Deuterated 1,4-benzodiazepine-2,5-dione compounds and their uses

Abstract

Deuterated 1,4-benzodiazepine-2,5-dione compounds and uses thereof are disclosed. The compound is represented by Formula I, or a pharmaceutically acceptable salt thereof. The disclosed 1,4-benzodiazepine-2,5-dione active compounds maintain their activity in inhibiting tumor cells and tumor stem cells, and also exhibit prolonged degradation of the compound in human liver microsomes in vitro, significantly extending its half-life, providing safer and more reliable candidates for the development of new antitumor drugs. JPEG2023550937000056.jpg5665

Description

[Technical field]

[0001] This application claims priority from Chinese patent application No. 202011287532X, filed on November 17, 2020. This application cites said Chinese patent application in its entirety.

[0002] The present invention relates to deuterated 1,4-benzodiazepine-2,5-dione compounds and their use in the treatment of proliferative disorders, particularly cancer. [Background technology]

[0003] Isotopes are different atoms of the same chemical element, with different masses due to the presence of different numbers of neutrons in the atomic nucleus. Isotopes can be divided into two types based on their physical properties: radioactive and stable. Hydrogen exists in nature in three isotopes: protium (1H, H), deuterium (2H, D), and tritium (3H, T). Among them, deuterium is a stable, non-radioactive isotope with a content of 0.015% in nature. There are two main ways to introduce deuterium into a compound: one is by proton exchange with hydrogen, and the other is synthesis using deuterated raw materials. Currently, the second method is more commonly used. The content of deuterium in the synthesized deuterated compound is much higher than the natural 0.015%, so it is considered a new type of compound.

[0004] The 1,4-benzodiazepine-2,5-dione compound disclosed in the patent number ZL201610154581.3 can not only inhibit the proliferation of 60 kinds of human tumor cell lines, but also inhibit the self-renewal ability of tumor stem cells, providing a new antitumor drug that can completely eliminate tumors and tumor stem cells. However, the metabolic stability and antitumor pharmacokinetics need to be further improved. Summary of the Invention [Problem to be solved by the invention]

[0005] The technical problem to be solved by the present invention is to provide a deuterated 1,4-benzodiazepine-2,5-dione compound and its use, in order to overcome the short half-life and other shortcomings of the 1,4-benzodiazepine-2,5-dione compounds in the prior art. The 1,4-benzodiazepine-2,5-dione active compound of the present invention maintains the activity of inhibiting tumor cells and tumor stem cells, and also prolongs the decomposition effect of the compound in human liver microsomes in vitro, significantly prolonging the half-life, providing a safer and more reliable candidate for the development of new antitumor drugs. [Means for solving the problem]

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] The present invention provides a compound represented by Formula I, or a pharma- ceutically acceptable salt thereof.

[0008] [ka]

[0009] where X is hydrogen, fluorine, chlorine, bromine or iodine; R 1a and R 1b are independently hydrogen, deuterium, and C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 2a , R 2b and R 2c are independently hydrogen or deuterium; R 3 , R 4 and R 5 is independently C 1-3 Alkyl, C 1-3 Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C 1-3 alkyl-O-; R 6 , H, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl or deuterated C 1-3 is alkyl, R 7 is -OR 12 、-NR 13 R 14 or -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ) where R 12 、R 17 and R 18 are independently C 1-3 alkyl, deuterated C 1-3 alkyl or deuterated C 1-3 alkyl -O-, R 15 and R 16 are independently H, C 1-3 alkyl or deuterated C 1-3 alkyl, R 13 and R 14 are independently OH, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkyl -O- or deuterated C 1-3 alkyl -O-, or, R 13 and R 14 together with the linked nitrogen atom form a 4 - 6 membered aliphatic heterocycle or a 4 - 6 membered aliphatic heterocycle substituted by one or more R 19 In the 4 - 6 membered aliphatic heterocycle of the 4 - 6 membered aliphatic heterocycle and the 4 - 6 membered aliphatic heterocycle substituted by one or more R 19 In addition to the connection of one of the N and the carbonyl, it further contains 0 - 2 optional heteroatoms selected from N, O or S, R 19 is halogen, O=, C 1-3 alkyl or deuterated C 1-3 alkyl, R 8 、R 9 、R 10 and R 11 are independently hydrogen or deuterium, where, R 1a, R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 At least one of is deuterium or a deuterated group.

[0010] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): X is chlorine or bromine, for example bromine.

[0011] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 1a and R 1b is the same.

[0012] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 1a and R 1b is independently C 1-3 Alkyl (e.g., methyl) or deuterated C 1-3 Alkyl (e.g., CD 3 ), for example, C 1-3 It is an alkyl.

[0013] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R2a , R 2b and R 2c is the same.

[0014] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 2a , R 2b and R 2c are independently hydrogen.

[0015] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 3 , R 4 and R 5 Any two or three of the following are the same: 3 , R 4 and R 5 is the same.

[0016] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 3 , R 4 and R 5 is independently C 1-3 Alkyl-O- (e.g., methyl-O-), deuterated C 1-3 Alkyl (e.g., CD 3 or -CD 2 -CD 3 ) or deuterated C 1-3 Alkyl-O- (e.g., CD 3 -O-) For example, R 4 is C 1-3 Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C1-3 Alkyl-O-, methyl-O-, CD 3 or CD 3 may be -O-, R 3 and R 5 is independently C 1-3 Alkyl-O- or deuterated C 1-3 Alkyl-O-, methyl-O- or CD 3 It may also be -O-.

[0017] For example, R 3 , R 4 and R 5 is independently C 1-3 Alkyl-O- or deuterated C 1-3 Alkyl-O- and deuterated C 1-3 It may be alkyl-O-.

[0018] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 , H, C 1-3 Alkyl (e.g., methyl), C 2-4 Alkynyl or deuterated C 1-3 Alkyl (e.g., CD 3 ), for example, H, C 1-3 Alkyl or deuterated C 1-3 alkyl, e.g. H or C 1-3 Alkyl, for example H.

[0019] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 7 -OR 12 and R 12 is C 1-3 Alkyl or deuterated C 1-3Alkyl, e.g., deuterated C 1-3 alkyl, e.g., CD 3 It is.

[0020] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 7 -NR 13 R 14 and R 13 and R 14 are independently OH, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl-O- or deuterated C 1-3 Alkyl-O-, e.g., OH, methyl, ethyl, CD 3 , -CD 2 -CD 3 or CD 3 -O-, For example, R 13 OH, C 1-3 Alkyl (e.g., methyl or ethyl), deuterated C 1-3 Alkyl (e.g., CD 3 or -CD 2 -CD 3 ), C 1-3 Alkyl-O- (e.g., methyl-O-) or deuterated C 1-3 Alkyl-O- (e.g., CD 3 -O-) R 14 is C 1-3 Alkyl or deuterated C 1-3 Alkyl (e.g., CD 3 or -CD 2 -CD 3 ) and For example, R 13 and R 14 is independently C 1-3 It is alkyl and may be methyl.

[0021] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 7 -NR 13 R 14 and R 13 and R 14 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 19 For example, a 4- to 6-membered heterocycloalkyl group is formed, which is substituted with one or more of R 19 wherein the 4- to 6-membered heterocycloalkyl and one or more R 19 In the 4- to 6-membered heterocycloalkyl substituted by, in addition to one N and carbonyl bond, 0 to 1 heteroatom optionally selected from N, O, or S is further contained, for example,

[0022] [ka]

[0023] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 7 is -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ) and R 15 and R 16 is independently C 1-3 alkyl, for example methyl; R 17 and R 18 is independently C 1-3 It is alkyl, for example, methyl.

[0024] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 15 and R 16 is the same.

[0025] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 17 and R 18 is the same.

[0026] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 19 is halogen, O=, C 1-3 Alkyl or deuterated C 1-3 Alkyl, for example halogen (e.g. F), O= or C 1-3 Alkyl (eg methyl), also for example F or methyl.

[0027] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 8 is hydrogen.

[0028] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 9 is hydrogen.

[0029] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 10 is hydrogen.

[0030] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 11 is hydrogen.

[0031] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 1a and R 1b is independently C 1-3 is alkyl, R 2a , R 2b and R 2c are independently hydrogen; For example, R 1a and R 1b are the same, and / or R 2a , R 2b and R 2c is the same.

[0032] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): X is chlorine or bromine; R 4 is C1-3 Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C 1-3 alkyl-O-; R 3 and R 5 is independently C 1-3 Alkyl-O- or deuterated C 1-3 alkyl-O-; For example, R 3 , R 4 and R 5 is independently C 1-3 Alkyl-O- or deuterated C 1-3 alkyl-O-; and / or R 3 , R 4 and R 5 is the same.

[0033] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 is H and R 7 -OR 12 It is.

[0034] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 is H and R 7 is -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ), for example, -C(Me) 2 P(=O)(OMe) 2 , -CH 2 -P(=O)(OMe) 2 It is.

[0035] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 is H and R 7 -NR 13 R 14 and R 13 and R 14 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 19 R 19 is a halogen, for example,

[0036] [ka]

[0037] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 is H and R 7 -NR 13 R 14 and R 13 is methyl, deuterated C 1-3 Alkyl (e.g., CD 3 or -CD 2 -CD 3 ), C 1-3 Alkyl-O- (e.g., methyl-O-) or deuterated C 1-3 Alkyl-O- (e.g., CD 3 -O-)

[0038] R 14 is methyl or deuterated C 1-3 Alkyl (e.g., CD 3 or -CD 2 -CD 3 ) and for example,

[0039] [ka]

[0040] It is.

[0041] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 is C 1-3 is alkyl, R 7 -NR 13 R 14 and R 13 OH, C 1-3 Alkyl (e.g., methyl), deuterated C 1-3 Alkyl (e.g., CD 3 ) or deuterated C 1-3 Alkyl-O- (e.g., CD 3 -O-) R 14 is C 1-3 Alkyl (e.g., methyl) or deuterated C 1-3 Alkyl (e.g., CD 3 ) and

[0042] for example,

[0043] [ka]

[0044] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 1a , R 1b , R 3 , R 4 , R 5 , R6 and R 7 at least one of is deuterium or a deuterated group; For example, "R 1a and R 1b ", "R 3 , R 4 and R 5 ", R 6 and R 7 at least one or a group of is deuterium or a deuterated group; For example, "R 1a and R 1b ", "R 3 , R 4 and R 5 ", R 6 and R 7 At least one or a group of is deuterium or a deuterated group, and R 2a , R 2b and R 2c are independently hydrogen.

[0045] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 3 , R 4 , R 5 , R 6 and R 7 at least one of is deuterium or a deuterated group; For example, "R 3 , R 4 and R 5 ", R 6 and R 7 at least one or a group of is deuterium or a deuterated group; For example, "R 3 , R 4 and R 5 ", R 6 and R 7 At least one or a group of is deuterium or a deuterated group, and R 1a and R 1b are independently hydrogen or C 1-3 is alkyl, R2a , R 2b and R 2c are independently hydrogen.

[0046] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): "R 3 , R 4 and R 5 ", R 6 and R 7 one or two (groups) of are deuterium or deuterated groups; For example, "R 3 , R 4 and R 5 " and / or R 7 is a deuterated group, R 6 and / or R 7 is a deuterium or a deuterated group, and the remaining groups of formula I are not deuterium or deuterated groups.

[0047] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): where X is chlorine or bromine; R 1a and R 1b is independently C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 2a , R 2b and R 2c are independently hydrogen or deuterium; R 3 , R 4 and R 5 is independently C 1-3 Alkyl, C 1-3 Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C 1-3 Alkyl-O-, for example, C 1-3Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C 1-3 alkyl-O-; R 6 , H, C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 7 -OR 12 , -NR 13 R 14 Or -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ), where R 12 is deuterated C 1-3 is alkyl, R 15 and R 16 is independently C 1-3 is alkyl, R 17 and R 18 is independently C 1-3 is alkyl, R 13 OH, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl-O- or deuterated C 1-3 alkyl-O-, R 14 is C 1-3 Alkyl or deuterated C 1-3 is alkyl, Or, R 13 and R 14 is a 4- to 6-membered aliphatic heterocycle together with the nitrogen atom to which it is linked, or at least one R 19 forming a 4- to 6-membered aliphatic heterocycle substituted by R 19 is halogen, O=, C 1-3 Alkyl or deuterated C 1-3 alkyl, e.g., halogen or C 1-3 is alkyl, R 8 , R 9 , R 10 and R 11 is hydrogen, Here, R 1a , R1b , R 3 , R 4 , R 5 , R 6 and R 7 at least one of is deuterium or a deuterated group; For example, R 1a and R 1b are the same, and / or R 2a , R 2b and R 2c are the same, and / or R 3 , R 4 and R 5 is the same.

[0048] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): where X is chlorine or bromine; R 1a and R 1b is independently C 1-3 Alkyl and R 1a and R 1b are the same, R 2a , R 2b and R 2c are independently hydrogen, R 2a , R 2b and R 2c are the same, R 3 , R 4 and R 5 is independently C 1-3 Alkyl-O- or deuterated C 1-3 alkyl-O- and R 3 , R 4 and R 5 are the same, R 6 is H and R 7 -OR 12 , -NR 13 R 14 Or -C(R 15 R16 )-P(=O)(OR 17 OR 18 ), where R 12 are independently deuterated C 1-3 is alkyl, R 15 and R 16 is independently C 1-3 is alkyl, R 17 and R 18 is independently C 1-3 is alkyl, R 13 is methyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl-O- or deuterated C 1-3 alkyl-O-, R 14 is methyl or deuterated C 1-3 alkyl, or R 13 and R 14 is a 4- to 6-membered aliphatic heterocycle together with the nitrogen atom to which it is linked, or at least one R 19 R 15 , R 16 , R 17 and R 18 is independently C 1-3 is alkyl, R 19 is a halogen, Or R 6 is C 1-3 is alkyl, R 7 -NR 13 R 14 and R 13 OH, C 1-3 Alkyl, deuterated C 1-3 Alkyl or deuterated C 1-3 alkyl-O-, R 14 is C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 8 , R 9 , R 10 and R 11 is hydrogen, Here, R 3 , R 4 , R 5 , R 6 and R7 at least one of is deuterium or a deuterated group;

[0049] for example,

[0050] [ka]

[0051] for example,

[0052] [ka]

[0053] for example,

[0054] [ka]

[0055] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 1a and R 1b But independently, C 1-3 Alkyl or deuterated C 1-3 When it is alkyl, the C 1-3 Alkyl and deuterated C 1-3 Alkyl C 1-3 Alkyl may be methyl, ethyl, n-propyl or isopropyl, for example methyl.

[0056] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 3 , R 4 and R 5 But independently, C1-3 Alkyl, C 1-3 Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C 1-3 When R is alkyl-O-, 3 , R 4 and R 5 is independently C 1-3 Alkyl, C 1-3 Alkyl-O-, deuterated C 1-3 Alkyl and deuterated C 1-3 Alkyl-O-C 1-3 Alkyl may be methyl, ethyl, n-propyl or isopropyl, for example methyl.

[0057] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 But, C 1-3 Alkyl or deuterated C 1-3 When it is alkyl, the C 1-3 Alkyl and deuterated C 1-3 Alkyl C 1-3 Alkyl may be methyl, ethyl, n-propyl or isopropyl, for example methyl.

[0058] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 C 2-4 When C is alkenyl, 2-4 Alkenyl is vinyl, 1-propenyl,

[0059] [ka]

[0060] may be also possible.

[0061] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 6 But, C 2-4 When C is alkynyl, 2-4 Alkynyl is ethynyl or

[0062] [ka]

[0063] may be also possible.

[0064] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 12 , R 17 and R 18 But independently, C 1-3 Alkyl or deuterated C 1-3 When it is alkyl, the C 1-3 Alkyl and deuterated C 1-3 Alkyl C 1-3 Alkyl may be methyl, ethyl, n-propyl or isopropyl, for example methyl.

[0065] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 15 and R 16 But independently, C 1-3 Alkyl or deuterated C 1-3 When it is alkyl, the C 1-3 Alkyl and deuterated C1-3 Alkyl C 1-3 Alkyl may be methyl, ethyl, n-propyl or isopropyl, for example methyl or ethyl.

[0066] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 13 and R 14 But independently, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl-O- or deuterated C 1-3 When it is alkyl-O-, 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl-O- and deuterated C 1-3 Alkyl-O-C 1-3 Alkyl may be methyl, ethyl, n-propyl or isopropyl, for example methyl or ethyl.

[0067] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as defined in any one of the embodiments of the present application): R 13 and R 14 together with the nitrogen atom to which it is linked, form a 4- to 6-membered aliphatic heterocycle or one or more R 19 In the case where a 4- to 6-membered aliphatic heterocycle is formed substituted with one or more of R 19 The 4- to 6-membered aliphatic heterocycle of the 4- to 6-membered aliphatic heterocycle substituted by is a 4- to 6-membered heterocycloalkyl, in which, in addition to one of the N and the carbonyl, further contains 0 to 1 heteroatom optionally selected from N, O, or S, and for example,

[0068] [ka]

[0069] For example, it is a 6-membered heterocycloalkyl, in which in addition to the one N and the carbonyl bonded thereto, it further contains 0 to 1 heteroatom selected from N, and for example,

[0070] [ka]

[0071] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 19 When is a halogen, said halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine, also for example fluorine.

[0072] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): R 19 C 1-3 Alkyl or deuterated C 1-3 When it is alkyl, the C 1-3 Alkyl and deuterated C 1-3 Alkyl C 1-3 Alkyl may be methyl, ethyl, n-propyl or isopropyl, for example methyl.

