150 mg, 0.6 mmol), concentrated sulfuric acid (0.3 ml) and solvent methanol (10 mL) to a 100 ml single-mouth bottle, stir and reflux at 80 ° C for 3 hours. TLC monitoring shows that there is no residual raw material. Add saturated sodium bicarbonate to the reaction solution to adjust it to neutrality, extract the aqueous phase with 3*30 ml ethyl acetate, combine the organic phases, wash with 1*10 ml saturated brine, and dry over anhydrous sodium sulfate. Reduce pressure and spin dry to obtain 3-bromo-4-(difluoromethyl)benzoic acid methyl ester (20-b, 120 mg, 0.45 mmol, 75% yield).

[0323] Step 2: methyl 3-bromo-4-(difluoromethyl)benzoate (20-b, 120 mg, 0.45 mmol), Pd2(dba)3 (41 mg, 0.05 mmol), tri-tert-butylphosphine (9.2 mg,

[0324] 0.05mmol), sodium deuterated formate (124mg, 1.8mmol) and solvent DMSO (2mL), replaced with nitrogen three times, and stirred at 80℃ for 12hr under nitrogen atmosphere. LCMS monitoring showed that no raw material remained. The reaction solution was cooled to room temperature, filtered, and the filtrate was dried under reduced pressure. The crude product was purified by prep-TLC (EA:PE=1:10) to obtain 4-(difluoromethyl)benzoic acid methyl ester-3-d (20-c, 70mg, 0.37mmol, 82%yield).

[0325] Step 3: methyl 4-(difluoromethyl)benzoate-3-d (20-c, 70 mg, 0.37 mmol), hydrazine hydrate (0.5 ml) and methanol (5 ml) were added to a 50 ml single-mouth bottle in sequence, and the mixture was stirred and refluxed at 80°C for 2 hr. No raw material remained after TLC monitoring. The reaction solution was dried under reduced pressure, 20 ml of DCM was added, and 3*5 ml of saturated brine was washed. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by prep-TLC (DCM: MeOH = 30: 1) to obtain 4-(difluoromethyl)benzohydrazide-3-d (20-d, 60 mg, 0.32 mmol, 85% yield). MS Calcd: 187.01; MS Found: 188.08 ([M+H] + ).

[0326] Step 4: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 73 mg, 0.38 mmol), 4-(difluoromethyl)benzohydrazide-3-d (20-d, 60 mg, 0.32 mmol), DIPEA (82 mg, 0.64 mmol) and solvent ethanol (10 ml) to a 50 ml single-mouth bottle, stir at 80°C for 12 hr. LCMS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 20 ml of DCM is added, and 3*5 ml of saturated brine is washed, the organic phase is dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to give the title compound: N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3,3a, 4,4a, 5,5a, 6,6a-octahydro-4,6-vinylidenecyclopropane [f] isoindole-2 (1H) -yl)-4-(difluoromethyl)benzamide-3-d (20, 40 mg, 0.11 mmol, 34% yield). MS Calcd: 359.12; MS Found: 360.14 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.24(brs,1H),8.05-8.00(m,2H),7.75(d,J=8.4Hz,1H),7.15(t,J=55.6Hz ,1H),5.83-5.78(m,2H),3.32-3.24(m,4H),1.22-1.18(m,2H),0.32-0.26(m,1H),0.11–0.06(m,1H).

[0327] Embodiment 21

[0328] 4-Cyano-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)benzamide-2,6-d2

[0329]

[0330] Step 1: Compound 4-cyanobenzoic acid (21-a, 294.2 mg, 2 mmol), catalyst di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (III) (59.7 mg, 0.1 mmol) and sodium acetate (196.8 mg, 2.4 mmol) were placed in a 10 mL microwave tube, 2 mL of D2O was added thereto, and the reaction was stirred at 90°C for 24 h. LC-MS detected that the reaction of the raw materials was complete, and 15 mL of 1M HCl solution was added to the reaction solution. 20 mL of DCM was added, and then the liquids were separated. The aqueous phase was extracted with DCM (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, 4-cyanobenzoic acid-2,6-d2 (21-b, 289 mg, 1.94 mmol, 96.9% yield) was obtained. MS Calcd: 149.04; MS Found: 148.05 ([MH] - ).

[0331] Step 2: Add compound 4-cyanobenzoic acid-2,6-d2 (21-b, 289 mg, 1.94 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.05 mL, 0.97 mmol) dropwise, stir and reflux at 80 ° C for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (1.23 mL, 38.77 mmol) and continue to reflux for 0.5 hours. The reaction solution was dried under reduced pressure, 50 mL DCM was added, and the organic phase was washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the target compound: 4-cyanobenzohydrazide-2,6-d2 (21-c, 124 mg, 0.76 mmol, 39.2% yield). MS Calcd: 163.07; MS Found: 164.06 ([M+H] + ).

