Benzodiazepine compound, pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are a benzodiazepine compound, a pharmaceutical composition and the use thereof. Specifically provided is a compound represented by formula I, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. The compound provided in the present invention has one or more of the following advantageous effects: (1) the compound of the present invention exhibits good intravenous sedative and anesthetic effects; (2) the compound of the present invention exhibits low drug accumulation and a good tolerance; and (3) the compound of the present invention achieves an anesthetic effect with faster recovery.

Description

Benzodiazepines, pharmaceutical compositions and their uses

[0001] This application claims priority to Chinese patent applications 2024109278800 (filed July 11, 2024), 2024116549173 (filed November 19, 2024), and 2025102638903 (filed March 6, 2025), and priority to Chinese patent application 2025109189801 (filed July 3, 2025). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical technology, specifically to a benzodiazepine. Class of compounds, pharmaceutical compositions and their uses. Background Technology

[0003] benzodiazepine BDZs are the most commonly used sedative-hypnotic drugs in recent years. Sedative-hypnotic drugs can produce pharmacological effects such as anticonvulsant, anti-anxiety, hypnotic, and central skeletal muscle relaxant effects. Some drugs, such as midazolam, can also be used as anesthetics. Since γ-aminobutyric acid (GABA) neurons account for about one-third of the total central nervous system, and benzodiazepines... These drugs exhibit highly selective inhibitory effects on the limbic system of the brain, through stimulation of benzodiazepines. By stimulating GABA receptors, the drug enhances the postsynaptic inhibitory effect of GABA. At this time, the GABA-A receptor that controls the chloride ion channel binds to the GABA receptor, causing a conformational change in the GABA receptor coupled to the chloride ion channel. This leads to an increase in the frequency of chloride ion channel opening, resulting in hyperpolarization. Ultimately, this causes the inhibitory effect of long-acting, intermediate-acting, or short-acting drugs on the central nervous system, thus enabling the drug to exert its significant pharmacological properties.

[0004] Among them, ultra-short-acting benzodiazepines Remimazolam, a representative drug in this class, has sedative, amnesic, and anti-anxiety effects, exhibiting anterograde amnesia. It is metabolized by esterases, and its metabolites are inactive. Although clinical studies show a slightly slower onset of action than propofol, it is still rapid (around 1 minute). The complete recovery time after colonoscopy or gastroscopy is similar to propofol (within 10 minutes), but for sedation during general anesthesia or bronchoscopy, the complete recovery time with remimazolam is slower than with propofol. Common adverse reactions include: motor dysfunction and dizziness during recovery, hypotension, nausea, and decreased heart rate. However, the overall incidence of adverse reactions, hypotension, and respiratory depression is significantly lower than with propofol or propofol medium / long-chain lipid emulsions.

[0005] In summary, benzodiazepines These drugs still suffer from problems such as delayed onset of action and drug accumulation. Therefore, it is crucial to develop benzodiazepines that have rapid onset of action, short onset time, and minimal drug accumulation. The availability of such drugs is a problem that urgently needs to be solved. Summary of the Invention

[0006] To solve the above-mentioned technical problems, the present invention provides benzodiazepine Class of compounds, pharmaceutical compositions and their uses. The compounds provided by the present invention have one or more of the following advantages: (1) the compounds of the present invention have good intravenous sedation and anesthesia effects; (2) the compounds of the present invention have low drug accumulation and good tolerability; (3) the compounds of the present invention have a faster recovery anesthetic effect.

[0007] The present invention provides a compound of Formula I, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof;

[0008] in,

[0009] X1 and X2 are independently N or CR 6 ;

[0010] R 6 H and C independently 1-6 Alkyl, hydroxyl, or halogen;

[0011] L2 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkyl groups may be optionally coated with one or more deuterium (D), halogens, hydroxyl groups, or C atoms. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0012] R 4 R 5 R 8 and R 9 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0013] Or, R 4 and R 5 Together with the C atoms attached thereto, they form a 4-6 membered carbon ring or a 4-6 membered heterocycle, wherein the 4-6 membered carbon ring and the 4-6 membered heterocycle are optionally separated by one or more R atoms. b replace;

[0014] R b Independently hydroxyl and oxygen groups Halogen, C1-6 Alkyl, C 1-6 alkoxy or -NR b-1 R b-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may optionally be replaced by one or more hydroxyl groups or halogens;

[0015] R b-1 and R b-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens;

[0016] for X4 is hydrogen or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens;

[0017] or, for X3 is either N or CH;

[0018] R 7 Independently, it is H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkyl or C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace;

[0019] R 7-1 Independently for C 1-6 Alkoxy, C 1-6 Alkyl, halogen, or hydroxyl;

[0020] R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 Alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl;

[0021] X5 is

[0022] L1 is the connection key, C 1-6 Alkylene, C 1-6 Alkylene-NR L-1 - C 1-6 Alkylene-OR L-2 - C 1-6 alkylene-CO-, wherein the C 1-6 Alkyl groups may be optionally coated with one or more deuterium (D), halogens, hydroxyl groups, or C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl, 3-7 membered cycloalkyl (preferably two substituents on the same C atom are linked to form a 3-7 membered cycloalkyl) or 3-7 membered heterocycloalkyl (preferably two substituents on the same C atom are linked to form a 3-7 membered heterocycloalkyl) substitution;

[0023] R L-1 It is hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens;

[0024] R L-2 For single bond or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens;

[0025] R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, 4-10 membered heterocyclic, 4-6 membered heteroaryl or -NR 2 R 3 The 3-7 membered cycloalkyl, 4-10 membered heterocyclic and 4-6 membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0026] R 2 and R 3 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens;

[0027] R a Independently deuterium (D), hydroxyl group, and oxo group Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a-1 R a-2 or -COOR a- 3 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may optionally be replaced by one or more hydroxyl groups or halogens;

[0028] Ra-1 R a-2 and R a-3 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens;

[0029] R 11 and R 12 It is attached to an N atom to form a 4-10 membered heterocyclic group or a 4-6 membered heteroaryl group; wherein the 4-10 membered heterocyclic group and the 4-6 membered heteroaryl group are optionally connected to one or more R atoms. d replace;

[0030] R d Independently deuterium (D), hydroxyl group, and oxo group Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a-4 R a-5 or -COOR a- 6 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may optionally be replaced by one or more hydroxyl groups or halogens;

[0031] R a-4 R a-5 and R a-6 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0032] When L1 is the connector, X1 is N, X2 is CH, X3 is CH, and R... 4 For H, R 5 For Br, R 7 When it is methyl, R 1 Not cyclohexane;

[0033] when for At that time, R 1 It is a 6-membered heterocyclic group, wherein the 6-membered heterocyclic group is optionally converted by one or more R a Substitution; the heteroatom of the 6-membered heterocyclic group is one or more of O, N and S, the number of heteroatoms is 1, 2 or 3, and it contains at least one N;

[0034] The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0035] The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0036] The heteroatoms of the 4-10 member heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0037] The heteroatoms of the 4-6 membered heteroaryl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0038] The present invention provides a compound of Formula I, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof;

[0039] in,

[0040] X1 and X2 are independently N or CR 6 ;

[0041] X3 is either N or CH;

[0042] R 6 H and C independently 1-6 Alkyl, hydroxyl, or halogen;

[0043] L2 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene is optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0044] Hal is a halogen;

[0045] R 10 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-9-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-9-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c Replacement; preferably, R 10 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-10-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-10-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c replace;

[0046] R c Independently hydroxyl and oxygen groups Halogen, C1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkyl groups are optionally surrounded by one or more R groups. c-1 Replace; R c-1 Independently hydroxyl or halogen;

[0047] R 4 R 5 R 8 and R 9 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0048] Or, R 4 and R 5 Together with the C atoms attached thereto, they form a 4-6 membered carbon ring or a 4-6 membered heterocycle, wherein the 4-6 membered carbon ring and the 4-6 membered heterocycle are optionally separated by one or more R atoms. b replace;

[0049] R b Independently hydroxyl and oxygen groups Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -NR b-1 R b-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0050] R b-1 and R b-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0051] R 7 Independently, it is H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkyl or C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace;

[0052] R 7-1 Independently for C 1-6 Alkoxy, C 1-6Alkyl, halogen, or hydroxyl;

[0053] R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 Alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl;

[0054] The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0055] The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0056] The heteroatoms of the 4-9 membered heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0057] The heteroatoms of the 4-6 membered heteroaryl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0058] In one scheme, the compound represented by Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof;

[0059] Replaced with

[0060] in,

[0061] L1 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene is optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0062] R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, 4-9 membered heterocyclic, 4-6 membered heteroaryl or -NR 2 R 3 The 3-7-membered cycloalkyl, 4-9-membered heterocyclic and 4-6-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0063] R 2 and R 3 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0064] R a Independently hydroxyl and oxygen groups Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -NR a-1 R a-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0065] R a-1 and R a-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0066] When L1 is the connector, X1 is N, X2 is CH, X3 is CH, and R... 4 For H, R 5 For Br, R 7 When it is methyl, R 1 Not cyclohexane;

[0067] R 8 and R 9 For H.