[0073] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): X is hydrogen, fluorine, chlorine, bromine or iodine; R 1a and R 1b is independently C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 2a , R 2b and R 2c are independently hydrogen or deuterium; R 3 , R 4 and R 5 is independently C 1-3 Alkyl, C 1-3 Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C 1-3 alkyl-O-; R 6 , H, C 1-3 Alkyl, C 2-4 Alkynyl or deuterated C 1-3 is alkyl, R 7 -OR 12 , -NR 13 R 14 Or -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ), where R 12 , R 17 and R 18 is independently C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 15 and R 16 are independently H, C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 13 and R 14 are independently OH, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl-O- or deuterated C 1-3 alkyl-O-; or R 13 and R 14 Together with the nitrogen atom to which R is linked, a 4- to 6-membered aliphatic heterocycle or at least one R 19or at least one R 19 R 19 is halogen, O=, C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 8 , R 9 , R 10 and R 11 are independently hydrogen or deuterium; Here, R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 At least one of is deuterium or a deuterated group.

[0074] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): X is hydrogen, fluorine, chlorine, bromine or iodine; R 1a and R 1b is independently C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 2a , R 2b and R 2c are independently hydrogen or fluorine; R 3 , R 4 and R 5 is independently C 1-3 Alkyl, C 1-3 Alkyl-O-, deuterated C 1-3 Alkyl or deuterated C 1-3 alkyl-O-; R 6 , H, C 1-3 Alkyl,

[0075] [ka]

[0076] or deuterated C 1-3 is alkyl, R 7 -OR 12 , -NR 13 R 14 Or -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ), where R 12 , R 17 and R 18 is independently C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 15 and R 16 are independently H, C 1-3 Alkyl or deuterated C 1-3 is alkyl, R 13 and R 14 are independently OH, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkyl-O- or deuterated C 1-3 alkyl-O-; or R 13 and R 14 Together with the nitrogen atom to which R is linked, a 4- to 6-membered aliphatic heterocycle or one or more R 19 or one or more R 19 forming a 4- to 6-membered aliphatic heterocycle substituted by R 8 , R 9 , R 10 and R 11 are independently hydrogen or deuterium;

[0077] Here, R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R7 , R 8 , R 9 , R 10 and R 11 At least one of is deuterium or a deuterated group.

[0078] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): X is fluorine, chlorine or bromine; R 1a and R 1b is independently methyl or deuterated methyl; R 2a , R 2b and R 2c are independently hydrogen or deuterium; R 3 , R 4 and R 5 are independently methyl, methyl-O-, and CD 3 or CD 3 -O-, R 6 is H, methyl,

[0079] [ka]

[0080] , or CD 3 and R 7 -OR 12 , -NR 13 R 14 Or -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ), where R 12 , R 17 and R 18 are independently methyl, ethyl, and CD 3 or -CD 2 -CD 3 and R15 and R 16 are independently methyl, ethyl, and CD 3 or -CD 2 -CD 3 and R 13 and R 14 are independently OH, methyl, ethyl, and CD 3 , -CD 2 -CD 3 or CD 3 -O- or R 13 and R 14 together with the nitrogen atom to which it is linked

[0081] [ka]

[0082] R 8 , R 9 , R 10 and R 11 are independently hydrogen or deuterium; Here, R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 At least one of is deuterium or a deuterated group.

[0083] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application): X is chlorine or bromine; R 1a and R 1b are independently methyl or CD 3 and R 2a , R 2b and R 2care independently hydrogen or deuterium; R 3 , R 4 and R 5 are independently methyl, methyl-O-, and CD 3 or CD 3 -O-, R 6 is H, methyl or CD 3 and R 7 -OR 12 , -NR 13 R 14 Or -C(R 15 R 16 )-P(=O)(OR 17 OR 18 ), where R 12 , R 17 and R 18 are independently methyl, ethyl, and CD 3 or -CD 2 -CD 3 For example, methyl or CD 3 and R 15 and R 16 are independently methyl; R 13 and R 14 are independently methyl, ethyl, methyl-O-, CD 3 , -CD 2 -CD 3 or CD 3 -O-, Or, R 13 and R 14 together with the nitrogen atom to which it is linked

[0084] [ka]

[0085] Forming R 8 , R 9 , R 10 and R 11 are independently hydrogen or deuterium; Here, R 1a , R1b , R 3 , R 4 , R 5 , R 6 and R 7 At least one of is deuterium or a deuterated group.

[0086] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application):

[0087] [ka]

[0088] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application):

[0089] [ka]

[0090] In some preferred embodiments of the present invention, certain groups of the compound of formula I or a pharma- ceutically acceptable salt thereof are defined as follows (groups not mentioned are as described in any one of the embodiments of the present application):

[0091] [ka]

[0092] In some preferred embodiments of the invention, the compound of formula I or a pharma- ceutically acceptable salt thereof is any one of the following compounds:

[0093] [ka]

[0094] [ka]

[0095] The compound represented by formula I or its pharma- ceutically acceptable salt according to the present invention can be synthesized by a method including a method similar to a method known in the chemical art, and the steps and conditions can refer to the steps and conditions of similar reactions in the art, and can be synthesized according to the description in this specification. The starting materials are generally available from commercial manufacturers such as Aldrich, or can be easily prepared using methods known to those skilled in the art (available from SciFinder, Reaxys online database).

[0096] The raw materials or reagents required for the compound of formula I or its pharma- ceutically acceptable salts are commercially available or can be prepared by synthetic methods known in the art. The compounds of the present invention, either free base or acid addition salts, can be prepared by the methods described in the experimental section below. The term pharma- ceutically acceptable salt refers to a pharma- ceutically acceptable salt as defined herein, which has all the effects of the parent compound. The pharma- ceutically acceptable salt can be prepared by adding an acid corresponding to the appropriate organic solvent of the organic base, and following the usual methods to prepare the pharma- ceutical acceptable salt.

[0097] As an illustration of salt formation, in the case of base addition salts, alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., aluminum, magnesium, calcium, zinc or bismuth) salts can be prepared by treating a compound of the present invention having a suitable acidic proton in an aqueous medium with an alkali metal or alkaline earth metal hydroxide or an alcohol salt (e.g., an ethanol salt or a methanol salt) or a suitable basic organic amine (e.g., diethanolamine, choline or glucosamine).

[0098] Alternatively, examples of acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and salts formed with inorganic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoflic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid, and trimethylacetic acid.

[0099] In the present invention, the compound represented by formula I or a pharma- ceutically acceptable salt thereof can be further produced, and the compound represented by formula I or a pharma- ceutically acceptable salt thereof can be peripherally modified by a method commonly used in the art to obtain another carbonyl heterocyclic compound represented by formula I or a pharma- ceutically acceptable salt thereof.

[0100] In general, the compounds of this invention can be prepared by the methods described in this invention, and unless otherwise specified, the substituents are as defined in Formula I.

[0101] The second aspect of the present invention also relates to a pharmaceutical composition containing the compound of the present invention as an active ingredient.

[0102] The present invention provides a pharmaceutical composition comprising a compound represented by formula I or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier. In the pharmaceutical composition, the compound represented by formula I or a pharma- ceutical acceptable salt thereof may be administered in a therapeutically effective amount.

[0103] The composition can be prepared according to a method known in the art. The compound of the present invention may be combined with at least one pharma- ceutically acceptable carrier (solid or liquid excipient and / or additive) to prepare any dosage form suitable for human or animal use. The content of the compound of the present invention in the pharmaceutical composition is usually 0.1-95%.

[0104] The compound of the present invention or a pharmaceutical composition containing the same can be administered in a unit dosage form, and the route of administration may be oral, intravenous injection, intramuscular injection, subcutaneous injection, enteral such as nasal cavity, oral mucosa, eye, lung and airway, skin, vagina, rectum, or parenteral.

[0105] The dosage form may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form may be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and double emulsion), a suspension, an injection (including water injection, powder injection and drops), an eye drop, a nose drop, a detergent and a liniment, the solid dosage form may be a tablet (including normal tablet, enteric tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric capsule), a granule, a powder, a pellet, a drop pill, a suppository, a film, a patch, a gas (powder) mist, a spray, etc., and the semi-solid dosage form may be an ointment, a gel, a paste.

[0106] The compounds of the present invention may be prepared into conventional formulations as well as into sustained release, controlled release, targeted formulations and various particulate delivery systems.

[0107] To prepare the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, wetting agents, binders, disintegrants, lubricants, glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose, crosslinked polyethylenepyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol.

[0108] Tablets can further be prepared into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered tablets and multi-layered tablets.

[0109] To prepare the dosage unit in capsules, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly put into a hard or soft capsule. The active ingredient compound of the present invention can also be made into granules or pellets using a diluent, a binder, and a disintegrant, and then put into a hard or soft capsule. The various diluents, wetting agents, binders, disintegrants, and glidants used in the preparation of tablets of the compound of the present invention can also be used in the preparation of capsules of the compound of the present invention.

[0110] To prepare the compound of the present invention into an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and an appropriate amount of a solubilizer, co-solvent, pH adjuster, or osmotic pressure adjuster commonly used in the art can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc., the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc., and the osmotic pressure adjuster can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. To prepare a lyophilized powder injection, mannitol, glucose, etc. can be added as a proppant.

[0111] Furthermore, coloring agents, preservatives, fragrances, flavoring agents or other additives may be added to the pharmaceutical preparations, if necessary.

[0112] A third aspect of the invention relates to the use of said compounds for the prevention and treatment of proliferative diseases.

[0113] The present invention provides use of a compound represented by formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament. Specifically, the present invention provides use of a compound represented by formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating a proliferative disease.

[0114] The proliferative disease may be cancer; For example, the cancer may be bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, adrenal cancer, prostate cancer, stomach cancer, vaginal cancer, cervical cancer, endometrial cancer, central nervous system tumors, melanoma, leukemia, thyroid cancer, and skin cancer, etc. Lymphohematopoietic tumors include acute lymphoblastic leukemia, B-cell lymphoma, and Burkitt's lymphoma. Myeloid hematopoietic tumors include acute and chronic myeloid leukemia and promyelocytic leukemia; Stromal tumors include fibrosarcoma and rhabdomyosarcoma; Other tumors include melanoma, seminoma, teratoma, neuroblastoma, glioma, and the like.

[0115] Preferably, the cancer is lung cancer, colon cancer, central nervous system tumor, melanoma, kidney cancer, leukemia, prostate cancer, ovarian cancer or breast cancer, and the lung cancer cells may be A549 (non-small cell lung cancer) cells, the colon cancer cells may be HCT116 (colon cancer) cells, the central nervous system tumor cells may be SF295 (central nervous system tumor) cells, the melanoma cells may be LOX-IMVI (melanoma) cells, the kidney cancer cells may be 786-0 (kidney cancer) cells, the leukemia cells may be K562 (leukemia) cells, the prostate cancer cells may be PC-3 (prostate cancer) cells, the ovarian cancer cells may be OVCAR-3 (ovarian cancer) cells, and the breast cancer cells may be HS578T (breast cancer) cells.

[0116] The present invention also provides a pharmaceutical agent (or a pharmaceutical composition) comprising a compound represented by the above formula I or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.

[0117] The present invention also provides a medicine (or a pharmaceutical composition) for preventing and treating a proliferative disease, comprising a compound represented by formula I or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.

[0118] The present invention also provides the use of a compound of formula I or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, or the pharmaceutical composition, in the manufacture of a medicament, which may be for treating and / or preventing a proliferative disease.

[0119] The present invention also provides a method for treating and / or preventing a proliferative disease, comprising administering a therapeutically effective amount of a compound represented by formula I or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, or the pharmaceutical composition to an individual in need thereof.

[0120] The prevention and treatment of said proliferative diseases is as described above.

[0121] To achieve the intended purpose and enhance the therapeutic effect, the medicament or pharmaceutical composition of the present invention can be administered by any known administration method.

[0122] The dosage of the pharmaceutical composition of the compound of the present invention can vary within a wide range depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the administration route and dosage form, etc. Generally speaking, the suitable daily dose range of the compound of the present invention is 0.001-150 mg / Kg body weight, preferably 0.1-100 mg / Kg body weight, more preferably 1-60 mg / Kg body weight, and most preferably 2-30 mg / Kg body weight. The above dosage can be administered in one dosage unit or several dosage units, depending on the administration method including the clinical experience of the physician and the use of other therapeutic means.

[0123] The compound or composition of the present invention can be administered alone or in combination with other therapeutic or symptom-improving drugs.When the compound of the present invention has synergistic effects with other therapeutic drugs, its dosage should be adjusted according to actual situation. Effect of the Invention

[0124] Positive progressive effects of the present invention: The deuterated compounds provided by the present invention maintain the activity of inhibiting tumor cells and tumor stem cells, and also prolong the degradation effect of the compounds in human liver microsomes in vitro, significantly prolonging the half-life, providing safer and more reliable candidates for the development of new antitumor drugs. Specifically, the representative compounds all (1) exhibited excellent inhibitory activity against nine representative tumor cell lines, (2) significantly prolonged the half-life and significantly enhanced the metabolic stability, (3) inhibited breast cancer stem cells and their self-renewal ability, indicating that these compounds have the effect of killing tumor stem cells, and (4) the growth rate of mouse tumor volume in each treatment group was significantly slower than that of the solvent control group. [Brief description of the drawings]

[0125] [Figure 1]Inhibition experiment of the seven compounds of Example 44 against tumor stem cell sphere formation at a concentration of 50 nM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0126] The term "pharmaceutical acceptable" generally refers to salts, solvents, excipients, etc. that are non-toxic, safe and suitable for use by a patient. The "patient" is preferably a mammal, more preferably a human.

[0127] The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharma- ceutically acceptable acids.

[0128] The present invention relates to salts formed with alkali metals such as sodium, potassium, lithium, etc.; salts formed with alkaline earth metals such as calcium, magnesium, etc.; salts formed with other metals such as aluminum, iron, zinc, copper, nickel, cobalt, etc.; salts formed with inorganic bases such as ammonium, tert-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl esters, ethylenediamine, N-methylglucosamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzyl-phenylethylamine, piperazine, trimerazine, etc. The present invention claims protection for "pharmaceutically acceptable salts" of the compounds of formula I, including salts formed with organic bases, such as diethylamine, tri(hydroxymethyl)aminomethane, and the like; salts formed with inorganic acids, such as nitric acid, perchloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like; salts formed with sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like; salts formed with organic acids, such as formic acid, acetic acid, malic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, maleic acid, and the like; salts formed with amino acids, such as glycine, trimethylglycine, arginine, ornithine, glutamic acid, aspartic acid, and the like. The present invention is not limited to pharmaceutically acceptable salts.

[0129] "Treatment" refers to the treatment of diseases in the body of mammals, including (1) preventing diseases, i.e., the symptoms of clinical diseases do not occur; (2) inhibiting diseases, i.e., preventing the occurrence of clinical symptoms; (3) alleviating diseases, i.e., the clinical symptoms subside, including regression.

[0130] "Effective amount" refers to an amount sufficient to (i) treat a relevant disease, (ii) reduce, improve or eliminate at least one symptom of a specific disease, or (iii) delay the onset of at least one of the specific diseases or medical conditions described herein when a compound is administered to a patient in need of treatment. The amount corresponding to that amount of the carbonyl heterocyclic compound represented by Formula I, or its pharmaceutically acceptable salt, or the above pharmaceutical composition, varies depending on, for example, the specific compound, disease state and its severity, the characteristics of the patient in need of treatment (e.g., body weight), etc., but can nevertheless be routinely determined by those skilled in the art.

[0131] "Prevention" as described in the present invention refers to reducing the risk of contracting or developing a disease or disorder.

[0132] "Pharmaceutical composition" as described in the present invention refers to a formulation of at least one compound of the present invention or its salt and a carrier generally recognized in the art for delivering a biologically active compound to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate delivery to the organism.

[0133] The term "pharmaceutical acceptable carrier" refers to a substance that is co-administered with an active ingredient to facilitate administration of the active ingredient, and includes, but is not limited to, any flow aid, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the US Food and Drug Administration for use in humans or animals (e.g., livestock), including, but not limited to, calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0134] The pharmaceutical compositions according to the present invention can be prepared as solid, semi-solid, liquid or gas formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injectables, inhalants, gels, microspheres and aerosols.

[0135] The pharmaceutical compositions according to the present invention can be manufactured by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or other methods known in the art.

[0136] The routes of administration of the compounds according to the present invention or their pharma- ceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous, etc. The preferred route of administration is oral administration.

[0137] For oral administration, the pharmaceutical composition can be prepared by combining the active compound with a pharma- ceutically acceptable carrier known in the art. With such a carrier, the compound of the present invention can be prepared as a tablet, pill, troche, dragee, capsule, liquid, gel, slurry, suspension, etc., and used for oral administration to a patient. For example, a pharmaceutical composition for oral administration can be obtained as a tablet by the following method. The active ingredient is combined with at least one solid carrier, the mixture obtained is granulated if necessary, and the mixture or granules are processed by adding a small amount of excipients if necessary to form a tablet or tablet core. The tablet core can be optionally combined with a coating material suitable for enteric coating and processed into a coating formulation suitable for absorption by an organism (e.g., human).