[0332] Step 3: Compound 4-cyanobenzohydrazide-2,6-d2 (21-c, 124 mg, 0.76 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 173.4 mg, 0.91 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85°C overnight. TLC monitored the completion of the reaction of the raw materials, and the reaction solution was directly concentrated. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to obtain the title compound: 4-cyano-N-

[0333] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)benzamide-2,6-d2 (21,110 mg, 0.33 mmol, 43.2% yield). MS Calcd: 335.12; MS Found: 336.15 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.42(brs,1H),8.05(s,2H),5.82-5.78(m,2H),3 .32-3.25(m,4H),1.22-1.18(m,2H),0.32-0.26(m,1H),0.10-0.06(m,1H).

[0334] Embodiment 22

[0335] 2-Chloro-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-6-d

[0336]

[0337] Step 1: Place the compound 2-chloro-4-(trifluoromethyl)benzoic acid (22-a, 224 mg, 1 mmol), the catalyst di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (III) (29.8 mg, 0.05 mmol) and sodium acetate (98.1 mg, 1.2 mmol) in a 10 mL microwave tube, add 2 mL D2O, and stir at 90°C for 24 h. LC-MS detected that the reaction of the raw material was complete, and 15 mL 1M HCl solution was added to the reaction solution. Then 20 mL DCM was added, and then the liquids were separated. The aqueous phase was extracted with DCM (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, 2-chloro-4-(trifluoromethyl)benzoic acid-6-d (22-b, 210 mg, 0.93 mmol, 93.3% yield) was obtained. MS Calcd:224.99;MS Found:223.98([MH] - ).

[0338] Step 2: Add compound 2-chloro-4-(trifluoromethyl)benzoic acid-6-d (22-b, 210 mg, 0.93 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.02 mL, 0.47 mmol) dropwise, stir and reflux at 80 ° C for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (0.59 mL, 18.62 mmol) and continue to reflux for 0.5 hours. The reaction solution was dried under reduced pressure, 50 mL DCM was added, and the organic phase was washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain: 2-chloro-4-(trifluoromethyl)benzoylhydrazide-6-d (22-c, 207 mg, 0.86 mmol, 92.8% yield). MS Calcd: 239.02; MS Found: 240.05 ([M+H] + ).

[0339] Step 3: Compound 2-chloro-4-(trifluoromethyl)benzohydrazide-6-d (22-c, 207 mg, 0.86 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 197.2 mg, 1.04 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85°C overnight. TLC monitored the completion of the reaction of the raw material, and the reaction solution was directly concentrated. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to obtain the title compound: 2-chloro-N-

[0340] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-6-d (22, 110 mg, 0.27 mmol, 30.9% yield). MS Calcd: 411.07; MS Found: 412.06 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.32(brs,1H),8.05(d,J=1.6Hz,1H),7.88(d,J=1.6Hz,1H),5.82 -5.77(m,2H),3.32-3.26(m,4H),1.22–1.17(m,2H),0.31-0.26(m,1H),0.10-0.06(m,1H).

[0341] Embodiment 23

[0342] 3,5-Dibromo-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)benzamide-2,6-d2

[0343]

[0344] Step 1: Compound 3,5-dibromobenzoic acid (23-a, 279 mg, 1 mmol), catalyst di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (III) (29.8 mg, 0.05 mmol) and sodium acetate (98.1 mg, 1.2 mmol) were placed in a 10 mL microwave tube, and 2 mL of D2O was added thereto, and the mixture was stirred at 90°C for 24 h. LC-MS detected that the reaction of the raw material was complete, and 15 mL of 1M HCl solution was added to the reaction solution. 20 mL of DCM was added, and then the liquids were separated. The aqueous phase was extracted with DCM (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the target compound 3,5-dibromobenzoic acid-2,6-d2 (23-b, 244 mg, 0.87 mmol, 86.8% yield) was obtained. MS Calcd: 281.87; MS Found: 280.88 ([MH] - ).

[0345] Step 2: Add compound 3,5-dibromobenzoic acid-2,6-d2 (23-b, 244 mg, 0.87 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.02 mL, 0.43 mmol) dropwise, stir and reflux at 80 ° C for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (0.55 mL, 17.31 mmol) and continue to reflux for 0.5 hours. The reaction solution was dried under reduced pressure, 50 mL DCM was added, and the organic phase was washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the target compound: 3,5-dibromobenzoylhydrazide-2,6-d2 (23-c, 240 mg, 0.81 mmol, 93.7% yield). MS Calcd: 295.90; MS Found: 296.87 ([M+H] + ).