[0068] The present invention provides a compound of Formula I, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof;

[0069] in,

[0070] X1 and X2 are independently N or CR 6 ;

[0071] X3 is either N or CH;

[0072] R 6 H and C independently 1-6 Alkyl, hydroxyl, or halogen;

[0073] L1 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene is optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0074] R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6Alkoxy, 3-7 membered cycloalkyl, 4-9 membered heterocyclic, 4-6 membered heteroaryl or -NR 2 R 3 The 3-7-membered cycloalkyl, 4-9-membered heterocyclic and 4-6-membered heteroaryl groups are optionally surrounded by one or more R groups. a Replacement; preferably, R 1 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-10-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-10-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c replace;

[0075] R 2 and R 3 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0076] R a Independently hydroxyl and oxygen groups Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -NR a-1 R a-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0077] R a-1 and R a-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0078] R 4 and R 5 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0079] Or, R 4 and R 5 Together with the C atoms attached thereto, they form a 4-6 membered carbon ring or a 4-6 membered heterocycle, wherein the 4-6 membered carbon ring and the 4-6 membered heterocycle are optionally separated by one or more R atoms. b replace;

[0080] R bIndependently hydroxyl and oxygen groups Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -NR b-1 R b-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0081] R b-1 and R b-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0082] R 7 Independently H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, surrounded by one or more R 7-1 Substituted 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, with one or more R 7-2 Substituted 3-7 membered heterocyclic alkyl groups, C 1-6 Alkyl group, with one or more R 7-3 Replacement C 1-6 Alkyl, C 1-6 alkoxy or surrounded by one or more R 7-4 Replacement C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace;

[0083] R 7-1 Independently for C 1-6 Alkoxy, C 1-6 Alkyl, halogen, or hydroxyl;

[0084] R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 Alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl;

[0085] When L1 is the connector, X1 is N, X2 is CH, X3 is CH, and R... 4 For H, R 5 For Br, R 7 When it is methyl, R 1 Not cyclohexane;

[0086] The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0087] The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0088] The heteroatoms of the 4-9 membered heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0089] The heteroatoms of the 4-6 membered heteroaryl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0090] The present invention provides a compound of Formula I, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof;

[0091] in,

[0092] X1 is N or CR 6 ;

[0093] X3 is either N or CH;

[0094] R 6 H and C independently 1-6 Alkyl, hydroxyl, or halogen;

[0095] L2 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene is optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0096] Hal is a halogen;

[0097] R 10 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-9-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-9-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c replace;

[0098] R c Independently hydroxyl, (Oxygen), Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6Alkyl groups are optionally surrounded by one or more R groups. c-1 Replace; R c-1 Independently hydroxyl or halogen;

[0099] R 4 R 5 R 8 and R 9 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0100] R 7 Independently, it is H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkyl or C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace;

[0101] R 7-1 Independently for C 1-6 Alkoxy, C 1-6 Alkyl, halogen, or hydroxyl;

[0102] R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 Alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl;

[0103] The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0104] The heteroatoms of the 4-9 membered heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0105] The heteroatoms of the 4-6 membered heteroaryl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0106] In certain preferred embodiments of the present invention, certain groups in any of the compounds, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof described in the present invention are defined as follows, and groups not mentioned are the same as those described in any embodiment of the present invention (hereinafter referred to as "a certain embodiment").

[0107] In one embodiment, the compound represented by Formula I is

[0108] Where L1 is the connector key or C 1-6 alkylene, wherein the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1- 6-Hydroalkyl substitution;

[0109] R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, 4-9 membered heterocyclic, 4-6 membered heteroaryl or -NR 2 R 3 The 3-7-membered cycloalkyl, 4-9-membered heterocyclic and 4-6-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0110] R 2 R 3 Independently, they are hydrogen and C respectively. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens;

[0111] R a Each independently is a hydroxyl group, (Oxygen), Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1- The 6-alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0112] When L1 is a linking bond, R1 is not cyclohexane;

[0113] The heteroatoms of the 4-9 membered heterocyclic groups are O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0114] The heteroatoms of the 4-6 membered heteroaryl group are O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0115] In one scheme, the C 1-6 The alkylene group can be methylene, ethylene, n-propylene, or isopropylene.

[0116] In one embodiment, the halogen can independently be fluorine, chlorine, bromine, or iodine.

[0117] The phrase "optionally substituted by one or more" means "unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, 5 or 6)" substituents, where the substituents may be the same or different.

[0118] In one scheme, the C 1-6 The alkyl group can be methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0119] In one scheme, the C 1-6 Haloalkyl is a C that is substituted with one or more halogens. 1-6 Alkyl groups, preferably C substituted with one or more halogens. 1-3 Alkyl groups, more preferably C groups substituted with one or more fluorine molecules. 1-3 Alkyl groups, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3.

[0120] In one scheme, the C 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy.

[0121] In one embodiment, the 3-7 membered cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0122] In one embodiment, the 4-10 membered heterocyclic group can be a 4-10 membered heterocyclic alkyl group or a 4-10 membered heterocyclic alkenyl group, such as a 4-9 membered heterocyclic group, including bridged rings (there can be 1 or 2 bridging atoms), fused rings (e.g., 2-fused rings), and spirocyclic rings (e.g., four-membered spiro-four-membered rings, four-membered spiro-six-membered rings, or six-membered spiro-five-membered rings), such as piperazine, morpholino, piperidinyl, azacyclic butyl, tetrahydropyrrole, thiomorpholino, etc. For example The 4-9 membered heterocyclic alkenyl group, for example For example

[0123] In one embodiment, the 4-9 membered heterocyclic group may be a 4-9 membered heterocyclic alkyl group or a 4-9 membered heterocyclic alkenyl group, such as piperazinyl, morpholinyl, piperidinyl, azacyclic butyl, tetrahydropyrroleyl, thiomorpholinyl, etc. For example The 4-9 membered heterocyclic alkenyl group, for example For example

[0124] In one embodiment, the 4-9 membered heterocyclic group can be a 4-9 membered heterocyclic alkyl group or a 4-9 membered heterocyclic alkenyl group. The 4-9 membered heterocyclic alkyl group (preferably a 5-6 membered heterocyclic alkyl group) may have one or two heteroatoms selected from N, O, or S, and the number of heteroatoms may be one or two. These heteroatoms may be piperazine, morpholino, piperidinyl, azacyclic butyl, tetrahydropyrrole, thiomorpholino, etc. For example The 4-9 membered heterocyclic alkenyl group (preferably 5-6 membered heterocyclic alkenyl group) may contain one or two carbon-carbon double bonds, and the heteroatom may be one or two of N, O, or S, and the number of heteroatoms may be one or two. For example

[0125] In one embodiment, the 5-6 membered heterocyclic alkyl group contains two heteroatoms, namely N and O, such as morpholino.

[0126] In one embodiment, the 4-9 member heterocyclic group can be a single ring or multiple rings, and the multiple rings can be fused rings, helical rings, or bridged rings.

[0127] In one embodiment, the 4-6 heteroaryl group may be pyridyl, for example...

[0128] In one embodiment, the 4-6 membered carbon ring is a 4-6 membered cyclic alkenyl group containing a carbon-carbon double bond, with the carbon-carbon double bond side forming a fused ring with a phenyl group, for example...

[0129] In one embodiment, the 4-6 membered heterocycle is a 4-6 membered heterocyclic alkenyl group containing a carbon-carbon double bond, the heteroatom being N, O, or S, and a fused ring is formed with a phenyl group on the carbon-carbon double bond side, for example...

[0130] In one embodiment, the 3-7 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group, and the heteroatom can be N, O or S, and the number of heteroatoms is 1 or 2, such as oxocyclic butyl.