[0138] The following definitions are used herein unless otherwise stated. For the purposes of the present invention, the chemical elements are consistent with the CAS Periodic Table of the Elements and the Handbook of Chemistry and Physics, 75th Edition, 1994. General principles of organic chemistry may also be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0139] In this specification, groups and their substituents can be selected by one skilled in the art to provide stable structural moieties and compounds. When a substituent is depicted by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written from right to left.

[0140] Certain chemical groups defined herein are preceded by a shorthand symbol indicating the total number of carbon atoms present in that group. For example, C 1 ~C 6Alkyl refers to an alkyl, as defined below, having a total of 1, 2, 3, 4, 5, or 6 carbon atoms. The total number of carbon atoms in the mnemonic does not include carbons that may exist in substituents of said group.

[0141] In this specification, the numerical ranges defined for substituents, for example, 0-4, 1-4, 1-3, etc., indicate integers within the range; for example, 1-6 is 1, 2, 3, 4, 5, 6.

[0142] In addition to the above, as used in the specification and claims of this application, unless specifically stated otherwise, the following terms have the meanings set forth below.

[0143] The term "comprising" is intended to be open-ended, i.e. including the subject matter specified in the present invention but not excluding other aspects.

[0144] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, including deuterium and hydrogen variants, provided that the particular valence state is normal and the compound is stable after substitution.

[0145] In general, the term "substituted" refers to at least one hydrogen atom in a given structure being replaced with a specific substituent. Furthermore, when the substituent is replaced with one or more of the aforementioned substituents, the aforementioned substituents are independent of each other, i.e., the aforementioned one or more substituents may be different from each other or may be the same. Unless otherwise stated, a substituent may be replaced at each substitutable position of the group to be replaced. When multiple positions of a given structural formula may be replaced with at least one substituent selected from a specific group, the substituent may be replaced at each position in the same or different manner.

[0146] The terms "at least one" or "one or at least two" refer to one, two, three, four, five, six, seven, eight, nine or more, for example, one, two, three, four or five.

[0147] The term "comprising" is intended to be open-ended, i.e. including the subject matter specified in the present invention but not excluding other aspects.

[0148] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, including deuterium and hydrogen variants, provided that the particular valence state is normal and the compound is stable after substitution.

[0149] In general, the term "substituted" refers to at least one hydrogen atom in a given structure being replaced with a specific substituent. Furthermore, when the substituent is replaced with one or more of the aforementioned substituents, the aforementioned substituents are independent of each other, i.e., the aforementioned one or more substituents may be different from each other or may be the same. Unless otherwise stated, a substituent may be replaced at each substitutable position of the group to be replaced. When multiple positions of a given structural formula may be replaced with at least one substituent selected from a specific group, the substituent may be replaced at each position in the same or different manner.

[0150] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to radical types or ranges. In particular, the present invention includes each independent subcombination of each member of these radical types and ranges. x ~C y "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, the term "C 1 ~C 6 Alkyl" or "C 1-6 Alkyl" specifically includes the independently disclosed methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 Refers to alkyl, and "C 1-4 Alkyl" specifically includes the independently disclosed methyl, ethyl, C 3 Alkyl (i.e., propyl, including n-propyl and isopropyl), C 4 Refers to alkyl (ie, butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0151] The term "halogen" is selected from F, Cl, Br or I and particularly refers to F, Cl or Br.

[0152] The term "alkoxy" refers to an -OR X refers to the group, where R X is alkyl as defined above.

[0153] As used herein, the terms "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" refer to specific fragments or functional groups in a molecule. A chemical moiety is generally recognized as a chemical entity embedded in or attached to a molecule.

[0154] If a recited substituent does not indicate through which atom it is attached to a compound contained in a general chemical structure but not specifically mentioned, such substituent may be attached through any atom thereof. Combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0155] If a recited group is not specified to have substituents, then such group refers only to the unsubstituted form. For example, "C 1 ~C 4 If "alkyl" is not qualified by "substituted or unsubstituted," then "C 1 ~C 4 Alkyl" by itself or "unsubstituted C 1 ~C 4 Refers only to "alkyl."

[0156] In various parts of the present invention, linking substituents are described. If the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for this variable lists "alkyl," the "alkyl" should be understood to represent a linked alkylene group.

[0157] In some particular structures, where an alkyl group is explicitly depicted as the linking group, the alkyl group represents a linked alkylene group, e.g., "halo-C 1 ~C 6 "Alkyl" C 1 ~C 6 Alkyl is C 1 ~C 6 It should be understood as alkylene.

[0158] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon group. Illustrative examples of alkylene groups include methylene (-CH 2 -), ethylene {-CH 2 CH 2 - or -CH(CH 3 )-}, isopropylidene {-CH(CH 3 )CH 2 - or -C(CH 3 ) 2 -contains} and so on.

[0159] As used herein, the term "alkyl" as a group or part of another group (e.g., groups such as alkyl substituted with halogen) refers to a branched or straight-chain saturated aliphatic hydrocarbon containing a specified number of carbon atoms, such as a straight or branched saturated hydrocarbon chain containing 1 to 16 carbon atoms, and also includes, for example, C 1 ~C 6 It is an alkyl group. For example, "C 1 ~C 6 "Alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched configuration. 3 Alkyl (including isomers such as n-propyl or isopropyl), butyl is C 4 Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, and tert-butyl), and pentyl is C 5Alkyl (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-amyl, neopentyl, etc.), and hexyl is C 6 Alkyl (including such isomers as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2,3-dimethylbutyl).

[0160] The "C" described in the present invention 1-3 "Alkyl" refers to a straight or branched chain alkyl formed by removing one hydrogen atom from a hydrocarbon having 1 to 3 carbon atoms.

[0161] In this application, the term "alkenyl" as a group or part of another group refers to a straight or branched hydrocarbon chain radical composed solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and no carbon-carbon triple bonds, e.g., having 2-14 (preferably 2-10, more preferably 2-6) carbon atoms, and connected to the remainder of the molecule by a single bond. The at least one carbon-carbon double bond may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). The "cis" and "tans" orientations, or "E" and "Z" orientations, are included.

[0162] In some embodiments, the alkenyl group is an alkyl group having 2 to 4 carbon atoms ("C 2-4 Alkenyl or C 2 ~C 4 Preferably, one carbon-carbon double bond is present, and up to two non-aromatic carbon-carbon double bonds may be present. 2-4 Illustrative examples of alkenyl groups include:

[0163] [ka]

[0164] and isomers (eg, cis-trans isomers, isomers, or stereoisomers).

[0165] The "C" described in the present invention 2-4 "Alkenyl" refers to straight or branched chain alkenyl containing a double bond and having 2 to 4 carbon atoms.

[0166] In this application, unless otherwise defined, the term "alkynyl" as a group or part of another group refers to a straight or branched chain hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon triple bond, in which up to three carbon-carbon triple bonds can be present. For example, a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally at least one carbon-carbon double bond ("C 2 ~C 20 The at least one carbon-carbon triple bond may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). Thus, "C 2 ~C 4 Alkynyl" refers to an alkynyl having 2 to 4 carbon atoms. In some embodiments, the alkynyl group is an alkynyl having 2 to 4 carbon atoms ("C 2 ~C 4 alkynyl)

[0167] [ka]

[0168] The "C" described in the present invention 2-4 "Alkynyl" refers to straight or branched chain alkynyl having 2 to 4 carbon atoms containing a triple bond.

[0169] "Deuterium" as used herein refers to a single deuterium atom and is represented by the symbol 2H or D. Taking hydrogen atoms as an example, their natural abundance is about 99.985% in the form of protium, about 0.015% in the form of deuterium, and the non-natural abundance of deuterium is about 95% deuterium.

[0170] The term "deuterated substance" or "deuterated group" as used herein refers to a compound or group that is produced when hydrogen atoms in a compound or chemical group structure are partially or completely replaced by its isotope, deuterium.

[0171] The "deuterated C" described in the present invention 1-3 Alkyl means "C 1-3 "C" refers to a group in which some or all of the hydrogen atoms in the "alkyl" structure have been replaced with their isotope, deuterium. 1-3 "Alkyl" is as defined above.

[0172] The "deuterated C" described in the present invention 1-3 Alkoxy means "C 1-3 "Alkoxy" refers to a group in which some or all of the hydrogen atoms in the structure are replaced with their isotope, deuterium. 1-3 "Alkoxy" is as defined above.

[0173] The term "deuterated methyl" as used herein refers to a group in which some or all of the hydrogen atoms in a methyl structure have been replaced with their isotope, deuterium. 3 is a group obtained by replacing all hydrogen atoms in a methyl structure with its isotope, deuterium (which has a non-natural abundance of about 95%).

[0174] The term "deuterated methoxy" as used herein refers to a group obtained by partially or completely replacing hydrogen atoms in a methoxy structure with its isotope, deuterium. 3 -O- is the radical obtained when all hydrogen atoms in a methyl-O- structure are replaced with their isotope, deuterium (which has a non-natural abundance of about 95%).

[0175] The term "deuterated ethyl" as used herein refers to a group obtained by partially or completely replacing hydrogen atoms in an ethyl structure with its isotope, deuterium. 3 -CD 2 - is a group obtained by replacing all hydrogen atoms in an ethyl-O- structure with its isotope, deuterium (which has a non-natural abundance of about 95%).

[0176] The term "aliphatic heterocycle" as used herein refers to a stable 4-7 membered monocyclic ring, which may be saturated or partially unsaturated, and is composed of carbon atoms and optionally 1-4 heteroatoms selected from N, O and S, preferably a 4-6 membered heterocyclic heterocycloalkyl or heterocycloalkenyl. An "aliphatic heterocycle" can be linked to the rest of the molecule by a single bond through a carbon atom, and in an "aliphatic heterocycle" group containing at least one nitrogen atom, the point of attachment can be a carbon atom or a nitrogen atom, or, as far as valence allows, a parallel ring link to the rest of the molecule. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, dioxolanyl, dioxanyl, etc. Preferred heterocyclic groups are 1,3-dioxolanyl and 1,4-dioxanyl.

[0177] Unless otherwise defined, all technical and scientific terms used herein have standard meanings within the art to which the claimed subject matter belongs. In the event that there are a plurality of definitions for a term, those set forth in the specification prevail.

[0178] As used herein, singular terms such as "a" and "an" are understood to include the plural unless otherwise defined. Also, the term "comprises" is an open rather than closed limitation, i.e., includes the subject matter specified in the present invention but does not exclude other aspects.

[0179] Unless otherwise defined, the present invention employs conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operational steps and conditions in the art.

[0180] Unless otherwise defined, this invention uses standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard procedures are used for chemical syntheses, chemical analyses, and performance testing of light emitting devices.

[0181] Unless otherwise defined, the description method "independently ..." used in the present invention should be understood in a broad sense, and means that each described individual is independent of each other and may be the same or different specific groups independently. More specifically, the description method "independently ..." means that specific options represented by the same symbol in different groups do not affect each other, and also means that specific options represented by the same symbol in the same group do not affect each other.

[0182] Those skilled in the art will recognize, in accordance with conventions used in the art, the "alkyl" and "alkylene" used in the structural formulae of groups described in this application.

[0183] [ka]

[0184] " refers to the corresponding group being connected to other fragments and groups within the compound via that location point.

[0185] The above preferred conditions can be combined in any manner to obtain each preferred embodiment of the present invention, without violating the ordinary skill in the art.

[0186] The reagents and materials used in the present invention are commercially available. EXAMPLES

[0187] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which no specific conditions are described are selected according to ordinary methods and conditions or product instructions. All technologies realized based on the above content of the present invention are within the scope of the present invention.

[0188] Unless otherwise stated, the reagents used in the experiments were purchased from Beijing Ouhe Technology Co., Ltd., Beijing J&K Scientific Ltd, Acros Organics, Alfa Aesar, Sigma-Aldrich, and TCI and used directly without purification. The solvents used in the experiments were mainly purchased from Beijing Chemical Works and Xilong Chemical Co., ltd., and the rest were used directly without any treatment except for THF and DMF, which were further treated in the solvent purification system of VAC (Vacuum atmospheres company) in the United States. GF 254 Thin-layer chromatography silica gel plates, preparative GF254 thick-layer silica gel plates, and silica gel powders for column chromatography (60–100 mesh, 160–200 mesh, 200–300 mesh) were all purchased from Qingdao Ocean Chemical Factory.

[0189] HPLC-MS analyzer: The HPLC analyzer used was an Agilent 1100 HPLC system, Agilent G1312A pump, Agilent G1314A UV detector, Agilent G1313A autosampler, Agilent G1316A column thermostat and diverter valve. The chromatography column was a Kromasil C18 analytical column (4.6 μm, 4.6 mm × 50 mm) purchased from DIKMA. The mobile phase was acetonitrile and water containing 0.05% HCOOH. The linear gradient elution was 5:95 (v:v) acetonitrile-HCOOH. 2 O-95:5 (v:v) acetonitrile-H 2The run duration was 5 min and the flow rate was 1 mL / min. The UV detection wavelength was 254 nm. The ThermoFinnigan LCQ-Advantage mass spectrometer used positive or negative ion scanning mode with an electrospray ion source (ESI) with 5% of the eluent flowing into the mass spectrometer. It was primarily used for reaction monitoring and preliminary determination of compound purity.

[0190] UPLC-MS analyzer: Waters Acquity UPLC-MS system, including a binary solution manager, a sample manager, a chromatography column manager, a PDA detector, and an SQ mass spectrometer detector. The chromatography column is a Waters Acquity UPLC (R) The column was a BEH C18 column (1.7 μm, 2.1 mm × 50 mm). The mobile phase was acetonitrile and water containing 0.05% HCOOH. The linear gradient elution was 5:95 (v:v) acetonitrile-HCOOH. 2 O-95:5 (v:v) acetonitrile-H 2 The flow rate was 0.3 mL / min, the duration was 3 min, and the flow rate was 0.3 mL / min. The UV detection wavelength was 254 nm. The SQ mass spectrometer used positive or negative ion scanning mode, electrospray ion source (ESI). It was mainly used for reaction monitoring and preliminary determination of compound purity.

[0191] HPLC analyzer: Agilent 1260 HPLC system, Agilent G1311C quaternary pump, Agilent G4212B UV detector, Agilent G1367E high performance autosampler, Agilent G1316A column thermostat. Chiral analysis column: DAICEL CHIRALPAK AD-H, 250 x 4.6 mm, 5 μM (manufactured by Daicel Japan). The mobile phase was n-hexane / isopropanol, with isocratic elution. The UV detection wavelength was 254 nm. It was mainly used for the optical purity analysis of the target compounds.

[0192] High-resolution mass spectrometer: Agilent LC / MSD TOF system. Chromatography column: Agilent ZORBAX SB-C18 (Rapid resolution, 3.5 μm, 2.1 × 30 mm). Mobile phase: MeOH:H 2 The mixture was 75:25 (v:v) with 5 mmol / L formic acid and was eluted isocratically. The time was 5 min and the flow rate was 0.40 mL / min. The mass spectrometer was used in positive ion scanning mode with an electrospray ion source (ESI). It was mainly used to measure the exact molecular weight of the target compounds.

[0193] Nuclear magnetic resonance apparatus: Varian Mercury 300 MHz, 400 MHz, 500 MHz, 600 MHz and Bruker Avance 400 MHz. Solvent: CDCl 3 , DMSO-d 6 , acetone-d 6 or methanol-d 4 It was.

[0194] Melting point apparatus: Yanaco micro melting point apparatus, OptiMelt melting point apparatus, both uncalibrated.

[0195] Example 1 (S)-2-chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 1)

[0196] Preparation of 5-chloro-2,4-dinitrobenzoic acid (Intermediate 42): 3-chlorobenzoic acid (63.9 mmol) was dissolved in 120 mL of concentrated sulfuric acid under stirring at room temperature, and potassium nitrate (163.2 mmol) was added in batches within 15 minutes. The reaction solution was reacted at 80°C for 30 minutes, 110°C for 2 hours, and 120°C for 2 hours in sequence. The reaction solution was poured into 660 g of ice water, filtered, and the resulting white solid was recrystallized with a mixed solvent of ethanol and water to obtain 8.08 g of pale yellow crystals, with a yield of 51.3%.1 H NMR (400 MHz, DMSO-d 6 ) δ 14.21 (brs, 1H), 8.85 (s, 1H), 8.28 (s, 1H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 163.78, 147.95, 145.70, 132.86, 132.06, 130.52, 122.05.

[0197] Preparation of 5-(3,5-dimethylphenoxy)-2,4-dinitrobenzoic acid (Intermediate 43): Intermediate 42 (20.0 mmol), 3,5-dimethylphenol (21.2 mmol) and sodium bicarbonate (42.4 mmol) were mixed in 20 mL of water and reacted under reflux for 2 hours. The reaction was monitored for completion by HPLC-MS, diluted with 30 mL of water, adjusted to acidic pH with hydrochloric acid, filtered and dried to give 5.50 g of an off-white solid, with a yield of 82.7%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 7.14 (s, 1H), 6.99 (s, 1H), 6.89 (s, 2H), 2.30 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.56, 153.58, 153.56, 140.60, 140.38, 139.33, 135.32, 127.78, 122.66, 118.76, 117.64, 20.78.