[0346] Step 3: Compound 3,5-dibromobenzoylhydrazide-2,6-d2 (23-c, 240 mg, 0.81 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 185 mg, 0.97 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85°C overnight. TLC monitored the completion of the reaction of the raw material, and the reaction solution was directly concentrated. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to obtain the title compound: 3,5-dibromo-N-

[0347] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)benzamide-2,6-d2 (23,147 mg, 0.31 mmol, 38.7% yield). MS Calcd: 467.95; MS Found: 468.93 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.35(brs,1H),8.18(s,1H),5.82-5.77(m,2H),3 .31-3.24(m,4H),1.21–1.17(m,2H),0.31-0.26(m,1H),0.10-0.06(m,1H).

[0348] Embodiment 25

[0349] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-3-fluoro-4-(trifluoromethyl)benzamide-2,6-d2

[0350]

[0351] Step 1: Place 3-fluoro-4-(trifluoromethyl)benzoic acid (25-a, 200 mg, 0.96 mmol), catalyst di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III) (29.9 mg, 0.05 mmol) and potassium acetate (157 mg, 1.15 mmol) in a 10 mL microwave tube, add 2 mL of D2O, and stir at 90°C for 72 h. LC-MS detected that the reaction of the raw material was complete, and 15 mL of 1M HCl solution was added to the reaction solution. Then 20 mL of DCM was added, and then the liquids were separated. The aqueous phase was extracted with DCM (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, 2,6-dideutero-4-(trifluoromethyl)-3-fluorobenzoic acid (25-b, 200 mg, 1.04 mmol, 99.0% yield) was obtained. MS Calcd:210.12;MS Found:208.96([MH] - ).

[0352] Step 2: Add compound 2,6-dideutero-4-(trifluoromethyl)-3-fluorobenzoic acid (25-b, 200 mg, 1.04 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.5 mL, 9.38 mmol) dropwise, stir and reflux at 80 ° C for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (2 mL, 41.12 mmol) and continue to reflux overnight. The reaction solution was dried under reduced pressure, 50 mL DCM was added, and the organic phase was washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 3-fluoro-4-(trifluoromethyl)benzoylhydrazide-2,6-d2 (25-c, 120 mg, 0.54 mmol, 56.2% yield) MS Calcd: 224.15; MS Found: 225.03 ([M+H] + ).

[0353] Step 3: 3-Fluoro-4-(trifluoromethyl)benzoylhydrazide-2,6-d2 (25-c, 120 mg, 0.54 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 120 mg, 0.64 mmol) were placed in a 25 mL eggplant-shaped bottle, 10 mL of ethanol solution was added, and refluxed at 85° C. overnight. After the reaction of the raw materials was completed by LCMS monitoring, the reaction solution was directly concentrated. The crude product was purified by Prep-HPLC to give the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-3-fluoro-4-(trifluoromethyl)benzamide-2,6-d2 (25, 14.3 mg, 0.04 mmol, 6.7% yield). MS Calcd: 396.34; MS Found: 397.10 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.49(brs,1H),8.03(d,J=7.6Hz,1H),5.82-5.78(m,2 H),3.31-3.26(m,4H),1.22-1.18(m,2H),0.32-0.26(m,1H),0.09-0.06(m,1H).

[0354] Embodiment 26

[0355] 3-Bromo-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-5-fluorobenzamide-2,6-d2

[0356]

[0357] Step 1: Place the compound 3-bromo-5-fluorobenzoic acid (26-a, 200 mg, 0.91 mmol), the catalyst di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (III) (27.2 mg, 0.05 mmol) and potassium acetate (124 mg, 1.00 mmol) in a 10 mL microwave tube, add 2 mL of D2O, and stir at 90°C for 72 h. LC-MS detected that the reaction of the raw materials was complete, and 15 mL of 1 M HCl solution was added to the reaction solution. Then 20 mL of DCM was added, and then the liquids were separated. The aqueous phase was extracted with DCM (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, 3-bromo-2,6-dideutero-5-fluorobenzoic acid (26-b, 200 mg, 0.90 mmol, 99.1%

[0358] yield). MS Calcd:221.02;MS Found:218.94([MH] - ).

[0359] Step 2: Add compound 3-bromo-2,6-dideutero-5-fluorobenzoic acid (26-b, 200 mg, 0.90 mmol) and solvent methanol (10 mL) to a 50 mL eggplant-shaped bottle. Then add concentrated sulfuric acid (0.5 mL, 9.38 mmol) dropwise, stir and reflux at 80 ° C for 4 hours, TLC detection shows that the reaction of the raw material is complete, then add hydrazine hydrate (2 mL, 41.12 mmol) and continue to reflux overnight. The reaction solution was dried under reduced pressure, 50 mL DCM was added, and the organic phase was washed with 2×20 mL saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain: 3-bromo-5-fluorobenzoylhydrazide-2,6-d2 (26-c, 115 mg, 0.49 mmol, 54.1% yield) MS Calcd: 235.05; MS Found: 236.99 ([M+H] + ).