[0131] In one scheme, the C 1-6 A haloalkoxy group is a C- group independently substituted with one or more halogens. 1-6 Alkoxy groups, preferably C groups substituted with one or more halogens. 1-3 Alkoxy, more preferably C substituted with one or more fluorine atoms. 1-3Alkyl groups, such as -OCH2F, -OCH2Cl, -OCHF2, -OCHCl2, -OCCl3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3 or -OCF2CF3.

[0132] In a certain scheme, X1 and X2 are independently N or CR. 6 R 6 It can be H or halogen independently.

[0133] In one scheme, X3 is CH.

[0134] In one scheme, L1 is the link key or C 1-3 Alkylene, the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl substitution.

[0135] In a given scheme, L1 is a link key, not replaced, or replaced by one or more Rs. L1 Replacement C 1-6 Alkylene, R L1 Independently halogen or C 1-6 Haloalkyl, such as L1, is an unsubstituted C. 1-6 Alkylene.

[0136] In one of the schemes, R 1 Halogen, hydroxyl, -C(O)NH2, C 1-3 Haloalkyl, C 1-3 alkoxy, pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group or -NR2R3, wherein the pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace.

[0137] In one of the schemes, R 1 Halogen, hydroxyl, -C(O)NH2, C 1-3 Haloalkyl, C 1-3 alkoxy, pyridine, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group or -NR2R3, wherein the pyridine, 3-7 membered cycloalkyl, 4-10 membered heterocyclic group is optionally surrounded by one or more R groups. a replace.

[0138] In one of the schemes, R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, 4-9 membered heterocyclic group, 4-6 membered heteroaryl group or -NR 2 R 3The 4-9 membered heterocyclic group and the 4-6 membered heteroaryl group are optionally surrounded by one or more R a replace.

[0139] In one of the schemes, R 1 Halogen, hydroxyl, C 1-6 Halogenated alkyl, unsubstituted or with one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 For example, R 1 For not replaced or by one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 .

[0140] In one of the schemes, R 1 Halogen, hydroxyl, C 1-6 Halogenated alkyl, unsubstituted or with one or more R a Substituted 4-10 membered heterocyclic groups or -NR 2 R 3 For example, R 1 For not replaced or by one or more R a Substituted 4-10 membered heterocyclic groups or -NR 2 R 3 .

[0141] In one of the schemes, R 2 R 3 Independently, they are hydrogen and C respectively. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens.

[0142] In one of the schemes, R 2 and R 3 Independently hydrogen, unsubstituted or by one or more R 2-1 Replacement C 1-6 Alkyl groups, such as hydrogen.

[0143] In one of the schemes, R 2-1 It is a hydroxyl group.

[0144] In one of the schemes, R a Each independently consists of hydrogen, hydroxyl, and Halogen, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens.

[0145] In one of the schemes, R aIndependently hydroxyl, oxo, halogen, unsubstituted, or modified by one or more R groups a-3 Replacement C 1-6 Alkyl, unsubstituted or with one or more R a-4 Replacement C 1-6 Alkoxy or -NR a-1 R a-2 For example, R a Independently an oxo group, hydroxyl group, or C 1-6 Alkyl group. Preferably, R a Independently deuterium, halogen, or carbon 1-6 alkyl.

[0146] In one of the schemes, R a-3 and R a-4 It can be hydroxyl or halogen independently.

[0147] In one of the schemes, R a-1 and R a-2 Independently hydrogen or C 1-6 alkyl.

[0148] In one of the schemes, R 4 and R 5 Independently H or halogen, such as R 4 For H, R 5 It is a halogen (e.g., bromine).

[0149] In one of the schemes, R 4 and R 5 Together with the C atoms it is attached to, they form 4-6 membered carbon rings, for example

[0150] In one of the schemes, R 7 C 1-6 Alkyl (e.g., methyl).

[0151] In a certain scheme, X1 is N or CR 6 .

[0152] In one scheme, X2 is CH.

[0153] In one possible solution, X3 is N.

[0154] In one of the schemes, R 6 It is a halogen, such as fluorine.

[0155] In one scheme, L2 is C 1-6 Alkylene, preferably C 1-3 Alkylene, such as methylene.

[0156] In one particular scheme, Hal is F.

[0157] In one of the schemes, R 10H, Cl, Br, I, hydroxyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-9-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-9-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c Replacement, for example, R 10 H, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-9-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-9-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c replace.

[0158] In one of the schemes, R 10 H, Cl, Br, I, hydroxyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-10-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-10-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c Replacement, for example, R 10 H, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3-7-membered cycloalkyl, 4-10-membered heterocyclic or 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-10-membered heterocyclic and 4-6-membered heteroaryl are optionally represented by one or more R c replace.

[0159] In one of the schemes, R 10 For H.

[0160] In one of the schemes, R 4 R 5 R 8 and R 9 Independently H, halogen, or nitro, such as R 4 R 8 and R 9 For H, R 5 It is either halogenated or nitro.

[0161] In one of the schemes, R 7 C1-6 Alkyl groups, such as methyl groups.

[0162] The present invention provides a compound of Formula I, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof;

[0163] X1 and X2 are independently N or CR 6 ;

[0164] X3 is CH;

[0165] R 6 Independently H or halogen;

[0166] L1 is a linker key, not replaced, or occupied by one or more R keys. L1 Replacement C 1-6 Alkylene, R L1 Independent of halogen, C 1-6 Alkyl or C 1- 6-Hydroalkyl;

[0167] R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, unsubstituted, or substituted with one or more R a Substituted 3-7 membered cycloalkyl, unsubstituted or with one or more R a Substituted 4-9 membered heterocyclic groups, unsubstituted or substituted with one or more R groups a Substituted 4-6 aryl or -NR 2 R 3 ;

[0168] R 2 and R 3 Independently hydrogen, unsubstituted or by one or more R 2-1 Replacement C 1-6 Alkyl, R 2-1 It is a hydroxyl group;

[0169] R a Independently hydroxyl, oxo, halogen, unsubstituted, or modified by one or more R groups a-3 Replacement C 1-6 Alkyl, unsubstituted or with one or more R a-4 Replacement C 1-6 Alkoxy or -NR a-1 R a-2 R a-3 and R a-4 Independently hydroxyl or halogen;

[0170] R a-1 and R a-2 Independently hydrogen or C 1-6 alkyl;

[0171] R 4 and R 5 Independently H or halogen;

[0172] Or, R 4 and R 5 Together with the C atoms attached to it, it forms a 4-6 membered carbon ring or a 4-6 membered heterocycle;

[0173] R 7 C 1-6 alkyl;

[0174] When L1 is the connector, X1 is N, X2 is CH, X3 is CH, and R... 4 For H, R 5 For Br, R 7 When it is methyl, R 1 Not cyclohexane;

[0175] The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0176] The heteroatoms of the 4-9 membered heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0177] The heteroatoms of the 4-6 membered heteroaryl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0178] In one embodiment, the compound represented by Formula I,

[0179] Where L1 is the connector key or C 1-3 alkylene, wherein the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1- 3-Halogenated alkyl substitution;

[0180] R1 is a halogen, hydroxyl group, -C(O)NH2, or C 1-3 Haloalkyl, C 1-3 alkoxy, pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group or -NR2R3, wherein the pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace;

[0181] R2 and R3 are independently hydrogen and C, respectively. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens;

[0182] R a Each independently is a hydroxyl group, Halogen, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl and C 1-3 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0183] When L1 is a linking bond, R1 is not cyclohexane.

[0184] The present invention provides a compound of Formula I, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof;

[0185] X1 and X2 are independently N or CR 6 ;

[0186] X3 is CH;

[0187] R 6 Independently H or halogen;

[0188] L1 is a linker key, not replaced, or occupied by one or more R keys. L1 Replacement C 1-6 Alkylene, R L1 Independently halogen or C 1-6 Halogenated alkyl groups;

[0189] R 1 Halogen, hydroxyl, C 1-6 Halogenated alkyl, unsubstituted or with one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 ;

[0190] R 2 and R 3 Independently hydrogen;

[0191] R a Independently an oxo group, hydroxyl group, or C 1-6 alkyl;

[0192] R 4 and R 5 Independently H or halogen;

[0193] Or, R 4 and R 5 Together with the C atoms attached to it, they form 4-6 membered carbon rings;

[0194] R 7 C 1-6 alkyl;

[0195] The heteroatoms of the 4-9 membered heterocyclic groups are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0196] In one embodiment, the compound represented by Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof;

[0197] X1 is N or CR 6 ;

[0198] X2 is CH;

[0199] X3 is CH or N;

[0200] R 6 H and C independently 1-6 Alkyl, hydroxyl, or halogen;

[0201] L2 is the connection key or C 1-6 Alkylene;

[0202] Hal is a halogen; R 10 For H;

[0203] R 4 R 5 R 8 and R 9 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; R 7 C 1-6 alkyl.