[0198] Preparation of (S)-2-[5-(3,5-dimethylphenoxy)-2,4-dinitrobenzamido]butanedioic acid dimethyl ester (intermediate 44): Intermediate 43 (10.0 mmol) was dissolved in 10 mL of DCM, and 50 μL of DMF and oxalyl chloride (30.0 mmol) were added in sequence, and the mixture was allowed to react for 1 hour under reflux. The reaction solution was evaporated to dryness, and the residue was dissolved in DCM, and the mixture was added dropwise to a mixture of L-aspartic acid dimethyl ester hydrochloride (10.1 mmol), triethylamine (22.0 mmol) and 20 mL of DCM, and allowed to react at room temperature for 15 minutes. The mixture was diluted with about 100 mL of DCM, and washed successively with 1 M dilute hydrochloric acid, saturated sodium bicarbonate solution, and water, and the organic phase was separated and evaporated to dryness to obtain 4.23 g of a reddish brown oil, with a yield of about 89.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (d, J = 7.9 Hz, 1H), 8.84 (s, 1H), 7.00 (s, 1H), 6.97 (s, 1H), 6.90 (s, 2H), 4.74 (dd, J = 13.7, 7.1 Hz, 1H), 3.61 (s, 3H), 3.55 (s, 3H), 2.88 (dd, J = 16.5, 5.7 Hz, 1H), 2.80 (dd, J = 16.5, 7.3 Hz, 1H), 2.30 (s, 6H).

[0199] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid methyl ester (intermediate 45): Intermediate 44 (5.0 mmol) was dissolved in 80 mL of glacial acetic acid, 6.0 g of iron powder was added, and the mixture was reacted at 90° C. for 5 hours. The reaction solution was diluted with DCM, filtered, and the filtrate was evaporated to dryness and subjected to silica gel column chromatography, eluted with petroleum ether / ethyl acetate to obtain 1.25 g of a pale yellow solid, with a yield of about 65.0%. 1 H NMR (300 MHz, DMSO-d 6) δ 10.23 (s, 1H), 8.16 (d, J = 5.0 Hz, 1H), 7.00 (s, 1H), 6.74 (s, 1H), 6.59 (s, 2H), 6.42 (s, 1H), 5.75 (s, 2H), 4.04 (dt, J = 8.8, 5.5 Hz, 1H), 3.58 (s, 3H), 2.85 (dd, J = 17.0, 8.8 Hz, 1H), 2.68 (dd, J = 17.0, 5.6 Hz, 1H), 2.23 (s, 6H).

[0200] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-diethylacetamide (Intermediate 46): Intermediate 45 (2.0 mmol) and lithium hydroxide (6.0 mmol) were mixed, 20 mL of water and 20 mL of THF were added, and the mixture was reacted at room temperature for 30 minutes. The mixture was evaporated under reduced pressure to remove THF, and the pH was adjusted to acidic with 1 M hydrochloric acid to separate the precipitate, which was then filtered and dried. The resulting white solid was mixed with DIC (4.0 mmol), HOSu (4.0 mmol) and 20 mL of THF, and the mixture was reacted at room temperature for 12 hours. Diethylamine (6.0 mmol) was added, and the reaction was continued for 1 hour. Silica gel column chromatography eluting with DCM / MeOH gave 508 mg of a pale yellow solid, the yield was 59.8%. 1 H NMR (400 MHz, DMSO-d 6) δ 10.11 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H), 7.01 (d, J = 3.5 Hz, 1H), 6.74 (s, 1H), 6.60 (s, 2H), 6.43 (d, J = 2.9 Hz, 1H), 5.72 (s, 2H), 4.14 (dd, J = 5.4, 2.7 Hz, 1H), 3.32-3.16 (m, 4H), 2.96 (dd, J = 16.1, 8.6 Hz, 1H), 2.55 (dd, J = 16.4, 4.8 Hz, 1H), 2.24 (s, 6H), 1.16 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.79, 168.09, 167.54, 157.04, 144.26, 139.27, 139.16, 134.30, 124.62, 120.39, 115.29, 113.73, 105.53, 49.14, 41.37, 31.35, 20.96, 13.94, 13.06.

[0201] Preparation of 2-chloro-3,4,5-tris(trideuteromethoxy)benzoic acid (intermediate 47): gallic acid (23.51 mmol), potassium carbonate (188.10 mmol) were dissolved in 20 mL of DMF, deuterated iodomethane (117.56 mmol) was added, and the mixture was reacted at 35° C. overnight. The reaction solution was evaporated to dryness, DCM was added to dissolve, and the mixture was washed three times with water. The organic phase was separated, dried, and concentrated to obtain 5.34 g of crude product, with a yield of 95.4%. The above intermediate (3.0 mmol) and NCS (3.6 mmol) were dissolved in 5 mL of DMF, and the mixture was reacted at room temperature overnight. The reaction solution was evaporated to dryness, and the mixture was subjected to silica gel column chromatography, and eluted with petroleum ether / ethyl acetate to obtain 292 mg of crude product, with a yield of 53.2%. The intermediate (1.07 mmol) and lithium hydroxide (5.37 mmol) were dissolved in 8 mL of THF and 4 mL of water, and reacted at room temperature overnight. The THF was removed by evaporation under reduced pressure, and the mixture was diluted with water and adjusted to an acidic pH with 1 M hydrochloric acid to precipitate a solid, which was filtered and dried to obtain 260 mg of a white solid, with a yield of 94.9%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.30 (s, 1H), 7.19 (s, 1H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.38, 151.59, 149.74, 145.14, 126.75, 118.39, 109.41.

[0202] Title compound (1) Intermediate 47 (0.5 mmol) was dissolved in 5 mL of DCM, and 20 μL of DMF and oxalyl chloride (1.5 mmol) were added in sequence, and the mixture was reacted at 40° C. for 1 hour. The reaction solution was evaporated to dryness and recrystallized with 50 mL of petroleum ether. The white solid obtained above, intermediate 46 (0.2 mmol), and pyridine (0.6 mmol) were mixed in 2 mL of THF, and the mixture was reacted under reflux for 1 hour. The mixture was subjected to silica gel column chromatography and eluted with DCM / MeOH to obtain 113 mg of a yellow solid, with a yield of 85.5%. 1 H NMR (400 MHz, DMSO-d 6) δ 10.38 (s, 1H), 10.23 (s, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.00 (s, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.18 (dt, J = 8.9, 5.2 Hz, 1H), 3.32-3.17 (m, 4H), 2.98 (dd, J = 16.2, 8.6 Hz, 1H), 2.60 (dd, J = 16.1, 5.0 Hz, 1H), 2.25 (s, 6H), 1.17 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.79, 167.90, 166.79, 164.93, 156.20, 151.90, 149.32, 144.27, 143.86, 139.37, 132.73, 132.66, 131.58, 125.42, 122.93, 119.15, 116.35, 116.25, 115.53, 107.92, 49.01, 41.36, 31.24, 20.88, 13.91, 13.05.

[0203] Example 2 (S)-2-chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,5-dimethoxy-4-(trideuteromethoxy)benzamide (Compound 2)

[0204] Preparation of 2-chloro-3,5-dimethoxy-4-(trideuteromethoxy)benzoic acid (intermediate 48): syringic acid (2.52 mmol), potassium carbonate (10.10 mmol) were dissolved in 5 mL of DMF, deuterated iodomethane (5.05 mmol) was added, and the mixture was reacted at 35° C. overnight. A small amount of substrate was detected to be incompletely reacted, so deuterated iodomethane (5.05 mmol) was further added, and the reaction was continued for 9 hours to complete the reaction. The reaction solution was evaporated to dryness, DCM was added to dissolve the substrate, and the organic phase was separated, dried, and concentrated to obtain 544 mg of intermediate product, with a yield of 93.0%. The above intermediate (2.34 mmol) and NCS (2.81 mmol) were dissolved in 5 mL of DMF and reacted at room temperature overnight. The mixture was subjected to silica gel column chromatography and eluted with DCM to obtain 300 mg of intermediate product, with a yield of 48.2%. The intermediate (1.13 mmol) and lithium hydroxide (5.64 mmol) were dissolved in 8 mL of THF and 4 mL of water, and reacted at room temperature for 4 hours. The THF was removed by evaporation under reduced pressure, and the mixture was diluted with water and adjusted to an acidic pH with 1 M hydrochloric acid. The solid was precipitated, filtered, and dried to obtain 273 mg of a white solid, with a yield of 97.5%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.28 (s, 1H), 7.20 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.54, 151.73, 149.93, 145.36, 126.81, 118.74, 109.64, 61.01, 56.22.

[0205] The title compound (2) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 46 (0.2 mmol) and intermediate 48 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.38 (s, 1H), 10.23 (s, 1H), 8.53 (d, J = 5.3 Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.18 (dt, J = 8.5, 5.3 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.30-3.19 (m, 4H), 2.98 (dd, J = 16.3, 8.4 Hz, 1H), 2.60 (dd, J = 16.3, 4.8 Hz, 1H), 2.25 (s, 6H), 1.17 (t, J = 6.9 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.79, 167.91, 166.80, 164.93, 156.21, 151.91, 149.34, 144.28, 143.90, 139.38, 132.74, 132.68, 131.59, 125.42, 122.94, 119.17, 116.35, 116.31, 115.54, 107.98, 61.01, 56.22, 49.02, 41.37, 31.25, 20.88, 13.92, 13.06.

[0206] Example 3 (S)-2-chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,5-dimethoxy-4-(trideuteromethoxy)benzamide (compound 3)

[0207] Preparation of 2-chloro-3,5-dimethoxy-4-(trideuteromethoxy)benzoic acid (Intermediate 49): Potassium tert-butoxide (4.38 mmol) was dissolved in 10 mL of anhydrous THF, stirred and added with 3,5-dimethylbenzoic acid (1.10 mmol) in 10 mL of anhydrous THF under argon gas at -78°C. Butyllithium (4.38 mmol, 2.5 M in hexane) was added and the reaction was continued at -78°C for 40 minutes. Deuterated iodomethane (2.20 mmol) was added and the reaction was continued at -78°C for 1 hour. The reaction solution is warmed to room temperature, quenched by adding 6mL of saturated ammonium chloride solution, washed twice with 10mL of ether, separated aqueous phase, adjusted pH of aqueous phase to acidic with 2M hydrochloric acid, precipitated white precipitate, extracted twice with ether, separated organic phase, dried, concentrated in vacuum, and subjected to reverse phase column chromatography to obtain intermediate 202mg, yield 61.59%. The above product is chlorinated according to the synthesis method of intermediate 47 described in Example 1 to obtain intermediate 49.

[0208] The title compound (3) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 46 (0.2 mmol) and intermediate 49 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 10.22 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 7.99 (s, 1H), 7.17 (s, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.68 (s, 2H), 4.19 (dt, J = 9.0, 5.3 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.30-3.19 (m, 4H), 2.98 (dd, J = 16.3, 8.6 Hz, 1H), 2.60 (dd, J = 16.2, 4.9 Hz, 1H), 2.25 (s, 6H), 1.17 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6) δ 170.79, 167.91, 166.79, 165.17, 156.49, 156.21, 154.23, 144.28, 139.36, 134.76, 132.74, 132.69, 125.38, 122.98, 122.26, 119.25, 116.27, 115.94, 115.66, 106.56, 60.26, 55.95, 49.01, 41.36, 31.24, 20.87, 13.91, 13.05.

[0209] Example 4 (S)-2-Bromo-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 4)

[0210] Preparation of 2-bromo-3,4,5-tris(trideuteromethoxy)benzoic acid (Intermediate 50): Prepared according to the synthesis method of Intermediate 47 described in Example 1 using the corresponding reagent and NBS (3.6 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.33 (s, 1H), 7.17 (s, 1H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 167.12, 152.29, 150.64, 144.67, 129.47, 109.58, 107.02.

[0211] The title compound (4) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 46 (0.2 mmol) and intermediate 50 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.39 (s, 1H), 10.22 (s, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.18 (m, 1H), 3.32-3.13 (m, 4H), 2.99 (dd, J = 16.1, 8.5 Hz, 1H), 2.59 (dd, J = 16.1, 4.2 Hz, 1H), 2.25 (s, 6H), 1.17 (t, J = 6.7 Hz, 3H), 0.99 (t, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 171.23, 168.35, 167.25, 166.37, 156.66, 152.97, 150.70, 144.74, 144.00, 139.80, 134.38, 133.24, 133.08, 125.85, 123.36, 119.56, 116.86, 115.97, 108.69, 106.10, 49.45, 41.81, 31.68, 21.33, 14.36, 13.50.

[0212] Example 5 (S)-2-Bromo-N-[3-[2-[bis(pentadeuteroethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tri(trideuteromethoxy)benzamide (Compound 5)

[0213] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-bis(pentadeuteroethyl)acetamide (Intermediate 51): This was prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 45 (2.0 mmol) and deuterated diethylamine (6.0 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.10 (s, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.00 (s, 1H), 6.74 (s, 1H), 6.60 (s, 2H), 6.42 (s, 1H), 5.72 (s, 2H), 4.19-4.08 (m, 1H), 2.95 (dd, J = 16.2, 8.7 Hz, 1H), 2.58-2.52 (m, 1H), 2.24 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.80, 168.04, 167.53, 157.04, 144.26, 139.25, 139.14, 134.29, 124.60, 120.38, 115.29, 113.70, 105.49, 49.12, 31.31, 20.95.

[0214] The title compound (5) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 51 (0.2 mmol) and intermediate 50 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 10.21 (s, 1H), 8.52 (d, J = 4.3 Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.20-4.15 (m, 1H), 2.98 (dd, J = 16.0, 8.6 Hz, 1H), 2.59 (dd, J = 16.1, 3.8 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.74, 167.86, 166.76, 165.86, 156.19, 152.49, 150.23, 144.26, 143.54, 139.31, 133.89, 132.73, 132.61, 125.36, 122.88, 119.09, 116.36, 115.50, 108.24, 105.61, 48.97, 31.17, 20.84.

[0215] Example 6 (S)-2-chloro-N-[3-[2-[bis(pentadeuteroethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 6)

[0216] The title compound (6) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 51 (0.2 mmol) and intermediate 47 (0.5 mmol). 1 H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 7.11 (d, J = 4.9 Hz, 1H), 6.80 (s, 1H), 6.66 (s, 2H), 4.51 (dd, J = 11.7, 5.7 Hz, 1H), 3.07 (dd, J = 15.7, 7.4 Hz, 1H), 2.69 (dd, J = 15.6, 4.8 Hz, 1H), 2.29 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 171.33, 168.45, 168.22, 164.15, 155.94, 152.53, 150.09, 145.97, 143.43, 140.18, 133.44, 132.52, 128.98, 126.39, 121.26, 119.10, 117.65, 116.70, 112.54, 109.64, 49.86, 31.57, 21.40.

[0217] Example 7 (S)-2-Bromo-N-[3-[2-[bis(pentadeuteroethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 7)

[0218] Preparation of 2-bromo-3,4,5-trimethoxybenzoic acid (intermediate 52): 3,4,5-trimethoxybenzoic acid (10.0 mmol) was dissolved in 100 mL of chloroform, bromine water (20.0 mmol) was added, and the mixture was reacted for 5 hours under reflux. The reaction solution was washed with saturated sodium thiosulfate solution and water, and the organic phase was separated, evaporated to dryness, and recrystallized with water and ethanol to obtain 2.74 g of a white solid, with a yield of 94.2%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.31 (brs, 1H), 7.17 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H).

[0219] The title compound (7) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 51 (0.2 mmol) and intermediate 52 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 10.21 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.01 (s, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.18 (dt, J = 8.4, 5.3 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.98 (dd, J = 16.3, 8.6 Hz, 1H), 2.59 (dd, J = 16.3, 4.9 Hz, 2H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6) δ 170.77, 167.88, 166.79, 165.88, 156.20, 152.52, 150.28, 144.27, 143.60, 139.34, 133.94, 132.75, 132.63, 125.38, 122.91, 119.12, 116.37, 115.53, 108.30, 105.68, 60.86, 60.74, 56.22, 49.00, 31.19, 20.86.

[0220] Example 8 (S)-2-chloro-N-[3-[2-[bis(pentadeuteroethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 8)

[0221] Preparation of 2-chloro-3,4,5-trimethoxybenzoic acid (intermediate 53): 3,4,5-trimethoxybenzoic acid (10.0 mmol) was dissolved in 50 mL of chloroform and 25 mL of glacial acetic acid, and NCS (10.0 mmol) was added and reacted for 5 hours under reflux. The reaction solution was evaporated to dryness and recrystallized with water and ethanol to obtain 1.80 g of a white solid, with a yield of 73.1%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.31 (s, 1H), 7.20 (s, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.32, 151.58, 149.74, 145.13, 126.79, 118.36, 109.42, 60.91, 60.79, 56.15.

[0222] The title compound (8) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 51 (0.2 mmol) and intermediate 53 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d6 ) δ 10.38 (s, 1H), 10.23 (s, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.18 (dt, J = 8.9, 5.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 2.97 (dd, J = 16.2, 8.5 Hz, 1H), 2.59 (dd, J = 16.3, 5.0 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.82, 167.92, 166.83, 164.95, 156.23, 151.94, 149.38, 144.31, 143.93, 139.41, 132.75, 132.68, 131.64, 125.44, 122.97, 119.20, 116.36, 116.32, 115.58, 107.99, 61.04, 60.82, 56.24, 49.03, 31.23, 20.90.