[0360] Step 3: Place 3-bromo-5-fluorobenzoylhydrazide-2,6-d2 (26-c, 115 mg, 0.49 mmol) and (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane [f] isobenzofuran-1,3 (3aH) -dione (1-c, 148 mg, 0.78 mmol) in a 25 mL eggplant-shaped bottle, add 10 mL of ethanol solution, and reflux at 85 ° C overnight. TLC monitored the reaction of the raw material and concentrated the reaction solution directly. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to obtain the title compound: 3-bromo-N-

[0361] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-5-fluorobenzamide-2,6-d2 (26, 120 mg, 0.29 mmol, 69.3% yield). MS Calcd: 407.24; MS Found: 408.98 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.35(brs,1H),7.91(d,J=8.0Hz,1H),5.83–5.78(m,2 H),3.32-3.25(m,4H),1.22-1.18(m,2H),0.32-0.26(m,1H),0.10-0.06(m,1H).

[0362] Embodiment 28

[0363] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-3,5-d2

[0364]

[0365] Step 1: Add 4-aminobenzonitrile (28-a, 1000 mg, 8.47 mmol), deuterated hydrochloric acid (1.5 ml, 20% MW), and solvent heavy water (10 mL) to a 30 ml microwave tube, and stir at 180 ° C for 30 min. TLC monitoring shows that there is no residual raw material. Add sodium carbonate to the reaction solution to adjust the pH to alkaline, take the aqueous phase with 3*30 ml DCM, combine the organic phases, wash with 1*30 ml saturated brine, and dry over anhydrous sodium sulfate. Dry under reduced pressure, and purify the crude product by rapid column chromatography (EA: PE = 0 to 30% in 20 min) to obtain 4-aminobenzonitrile-3,5-d2 (28-b, 600 mg, 5.1 mmol, 60%).

[0366] Step 2: 4-aminobenzonitrile-3,5-d2 (28-b, 500 mg, 5.1 mmol), concentrated hydrochloric acid (1.5 ml) and solvent water (10 mL) were added to a 50 ml single-mouth bottle in sequence, and sodium nitrite (373 mg,

[0367] 5.41mmol) was dissolved in 2ml water and slowly added to the reaction system under ice bath. Keep the ice bath and continue the reaction for 30min, and monitor the formation of diazonium salt by TLC. Potassium iodide (1035mg, 6.24mmol) was dissolved in 3ml water and slowly added to the reaction system, and naturally warmed to room temperature and stirred for 3hr. TLC monitoring showed that there was no residual raw material. The reaction solution was quenched by adding 10% sodium thiosulfate solution, and the aqueous phase was extracted with 3*30ml EA, the organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by rapid column chromatography (EA:PE=0to 20%in 20min) to obtain 4-iodobenzonitrile-3,5-d2 (28-c, 650mg, 2.81mmol, 67% yield).

[0368] Step 3: Add 4-iodobenzonitrile-3,5-d2 (28-c, 600 mg, 2.6 mmol), boron trifluoride ether solution (2 ml, 48% mw) and solvent methanol (20 mL) to a 50 ml single-mouth bottle, replace with nitrogen 3 times, and stir at 90 ° C for 48 hours under nitrogen atmosphere. TLC monitoring shows that there is no residual raw material. The reaction solution is quenched with water, the aqueous phase is extracted with 3*50 ml EA, the organic phases are combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product is purified by rapid column chromatography (EA: PE = 0 to 20% in 20 min) to obtain 4-iodobenzoic acid methyl ester-3,5-d2 (28-d, 550 mg, 2.2 mmol, 80% yield).

[0369] Step 4: Add methyl 4-iodobenzoate-3,5-d2 (28-d, 500 mg, 1.8 mmol), hydrazine hydrate (2 ml) and solvent methanol (15 ml) to a 50 ml single-mouth bottle, stir and reflux at 80°C for 2 hours. LCMS monitors the reaction to be complete. The reaction solution is dried under reduced pressure, 50 ml of DCM is added, and 3*5 ml of saturated brine is washed. The organic phase is dried over anhydrous sodium sulfate. The crude product is purified by prep-TLC (DCM: MeOH = 30: 1) to obtain 4-iodobenzoylhydrazide-3,5-d2 (28-e, 440 mg, 1.6 mmol, 92% yield). MS Calcd: 263.97; MS Found: 265.14 ([M+H] + ).