[0204] In one embodiment, the compound represented by Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof;

[0205] X1 is N or CR 6 ;

[0206] X2 is CH;

[0207] X3 is CH or N;

[0208] R 6 Independently H or halogen;

[0209] L2 is C 1-6 Alkylene;

[0210] Hal is a halogen; R 10 For H;

[0211] R 4 R 5 R 8 and R 9 Independently H, halogen, or nitro;

[0212] R 7 C1-6 alkyl.

[0213] In one embodiment, the compound represented by Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof;

[0214] in,

[0215] X1 and X2 are independently N or CR 6 ;

[0216] X3 is either N or CH;

[0217] R 6 H and C independently 1-6 Alkyl, hydroxyl, or halogen;

[0218] L1 is the connection key or C 1-6 Alkylene;

[0219] R 1 Halogen, C 1-3 Halogenated alkyl, 4-9 membered heterocyclic group, wherein the 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace;

[0220] R a Independently hydroxyl and oxygen groups Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0221] R 4 and R 5 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0222] Or, R 4 and R 5 Together with the C atoms attached thereto, they form a 4-6 membered carbon ring or a 4-6 membered heterocycle, wherein the 4-6 membered carbon ring and the 4-6 membered heterocycle are optionally separated by one or more R atoms. b replace;

[0223] R b Independently hydroxyl and oxygen groups Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -NR b-1 R b-2 Wherein C 1-6 Alkyl and C1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0224] R b-1 and R b-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0225] R 7 Independently H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, surrounded by one or more R 7-1 Substituted 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, with one or more R 7-2 Substituted 3-7 membered heterocyclic alkyl groups, C 1-6 Alkyl group, with one or more R 7-3 Replacement C 1-6 Alkyl, C 1-6 alkoxy or surrounded by one or more R 7-4 Replacement C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace;

[0226] R 7-1 Independently for C 1-6 Alkoxy, C 1-6 Alkyl, halogen, or hydroxyl;

[0227] R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 Alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl;

[0228] The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0229] The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3;

[0230] The heteroatoms of the 4-9 membered heterocyclic groups are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0231] In one embodiment, the compound represented by Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof;

[0232] in,

[0233] X1 and X2 are independently N or CR 6 ;

[0234] X3 is CH;

[0235] R 6 Independently H or halogen;

[0236] L1 represents unsubstituted C. 1-6 Alkylene;

[0237] R 1 Halogen, C 1-3 Halogenated alkyl, 4-9 membered heterocyclic group, wherein the 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace;

[0238] R a Independently hydroxyl and oxygen groups Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0239] R 4 and R 5 Independently H or halogen;

[0240] Or, R 4 and R 5 Together with the C atoms attached to it, they form 4-6 membered carbon rings;

[0241] R 7 Independently for C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace;

[0242] R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 Alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl;

[0243] The heteroatoms of the 4-9 membered heterocyclic groups are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0244] In one embodiment, the compound represented by Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof;

[0245] in,

[0246] X1 and X2 are independently N or CR 6 ;

[0247] X3 is CH;

[0248] R 6 H is independent;

[0249] L1 is C 1-6 Alkylene;

[0250] R 1 It is a halogenated, 4-9 membered heterocyclic group (e.g., morpholino), wherein the 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace;

[0251] R a Independently for C 1-6 alkyl;

[0252] R 4 and R 5 Independently H or halogen;

[0253] Or, R 4 and R 5 Together with the C atoms attached to it, they form 4-6 membered carbon rings;

[0254] R 7 Independently for C 1-6 alkyl;

[0255] The heteroatoms of the 4-9 membered heterocyclic groups are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0256] In one embodiment, the compound represented by Formula I is the same as the compound represented by Formula II;

[0257] Where L1 is C 1-6 Alkylene, the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0258] R 4a R 5a Independently, they are hydrogen and C respectively. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens;

[0259] Or, R 4a and R 5a Together with the N atom it is attached to, a 4-10 membered heterocyclic group is formed, wherein the 4-10 membered heterocyclic group is optionally surrounded by one or more R atoms. a Replace; R a As described in any embodiment of the present invention.

[0260] In one embodiment, the compound represented by Formula II contains... L1 is C 1-6 Alkylene, the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0261] R 4a R 5a Independently, they are hydrogen and C respectively. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens;

[0262] Or, R 4a and R 5a Together with the N atom it is attached to, a 4-9 membered heterocyclic group is formed, wherein the 4-9 membered heterocyclic group is optionally bonded by one or more R atoms. a replace;

[0263] R a Each independently is a hydroxyl group, Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens.

[0264] In one embodiment, the compound represented by formula II,

[0265] Where L1 is C 1-3 Alkylene, the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl substitution;

[0266] R 4a R 5a Independently, they are hydrogen and C respectively. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens;

[0267] Or, R 4a and R 5aTogether with the N atom it is attached to, a 4-9 membered heterocyclic group is formed, wherein the 4-9 membered heterocyclic group is optionally bonded by one or more R atoms. a replace;

[0268] R a Each independently is a hydroxyl group, Halogen, C 1-3 Alkyl, C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens.

[0269] In one embodiment, the compound represented by Formula I is the same as the compound represented by Formula III;

[0270] Where L1 is C 1-6 Alkylene, the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0271] Selected from single or double bonds;

[0272] R 6a It is hydrogen, halogen, hydroxyl or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more halogens or hydroxyl groups.

[0273] In one embodiment, the compound represented by Formula III,

[0274] Where L1 is C 1-3 Alkylene, the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl substitution;

[0275] Selected from single or double bonds;

[0276] R 6a It is hydrogen, halogen, hydroxyl or C 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted with one or more halogens or hydroxyl groups.

[0277] In one scheme, L1 is the link key or C 1-6 alkylene, wherein the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0278] R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy or -NR 2 R 3 ;

[0279] R 2 R 3 Independently, they are hydrogen and C respectively. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens;

[0280] When L1 is the connection key, R 1 It is not cyclohexane.

[0281] In one of the schemes, R 1 Halogen or C 1-3 Halogenated alkyl; preferably, R 1 Fluorine or C 1-3 Fluorinated alkyl groups.

[0282] In one scheme, L1 is C 1-3 alkylene, wherein the C 1-3 Alkylene oxides are reacted with one or more halogens or C 1-6 Halogenated alkyl substitution;

[0283] R 1 It is a hydroxyl group.

[0284] In one scheme, L1 is the link key or C 1-6 alkylene, wherein the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution;

[0285] R 1 It is a 3-7-membered cycloalkyl, a 4-9-membered heterocyclic, or a 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-9-membered heterocyclic, and 4-6-membered heteroaryl are optionally surrounded by one or more R a replace;

[0286] R a Each independently is a hydroxyl group, (Oxygen), Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0287] When L1 is the connection key, R 1 Not cyclohexane;

[0288] The heteroatoms of the 4-9 membered heterocyclic groups are O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0289] The heteroatoms of the 4-6 membered heteroaryl group are O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0290] In one of the schemes, R 1 It is a 4-10 member heterocyclic group, wherein the 4-10 member heterocyclic group is optionally surrounded by one or more R a Substitution (preferably, the heteroatom in the 4-10 membered heterocyclic group is selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3, and it contains at least one N;), preferably, R 1 for (For example ), where R 1a For O or NR 1f ;

[0291] R 1b R 1c R 1d and R 1e Independently, it can be H, deuterium, hydroxyl, oxo group, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, -NR a-1 R a-2 or -COOR a-3 R 1g and R 1f Independently H or C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally substituted with one or more hydroxyl groups or halogens, R a-1 R a-2 and R a-3 As described in any embodiment of the present invention;

[0292] Or, R 1b and R 1d The links form a bridge ring, with one or two bridge atoms (preferably CH2).

[0293] Or, R 1c and R 1d The links form a bridge ring, with one or two bridge atoms (preferably CH2).