[0223] Example 9 (S)-2-[8-(2-chloro-3,4,5-trimethoxybenzamido)-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid trideuteromethyl ester (Compound 9)

[0224] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid deuteromethyl ester (Intermediate 54): This was prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 45 (2.0 mmol) and deuterated methanol (6.0 mmol). 1 H NMR (300 MHz, DMSO-d 6) δ 10.21 (s, 1H), 8.15 (d, J = 5.0 Hz, 1H), 7.00 (s, 1H), 6.72 (s, 1H), 6.58 (s, 2H), 6.41 (s, 1H), 5.74 (s, 2H), 4.02 (dt, J = 8.8, 5.5 Hz, 1H), 2.83 (dd, J = 17.0, 8.8 Hz, 1H), 2.67 (dd, J = 17.0, 5.5 Hz, 1H), 2.22 (s, 6H).

[0225] The title compound (9) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 54 (0.2 mmol) and intermediate 53 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 10.25 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.68 (s, 2H), 4.12 (dt, J = 8.1, 5.4 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 2.88 (dd, J = 16.9, 8.8 Hz, 1H), 2.73 (dd, J = 17.2, 5.4 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.58, 170.45, 166.73, 164.97, 156.18, 151.94, 149.37, 144.37, 143.93, 139.40, 132.87, 132.45, 131.61, 125.47, 122.68, 119.23, 116.39, 116.30, 115.50, 108.00, 61.03, 60.79, 56.23, 48.60, 32.49, 20.87.

[0226] Example 10 (S)-2-chloro-N-[3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tri(trideuteromethoxy)benzamide (Compound 10)

[0227] Preparation of (S)-8-amino-3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]-7-(3,5-methylphenoxy)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (Intermediate 55): Prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 45 (2.0 mmol) and 4,4-difluoropiperidine (4.0 mmol).

[0228] The title compound (10) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 55 (0.2 mmol) and intermediate 47 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 10.22 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.68 (s, 2H), 4.18 (dd, J = 12.5, 5.9 Hz, 1H), 3.67-3.42 (m, 4H), 3.02 (dd, J = 16.3, 7.7 Hz, 1H), 2.70 (dd, J = 16.5, 5.6 Hz, 1H), 2.25 (s, 6H), 2.09 (brs, 2H), 1.89 (brs, 2H). 13 C NMR (100 MHz, DMSO-d 6) δ 170.78, 167.80, 166.78, 164.95, 156.17, 151.90, 149.31, 144.32, 143.86, 139.38, 132.76, 132.58, 131.57, 125.45, 122.80, 119.10, 116.39, 116.23, 115.51, 107.92, 49.07, 41.87, 38.23, 31.01, 20.87.

[0229] Example 11 (S)-2-Bromo-N-[3-[2-[bis(pentadeuteroethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 11)

[0230] Preparation of (S)-2-[5-(3,5-dimethylphenoxy)-N-methyl-2,4-dinitrobenzamido]butanedioic acid dimethyl ester (intermediate 56): Intermediate 44 (5.0 mmol) was dissolved in 10 mL of DMF, potassium carbonate (12.5 mmol) and methyl iodide (25.0 mmol) were added, and the mixture was reacted at 30° C. for 24 hours. The mixture was filtered and evaporated to remove DMF, and then subjected to silica gel column chromatography and eluted with petroleum ether / ethyl acetate to obtain 1.99 g of a pale yellow solid, with a yield of 81.3%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (s, 1H), 7.01 (s, 1H), 6.93 (s, 2H), 6.83 (s, 1H), 5.03 (t, J = 7.1 Hz, 1H), 3.58 (s, 3H), 3.53 (s, 3H), 3.05 (dd, J = 16.5, 6.6 Hz, 1H), 2.95 (dd, J = 16.7, 7.5 Hz, 1H), 2.78 (s, 3H), 2.30 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6) δ 170.50, 169.27, 165.08, 154.90, 153.45, 140.41, 139.09, 137.93, 137.16, 127.78, 123.86, 117.50, 116.86, 55.02, 52.23, 51.50, 35.36, 32.60, 20.72.

[0231] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid methyl ester (Intermediate 57): Prepared according to the synthesis of Intermediate 45 described in Example 1 using Intermediate 56. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 7.02 (s, 1H), 6.74 (s, 1H), 6.60 (s, 2H), 6.44 (s, 1H), 5.75 (brs, 2H), 4.41-4.32 (m, 1H), 3.60 (s, 3H), 3.10 (dd, J = 19.2, 6.0 Hz, 1H), 2.97 (dd, J = 15.8, 0.8 Hz, 1H), 2.84 (s, 3H), 2.24 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.69, 169.09, 167.12, 156.94, 144.22, 139.31, 139.12, 134.07, 124.60, 120.67, 115.25, 114.06, 105.04, 52.03, 51.74, 30.92, 29.02, 20.94.

[0232] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-bis(pentadeuteroethyl)acetamide (Intermediate 58): This was prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 57 (2.0 mmol) and deuterated diethylamine (4.0 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.15 (s, 1H), 7.01 (s, 1H), 6.74 (s, 1H), 6.60 (s, 2H), 6.42 (s, 1H), 5.71 (s, 2H), 4.44 (dd, J = 9.9, 4.1 Hz, 1H), 3.40 (d, J = 6.7 Hz, 1H), 2.87 (s, 3H), 2.81 (dd, J = 16.3, 3.7 Hz, 1H), 2.24 (s, 6H).

[0233] The title compound (11) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 58 (0.2 mmol) and intermediate 52 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 10.22 (s, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J = 9.3, 2.3 Hz, 1H), 3.79 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.17 (dd, J = 15.1, 10.6 Hz, 1H), 2.92 (s, 3H), 2.85 (dd, J = 17.1, 1.9 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6) δ 169.43, 167.66, 166.44, 165.90, 156.14, 152.53, 150.28, 144.16, 143.59, 139.33, 133.97, 132.63, 132.55, 125.37, 123.50, 119.30, 116.35, 115.11, 108.30, 105.66, 60.86, 60.74, 56.22, 52.40, 29.69, 29.49, 20.85.

[0234] Example 12 (S)-2-Chloro-N-[3-[2-[bis(pentadeuterioethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 12)

[0235] The title compound (12) was prepared using intermediate 58 (0.2 mmol) and intermediate 53 (0.5 mmol) according to the synthetic method of compound 1 described in Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 10.22 (s, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J = 9.6, 3.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.17 (dd, J = 15.6, 10.2 Hz, 1H), 2.92 (s, 3H), 2.85 (dd, J = 16.2, 3.0 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6) δ 169.48, 167.69, 166.48, 164.97, 156.16, 151.94, 149.37, 144.20, 143.92, 139.39, 132.68, 132.54, 131.65, 125.43, 123.57, 119.39, 116.33, 116.30, 115.17, 107.99, 61.03, 60.81, 56.23, 52.44, 29.72, 29.53, 20.89.

[0236] Example 13 (S)-2-Bromo-N-[3-[2-[bis(pentadeuteroethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 13)

[0237] The title compound (13) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 58 (0.2 mmol) and intermediate 50 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 10.21 (s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.82 (s, 2H), 6.69 (s, 2H), 4.48 (brs, 1H), 3.17 (dd, J = 14.3, 10.2 Hz, 1H), 2.92 (s, 3H), 2.86 (d, J = 15.6 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6) δ 169.90, 168.13, 166.90, 166.38, 156.62, 152.99, 150.72, 144.63, 144.02, 139.79, 134.40, 133.10, 133.02, 125.84, 123.97, 119.77, 116.84, 115.56, 108.72, 106.09, 52.87, 30.15, 29.96, 21.32.

[0238] Example 14 (S)-2-Bromo-N-[3-[2-[bis(trideuteromethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 14)

[0239] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-bis(trideuteromethyl)acetamide (Intermediate 59): This was prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 57 (2.0 mmol) and deuterated dimethylamine (4.0 mmol).

[0240] The title compound (14) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 59 (0.2 mmol) and intermediate 50 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.46 (s, 1H), 10.21 (s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.43 (dd, J = 10.0, 3.7 Hz, 1H), 3.18 (dd, J = 16.0, 10.2 Hz, 1H), 2.93 (s, 3H), 2.86 (dd, J = 16.0, 3.2 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 169.85, 169.15, 166.91, 166.38, 156.64, 152.99, 150.72, 144.61, 144.03, 139.79, 134.38, 133.10, 125.82, 123.95, 119.84, 116.80, 115.57, 108.74, 106.09, 52.91, 30.36,29.97, 21.32.

[0241] Example 15 (S)-2-Bromo-N-[3-[2-[bis(trideuteromethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 15)

[0242] The title compound (15) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 59 (0.2 mmol) and intermediate 52 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.46 (s, 1H), 10.21 (s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.43 (dd, J = 10.0, 3.7 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.18 (dd, J = 16.0, 10.2 Hz, 1H), 2.93 (s, 3H), 2.86 (dd, J = 15.9, 3.2 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 169.85, 169.15, 166.91, 166.37, 156.64, 153.00, 150.75, 144.60, 144.07, 139.79, 134.43, 133.11, 125.82, 123.95, 119.84, 116.80, 115.57, 108.79, 106.13, 61.33, 61.21, 56.70, 52.91, 30.35, 29.97, 21.32.

[0243] Example 16 (S)-2-Bromo-N-[3-[2-(dimethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 16)

[0244] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-dimethylacetamide (Intermediate 60): Prepared according to the synthesis method of Intermediate 46 described in Example 1 using 57 (2.0 mmol) and dimethylamine (4.0 mmol).

[0245] The title compound (16) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 60 (0.2 mmol) and intermediate 50 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 10.21 (s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.43 (d, J = 6.7 Hz, 1H), 3.19 (dd, J = 14.6, 10.9 Hz, 1H), 3.06 (s, 3H), 2.93 (s, 3H), 2.87 (d, J = 16.4 Hz, 1H), 2.79 (s, 3H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 169.84, 169.13, 166.90, 166.38, 156.64, 152.98, 150.71, 144.60, 144.02, 139.78, 134.38, 133.10, 125.82, 123.94, 119.83, 116.80, 115.56, 108.73, 106.09, 52.91, 36.95, 35.17, 30.37, 29.97, 21.32.

[0246] Example 17 (S)-2-chloro-N-[3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 17)

[0247] Preparation of (S)-8-amino-3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]-7-(3,5-methylphenoxy)-4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (Intermediate 61): Prepared according to the synthesis method of Intermediate 46 described in Example 1 using 48 (2.0 mmol) and 4,4-difluoropiperidine (4.0 mmol).

[0248] The title compound (17) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 61 (0.2 mmol) and intermediate 47 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 10.22 (s, 1H), 8.02 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.44 (dd, J = 9.7, 3.1 Hz, 1H), 3.79-3.38 (m, 4H), 3.31-3.25 (m, 1H), 2.97 (s, 1H), 2.94 (s, 3H), 2.25 (s, 6H), 2.06 (brs, 2H), 1.87 (brs, 2H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 169.42, 167.81, 166.44, 164.98, 156.16, 151.91, 149.32, 144.19, 143.85, 139.36, 132.63, 132.58, 131.59, 125.41, 123.49, 119.38, 116.31, 116.22, 115.13, 107.91, 52.48, 41.68, 38.24, 29.63, 20.87.

[0249] Example 18 (S)-2-Bromo-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-trideuteromethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 18)

[0250] Preparation of (S)-dimethyl 2-[5-(3,5-dimethylphenoxy)-N-trideuteromethyl-2,4-dinitrobenzamido]butanedioate (Intermediate 60): Prepared according to the synthesis method of Intermediate 56 described in Example 11 using Intermediate 44 (5.0 mmol) and deuterated iodomethane (0.25.0 mmol).

[0251] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-4-trideuteromethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid methyl ester (Intermediate 63): Prepared according to the synthesis method of Intermediate 45 described in Example 1 using Intermediate 62. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 7.01 (s, 1H), 6.74 (s, 1H), 6.60 (s, 2H), 6.43 (s, 1H), 5.76 (brs, 2H), 4.36 (dd, J = 9.4, 5.1 Hz, 1H), 3.59 (s, 3H), 3.09 (dd, J = 16.1, 9.6 Hz, 1H), 2.97 (dd, J = 15.7, 3.1 Hz, 1H), 2.24 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.70, 169.13, 167.22, 156.97, 144.24, 139.33, 139.15, 134.07, 124.63, 120.70, 115.26, 114.10, 105.08, 52.00, 51.76, 30.91, 20.95.

[0252] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-4-trideuteromethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-diethylacetamide (Intermediate 64): This was prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 63 (2.0 mmol) and diethylamine (4.0 mmol).

[0253] The title compound (18) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 64 (0.2 mmol) and intermediate 52 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 10.21 (s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J = 9.6, 3.6 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.49-3.36 (m, 2H), 3.28-3.15 (m, 3H), 2.85 (d, J = 15.8 Hz, 1H), 2.25 (s, 6H), 1.17 (t, J = 6.4 Hz, 3H), 0.97 (t, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 169.44, 167.67, 166.45, 165.89, 156.13, 152.52, 150.27, 144.16, 143.58, 139.31, 133.96, 132.62, 132.54, 125.36, 123.50, 119.30, 116.35, 115.12, 108.29, 105.65, 60.85, 60.73, 56.22, 52.36, 41.17, 29.70, 20.84, 13.94, 12.96.

[0254] Example 19 (S)-2-chloro-N-[3-[2-[bis(pentadeuteroethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-4-(trideuteromethyl)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 19)

[0255] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-4-trideuteromethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-bis(pentadeuteroethyl)acetamide (Intermediate 65): This was prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 63 (2.0 mmol) and deuterated diethylamine (4.0 mmol).

[0256] The title compound (19) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 65 (0.2 mmol) and intermediate 53 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 10.22 (s, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.51-4.41 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.16 (dd, J = 15.1, 10.2 Hz, 1H), 2.85 (dd, J = 15.0, 1.4 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6) δ 169.48, 167.68, 166.47, 164.96, 156.15, 151.92, 149.36, 144.17, 143.89, 139.37, 132.68, 132.55, 131.67, 125.41, 123.54, 119.36, 116.33, 116.29, 115.13, 107.97, 61.02, 60.79, 56.21, 52.39, 29.70, 20.87.

[0257] Example 20 (S)-2-Bromo-N-[3-[2-(dimethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 20)

[0258] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-dimethylacetamide (Intermediate 66): Prepared according to the synthesis method of Intermediate 46 described in Example 1 using Intermediate 45 (2.0 mmol) and dimethylamine (4.0 mmol).

[0259] The title compound (20) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 66 (0.2 mmol) and intermediate 50 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.40 (s, 1H), 10.21 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.15 (dt, J = 8.0, 5.3 Hz, 1H), 3.00 (s, 3H), 2.95 (dd, J = 16.8, 8.6 Hz, 1H), 2.81 (s, 3H), 2.62 (dd, J = 16.4, 5.0 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.71, 168.84, 166.74, 165.87, 156.17, 152.49, 150.23, 144.28, 143.54, 139.32, 133.87, 132.74, 132.59, 125.38, 122.84, 119.07, 116.39, 115.50, 108.25, 105.61, 48.99, 36.49, 34.73, 31.36, 20.84.

[0260] Example 21 (S)-2-Bromo-N-[3-[2-[bis(trideuteromethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 21)

[0261] Preparation of (S)-2-[8-amino-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]-N,N-bis(trideuteromethyl)acetamide (Intermediate 67): This was prepared according to the synthesis method of Intermediate 46 described in Example 1, using Intermediate 45 (2.0 mmol) and deuterated dimethylamine (4.0 mmol).

[0262] The title compound (21) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 67 (0.2 mmol) and intermediate 50 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 10.20 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.03 (s, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.16 (dt, J = 8.2, 5.4 Hz, 1H), 2.94 (dd, J = 16.5, 8.3 Hz, 1H), 2.61 (dd, J = 16.5, 5.2 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 171.21, 169.35, 167.24, 166.35, 156.66, 152.99, 150.72, 144.76, 144.05, 139.81, 134.35, 133.25,133.09, 125.86, 123.32, 119.58, 116.86, 115.98, 108.75, 106.11, 49.49, 31.83, 21.33.

[0263] Example 22 (S)-2-Bromo-N-[3-[2-[bis(trideuteromethyl)amino]-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 22)

[0264] The title compound (22) was prepared according to the synthesis method of compound 1 described in Example 1 using intermediate 67 (0.2 mmol) and intermediate 52 (0.5 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.40 (s, 1H), 10.21 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.15 (dt, J = 8.3, 5.4 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.94 (dd, J = 16.5, 8.3 Hz, 1H), 2.61 (dd, J = 16.5, 5.2 Hz, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 171.21, 169.35, 167.24, 166.34, 156.66, 152.99, 150.75, 144.77, 144.08, 139.81, 134.40, 133.23, 133.08, 125.86, 123.33, 119.57, 116.87, 116.00, 108.80, 106.14, 61.33, 61.21, 56.70, 49.48, 31.82, 21.33.