[0370] Step 5: Add (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropyl[f]isobenzofuran-1,3(3aH)-dione (1-c, 432 mg, 2.27 mmol), 4-iodobenzohydrazide-3,5-d2 ((28-e, 500 mg, 1.89 mmol), DIPEA (489 mg, 3.79 mmol) and solvent ethanol (20 ml) to a 50 ml single-mouth bottle, stir at 80 ° C for 12 hr. LCMS monitors the reaction to completion. The reaction solution is dried under reduced pressure and 50 ml is added. DCM, 2*20ml saturated brine, the organic phase was dried over anhydrous sodium sulfate, and then dried under reduced pressure. The crude product was purified by Prep-TLC (DCM: MeOH = 30: 1) to obtain N-((3aR, 4R, 4aR, 5aS, 6S, 6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-iodobenzamide-3,5-d2 (28-f, 650mg, 1.5mmol, 78% yield). MS Calcd: 436.03; MS Found: 437.21 ([M+H] + ).

[0371] Step 6: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-iodobenzamide-3,5-d2 (28-f, 100 mg, 0.23 mmol), cuprous iodide (80 mg, 0.25 mmol), methyl fluorosulfonyldifluoroacetate (132 mg, 0.69 mmol) and solvent anhydrous DMF (5 ml) were added to a 25 ml single-necked bottle, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 80° C. for 24 hr. LC-MS monitoring showed 50% conversion to the product. The reaction solution was filtered, the filtrate was dried under reduced pressure, and the crude product was purified by Prep-HPLC to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-3,5-d2 (28, 20 mg, 0.05 mol, 22% yield). MS Calcd: 378.12; MS Found: 379.13 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),8.10(s,2H),5.82-5.78(m,2H),3.30-3.25(m,4H),1.21-1.18(m,2H),0.31-0.26(m,1H),0.10-0.06(m,1H).

[0372] Embodiment 29

[0373] 4-(Difluoromethyl)-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxy-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-

[0374] Vinylenecyclopropyl[f]isoindol-2(1H)-yl)-2-fluorobenzamide-6-d

[0375]

[0376] Step 1: Add methyl 2-fluoro-4-formylbenzoate (29-a, 350 mg, 1.92 mmol) to dichloromethane (10 ml), lower the temperature to 0°C, then add DAST (773 mg, 4.8 mmol) dropwise, and stir at this temperature for 2 hours. TLC shows that the reaction of the raw materials is complete. Pour the reaction system into saturated aqueous sodium bicarbonate solution and extract with DCM (10 ml x 2). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain methyl 4-(difluoromethyl)-2-fluorobenzoate (29-b, 320 mg, 1.57 mmol, 82% yield).

[0377] Step 2: Add methyl 4-(difluoromethyl)-2-fluorobenzoate (29-b, 320 mg, 1.57 mmol) to methanol (10 ml), then add an aqueous solution (2 ml) of sodium hydroxide (188 mg, 4.71 mmol), stir at room temperature for 3 hours, LCMS shows that the raw material reaction is complete, concentrate under reduced pressure, adjust the pH to 5 with hydrochloric acid (1N), and then extract with DCM (3 ml x 3), the organic layer is concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 30: 1) to give 4-(difluoromethyl)-2-fluorobenzoic acid (29-c, 230 mg, 1.21 mmol, 77% yield) MS Calcd: 190.02; MS Found: 189.02 ([MH] - ).

[0378] Step 3: Add 4-(difluoromethyl)-2-fluorobenzoic acid (29-c, 100 mg, 0.53 mmol), potassium acetate (54 mg, 0.55 mmol), tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium di(hexafluoroantimonate) (16 mg, 0.03 mmol) to heavy water (2 ml), raise the temperature to 90°C, stir for 48 hours, LCMS shows that the raw material reaction is complete, cool to room temperature, add hydrochloric acid (1N) to adjust the pH to 5, extract with DCM (5 ml x 3), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target compound 4-(difluoromethyl)-2-fluorobenzoic acid-6-d, without purification, directly react in the next step (29-d, 94 mg, 0.49 mmol, 93% yield). MS Calcd: 191.03; MS Found: 190.03 ([MH] - ).

[0379] Step 4: Add 4-(difluoromethyl)-2-fluorobenzoic acid-6-d (29-d, 94 mg, 0.49 mmol) to a methanol solution (2 ml), then drop a catalytic amount of concentrated sulfuric acid, heat to 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, add hydrazine hydrate (2 ml) to the reaction system, continue to maintain at 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, stop stirring, concentrate under reduced pressure, extract the residue with DCM (3 ml x 3), combine the organic layers, concentrate under reduced pressure, and purify the residue by silica gel column (EA: PE = 1: 1) to obtain 4-(difluoromethyl)-2-fluorobenzoylhydrazide-6-d (29-e, 41 mg, 0.20 mmol, 41% yield). MS Calcd: 205.06; MS Found: 206.06 ([M+H] + ).