[0294] Preferably, R 1 F, Br, Cl, hydroxyl, pyridyl, oxacyclohexyl or the aforementioned The pyridyl group and oxetane group are optionally coupled with one or more R a replace.

[0295] In one of the schemes, R 1 It is a 4-9 membered heterocyclic group, wherein the 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace;

[0296] R a Each independently is a hydroxyl group, (Oxygen), Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens;

[0297] The heteroatoms of the 4-9 membered heterocyclic groups are O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0298] Preferably, the heteroatom of the 4-9 membered heterocyclic group is nitrogen, and the number of heteroatoms is 1 or 2.

[0299] In one of the schemes, R 1 The morpholino group is optionally surrounded by one or more R groups. a replace;

[0300] R a Halogen and C are independent of each other. 1-6 Alkyl or C 1-6 Alkyl group.

[0301] In one embodiment, the compound represented by Formula I is the same as the compound represented by Formula IV;

[0302] M1, M2 and M3 are independently NH, O, S, CH2 or C(O);

[0303] Alternatively, M2 is a connecting bond, and M1 and M3 are independently NH, O, S, CH2 or C(O);

[0304] X1, X2, L1, and R 1 As described in any embodiment of the present invention.

[0305] In one scheme, in the compound shown in Formula IV,

[0306] M1, M2 and M3 are CH2;

[0307] X1 and X2 are independently N or CR 6 ;

[0308] R 6 Independently H or halogen;

[0309] L1 is C 1-6 Alkylene;

[0310] R 1 For not replaced or by one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 ;

[0311] R 2 and R 3 Independently hydrogen;

[0312] R a It is a hydroxyl group.

[0313] In one embodiment, the compound represented by formula I is the same as the compound represented by formula V;

[0314] Among them, L 2 X1, X3, R 5 and R 10 Independently as described in any embodiment of the present invention.

[0315] In one scheme, L1 is the connection key.

[0316] In one scheme, L1 is the connection key. Where end a and R 1 Connected.

[0317] In one scheme, L1 is the connection key. Where end a and R 1 Connected.

[0318] In one of the schemes, R 1 For fluorine, bromine, trifluoromethyl, hydroxyl, -C(O)NH2, amino,

[0319] In one of the schemes, R 1 The compounds are fluorine, methoxy, bromine, trifluoromethyl, hydroxyl, -C(O)NH2, and amino(-NH2).

[0320] In one of the schemes, R 1 The compounds are fluorine, methoxy, bromine, trifluoromethyl, hydroxyl, -C(O)NH2, and amino(-NH2).

[0321] In one of the schemes, R 4 For H, R 5 It is Br.

[0322] In one scheme, L2 is methylene or In one of the schemes, R 4 H, methyl, or F; R 5 It can be -NO2, Br, Cl or F.

[0323] In one of the schemes, R 4 and R 5 It forms together with the C atoms it is attached to.

[0324] In one of the schemes, R 7 It is a methyl group.

[0325] In one of the schemes, R 7 It can be methyl, cyclopropyl, or H.

[0326] In one of the schemes, R 8 and R 9 For H.

[0327] In one of the schemes, for

[0328] In one of the schemes, for

[0329] In one embodiment, the compound represented by Formula I is not any of the following compounds;

[0330] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0331] This invention provides a pharmaceutical composition comprising a compound of Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, and at least one pharmaceutical excipient. Preferably, the compound of Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof are the active ingredients.

[0332] The present invention provides the use of a compound of Formula I, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention in the preparation of anesthetic and sedative drugs.

[0333] This invention provides a compound of Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use as an anesthetic sedative, preferably for intravenous administration in the following clinical treatment regimens: preoperative sedation, anxiolytic and amnesic effects during surgery; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; as a component for induction and maintenance of general anesthesia before and / or simultaneously with the administration of other anesthetics and analgesics; ICU sedation, etc.

[0334] This invention provides a method of anesthesia and sedation comprising administration, preferably via intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or percutaneous route, of an effective amount of the compound or pharmaceutical composition of the invention. This method of anesthesia and sedation is preferably used for the following clinical treatment regimens: preoperative sedation, anxiolytic and amnesic effects during surgery; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; induction and maintenance of general anesthesia before and / or simultaneously with the administration of other anesthetics and analgesics; ICU sedation, etc.

[0335] The present invention provides a method for preparing the compound shown in Formula I above, comprising the following steps: esterifying 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and compound Ia to obtain the compound shown in Formula I;

[0336] Among them, L1 and R 1 Each is independently described as in any embodiment of the present invention.

[0337] This invention provides a compound represented by formula Ic;

[0338] R 1 ' is hydroxyl, halogen (e.g., bromine) or NH2 substituted with an amino protecting group (e.g., NHBoc);

[0339] Wherein, M1, M2, M3, L1, X1, and X2 are independently as described in any embodiment of the present invention.

[0340] In one embodiment, the compound represented by formula Ic is

[0341] The present invention provides a method for preparing the compound of formula I from the compound of formula Ic, comprising the following steps: hydrolyzing, esterifying (e.g., esterifying with compound Ia) or coupling reaction of the compound of formula Ic in a solvent to obtain the compound of formula I.

[0342] The terms used in this invention are explained as follows; terms not specifically explained are interpreted according to the conventional understanding and knowledge in the art:

[0343] Those skilled in the art will understand that, according to convention in the art, the structural formulas used to describe the functional groups in this invention... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0344] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0345] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0346] The terms “substituted” or “replaced by” refer to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The terms “optionally substituted” or “optionally replaced by” mean that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on a chemically feasible basis.

[0347] In this paper, the numerical ranges defined in the substituents, such as 1-3, 1-6, 3-7, 4-9, 4-10, 4-6, etc., indicate integers within that range. For example, 1-6 represents 1, 2, 3, 4, 5, or 6.

[0348] The term "halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0349] The term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.

[0350] Term "C" 1-6"Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-3 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl. The alkyl group in this application is preferably C10. 1-3 alkyl.

[0351] The term "alkylene" refers to a divalent group formed by removing one hydrogen atom from the alkyl group. The "C"... 1-6 "alkylene" includes, but is not limited to: methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, etc.

[0352] Term "C" 1-6 "Alkoxy" refers to the group -OR, where R is C 1-6 Alkyl group. In some embodiments, C 1-3 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0353] Term "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" refers to an alkyl group that is substituted with one or more halogen groups. "C" 1-3 "Halogenated alkyl" refers to the above "C 1-3 "Alkyl" refers to an alkyl group that is substituted with one or more halogen groups. Exemplary alkyl halogens include, but are not limited to: -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, etc.

[0354] The term "3-7 membered cycloalkyl" refers to a saturated cyclic hydrocarbon group having 3 to 7 ring carbon atoms, including monocyclic, bicyclic, and tricyclic systems (preferably monocyclic), wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The 3-7 membered cycloalkyl group includes, but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0355] The term "heterocyclic group" refers to a 4- to 10 (e.g., 4-9) membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, including monocyclic, bicyclic, and tricyclic systems (preferably monocyclic), wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The heteroatoms of the heterocyclic group are independently selected from nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. The heterocyclic group may be a 4-10 membered heterocyclic alkyl (e.g., 4-9 membered heterocyclic alkyl) or a 4-10 membered heterocyclic alkenyl (e.g., 4-9 membered heterocyclic alkenyl). In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. The 4-9 membered heterocyclic alkyl groups include, but are not limited to: piperazinyl, morpholinyl, piperidinyl, azacyclic butyl, tetrahydropyrrolyl, thiomorpholinyl, etc. For example The 4-9 membered heterocyclic alkenyl groups include, but are not limited to: For example

[0356] "4-6 membered heteroaryl" refers to a 4n+2 aromatic ring system with a 4-6 membered ring containing a cyclic carbon atom and 1-3 heteroatoms, wherein the heteroatoms are oxygen, nitrogen, or sulfur. The 4-6 membered heteroaryl includes, but is not limited to, pyridyl.

[0357] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0358] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0359] The term "prevention" refers to reducing the risk of developing a disease.

[0360] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0361] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0362] The reagents and raw materials used in this invention are all commercially available.

[0363] The positive and progressive effects of this invention are as follows: the compound provided by this invention has one or more of the following advantages:

[0364] (1) The compounds of the present invention have good intravenous sedation and anesthesia effects.

[0365] (2) The compounds of the present invention have low drug accumulation and good tolerability.