[0265] Example 23 (S)-2-chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-[3,5-bis(trideuteromethyl)phenoxy]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 23)

[0266] Preparation of 3,5-bis(trideuteromethyl)phenol (intermediate 68): 3,5-dimethylphenol (32.79 mmol) and potassium carbonate (65.57 mmol) were dissolved in 30 mL of acetone, dimethyl sulfate (65.58 mmol) was added, and the mixture was reacted at 60° C. for 2 hours. The reaction solution was evaporated to dryness, DCM was added to dissolve the mixture, and the mixture was washed with water. The organic phase was separated, dried, concentrated, and subjected to silica gel column chromatography and eluted with petroleum ether / ethyl acetate to obtain 3.07 g of intermediate product, with a yield of 84.1%. The above intermediate (14.71 mmol) and potassium tert-butoxide (63.24 mmol) were dissolved in 12 mL of DMSO-d 6 The mixture was mixed and reacted at 100°C for 3 hours. The reaction solution was poured into 20 mL of deuterium oxide, extracted with ether, and concentrated to obtain a yellow oil. The oil and potassium tert-butoxide (28.79 mmol) were dissolved in 8 mL of DMSO-d 6 The mixture was mixed with 10 mL of deuterium oxide and reacted at 100°C for 2 hours. The reaction solution was poured into 20 mL of deuterium oxide, extracted with ether, dried, concentrated, subjected to silica gel column chromatography, and eluted with petroleum ether to obtain 1.57 g of intermediate product, the yield was 75.5%, the deuteration rate was 97.2%, and some hydrogen was replaced on the benzene ring. The intermediate (10.56 mmol) was dissolved in 30 mL of DCM, and 10 mL of DCM solution containing boron tribromide (21.13 mmol) was added dropwise at 0°C, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding 8 mL of deuterium oxide, and the organic phase was separated, dried, concentrated, subjected to silica gel column chromatography, and eluted with petroleum ether / ethyl acetate to obtain 1.0 g of intermediate product, the yield was 71.9%. The intermediate (7.0 mmol) and sodium hydroxide (7.0 mmol) were dissolved in 20 mL of water and reacted at 100° C. overnight. The pH was adjusted to acidic with 1 M hydrochloric acid, extracted with DCM, and dried to obtain 698 mg of the target compound, with a yield of 77.6%. The deuteration rate of the target compound was about 98%. 1 1 H NMR detected no substitution of hydrogen on the benzene ring.

[0267] Preparation of (S)-2-[8-amino-7-[3,5-cis(trideuteromethyl)phenoxy]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid methyl ester (Intermediate 69): Prepared according to the method for preparing Intermediate 45 described in Example 1 using Intermediate 68 (2.12 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.17 (d, J = 4.9 Hz, 1H), 7.00 (s, 1H), 6.75 (s, 1H), 6.60 (s, 2H), 6.42 (s, 1H), 5.77 (s, 2H), 4.10-4.00 (m, 1H), 3.58 (s, 3H), 2.85 (dd, J = 16.9, 8.9 Hz, 1H), 2.69 (dd, J = 17.0, 5.5 Hz, 1H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.69, 170.41, 167.42, 156.98, 144.37, 139.40, 139.05, 134.05, 124.66, 120.36, 115.36, 113.42, 105.46, 51.54, 48.73, 32.59.

[0268] The title compound (23) was prepared by a three-step reaction using intermediate 69 (0.2 mmol), 2-chloro-3,4,5-trimethoxybenzoic acid (0.5 mmol) and diethylamine (0.4 mmol) according to the synthesis method of compound 1 described in Example 1. 1 H NMR (400 MHz, DMSO-d 6) δ 10.38 (s, 1H), 10.23 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.18 (dt, J = 8.9, 5.1 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.32-3.17 (m, 4H), 2.98 (dd, J = 16.3, 8.5 Hz, 1H), 2.60 (dd, J = 16.4, 4.8 Hz, 1H), 1.17 (t, J = 6.9 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.79, 167.92, 166.80, 164.92, 156.20, 151.92, 149.36, 144.29, 143.91, 139.27, 132.72, 132.66, 131.63, 125.43, 122.94, 119.16, 116.37, 116.30, 115.54, 107.98, 61.02, 60.79, 56.22, 49.01, 41.36, 31.25, 13.91, 13.05.

[0269] Example 24 (S)-2-chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethyl-2,4,6-trideuterophenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 24)

[0270] Preparation of 3,5-dimethyl-2,4,6-trideuterophenol (intermediate 70): 3,5-dimethylphenol (10.0 mmol) was dissolved in 100 mmol of deuterium oxide, 200 μL of sodium deuterium oxide (40.0% in DO) was added, and the mixture was reacted at 100° C. for 22 hours. 600 μL of concentrated sulfuric acid was dissolved in 1.4 mL of deuterium oxide, extracted with DCM, and evaporated to dryness. The above steps were repeated five times for the crude product obtained. The crude product was subjected to silica gel column chromatography and eluted with petroleum ether / ethyl acetate to obtain 1.2 g of the target compound, with a yield of 82.8% and a deuteration rate of 97.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 2.15 (s, 6H).

[0271] Preparation of (S)-2-[8-amino-7-(3,5-dimethyl-2,4,6-trideuterophenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid methyl ester (Intermediate 71): Prepared according to the method for preparing Intermediate 45 described in Example 1 using Intermediate 70 (2.12 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.16 (d, J = 4.6 Hz, 1H), 7.01 (s, 1H), 6.43 (s, 1H), 5.75 (s, 2H), 4.05 (dt, J = 10.1, 5.1 Hz, 1H), 3.59 (s, 3H), 2.86 (dd, J = 16.9, 8.8 Hz, 1H), 2.69 (dd, J = 16.9, 5.5 Hz, 1H), 2.24 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.68, 170.40, 167.40, 156.87, 144.35, 139.40, 138.95, 134.04, 120.34, 113.41, 105.45, 51.52, 48.72, 32.58, 20.82.

[0272] Title Compound (24) was prepared by a three-step reaction using Intermediate 71 (0.2 mmol), 2-chloro-3,4,5-trimethoxybenzoic acid (0.5 mmol) and diethylamine (0.4 mmol) according to the synthesis method of Compound 1 described in Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 10.23 (s, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 4.18 (dt, J = 8.9, 5.3 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.30-3.19 (m, 4H), 2.98 (dd, J = 16.3, 8.5 Hz, 1H), 2.60 (dd, J = 16.2, 4.9 Hz, 1H), 2.25 (s, 6H), 1.17 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.77, 167.89, 166.77, 164.90, 156.09, 151.90, 149.34, 144.27, 143.88, 139.16, 132.70, 132.64, 131.62, 122.93, 119.12, 116.28, 115.51, 107.96, 61.00, 60.77, 56.20, 48.99, 41.35, 31.23, 20.74, 13.90, 13.04.

[0273] Example 25 (S)-2-chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-[3,5-bis(trideuteromethyl)-2,4,6-trideuterophenoxy]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-trimethoxybenzamide (Compound 25)

[0274] Preparation of 3,5-bis(trideuteromethyl)-2,4,6-trideuterophenol (intermediate 72): 3,5-dimethylphenol (32.79 mmol) and potassium carbonate (65.57 mmol) were dissolved in 30 mL of acetone, dimethyl sulfate (65.58 mmol) was added, and the mixture was reacted at 60°C for 2 hours. The reaction solution was evaporated to dryness, DCM was added to dissolve the mixture, and the mixture was washed with water. The organic phase was separated, dried, concentrated, and subjected to silica gel column chromatography and eluted with petroleum ether / ethyl acetate to obtain 3.07 g of intermediate product, with a yield of 84.1%. The above intermediate (14.71 mmol) and potassium tert-butoxide (63.24 mmol) were dissolved in 12 mL of DMSO-d 6 The mixture was mixed and reacted at 100°C for 3 hours. The reaction solution was poured into 20 mL of deuterium oxide, extracted with ether, and concentrated to obtain a yellow oil. The oil and potassium tert-butoxide (28.79 mmol) were dissolved in 8 mL of DMSO-d 6The mixture was mixed with 100°C and reacted for 2 hours. The reaction solution was poured into 20mL of deuterium oxide, extracted with ether, dried, concentrated, subjected to silica gel column chromatography, and eluted with petroleum ether to obtain 1.57g of intermediate product, the yield was 75.5%, the deuteration rate was 97.2%, and some hydrogen was replaced on the benzene ring. The intermediate (10.56mmol) was dissolved in 30mL of DCM, and added dropwise to 10mL of DCM solution containing boron tribromide (21.13mmol) at 0°C, and reacted at room temperature for 2 hours. The reaction was quenched by adding 8mL of deuterium oxide, and the organic phase was separated, dried, concentrated, subjected to silica gel column chromatography, and eluted with petroleum ether / ethyl acetate to obtain 1.0g of intermediate, the yield was 71.9%. The intermediate (7.30 mmol) was dissolved in 73.05 mmol of deuterium oxide, and 161 μL of deuterated sodium oxide (40% in D2O) was added and reacted at 100°C for 22 hours. 426 μL of concentrated sulfuric acid was dissolved in 1.1 mL of deuterium oxide, extracted with DCM, evaporated, and the above steps were repeated 7 times for the crude product obtained. The crude product was subjected to silica gel column chromatography and eluted with petroleum ether / ethyl acetate to obtain 640 mg of the target compound, with a yield of 67.0%. The deuteration rate was 97.3%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (s, 1H).

[0275] Preparation of (S)-2-[8-amino-7-[3,5-bis(trideuteromethyl)-2,4,6-trideuterophenoxy]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid methyl ester (Intermediate 73): Prepared according to the method for preparing Intermediate 45 described in Example 1 using Intermediate 72 (2.12 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.23 (s, 1H), 8.16 (d, J = 4.6 Hz, 1H), 7.01 (s, 1H), 6.43 (s, 1H), 5.75 (s, 2H), 4.11-3.98 (m, 1H), 3.59 (s, 3H), 2.86 (dd, J = 16.9, 8.9 Hz, 1H), 2.69 (dd, J = 16.9, 5.3 Hz, 1H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.67, 170.39, 167.40, 156.86, 144.34, 139.41, 138.84, 134.03, 120.32, 113.41, 105.44, 51.52, 48.72, 32.57.

[0276] The title compound (25) was prepared by a three-step reaction using intermediate 73 (0.2 mmol), 2-chloro-3,4,5-trimethoxybenzoic acid (0.5 mmol) and diethylamine (0.4 mmol) according to the synthesis method of compound 1 described in Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 10.22 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.00 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 4.18 (dt, J = 8.6, 5.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.36-3.18 (m, 4H), 2.98 (dd, J = 16.3, 8.6 Hz, 1H), 2.60 (dd, J = 16.3, 4.9 Hz, 1H), 1.17 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6) δ 170.76, 167.89, 166.76, 164.90, 156.08, 151.89, 149.33, 144.29, 143.88, 139.05, 132.68, 132.63, 131.62, 122.92, 119.10, 116.27, 115.51, 107.96, 60.99, 60.77, 56.20, 48.99, 41.34, 31.22, 13.90, 13.04.

[0277] Example 26 (S)-Dimethyl-(4-8-(2-bromo-3,4,5-tris(trideuteromethoxy)benzoyl)-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)-2-methyl-3-oxobutyl-2-yl)diethyl phosphate (Compound 26)

[0278] The title compound (26) was prepared according to the following route.

[0279] [ka]

[0280] Title compound (26) Mp 141-143 °C. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 10.24 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.13 (dd, J = 11.7, 5.6 Hz, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 3.42 (dd, J = 18.5, 8.4 Hz, 1H), 2.97 (dd, J = 18.4, 4.3 Hz, 1H), 2.25 (s, 6H), 1.39 (d, J = 16.9 Hz, 3H), 1.34 (d, J = 16.8 Hz, 3H).

[0281] Example 27 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tri(trideuteromethoxy)benzamide hydrochloride (Compound 27)

[0282] Preparation of (S)-2-(8-(2-bromo-3,4,5-tris(trideuteromethoxy)benzamido)-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid (Intermediate 74): This was prepared in a two-step reaction according to the method described in Example 1 using Intermediate 45 (2.0 mmol), Intermediate 50 (5.0 mmol) and lithium hydroxide (5.0 mmol).

[0283] The title compound (27) was prepared in a two-step reaction according to the method described in Example 1 using intermediate 74 (1.0 mmol), N-methylpiperazine (2.0 mmol), and concentrated hydrochloric acid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 10.46 (s, 1H), 10.24 (s, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.81 (s, 2H), 6.67 (s, 2H), 4.33-4.43 (m, 1H), 4.15-4.23 (m, 1H), 3.60-3.67 (m, 2H), 3.55-3.32 (m, 5H), 2.97-3.02 (m, 2H), 2.76 (s, 3H), 2.25 (s, 6H).

[0284] Example 28 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-4-methyl-3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 28)

[0285] Preparation of (S)-2-(8-(2-bromo-3,4,5-tris(trideuteromethoxy)benzamido)-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid (Intermediate 75): This was prepared in a two-step reaction according to the method described in Example 1 using Intermediate 57 (2.0 mmol), Intermediate 50 (2.0 mmol) and lithium hydroxide (2.0 mmol).

[0286] The title compound (28) was prepared following the procedure described in Example 1 using intermediate 75 (0.2 mmol) and N-methylpiperazine (0.4 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 10.21 (s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.44 (dd, J = 10.2, 2.8 Hz, 1H), 3.56 (s, 2H), 3.39-3.45 (m, 2H), 3.22 (dd, J = 17.1, 10.8 Hz, 1H), 2.93 (s, 3H), 2.87 (s, 1H), 2.41 (s, 1H), 2.27-2.37 (m, 3H), 2.25 (s, 6H), 2.22 (s, 3H).

[0287] Example 29 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 29)

[0288] The title compound (29) was prepared following the procedure described in Example 1 using intermediate 74 (0.2 mmol) and N-methylpiperazine (0.4 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 10.21 (s, 1H), 8.51 (d, J = 4.5 Hz, 1H), 8.02 (s, 1H), 7.15 (s, 1H), 6.81 (s, 2H), 6.68 (s, 2H), 4.16 (dd, J = 12.6, 6.1 Hz, 1H), 3.36-3.52 (m, 4H), 2.95 (dd, J = 16.6, 7.9 Hz, 1H), 2.62 (dd, J = 16.4, 5.1 Hz, 1H), 2.28-2.40 (m, 4H), 2.25 (s, 6H), 2.20 (s, 3H).

[0289] Example 30 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(methoxymethylamino)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 30)

[0290] The title compound (30) was prepared following the procedure described in Example 1 using intermediate 74 (0.2 mmol) and methoxymethylamine (0.4 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.43 (s, 1H), 10.21 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.13 (dd, J = 12.7, 5.1 Hz, 1H), 3.73 (s, 3H), 3.19 - 3.12 (m, 1H), 3.08 (s, 3H), 2.70 (dd, J = 17.1, 4.6 Hz, 1H), 2.25 (s, 6H).

[0291] Example 31 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(hydroxymethylamino)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 31)

[0292] The title compound (31) was prepared following the procedure described in Example 1 using intermediate 74 (0.2 mmol) and hydroxymethylamine (0.4 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 10.22 (s, 1H), 9.96 (s, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.17 - 4.04 (m, 1H), 3.18 (dd, J = 16.8, 9.5 Hz, 1H), 3.07 (s, 3H), 2.62 (dd, J = 17.0, 4.1 Hz, 1H), 2.25 (s, 6H).

[0293] Example 32 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(methoxymethylamino)-2-oxoethyl]-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 32)

[0294] The title compound (32) was prepared following the procedure described in Example 1 using intermediate 75 (0.2 mmol) and methoxymethylamine (0.4 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 10.24 (s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.83 (s, 2H), 6.68 (s, 2H), 4.42 (dd, J = 8.8, 4.8 Hz, 1H), 3.76 (s, 3H), 3.28 - 3.20 (m, 1H), 3.08 (s, 3H), 3.00 (d, J = 15.8 Hz, 1H), 2.92 (s, 3H), 2.25 (s, 6H).

[0295] Example 33 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(hydroxymethylamino)-2-oxoethyl]-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tri(trideuteromethoxy)benzamide (Compound 33)

[0296] The title compound (33) was prepared following the procedure described in Example 1 using intermediate 75 (0.2 mmol) and hydroxymethylamine (0.4 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.49 (s, 1H), 10.23 (s, 1H), 10.07 (s, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.41 (dd, J = 8.6, 3.4 Hz, 1H), 3.21 (dd, J = 16.5, 9.3 Hz, 1H), 3.07 (s, 3H), 2.94 (d, J = 2.7 Hz, 1H), 2.89 (s, 3H), 2.25 (s, 6H).

[0297] Example 34 (S)-2-chloro-N-[7-(3,5-dimethylphenoxy)-3-[2-(deuteromethoxydeuteromethylamino)-2-oxoethyl]-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 34)

[0298] Preparation of deuteromethoxydeuteromethylamine hydrochloride (Intermediate 76): Prepared in a three-step reaction using benzyl chloroformate (10.0 mmol) according to the procedure shown in the figure.

[0299] [ka]

[0300] The title compound (34) was prepared following the procedure described in Example 1 using intermediates 75 (0.2 mmol) and 76 (0.4 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.52 (s, 1H), 10.21 (s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.43 (dd, J = 9.2, 5.1 Hz, 1H), 3.25 (d, J = 8.1 Hz, 1H), 2.99 (d, J = 15.8 Hz, 1H), 2.92 (s, 3H), 2.25 (s, 6H).

[0301] Example 35 (S)-2-chloro-N-[7-(3,5-dimethylphenoxy)-3-[2-(methoxymethylamino)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tri(trideuteromethoxy)benzamide (Compound 35)

[0302] Preparation of (S)-2-(8-(2-chloro-3,4,5-tris(trideuteromethoxy)benzamido)-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid (Intermediate 77): This was prepared in a two-step reaction according to the method described in Example 1 using Intermediate 45 (2.0 mmol), Intermediate 47 (5.0 mmol) and lithium hydroxide (4.0 mmol).