[0380] Step 5: 4-(difluoromethyl)-2-fluorobenzohydrazide-6-d (29-e, 41 mg, 0.20 mmol),

[0381] (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 46 mg, 0.24 mmol), DIPEA (52 mg, 0.4 mmol) were added to anhydrous ethanol (1 ml), placed in a microwave reactor, heated to 90 ° C, stirred for 1 hour, the reaction was completed, concentrated under reduced pressure, and the residue was purified by ethyl acetate. The mixture was slurried with ethyl acetate and petroleum ether as a mixed solvent of EA:PE=1:2 (3 ml) to obtain the title compound: 4-(difluoromethyl)-N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxy-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-2-fluorobenzamide-6-d (29, 41 mg, 0.11 mmol, 54% yield). MS Calcd: 377.11; MS Found: 378.11 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),7.62(d,J=10.4Hz,1H),7.57(s,1H),7.14(t,J=55.2Hz,1H ),5.82-5.76(m,2H),3.32-3.26(m,4H),1.21-1.17(m,2H),0.31-0.26(m,1H),0.10-0.06(m,1H).

[0382] Embodiment 30

[0383] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxy-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2,3,5,6-d4

[0384]

[0385] Step 1: Add 4-iodobenzonitrile-3,5-d2 (28-c, 300 mg, 1.3 mmol), cuprous iodide (371 mg, 1.95 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (494 mg, 2.6 mmol) to DMF (10 ml), replace with nitrogen for 3 minutes, then raise the temperature to 110°C, stir for 6 hours, cool to room temperature, pour the reaction system into water (20 ml), extract with EA (20 ml x 2), dry the organic layer, concentrate, and purify the residue by column chromatography (EA: PE = 1: 8) to obtain 4-(trifluoromethyl)benzonitrile-3,5-d2 (30-a, 210 mg, 1.2 mmol, 92% yield).

[0386] Step 2: Add 4-(trifluoromethyl)benzonitrile-3,5-d2 (30-a, 210 mg, 1.2 mmol) to an aqueous solution of sodium hydroxide (5 ml, 4 N) and raise the temperature to 95 ° C. Stir overnight, cool to room temperature, adjust the pH to 5 with hydrochloric acid (2 N), and then extract with DCM (5 ml x 3). The organic layer is dried and concentrated. The residue is purified by column chromatography (MeOH: DCM = 1:30) to obtain 4-(trifluoromethyl)benzoic acid-3,5-d2 (30-b, 75 mg, 0.39 mmol, 33% yield) MS Calcd: 192.04; MS Found: 191.04 ([MH] - ).

[0387] Step 3: Add 4-(trifluoromethyl)benzoic acid-3,5-d2 (30-b, 75 mg, 0.39 mmol), potassium acetate (46 mg, 0.47 mmol), tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium di(hexafluoroantimonate) (11 mg, 0.02 mmol) to heavy water (2 ml), raise the temperature to 90°C, stir for 48 hours, LCMS shows that the raw material reaction is complete, cool to room temperature, add hydrochloric acid (1N) to adjust the pH to 5, extract with DCM (5 ml x 3), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4-(trifluoromethyl)benzoic acid-2,3,5,6-d4, which is directly used for the next step without purification (30-c, 71 mg, 0.37 mmol, 94% yield). MS Calcd: 194.05; MS Found: 193.05 ([MH] - ).

[0388] Step 4: Add 4-(trifluoromethyl)benzoic acid-2,3,5,6-d4 (30-c, 71 mg, 0.37 mmol) to a methanol solution (2 ml), then drop a catalytic amount of concentrated sulfuric acid, heat to 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, add hydrazine hydrate (2 ml) to the reaction system, continue to maintain at 80°C, stir for 2 hours, TLC shows that the reaction of the raw material is complete, stop stirring, concentrate under reduced pressure, extract the residue with DCM (3 ml x 3), combine the organic layers, concentrate under reduced pressure, and purify the residue by silica gel column (EA: PE = 1: 1) to obtain 4-(trifluoromethyl)benzoylhydrazide-2,3,5,6-d4 (30-d, 43 mg, 0.21 mmol, 56% yield). MS Calcd: 208.08; MS Found: 209.08 ([M+H] + ).

[0389] Step 7: 4-(trifluoromethyl)benzoylhydrazide-2,3,5,6-d4 (30-d, 43 mg, 0.21 mmol),

[0390] (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 46 mg, 0.24 mmol), DIPEA (52 mg, 0.4 mmol) were added to anhydrous ethanol (1 ml), placed in a microwave reactor, heated to 90 ° C, stirred for 1 hour, the reaction was completed, concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound: N-

[0391] ((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxy-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide-2,3,5,6-d4 (30,8 mg, 0.02 mmol, 10% yield). MS Calcd: 380.13; MS Found: 379.13 ([MH] - ). 1 H NMR(400MHz,DMSO-d6)δ11.38(s,1H),5.83-5.81(m,2H),3.32-3.26(m,4H),1.19-1.21(m,2H),0.31-0.26(m,1H),0.10-0.06(m,1H)