[0366] (3) The compounds of the present invention have an anesthetic effect that is fast-acting and / or provides faster recovery.

[0367] (4) The compounds of the present invention have improved solubility and better drug-like properties. Detailed Implementation

[0368] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0369] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker Avance Neo 600MHz NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as the internal standard.

[0370] LCMS was determined using Waters ACQUITY UPLC.

[0371] High performance liquid chromatography (HPLC) was performed using a Thermo UltiMate 3000 liquid chromatograph with a Venusil ASB C18 (4.6*250mm, 5μm) column.

[0372] Thin-layer chromatography silica gel plates were prepared using West Asia Reagent GF254 silica gel plates.

[0373] Column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0374] The known starting materials used in this application can be synthesized using or according to methods known in the art, or can be purchased from companies such as Aladdin, Bidex Pharmaceuticals, WuXi AppTec, and Leyan Reagents.

[0375] The abbreviations used in this article have the following meanings:

[0376] HPLC: High Performance Liquid Chromatography

[0377] LCMS: Liquid Chromatography-Mass Spectrometry

[0378] ESI-MS: Electrospray ionization mass spectrometry

[0379] TLC: Thin-layer chromatography

[0380] 1 H NMR: Hydrogen nuclear magnetic resonance spectrum

[0381] DCM: Dichloromethane

[0382] HOBt: 1-Hydroxybenzotriazole

[0383] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0384] NBS: N-bromosuccinimide

[0385] NMP: N-methyl-2-pyrrolidone

[0386] n-BuLi: n-Butyllithium

[0387] DCC: N,N'-Dicyclohexylcarbodiimide

[0388] THF: Tetrahydrofuran

[0389] TEA: Triethylamine

[0390] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride

[0391] i-PrMgCl·LiCl: Isopropyl magnesium chloride-lithium chloride

[0392] DMSO: Dimethyl sulfoxide

[0393] PEG: Polyethylene Glycol

[0394] EA: Ethyl acetate

[0395] DIPEA: N,N-Diisopropylethylamine

[0396] MS: Mass Spectrometry

[0397] CPMI: N-(4-Carboxyphenyl)maleimide

[0398] CbzCl: Benzyl chloroformate

[0399] Pd / C: Palladium on Carbon Catalyst

[0400] PE: Petroleum ether

[0401] CMPI: 2-Chloro-1-methylpyridine iodide

[0402] m-CPBA: m-chloroperoxybenzoic acid

[0403] DIEA: N,N-Diisopropylethylamine

[0404] ACN: Acetonitrile

[0405] DMF: N,N-dimethylformamide

[0406] DMAP: 4-Dimethylaminopyridine

[0407] Example 1:

[0408] 1000 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid was weighed into a 100 mL single-necked flask. Cesium carbonate (919 mg, 1.2 eq) and acetonitrile (50 mL) were added and stirred until dissolved, resulting in a white turbid liquid. Then, 451 mg (1.2 eq) of fluoroiodomethane was weighed and added to the flask, and the mixture was stirred at room temperature. After the reaction was complete as monitored by MS, the solution was filtered through a 0.45 μm filter to obtain a colorless, transparent liquid. This liquid was concentrated and subjected to rapid column chromatography (EA: n-heptane = 10:1) to give compound 1 (1004.5 mg, 93.88% yield). ESI-MS m / z: 457.14 [M+H]+.

[0409] 1 H NMR(600MHz,DMSO-d6)δ8.81(d,J=5.1Hz,1H),8.15(d,J=7.9Hz,1H),8.04(t, J=7.8Hz,1H),7.77(dd,J=8.7,2.2Hz,1H),7.67(d,J=2.2Hz,1H),7.51(d,J=8 .7Hz,1H),7.40(d,J=1.3Hz,1H),7.27(s,1H),5.62(dd,J=17.1,2.0Hz,1H),5 .56–5.49(m,1H),4.44(dd,J=9.4,4.7Hz,1H),2.42–2.37(m,3H),2.33(s,4H).

[0410] Example 2:

[0411] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 270 mg (1.2 eq) of EDCI, 191 mg (1.2 eq) of HOBt·H2O, and 965 mg (10 eq) of 2,2-difluoroethanol. After stirring for 30 min, the mixture is moved to room temperature and the reaction solution is sky blue. After the reaction is complete, monitor by TLC (developing solvent: EA), concentrate and perform rapid column chromatography (EA: n-heptane = 10:1) to obtain RM-T05 (542.8 mg, 94.36% yield).

[0412] ESI-MS m / z: 489.09 [M+H] + .

[0413] 1 H NMR(600MHz,DMSO-d6)δ8.76(d,J=5.5Hz,1H),8.16(dd,J=8.2,4.4Hz,1H),8.0 0(t,J=7.7Hz,1H),7.77(dt,J=8.6,1.9Hz,1H),7.68(d,J=2.1Hz,1H),7.51(dd, J=8.7,3.1Hz,1H),7.42–7.38(m,1H),7.27(s,1H),5.86(t,J=4.0Hz,1H),4.42 (dd, J = 9.7, 4.6 Hz, 1H), 4.18 (tt, J = 13.9, 3.1 Hz, 2H), 2.39 (s, 3H), 2.33 (s, 4H).

[0414] Example 3:

[0415] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI, 6 mg (0.2 eq) of HOBt·H2O, and 71 mg (1.2 eq) of compound 3-a. Stir for 30 min and then move to room temperature to react. The reaction solution is pale blue. After the reaction is completed by MS monitoring, add purified water (10 mL * 3) to the reaction solution to wash, concentrate the organic phase, and obtain a pale blue oily substance 3-b.

[0416] Compound 3-b was dissolved using DCM (10 mL), and trifluoroacetic acid (1.0 mL) was added dropwise with stirring at room temperature. After the reaction was completed by MS monitoring, sodium bicarbonate solution was added, and the mixture was stirred until no bubbles were observed. The mixture was allowed to stand and separate into layers. The organic phase was separated, concentrated, and subjected to rapid column chromatography (EA: n-heptane = 10:1) to give compound 3 (98.3 mg, 77.85% yield, HPLC 96.93%).

[0417] ESI-MS m / z: 537.23 [M+H] + .

[0418] 1 H NMR (600MHz, DMSO-d6) δ8.56–8.52(m,1H),8.08(dq,J=8.0,1.3Hz,1H),7.94(td,J=7.7,1.7Hz,1H),7. 90–7.86(m,1H),7.66(dd,J=8.7,3.7Hz,1H),7.60(dd,J=2.4,1.1Hz,1H),7.50(ddd,J=7.5,4.8,1.2Hz ,1H),6.84–6.80(m,1H),6.61(s,1H),4.24(dd,J=12.6,3.6Hz,1H),4.16–4.10(m,1H),4.07(ddd,J=8. 1,5.8,2.5Hz,1H),4.03(q,J=7.1Hz,1H),2.78–2.67(m,2H),2.65–2.52(m,2H),2.30(d,J=1.1Hz,3H).

[0419] Example 4:

[0420] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 108 mg (1.2 eq), 13 mg (0.2 eq) of HOBt·H2O, and 203 mg (3.0 eq) of 1-(2-hydroxyethyl)-4-methylpiperazine. Stir for 30 min and then move to room temperature to react. After the reaction is completed by MS monitoring, concentrate and separate by thin-layer chromatography (developed with pure EA) to give compound 4 (57.1 mg, 22.07% yield, HPLC 98.51%).

[0421] ESI-MS m / z: 276.36 [M / 2+H] + .

[0422] 1 H NMR (600MHz, DMSO-d6) δ8.55 (dd, J=5.0, 1.7Hz, 1H), 8.08 (d, J=7.9Hz, 1H), 7. 95(td,J=7.7,1.8Hz,1H),7.89(dd,J=8.7,2.4Hz,1H),7.63–7.57(m,1H),7.3 5–7.27(m,2H),6.82(s,1H),4.15(t,J=5.8Hz,2H),4.07(dd,J=7.7,5.8Hz,1H ),2.70–2.65(m,2H),2.64–2.58(m,2H),2.50(p,J=1.8Hz,13H),2.30(s,3H).

[0423] Example 5:

[0424] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 108 mg (1.2 eq), 13 mg (0.2 eq) of HOBt·H2O, and 2-morpholinoethanol (203 mg, 3.0 eq). Stir for 30 min and then move to room temperature. After the reaction is completed by MS monitoring, concentrate and separate by thin-layer chromatography (developed with pure EA) to give compound 5 (82.4 mg, 33% yield, HPLC 96.27%).