[0303] The title compound (35) was prepared following the procedure described in Example 1 using intermediate 77 (0.5 mmol) and methoxymethylamine (1.0 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.44 (s, 1H), 10.23 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.13 (dd, J = 12.7, 5.5 Hz, 1H), 3.73 (s, 3H), 3.15 (d, J = 6.4 Hz, 1H), 3.08 (s, 3H), 2.71 (dd, J = 16.8, 4.1 Hz, 1H), 2.25 (s, 6H).

[0304] Example 36 (S)-2-chloro-N-[7-(3,5-dimethylphenoxy)-3-[2-(methoxymethylamino)-2-oxoethyl]-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 36)

[0305] Preparation of (S)-2-(8-(2-chloro-3,4,5-tris(trideuteromethoxy)benzamido)-7-(3,5-dimethylphenoxy)-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid (Intermediate 78): This was prepared in a two-step reaction according to the method described in Example 1 using Intermediate 57 (2.0 mmol), Intermediate 47 (5.0 mmol) and lithium hydroxide (4.0 mmol).

[0306] The title compound (36) was prepared following the procedure described in Example 1 using intermediate 78 (0.5 mmol) and methoxymethylamine (1.0 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.53 (s, 1H), 10.23 (s, 1H), 8.02 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.42 (dd, J = 8.7, 5.0 Hz, 1H), 3.75 (s, 3H), 3.24 (d, J = 11.4 Hz, 1H), 3.08 (s, 3H), 3.00 (d, J = 16.9 Hz, 1H), 2.92 (s, 3H), 2.25 (s, 7H).

[0307] Example 37 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(deuteromethoxydeuteromethylamino)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 37)

[0308] The title compound (37) was prepared following the procedure described in Example 1 using intermediate 74 (0.5 mmol) and intermediate 76 (1.0 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 10.23 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 6.82 (s, 2H), 6.68 (s, 2H), 4.12 (dd, J = 12.9, 5.3 Hz, 1H), 3.13 (dd, J = 17.0, 8.3 Hz, 1H), 2.70 (dd, J = 17.1, 4.6 Hz, 1H), 2.25 (s, 6H).

[0309] Example 38 (S)-2-chloro-N-[7-(3,5-dimethylphenoxy)-3-[2-(deuteromethoxydeuteromethylamino)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 38)

[0310] The title compound (38) was prepared following the procedure described in Example 1 using intermediate 77 (0.5 mmol) and intermediate 76 (1.0 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 10.23 (s, 1H), 8.58 (d, J = 4.7 Hz, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.13 (dd, J = 12.5, 5.5 Hz, 1H), 3.13 (dd, J = 17.4, 6.7 Hz, 1H), 2.70 (dd, J = 17.1, 4.9 Hz, 1H), 2.25 (s, 6H).

[0311] Example 39 (S)-2-chloro-N-[7-(3,5-dimethylphenoxy)-3-[2-(deuteromethoxydeuteromethylamino)-2-oxoethyl]-4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 39)

[0312] The title compound (39) was prepared following the procedure described in Example 1 using intermediate 78 (0.5 mmol) and intermediate 76 (1.0 mmol). 1 H NMR (400 MHz, DMSO-d 6) δ 10.53 (s, 1H), 10.24 (s, 1H), 8.02 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.68 (s, 2H), 4.42 (dd, J = 9.4, 5.0 Hz, 1H), 3.26 (dd, J = 12.7, 10.5 Hz, 1H), 2.99 (dd, J = 16.7, 1.7 Hz, 1H), 2.92 (s, 3H), 2.25 (s, 6H).

[0313] Example 40 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(deuteromethoxymethylamino)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 40)

[0314] The title compound (40) was prepared following the procedure described in Example 1 using intermediate 74 (0.5 mmol) and deuteromethoxymethylamine hydrobromide (1.0 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 10.25 (s, 1H), 8.59 (d, J = 5.3 Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.82 (s, 1H), 6.69 (s, 2H), 4.13 (dt, J = 8.5, 5.4 Hz, 1H), 3.17 (dd, J = 16.8, 9.5 Hz, 1H), 3.08 (s, 3H), 2.71 (dd, J = 17.2, 5.1 Hz, 1H), 2.26 (s, 6H).

[0315] Example 41 (S)-2-Bromo-N-[7-(3,5-dimethylphenoxy)-3-[2-(methoxydeuteromethylamino)-2-oxoethyl]-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]-3,4,5-tris(trideuteromethoxy)benzamide (Compound 41)

[0316] The title compound (41) was prepared following the procedure described in Example 1 using intermediate 74 (0.5 mmol) and methoxydeuteromethyl hydrobromide (1.0 mmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 10.25 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.03 (s, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 6.82 (s, 1H), 6.69 (s, 2H), 4.22 - 4.05 (m, 1H), 3.73 (s, 3H), 3.14 (dd, J = 16.8, 9.5 Hz, 1H), 2.70 (dd, J = 17.0, 4.1 Hz, 1H), 2.26 (s, 6H).

[0317] Example 42 In Vitro Antitumor Activity of Deuterated 1,4-Benzodiazepine-2,5-dione Compounds Described in the Present Invention

[0318] In this example, the antitumor activity of the compounds of the examples of the present invention was evaluated using the evaluation method of the National Cancer Institute (NCI). Nine representative cell lines, including A549 (non-small cell lung cancer), HCT116 (colon cancer), SF295 (central nervous system tumor), LOX-IMVI (melanoma), 786-0 (renal cancer), K562 (leukemia), PC-3 (prostate cancer), OVCAR-3 (ovarian cancer), and HS 578T (breast cancer), were selected to carry out activity evaluation.

[0319] The specific method is as follows. Using 60 tumor cell lines collected from 9 types of human cancers, the in vitro inhibitory activity of the test compound was evaluated. A test group, a parallel control group, and a solvent control group were set up. The parallel control group was fixed immediately before adding the compound, the cells in the test group were fixed after being treated with the compound for 48 hours, and the solvent control group was fixed after adding an equal volume of complete medium for 48 hours. Staining was performed using sulforhodamine B (SRB), and the OD value at a wavelength of 515 nm was measured. The specific calculation method is as follows. The OD value of the parallel control group was recorded as Tz, the OD value of the solvent control group was recorded as C, and the OD value of the test group was recorded as (Ti). When Ti≥Tz, it means that the cells are still growing after drug addition, and the growth rate % = [(Ti - Tz) / (C - Tz)]×100. When Ti<Tz, it means that the cells have died after drug addition, and the growth rate was % = [(Ti - Tz) / Tz]×100. In this method, three parameters were used to evaluate the antitumor activity of the compound: the 50% growth inhibitory concentration (GI 50 ): that is, the compound concentration when [(Ti - Tz) / (C - Tz)]×100 = 50; the complete growth inhibitory concentration (TGI): the compound concentration when Ti = Tz; the drug concentration required to kill 50% of the cells (LC 50 ): that is, the compound concentration when [(Ti - Tz) / Tz]×100 = -50 was used.

[0320] The evaluation results show that most of the compounds in the examples of the present invention have significant activity in inhibiting the growth of tumor cells.

[0321] Table 1 details the inhibitory activities of the example compounds against 9 representative tumor cell lines. Here, the GI 50 value represents the "50% growth inhibition rate", that is, the concentration at which the test compound can inhibit the growth of cells by 50%, and "ND" represents not measured.

[0322]

Table 1-1

[0323] [Table 1-2]

[0324] From the above, it can be seen that when only the H on the benzene ring of the compound of the general formula is deuterium-deuterized, the antitumor activity in vitro is significantly reduced, but the compound of the present invention maintains the activity of inhibiting tumor cells and tumor stem cells.

[0325] Example 43 Liver microsomal stability of deuterated 1,4-benzodiazepine-2,5-dione compounds described in this invention

[0326] Test compounds at a final concentration of 1 μM were incubated with 1 mg / mL human liver microsomes and 1 mM NADPH, and a group without NADPH was set as a negative control. The reaction solution was quenched with methanol at five time points: 0, 5, 15, 30, and 60 min, and then centrifuged at 2500 rpm for 20 min to precipitate proteins. The supernatant was analyzed by LC-MS / MS. The data was analyzed and compiled to obtain k values ​​and half-life T 1 / 2 , T 1 / 2 (min) = 0.693 / k was calculated.

[0327] Table 2 shows the half-life T of the target compounds in liver microsomes in vitro. 1 / 2 and the clearance Clint are shown. Here, compounds a, b, and c are active compounds disclosed in Patent No. ZL201610154581.3. As a result of comparison, it can be seen that the half-life of the deuterated compounds disclosed in the present application is significantly longer than that of conventional compounds such as compounds 1 (42 min), 3 (38 min), 6 (73 min), 7 (49.9 min), 8 (50.6 min), 9 (117 min), 10 (68 min), 13 (46.8 min), 16 (56.9 min), 19 (32.9 min), and 20 (330 min), and the metabolic stability is also significantly increased.

[0328] [Table 2-1]

[0329] [Table 2-2]

[0330] From the above effects, the following structure-activity relationship can be obtained in advance: (1)

[0331] [ka]

[0332] In the case of the R 2a , R 2b and R 2c If only one atom is deuterium, this may reduce the anticancer activity of the molecule; (2)

[0333] [ka]

[0334] For parts, R 3 , R 4 and R 5 When is a deuterated methoxy, it has the effect of increasing the metabolic stability of the molecule; in X, the effect of halogen atoms on the metabolism of the molecule is Br>Cl; (3)

[0335] [ka]

[0336] In the case of a part, R at the N-4 position 6 If H, then R 7 is a deuterium-modifying group, which has the effect of increasing the metabolic stability of the compound; R 6 is a deuterium-modifying group, such as deuterated methyl, R 6 and R 7 Deuterium modification of R has no significant effect on the metabolic stability of the molecule. 7 However, when it was dimethylamino, the metabolic stability of the molecule was excellent.

[0337] Example 44: Metabolic stability of deuterated 1,4-benzodiazepine-2,5-dione compounds according to the present invention

[0338] 1. Test substance: The group receiving intravenous injection of the example compound was prepared as a 0.2 mg / mL solution in a mixed solvent of DMA:PEG400:30%SBECD=5:25:70, and administered intravenously at 1 mg / kg body weight; the group receiving oral formulation was prepared as a 1 mg / mL solution in 0.5%MC, and administered intragastrically at 10 mg / kg body weight.

[0339] 2. Test animals: Male BALB / c nude mice, 4–5 weeks old, were purchased from Shanghai SLAC.

[0340] 3. Testing method: 3.1 Equipment Liquid chromatography system: Shimadzu liquid chromatography system Shimadzu LC-30AD MS / MS system: Applied Biosystems API5500 Data Collection: Analyst Software 1.5.2 3.2 Chromatographic conditions Analytical column: Kinetex 2.6u C18 100A column (3.0mm x 30mm) Mobile phase: A: 10mM NH4OAc (0.1% FA); B: Acetonitrile with 0.1% FA Flow rate: 1.0mL / min Gradient: Table 3

[0341] [Table 3]

[0342] Injection volume: 10.0μL Column temperature: RT

[0343] Mass spectrometry conditions The ion source was an electrospray ionization source (ESI source) with negative ion detection; spray injection voltage: 5500 V; ion source gas 1 (N 2 ): 50 psi; Ion source gas 2 (N 2 ): 50psi; Air curtain gas (N 2 ): 30 psi. The scan mode was multiple reaction monitoring (MRM), the scan time was 80 ms, and the collision gas pressure was 10 psi.

[0344] 3.3 Plasma sample pretreatment

[0345] The test was divided into groups of three animals, and administration was started on the same day according to the weight of each animal. Blood samples were taken 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration.

[0346] SAL-0101 Measurement To 25.0 μL of plasma, 25.0 μL of internal standard solution (tolbutamide (250 ng / mL) in acetonitrile), 25.0 μL of acetonitrile, and 100 μL of acetonitrile were added, vortexed for 1 minute, centrifuged for 5 minutes (14,000 rpm), 120 μL of the supernatant was removed, and 80.0 μL of water (containing 1% formic acid) was added. After uniform mixing, LC / MS / MS analysis was performed.

[0347] [ka]

[0348] [Table 4]

[0349] As can be seen from the above, comparing compound 13 with comparative compound a, compounds 5, 7, b, compounds 6, 8, c, compounds 20, 22 and d, it is shown that the compounds of the examples related to the present invention can effectively extend the hepatic microsomal metabolic stability of the active compounds disclosed in Patent ZL201610154581.3 in vitro, and the results of the in vivo DMPK test also show that the half-life of the disclosed compounds in vivo can be enhanced.

[0350] Example 45: Compounds of the Examples can kill cancer stem cells and inhibit their self-renewal ability

[0351] The compounds of the examples of the present invention not only effectively inhibit the proliferation of tumor cells, but also can inhibit the proliferation of tumor stem cells both in vivo and in vitro, and are expected to be developed as bifunctional drugs that inhibit both normal tumor cells and tumor stem cells.

[0352] Tumor stem cells can form spheres under appropriate in vitro culture conditions, but normal tumor cells do not have such ability, so tumor stem cells can be isolated under in vitro conditions and used to evaluate the effects of drugs on proliferation and differentiation. The following describes the inhibitory effects of example compounds 5, 7, 11, 13, 14, 20 and 21 on sphere formation in breast cancer cell line SUM159.

[0353] Sphere Cultivation: Breast cancer cell line SUM159 spheres were cultured in ultra-low attachment plates in serum-free medium, supplemented with basal medium DMEM / F12 (without phenol red), B27 (without vitamin A) (1x), EGF (20ng / ml), bFGF (20ng / ml), and insulin (5ug / ml).

[0354] Sphere drug treatment experiments: Equal amounts (4000 cells) of SUM159 cells were seeded into an ultra-low attachment 24-well plate in each well, cultured for 5 days, then spheres were photographed, the medium was replaced with fresh medium, and drug treatments were performed at predetermined concentrations. Compounds 5, 7, 11, 13, 14, 20, and 21 evaluated in this experiment were each treated at 50 nM. After drug treatment for about 3 days, the effect on the sphere phenotype could be observed. After drug treatment for 5 days, the spheres were photographed again, and then the spheres were passaged. After the spheres were subcultured for 7 days, they were photographed again.

[0355] The differences in the photos taken at three different stages were statistically analyzed and compared, and the killing effect of the test compounds on SUM159 spheres was tested based on the differences in sphere formation after passage, reflecting the inhibitory effects of different compounds on breast cancer stem cells.

[0356] Experimental results and conclusions: After treatment with test compounds 5, 7, 11, 13, 14, 20, and 21, the formation of spheres after cell passage decreased significantly. The specific sphere morphology is as shown in Figure 1.

[0357] The experimental results showed that compounds 5, 7, 11, 13, 14, 20, and 21 all had a strong killing effect on SUM159 spheres and caused them to lose their self-renewal ability.

[0358] Furthermore, the above experiment confirmed that compounds 5, 7, 11, 13, 14, 20, and 21 of the tested examples could all inhibit breast cancer stem cells and their self-renewal ability, indicating that these compounds have the effect of killing tumor stem cells.

[0359] Example 46 Inhibitory effect of the example compounds on the growth of human cancer xenograft tumors in nude mice

[0360] 1. Test substances: Example compounds were prepared in 40× DMSO stock solutions and diluted to dosing concentrations in saline containing 2.5% Tween 80 prior to use;

[0361] 2. Test animals and tumor lines: Oz BALB / c nude mice, 4-5 weeks old, were purchased from Beijing Charles River Laboratory Animal Technology Co., Ltd., the production license number was SCXK(Beijing)2012-0001, and the mice were bred in the SPF-level experimental animal center of Tsinghua University. The tumor lines used in the study were human lung cancer NCI-H522 xenograft tumors in nude mice, and human colon cancer HCT-116 xenograft tumors in nude mice.

[0362] 3. Testing method: Tumor-bearing animals with good tumor growth and general condition were selected and killed by cervical dislocation. Tumor masses were removed under aseptic conditions, cut into tumor masses with a diameter of 2-3 mm using a scalpel, and subcutaneously inoculated into the rear armpit of nude mice using a trocar. After the tumors grew naturally and the tumor volume reached 105 mm3, they were randomly divided into groups, and the day of group administration was designated as D0.

[0363] The animals were divided into groups, with 7-9 animals in each group, and administration was started from the same day according to the weight of each animal. During administration, the long and short diameters of the tumors of the animals and the body weight were measured every 2-3 days, and the tumor size was calculated by the formula: (1 / 2) x long diameter x (short diameter)2. The study was terminated on the 27th day (D27) after grouping. After the experiment, the animals were killed by cervical dislocation, the tumors were peeled off, and the tumors were weighed, and the inhibition rate of the drug against tumor growth was calculated. Tumor volume (TV) and relative tumor volume (RTV) were calculated. The statistical significance of the differences in indicators such as tumor weight, tumor volume, and RTV of the animals in each group was compared using t-test.

[0364] The calculation formula is as follows:

[0365]

number

[0366] 4. Test results and discussion: Compound 5 of the present invention was used to evaluate the in vivo tumor suppression ability against NCI-H522 lung cancer xenograft tumor model in mice. As can be seen from the results in Table 5, compared with active compound a disclosed in patent ZL201610154581.3, the in vivo antitumor ability of compound 5 is significantly enhanced, and when the concentration administered to the high dose group is 50mg / kg, the relative tumor inhibition rate T / C(%) of the compound reaches 14.2, and the tumor inhibition rate reaches 90.02%.