[0392] Embodiment 31

[0393] N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-3-(trifluoromethyl)benzamide-4-d

[0394]

[0395] Step 1: Weigh 4-bromo-3-(trifluoromethyl)benzoic acid methyl ester (31-a, 200 mg, 0.71 mmol), Pd2(dba)3 (64.7 mg, 0.07 mmol), tri-tert-butylphosphine (14.3 mg, 0.07 mmol), sodium deuterated carboxylate (195.1 mg, 2.83 mmol) into a 50 ml single-mouth bottle, add anhydrous DMSO (3 mL), replace with nitrogen three times after addition, and then react at 80 ° C for 6 hours. Samples were taken and sent to LC-MS for inspection, and no raw materials remained. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, and then concentrated to dryness under reduced pressure to obtain 3-(trifluoromethyl)benzoic acid methyl ester-4-d (31-b, 108 mg, 0.42 mmol, 59.6% Yield).

[0396] Step 2: Weigh 3-(trifluoromethyl)benzoic acid methyl ester-4-d (31-b, 108 mg, 0.42 mmol) into a 25 ml single-mouth bottle, add methanol (2 mL), then add hydrazine hydrate (0.10 mL, 2.11 mmol), and react at 80 ° C overnight. The reaction solution was concentrated to dryness under reduced pressure to obtain 3-(trifluoromethyl)benzoic acid methyl ester-4-d (31-c, 96 mg, 0.23 mmol, 55.6% Yield). MS Calcd: 205.06; MS Found: 206.12

[0397] ([M+H] + ).

[0398] Step 3: Operation steps: Weigh (3aR, 4R, 4aR, 5aS, 6S, 6aS)-4,4a, 5,5a, 6,6a-hexahydro-1H-4,6-vinylidenecyclopropane[f]isobenzofuran-1,3(3aH)-dione (1-c, 44.3 mg, 0.23 mmol), 3-(trifluoromethyl)benzoic acid methyl ester-4-d (31-c, 96 mg, 0.23 mmol) into a 25 ml single-necked bottle, add ethanol (1.5 mL), then add DIPEA (0.08 mL, 0.47 mmol), and react at 80 degrees Celsius for 2 hours. The sample was sent for LC-MS. The raw material disappeared, but some products were present. The reaction solution was concentrated to dryness under reduced pressure, enriched by plate chromatography, and then purified to obtain the title compound: N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-vinylidenecyclopropane[f]isoindol-2(1H)-yl)-3-(trifluoromethyl)benzamide-4-d (31,10 mg, 0.03 mmol, 10.8% Yield). MS Calcd: 377.11; MS Found: 378.21 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.25(s,1H),8.21(d,J=8.0Hz,1H),7.82(d,J=7.8Hz,1H) ,5.82-5.78(m,2H),3.32-3.26(m,4H),1.26-1.20(m,2H),0.32-0.26(m,1H),0.10-0.06(m,1H).

[0399] Test Example 1: Inhibitory activity of the test compound on HFF-1 cytopathic effect induced by vaccinia virus

[0400] 1) Compound dilution: First, the 2000 μM compound stock solution was diluted 5-fold with DMSO to 8 concentration points to obtain 2000, 400, 80, 16, 3.2, 0.64, 0.128, and 0.0256 μM compounds. Then, the compounds were further diluted 50-fold with culture medium to final concentrations of 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, and 0.000512 μM, respectively.

[0401] 2) Experimental steps: ① Cytopathic effect experiment: On the first day, HFF-1 cells (American Type Culture Collection, ATCC, catalog number SCRC-1041) were cultured. TM) were seeded into 96-well plates at a density of 6,000 cells per well and 100 μL per well, and cultured overnight in a 5% CO2, 37°C incubator. On the next day, 50 μL of the compound diluted in (1) (double wells) and 50 μL of Vaccinia Virus VP13 virus strain (China Center for Type Culture Collection, CCTCC, catalog number GDV088) were added to each well, and the virus inoculation amount was 0.1 pfu / cell (i.e., MOI = 0.1). Cell control (virus-uninfected cells, no compound treatment), virus control (virus-infected cells, no compound treatment) and culture medium control (only culture medium) were set up. The total volume of cell culture medium in each well was 200 μL, and the final concentration of DMSO in the culture medium was 0.5%. The cells were placed in a 5% CO2, 37°C incubator and continued to be cultured for 4 days to detect the cytopathic effect caused by the virus. ② Cytotoxicity experiment: The compound cytotoxicity experiment carried out simultaneously did not add virus infection, and other conditions were the same as the cytopathic experiment. On the sixth day, both experiments used the cell viability CCK8 detection kit (Shanghai Liji Biotechnology Co., Ltd., catalog number AC11L057) to detect cell viability.