[0425] ESI-MS m / z: 538.37 [M+H] + .

[0426] 1HNMR(600MHz,DMSO-d6)δ8.57–8.52(m,1H),8.09(dt,J=8.0,1.1Hz,1H),7.95(td,J=7.7,1.8Hz,1H ),7.88(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(ddd,J=7.5,4.8, 1.2Hz,1H),6.82(d,J=1.2Hz,1H),4.13(hept,J=5.7Hz,2H),4.06(dd,J=8.0,5.8Hz,1H),3.48(t,J =4.7Hz, 4H), 2.74–2.64 (m, 2H), 2.50 (p, J = 1.9Hz, 6H), 2.47 (t, J = 5.9Hz, 2H), 2.30 (d, J = 1.1Hz, 3H).

[0427] Example 6:

[0428] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 20 mL flask, add 5 mL of DCM and stir in an ice bath to dissolve. Then add 108.18 mg (1.2 eq) of EDCI and 13 mg (0.2 eq) of HOBt·H2O, rinse with 5 mL of DCM, and finally weigh (R)-(4-methylmorpholin-2-yl)methanol (73 mg, 1.2 eq) and rinse the flask wall with 3.5 mL of DCM. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3), concentrate to obtain compound 6 (121.3 mg, 47.93% yield, HPLC 91.79%). ESI-MS m / z: 269.91 [M / 2+H] + .

[0429] 1H NMR (600MHz, DMSO-d6) δ8.57–8.50(m,1H),8.08(d,J=7.8Hz,1H),7.95(td,J=7. 7,1.8Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.50(m,1H),7. 34–7.28(m,1H),6.82(s,1H),4.12–3.99(m,3H),3.86(d,J=77.2Hz,2H),3.60(d ,J=14.4Hz,1H),2.79–2.67(m,2H),2.50(p,J=1.9Hz,9H),2.30(d,J=1.1Hz,3H).

[0430] Example 7:

[0431] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 20 mL flask, add 5 mL of DCM and stir in an ice bath to dissolve. Then add 108 mg (1.2 eq) of EDCI and 13 mg (0.2 eq) of HOBt·H2O, rinse with 5 mL of DCM, and finally weigh (S)-(4-methylmorpholin-2-yl)methanol (73 mg, 1.2 eq) and rinse the flask wall with 3.5 mL of DCM. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3), concentrate to obtain compound 7 (60.3 mg, 23.83% yield, HPLC 97.49%). ESI-MS m / z: 269.94 [M / 2+H] + .

[0432] 1HNMR(600MHz,DMSO-d6)δ8.56–8.52(m,1H),8.10(ddt,J=8.0,4.1,1.1Hz,1H),7.95(tt,J=7.7,1.6Hz,1H),7.88(dd,J=8.7,2.4Hz,1 H),7.66(dd,J=8.7,2.0Hz,1H),7.61(dd,J=13.7,2.3Hz,1H),7.50(ddd,J=7.6,4.8,1.2Hz,1H),6.82(d,J=1.3Hz,1H),4.10–4.01(m ,2H),3.98(ddd,J=11.5,7.3,4.1Hz,1H),3.74–3.66(m,1H),3.58(dddd,J=16.0,12.6,8.4,5.2,2.5Hz,1H),3.43(td,J=11.2,2.5H z,1H),2.78–2.66(m,2H),2.65–2.57(m,2H),2.50(p,J=1.8Hz,2H),2.30(d,J=1.1Hz,3H),2.13(d,J=20.2Hz,3H),2.00–1.67(m,2H).

[0433] Example 8:

[0434] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 20 mL flask, add 5 mL of DCM and stir in an ice bath to dissolve. Then add 108 mg (1.2 eq) of EDCI and 13 mg (0.2 eq) of HOBt·H2O, rinse with 5 mL of DCM, and finally weigh 126 mg (1.5 eq) of 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide and rinse the flask wall with 3.5 mL of DCM. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3), concentrate to obtain compound 8 (147.5 mg, 53.51% yield, HPLC 97.92%).

[0435] ESI-MS m / z: 586.44 [M+H] + .

[0436] 1HNMR (600MHz, DMSO-d6) δ8.54 (ddd, J=4.8, 1.8, 0.9Hz, 1H), 8.09 (dt, J=7.9, 1.1Hz, 1H), 7.95 (td, J=7 .7,1.8Hz,1H),7.88(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.62(d,J=2.3Hz,1H),7.50(ddd,J =7.6,4.8,1.2Hz,1H),6.82(d,J=1.3Hz,1H),4.13(t,J=5.8Hz,2H),4.07(dd,J=7.8,5.9Hz,1H),3.05 –3.00(m,4H),2.95–2.89(m,4H),2.72(t,J=5.7Hz,2H),2.50(p,J=1.8Hz,4H),2.30(d,J=1.1Hz,3H).

[0437] Example 9:

[0438] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 20 mL flask, add 5 mL of DCM and stir in an ice bath to dissolve. Then add 108 mg (1.2 eq) of EDCI and 13 mg (0.2 eq) of HOBt·H2O, followed by rinsing with 5 mL of DCM. Finally, weigh 88 mg (1.5 eq) of 2-bromoethanol and rinse the flask walls with 3.5 mL of DCM. After the reaction is complete as monitored by MS, wash three times with purified water (10 mL x 3), concentrate, and obtain 9-a (156.3 mg, 62.48% yield, HPLC 90.78%) ESI-MS m / z: 531.29 [M+H). + .

[0439] Compound 9-a (150 mg, 1.0 eq) was weighed into a 20 mL single-necked flask, and acetonitrile (8 mL) was added and stirred to dissolve. The flask was placed in a parallel reactor at 40 °C, and triethylamine (57 mg, 2.0 eq), potassium carbonate (156 mg, 4.0 eq), and 2-oxa-6-azaspiro[3,3]heptane (84 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL) and stirred until the reaction was completed as monitored by MS (conversion ≥ 90%). The mixture was then filtered through a 0.45 μm filter and washed four times with saturated brine (10 mL * 4) to obtain the acetonitrile phase. The acetonitrile phase was concentrated to obtain compound 9 (163.2 mg, 96.35% yield, HPLC 92.79%).

[0440] ESI-MS m / z: 275.87 [M / 2+H] + .

[0441] 1 H NMR(600MHz,DMSO-d6)δ8.59–8.50(m,1H),8.09(d,J=7.9Hz,1H),7.95(td,J=7.8,1.8Hz,1H), 7.89(dd,J=8.7,2.3Hz,1H),7.67(d,J=8.8Hz,1H),7.61(d,J=2.3Hz,1H),7.50(ddd,J=7.6,4.8 ,1.2Hz,1H),6.82(d,J=1.3Hz,1H),4.54(d,J=1.2Hz,4H),4.06(dd,J=7.9,5.8Hz,1H),3.95(t d,J=5.3,3.0Hz,2H),3.26(s,4H),2.75–2.63(m,2H),2.51(p,J=1.8Hz,4H),2.34–2.26(m,3H).

[0442] Example 10:

[0443] Weigh 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid (300 mg, 1.0 eq) and N-p-carboxyphenylmaleimide (234 mg, 1.3 eq) into a 20 mL single-necked flask, add DCM (5 mL) and stir to dissolve. Then weigh hydroxymethyldioxacyclophenone (125 mg, 1.5 eq) and add it to the flask. Rinse with DCM (5 mL) and finally add DIPEA (273 mg, 3.0 eq). Stir the reaction at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with purified water (15 mL * 5) and concentrate to obtain compound 10 (367.1 mg, 99.06% yield, HPLC 100.00%).

[0444] ESI-MS m / z: 525.12 [M+H] + .

[0445] 1H NMR (600MHz, DMSO-d6) δ8.56–8.51(m,1H),8.11–8.05(m,1H),7.95(ddd,J=8.8,7.5,1.8Hz,1H ),7.88(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.61(dd,J=5.4,2.3Hz,1H),7.49(ddd,J= 7.5,4.8,1.2Hz,1H),6.82(s,1H),5.07–4.98(m,1H),4.55(dq,J=10.9,8.7Hz,1H),4.38–4.20 (m,3H),4.05(dt,J=23.5,7.0Hz,1H),2.83–2.65(m,2H),2.65–2.54(m,2H),2.34–2.22(m,3H).