[0367] [Table 5]

[0368] The example compounds 5, 16, and 20 involved in the present invention have been experimentally demonstrated to inhibit the growth of human intestinal cancer HCT-116 xenograft tumors in nude mice, indicating that these compounds are expected to be developed as tumor inhibitors.

[0369] [Table 6]

[0370] As can be seen from the tumor growth curves and Table 5, the tumor volume growth rate of mice treated with each example compound was significantly slower than that of the solvent control group. At the end of the test, the T / C values ​​of example compounds 5, 16, and 20 were 34%, 38%, and 30%, respectively, and the tumor inhibition rates were 69.6%, 63.4%, and 75.4%, respectively. Statistically significant (p<0.001). In this test, the example compounds can be evaluated as effective.

[0371] Although the specific embodiments of the present invention have been described above, those skilled in the art will recognize that these are merely illustrative examples and may make various changes and modifications to these embodiments without departing from the principles and substance of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims. [1] A compound of formula I or a pharma- ceutically acceptable salt thereof.

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[10] The use according to [9], characterized in that the lung cancer cells are A549 non-small cell lung cancer cells, the colon cancer cells are HCT116 colon cancer cells, the central nervous system tumor cells are SF295 central nervous system tumor cells, the melanoma cells are LOX-IMVI melanoma cells, the renal cancer cells are 786-0 renal cancer cells, the leukemia cells are K562 leukemia cells, the prostate cancer cells are PC-3 prostate cancer cells, the ovarian cancer cells are OVCAR-3 ovarian cancer cells, and the breast cancer cells are HS 578T breast cancer cells.

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (wherein X is chlorine or bromine; R １ａ and R １ｂ is independently C １－３ is alkyl, R ２ａ , R ２ｂ and R ２ｃ are independently hydrogen; R ３ , R ４ and R ５ is independently C １－３ Alkyl-O- or deuterated C １－３ alkyl-O-, R ６ is H or C １－３ is alkyl, R ７ is -OR １２ , -NR １３ R １４ Or -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), where R １２ , R １７ and R １８ is independently C １－３ Alkyl or deuterated C １－３ alkyl, R １５ and R １６ is independently C １－３ is alkyl, R １３ and R １４ are independently OH, C １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ alkyl-O-, Or, R １３ and R １４ represents, together with the nitrogen atom to which it is linked, a 4- to 6-membered aliphatic heterocycle or one or more R １９ and forming a 4- to 6-membered aliphatic heterocycle substituted with one or more of R １９ In the 4- to 6-membered aliphatic heterocycle substituted with one of the N and the carbonyl, the 4- to 6-membered aliphatic heterocycle further contains 0 to 2 heteroatoms selected from N, O, or S, R １９ is halogen or C １－３ is alkyl, R ８ , R ９ , R １０ and R １１ are independently hydrogen; Here, R ３ , R ４ , R ５ and R ７ At least one of the groups is a deuterated group.

2. R １ａ and R １ｂ are the same, Or, R ２ａ , R ２ｂ and R ２ｃ are the same, Or, R ３ , R ４ and R ５ are the same, Or, R ７ Ga-OR １２ If R １２ is C １－３ Alkyl or deuterated C １－３ is alkyl, Or, R ７ -NR １３ R １４ If R １３ and R １４ are independently OH, C １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ alkyl-O-, Or, R ７ -NR １３ R １４ and R １３ and R １４ represents, together with the nitrogen atom to which it is linked, a 4- to 6-membered aliphatic heterocycle or one or more R １９ When forming a 4- to 6-membered aliphatic heterocycle substituted with R １９ are independently halogen or C １－３ is alkyl, Or, R ７ -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), then R １５ and R １６ is independently C １－３ is alkyl, Or, R ７ -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), then R １５ and R １６ are the same, Or, R ７ -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), then R １７ and R １８ are the same, Or, R ７ -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), then R １７ and R １８ is independently C １－３ is alkyl, Or, R ６ is H, R ７ is -OR １２ , -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), -NR １３ R １４ Or, R ６ is C １－３ alkyl, R ７ is -NR １３ R １４ and Or, R ３ , R ４ , R ５ and R ７ 2. The compound of formula I according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein at least one of is a deuterated group.

3. X is bromine; Or, R ３ , R ４ and R ５ are the same, Or, R １２ is deuterated C １－３ is alkyl, Or, R ７ -NR １３ R １４ If R １３ OH, C １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ alkyl-O- and / or R １４ is C １－３ Alkyl or deuterated C １－３ is alkyl, Or, R ７ -NR １３ R １４ If R １３ and R １４ together with the nitrogen atom to which it is attached, represents a 4- to 6-membered heterocycloalkyl, or one or more R １９ and forming a 4- to 6-membered heterocycloalkyl substituted with said 4- to 6-membered heterocycloalkyl and one or more R １９ In the 4- to 6-membered heterocycloalkyl substituted by, in addition to the one N and the carbonyl bonded thereto, further contains 0 to 1 heteroatom optionally selected from N, O, or S; Or, R ７ -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), then R １５ and R １６ are independently methyl; Or, R ７ -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), then R １７ and R １８ are independently methyl; Or, R ３ , R ４ , R ５ and R ７ at least one of is a deuterated group; Or, R １ａ and R １ｂ But independently, C １－３ When it is alkyl, １－３ Alkyl is methyl, ethyl, n-propyl or isopropyl; Or, R ３ , R ４ and R ５ But independently, C １－３ Alkyl-O- or deuterated C １－３ When it is alkyl-O-, C １－３ Alkyl-O- and deuterated C １－３ Alkyl-O-C １－３ Alkyl is methyl, ethyl, n-propyl or isopropyl; Or, R ６ C １－３ When it is alkyl, １－３ Alkyl is methyl, ethyl, n-propyl or isopropyl; Or, R １２ , R １７ and R １８ But independently, C １－３ Alkyl or deuterated C １－３ When it is alkyl, １－３ Alkyl and deuterated C １－３ Alkyl C １－３ Alkyl is methyl, ethyl, n-propyl or isopropyl; Or, R １５ and R １６ But independently, C １－３ When it is alkyl, １－３ Alkyl is methyl, ethyl, n-propyl or isopropyl; Or, R １３ and R １４ But independently, C １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ When it is alkyl-O-, １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ Alkyl-O-C １－３ Alkyl is methyl, ethyl, n-propyl or isopropyl; Or, R １３ and R １４ together with the nitrogen atom to which it is linked form a 4- to 6-membered aliphatic heterocycle or one or more R １９ When forming a 4- to 6-membered aliphatic heterocycle substituted with one or more of R １９ The 4- to 6-membered aliphatic heterocycle substituted with is a 4- to 6-membered heterocycloalkyl, which further contains 0 to 1 heteroatom selected from N, O, or S in addition to the one N and the carbonyl connected thereto; Or, R １９ is a halogen, said halogen is fluorine, chlorine, bromine or iodine; Or, R １９ C １－３ When it is alkyl, １－３ 2. The compound of formula I according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein alkyl is methyl, ethyl, n-propyl or isopropyl.

4. R １ａ and R １ｂ But independently, C １－３ When it is alkyl, １－３ Alkyl is methyl; Or, R ３ , R ４ and R ５ But independently, C １－３ Alkyl-O- or deuterated C １－３ When it is alkyl-O-, １－３ Alkyl-O- and deuterated C １－３ Alkyl-O-C １－３ Alkyl is methyl; Or, R ６ C １－３ When it is alkyl, １－３ Alkyl is methyl; Or, R １２ , R １７ and R １８ But independently, C １－３ Alkyl or deuterated C １－３ When it is alkyl, １－３ Alkyl and deuterated C １－３ Alkyl C １－３ Alkyl is methyl; Or, R １５ and R １６ But independently, C １－３ When it is alkyl, １－３ Alkyl is methyl or ethyl; Or, R １３ and R １４ But independently, C １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ When it is alkyl-O-, １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ Alkyl-O-C １－３ Alkyl is methyl or ethyl; Or, R １３ and R １４ together with the nitrogen atom to which it is linked form a 4- to 6-membered aliphatic heterocycle or one or more R １９ When forming a 4- to 6-membered aliphatic heterocycle substituted with one or more of R １９ The 4- to 6-membered aliphatic heterocycle substituted with 【Chemistry 2】 and Or, R １９ is a halogen, said halogen is fluorine or chlorine; Or, R １９ C １－３ When it is alkyl, １－３ 4. The compound of formula I according to claim 3, wherein alkyl is methyl, or a pharma- ceutically acceptable salt thereof.

5. R １３ and R １４ together with the nitrogen atom to which it is linked form a 4- to 6-membered aliphatic heterocycle or one or more R １９ When forming a 4- to 6-membered aliphatic heterocycle substituted with one or more of R １９ The 4- to 6-membered aliphatic heterocycle substituted with is a 6-membered heterocycloalkyl, which further contains 0 to 1 heteroatom selected from N, O, or S in addition to the one N and the carbonyl connected thereto; Or, R １９ 4. The compound of formula I or a pharma- ceutically acceptable salt thereof according to claim 3, characterized in that when is halogen, said halogen is fluorine.

6. R １３ and R １４ together with the nitrogen atom to which it is linked form a 4- to 6-membered aliphatic heterocycle or one or more R １９ When forming a 4- to 6-membered aliphatic heterocycle substituted with one or more of R １９ The 4- to 6-membered aliphatic heterocycle substituted with 【Chemistry 3】 6. The compound of formula I according to claim 5, characterized in that:

7. R １ａ and R １ｂ are independently methyl; Or, R ３ , R ４ and R ５ are independently methyl-O- or CD ３ -O-, Or, R ６ is H or methyl, Or, R １２ CD ３ and Or, R １３ OH, methyl, CD ３ , -CD ２ - CD ３ or CD ３ -O-, Or, R １４ CD ３ or -CD ２ - CD ３ and Or, R １３ and R １４ together with the nitrogen atom to which it is linked 【Chemistry 4】 Forming Or, -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ) is -C(Me) ２ P(=O)(OMe) ２ and Or, R １９ is F or methyl, Or, "R ３ , R ４ and R ５ " and R ７ 2. The compound of formula I according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein one or two of are deuterated groups. 【Request 8】 【Chemical 5】 and / or 【Chemistry 6】 and / or 【Chemistry 7】 2. The compound of formula I according to claim 1, characterized in that:

9. The compound represented by formula I according to claim 1, characterized in that the compound represented by formula I is represented by the following scheme 1, scheme 2, scheme 3, scheme 4, or scheme 5, or a pharma- ceutically acceptable salt thereof. (Scheme 1, where X is chlorine or bromine; R １ａ and R １ｂ is independently C １－３ alkyl, and R １ａ and R １ｂ are the same, R ２ａ , R ２ｂ and R ２ｃ are independently hydrogen; R ２ａ , R ２ｂ and R ２ｃ are the same, R ３ , R ４ and R ５ is independently C １－３ Alkyl-O- or deuterated C １－３ alkyl-O- and R ３ , R ４ and R ５ are the same, R ６ is H, R ７ is -OR １２ , -NR １３ R １４ Or -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), where R １２ are independently deuterated C １－３ alkyl, R １５ and R １６ is independently C １－３ alkyl, R １７ and R １８ is independently C １－３ alkyl, R １３ is methyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ alkyl-O-; R １４ is methyl or deuterated C １－３ alkyl, or R １３ and R １４ represents, together with the nitrogen atom to which it is linked, a 4- to 6-membered aliphatic heterocycle or one or more R １９ R １５ , R １６ , R １７ and R １８ is independently C １－３ alkyl, R １９ is a halogen, Or, R ６ is C １－３ alkyl, R ７ is -NR １３ R １４ and R １３ OH, C １－３ Alkyl, deuterated C １－３ Alkyl or deuterated C １－３ alkyl-O-; R １４ is C １－３ Alkyl or deuterated C １－３ is alkyl, R ８ , R ９ , R １０ and R １１ is hydrogen, Here, R ３ , R ４ , R ５ and R ７ at least one of is a deuterated group; Scheme 2, X is chlorine or bromine; R １ａ and R １ｂ is independently C １－３ is alkyl, R ２ａ , R ２ｂ and R ２ｃ are independently hydrogen; R ３ , R ４ and R ５ is independently C １－３ Alkyl-O- or deuterated C １－３ alkyl-O-, R ６ is H or C １－３ is alkyl, R ７ is -OR １２ , -NR １３ R １４ Or -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), where R １２ , R １７ and R １８ is independently C １－３ Alkyl or deuterated C １－３ alkyl, R １５ and R １６ is independently C １－３ is alkyl, R １３ and R １４ are independently OH, C １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ alkyl-O-; or R １３ and R １４ represents, together with the nitrogen atom to which it is linked, a 4- to 6-membered aliphatic heterocycle or one or more R １９ R １９ is halogen or C １－３ is alkyl, R ８ , R ９ , R １０ and R １１ are independently hydrogen; Here, R ３ , R ４ , R ５ and R ７ at least one of is a deuterated group; Scheme 3, X is chlorine or bromine; R １ａ and R １ｂ is independently C １－３ is alkyl, R ２ａ , R ２ｂ and R ２ｃ are independently hydrogen; R ３ , R ４ and R ５ is independently C １－３ Alkyl-O- or deuterated C １－３ alkyl-O-, R ６ is H or C １－３ is alkyl, R ７ is -OR １２ , -NR １３ R １４ Or -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), where R １２ , R １７ and R １８ is independently C １－３ Alkyl or deuterated C １－３ alkyl, R １５ and R １６ is independently C １－３ is alkyl, R １３ and R １４ are independently OH, C １－３ Alkyl, deuterated C １－３ Alkyl, C １－３ Alkyl-O- or deuterated C １－３ alkyl-O- or R １３ and R １４ represents, together with the nitrogen atom to which it is linked, a 4- to 6-membered aliphatic heterocycle or one or more R １９ forming a 4- to 6-membered aliphatic heterocycle substituted by R ８ , R ９ , R １０ and R １１ are independently hydrogen; Here, R ３ , R ４ , R ５ and R ７ at least one of is a deuterated group; Scheme 4, X is chlorine or bromine; R １ａ and R １ｂ are independently methyl; R ２ａ , R ２ｂ and R ２ｃ are independently hydrogen; R ３ , R ４ and R ５ are independently methyl-O- or CD ３ -O-, R ６ is H or methyl, R ７ is -OR １２ , -NR １３ R １４ Or -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), where R １２ , R １７ and R １８ are independently methyl, ethyl, CD ３ or -CD ２ - CD ３ and R １５ and R １６ is independently methyl or ethyl; R １３ and R １４ are independently OH, methyl, CD ３ , -CD ２ - CD ３ or CD ３ -O-, or R １３ and R １４ together with the nitrogen atom to which it is linked 【Chemistry 8】 Forming R ８ , R ９ , R １０ and R １１ are independently hydrogen; Here, R ３ , R ４ , R ５ and R ７ at least one of is a deuterated group; Scheme 5, X is chlorine or bromine; R １ａ and R １ｂ are independently methyl; R ２ａ , R ２ｂ and R ２ｃ are independently hydrogen; R ３ , R ４ and R ５ are independently methyl-O- or CD ３ -O-, R ６ is H or methyl, R ７ is -OR １２ , -NR １３ R １４ Or -C(R １５ R １６ )-P(=O)(OR １７ OR １８ ), where R １２ , R １７ and R １８ are independently methyl or CD ３ and R １５ and R １６ are independently methyl; R １３ and R １４ are independently methyl, methyl-O-, CD ３ , -CD ２ - CD ３ or CD ３ -O-, Or, R １３ and R １４ together with the nitrogen atom to which it is linked 【Chemistry 9】 Forming R ８ , R ９ , R １０ and R １１ are independently hydrogen; Here, R ３ , R ４ , R ５ and R ７ At least one of the groups is a deuterated group.

10. The compound of formula I or a pharma- ceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the following compounds: 【Chemistry 10】 【Chemistry 11】

11. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, wherein the compound of formula I or a pharma- ceutically acceptable salt thereof is used in an amount that is therapeutically effective.

12. Use of a compound of formula I or a pharma- ceutical acceptable salt thereof according to any one of claims 1 to 10 in the manufacture of a medicament for the prevention or treatment of a proliferative disease, comprising The proliferative disease is cancer, lymphohematopoietic tumor, myelohematopoietic tumor, stromal tumor, melanoma, seminoma, teratoma, neuroblastoma, or glioma; the cancer being bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, adrenal cancer, prostate cancer, stomach cancer, vaginal cancer, cervical cancer, endometrial cancer, central nervous system tumors, melanoma, leukemia, thyroid cancer and skin cancer; The lymphohematopoietic tumors are acute lymphoblastic leukemia, B-cell lymphoma and Burkitt's lymphoma; The myelohematopoietic tumors are acute and chronic myeloid leukemia and promyelocytic leukemia; The stromal tumors are fibrosarcoma and rhabdomyosarcoma.

13. 13. The use according to claim 12, characterized in that the lung cancer cells are A549 non-small cell lung cancer cells, the colon cancer cells are HCT116 colon cancer cells, the central nervous system tumor cells are SF295 central nervous system tumor cells, the melanoma cells are LOX-IMVI melanoma cells, the renal cancer cells are 786-0 renal cancer cells, the leukemia cells are K562 leukemia cells, the prostate cancer cells are PC-3 prostate cancer cells, the ovarian cancer cells are OVCAR-3 ovarian cancer cells and the breast cancer cells are HS 578T breast cancer cells.

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