[0402] 3) Data analysis:

[0403] The antiviral activity and cytotoxicity of the test compound are respectively expressed by the inhibition rate (%) of the virus-induced cytopathic effect and the cell viability (%) at different concentrations. The calculation formula is as follows:

[0404] Cytopathic effect inhibition rate (%) = (compound test well reading - virus control average) / (cell control average - virus control average) × 100;

[0405] Cell viability (%) = (test well reading - average value of culture medium control) / (average value of cell control - average value of culture medium control) × 100;

[0406] GraphPad Prism was used to perform nonlinear fitting analysis on the inhibition rate and cell viability of the samples, and the half effective concentration (EC50) and half cytotoxic concentration (CC 50 ) value. The inhibition curve fitting method is log(inhibitor)vs.response--Variable slope.

[0407] 4) Experimental results:

[0408] Table 1. Inhibitory activity of the tested compounds on the cytopathic effect caused by vaccinia virus and cell viability

[0409]

[0410] Conclusion: According to Table 1, the compounds of the present invention have excellent antiviral activity against vaccinia virus of the genus Orthopoxvirus.

[0411] Experimental Example 2 Pharmacokinetics in mice

[0412] Main principles of the experiment:

[0413] The LC-MS / MS method was used to determine the drug concentration in the plasma of BALB / C mice at different time points after intravenous or oral administration of the example compounds, and the relevant pharmacokinetic parameters were calculated by Winnonlin to study the pharmacokinetic behavior of the compounds of the present invention in mice and evaluate their pharmacokinetic characteristics.

[0414] Experimental materials, plans and results analysis:

[0415] The experimental animals were healthy adult BALB / c female mice (provided by Beijing Huafukang Biotechnology Co., Ltd.);

[0416] Administration and sample collection: BALB / c female mice were intravenously administered (1 mg / kg) and orally administered (10 mg / kg). 60 μL of whole blood was collected from the orbital venous plexus of mice at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration and put into EDTA-K2 anticoagulant tubes. The blood was centrifuged at 4000 rpm and 4°C for 6 min to collect plasma.

[0417] Sample analysis: Take 10 μL of mouse plasma sample, add 290 μL of acetonitrile solution containing internal standard to precipitate protein, vortex for 10 minutes, then centrifuge at 4000 rpm for 10 minutes, take 200 μL of supernatant in a 96-well plate, place in LC-MS / MS detection and analysis, and the injection volume is 1 μL.

[0418] The pharmacokinetic parameters of the compounds of the present invention in mice at the same dosage and administration method are shown in Table 2 below:

[0419] Table 2 Pharmacokinetic parameters of compounds in mice

[0420]

[0421] As shown in Table 2, in the PO mode, compared with a meta-deuterated structure (Example 3) and two deuterated structures (Example 9 and Example 10), an ortho-deuterated structure (Example 2 and Example 6) showed higher exposure and bioavailability. The AUC values ​​of Example 2 / 6 were increased by about 30% and 10% compared with Tecovirimat, and the bioavailability (F%) was increased by about 37% and 56% compared with Tecovirimat. However, the AUC values ​​of a meta-deuterated structure (Example 3) and two deuterated structures (Example 9 and Example 10) were significantly reduced compared with Tecovirimat, with Example 3 reduced by about 28%, Example 9 reduced by about 63%, and Example 10 reduced by about 92%; the bioavailability (F%) was also reduced to varying degrees compared with Tecovirimat, with Examples 3 / 9 reduced by about 30% and 60% respectively compared with Tecovirimat.

[0422] Furthermore, it can be seen from the test data that in the PO mode, the bridged ring double bond structure (Example 2) shows higher exposure and bioavailability than the bridged ring single bond structure (Example 4). The AUC value of Example 2 is about 30% higher than that of Tecovirimat, while the AUC value of Example 4 is about 60% lower than that of Tecovirimat; the bioavailability (F%) of Example 2 is about 37% higher than that of Tecovirimat, while the bioavailability (F%) of Example 4 is about 57% lower than that of Tecovirimat.

[0423] Industrial Applicability

[0424] The compound of the present invention has excellent antiviral activity against orthopoxviruses and in a pharmacokinetic test in mice, various parameter indicators are improved to varying degrees, especially showing higher exposure and bioavailability (the exposure is increased by about 10% to 30% compared with Tecovirimat, and the bioavailability is increased by about 37% to 56% compared with Tecovirimat), which can significantly reduce the single dosage of patients and reduce potential medication risks, has unexpected technical effects, and can become a drug for treating or preventing diseases related to the effect.

[0425] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. The specific compound or a pharmaceutically acceptable salt thereof as follows:

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

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating diseases related to orthopoxvirus infection.

4. The use according to claim 3, wherein the orthopoxvirus is selected from the group consisting of smallpox virus, monkeypox virus, camelpox virus, cowpox virus, rabbitpox virus and mousepox virus.

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