[0446] Example 11

[0447] Weigh 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid (300 mg, 1.0 eq) and N-p-carboxyphenylmaleimide (234 mg, 1.3 eq) into a 20 mL single-necked flask. Add DCM (5 mL) and stir to dissolve. Then weigh 4-(hydroxymethyl)-5-methyl-[1,3]dioxanepenten-2-one (138 mg, 1.5 eq) and add to the flask. Rinse with DCM (5 mL). Finally, add DIPEA (273 mg, 3.0 eq) dropwise. Stir the reaction at room temperature until MS monitoring shows the reaction is complete (conversion ≥90%). Wash 5 times with purified water (15 mL * 5). Concentrate to obtain compound 11 (368.2 mg, 97.14% yield, HPLC). 96.75%.

[0448] ESI-MS m / z: 537.10 [M+H] + .

[0449] 1H NMR (600MHz, DMSO-d6) δ8.56–8.51(m,1H),8.08(d,J=8.0Hz,1H),7.94(td,J=7.8 ,1.8Hz,1H),7.88(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz, 1H),7.49(ddd,J=7.6,4.7,1.2Hz,1H),6.85–6.79(m,1H),4.97(s,2H),4.06(dd,J =8.0,5.9Hz,1H),2.81–2.68(m,2H),2.65–2.53(m,2H),2.30(s,3H),2.14(s,3H).

[0450] Example 12

[0451] NBS (16.7 g, 93.9 mmol, 1.00 eq) was added to a solution of compound 12-1 (12.5 g, 93.9 mmol, 1.00 eq) in acetonitrile (120 mL). The mixture was stirred at 0 °C for 0.5 h. LC-MS showed that compound 12-1 had reacted completely. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give a brown oily compound 12-2 (13.5 g, 67.6% yield, HPLC 99.6%).

[0452] ESI-MS m / z: 213.9 [M / 2+H] + .

[0453] Compound 12-2 (5.00 g, 23.6 mmol, 1.00 eq), Zn(CN)2 (5.54 g, 47.2 mmol, 2.99 mL, 2.00 eq), Zn (154 mg, 2.36 mmol, 0.10 eq), tri-tert-butylphosphine palladium (1.20 g, 2.36 mmol, 0.10 eq), and NMP (50.0 mL) were added to a reaction flask, degassed, and purged three times with nitrogen. The mixture was then stirred at 90 °C under a nitrogen atmosphere for 2 h. LC-MS showed that compound 12-2 was completely consumed. After cooling, the mixture was diluted with ammonia (50.0 mL) at 0 °C and extracted with ethyl acetate (50.0 mL × 2). The organic layers were washed with brine (50.0 mL × 2), and the combined organic layers were dried and concentrated. Further purification by column chromatography yielded a white solid compound 12-3 (2.80 g, 74.0% yield, HPLC 98.6%).

[0454] ESI-MS m / z: 159.1 [M / 2+H] +

[0455] Under nitrogen atmosphere, 2-bromopyridine (6.43 g, 40.7 mmol, 3.88 mL, 2.30 eq) was dissolved in toluene (28.0 mL), and n-BuLi (2.5 M, 16.3 mL, 2.30 eq) was added dropwise to the solution below -65 °C. After stirring at -65 °C for 30 min, a solution of compound 12-3 (2.80 g, 17.7 mmol, 1.00 eq) was added dropwise to the solution below -65 °C. After the addition was complete, the mixture was stirred at -65 °C for 30 min. Then the temperature was raised to 0 °C. The mixture was stirred at 0 °C for another 2 h. LCMS showed that compound 12-3 was completely consumed. The reaction mixture was quenched at 0 °C with 30.0 mL of saturated ammonium chloride, then diluted with 30.0 mL of ethyl acetate and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a brown colloidal compound 12-4 (2.00 g, 45.0% yield, HPLC 94.8%).

[0456] ESI-MS m / z: 239.1 [M / 2+H] +

[0457] DCC (1.97 g, 9.57 mmol, 1.00 eq) was added to a solution of compounds 12-4 (1.90 g, 7.97 mmol, 1.20 eq) in DCM (40.0 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed that compound 12-4 was completely consumed. The reaction mixture was quenched with 30.0 mL of water at 20 °C, followed by extraction with DCM (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give compound 12-6 (6.50 g, crude) as a yellow solid.

[0458] ESI-MS m / z: 604.3 [M / 2+H] +

[0459] Triethylamine (1.89 g, 18.6 mmol, 2.50 eq) was added to a solution of compound 12-6 (4.50 g, 7.45 mmol, 1.00 eq) in acetonitrile (40.0 mL). The mixture was stirred at 40 °C for 12 hours. Compound 12-6 was completely consumed by LCMS. The reaction mixture was concentrated under reduced pressure to give compound 12-7 (2.90 g, crude product) as a yellow solid.

[0460] ESI-MS m / z: 382.1 [M / 2+H] +

[0461] Ammonium acetate (1.17 g, 15.2 mmol, 2.00 eq) was added to a solution of compound 12-7 (2.90 g, 7.60 mmol, 1.00 eq) in acetic acid (20.0 mL). The mixture was stirred at 20 °C for 2 hours. LC-MS showed that compound 12-7 was completely consumed. The reaction mixture was cooled to 0 °C and the pH was adjusted to 10 with 2 M sodium hydroxide (aq). It was then diluted with 30.0 mL of ethyl acetate and extracted with ethyl acetate (30.0 mL × 3). The combined organic matter was washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give compound 12-8 (1.77 g, 62.9% yield, HPLC 98.2%) as a yellow solid.

[0462] ESI-MS m / z: 364.1 [M / 2+H] +

[0463] A mixture of sodium carbonate (437 mg, 4.13 mmol, 3.00 eq) and phosphorus pentasulfide (917 mg, 4.13 mmol, 3.00 eq) in 1,2-dichloroethane (5.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 1 hour under a nitrogen atmosphere. A solution of compound 12-8 (500 mg, 1.38 mmol, 1.00 eq) in 1,2-dichloroethane (3.00 mL) was then added. The mixture was stirred at 20 °C for 15 hours. LC-MS showed that compound 12-8 had been completely consumed. The reaction mixture was quenched with 10.0 mL of water and then extracted with dichloromethane (8.00 mL × 3). The combined organic compounds were washed with brine (6.00 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give a yellow solid compound 12-9 (270 mg, 51.3% yield, HPLC 99.2%).

[0464] ESI-MS m / z: 380.0 [M / 2+H] +

[0465] 2,2-Dimethoxypropyl-1-amine (691 mg, 5.80 mmol, 10.0 eq) was added to a solution of compound 12-9 (220 mg, 580 μmol, 1.00 eq) in THF (3.00 mL). The mixture was stirred at 70 °C for 12 h. LC-MS showed that compound 12-9 reacted completely. The reaction mixture was concentrated under reduced pressure to give compound 12-10 (300 mg, crude) as a yellow oil.

[0466] ESI-MS m / z: 465.2 [M / 2+H] +

[0467] To a MeOH solution of compound 12-10 (300 mg, 646 μmol, 1.00 eq) in 3.00 mL of MeOH, HCl / MeOH (2 M, 3.87 mL, 12.0 eq) was added. The mixture was stirred at 20 °C for 2 hours. LCMS showed that compound 12-10 was completely consumed. After concentration under reduced pressure, the compound was purified by pre-HPLC column chromatography to give a white solid compound 12-11 (100 mg, 38.3% yield, HPLC 99.0%).

[0468] ESI-MS m / z: 401.1 [M / 2+H] +

[0469] 1 H NMR: (400MHz, DMSO-d6) δ8.50(d,J=4.4Hz,1H),8.02(d,J=8.0Hz,1H),8.02(td,J=7.6,1.6Hz,1H),7.51(s,1H),7.44-7.7.47(m,4H) ,7.18(s,1H),6.77(s,1H),3.95(t,J=6.0Hz,1H),3.60(s,3H),2.85-3.08(m,4H),2.57-2.68(m,4H),2.30(s,3H),2.03-2.15(m,2H).

[0470] Sodium hydroxide (47.9 mg, 1.20 mmol, 2.00 eq) was added to a solution of compound 12-11 (240 mg, 599 μmol, 1.00 eq) in methanol (2.80 mL) and water (0.70 mL). The mixture was stirred at 40 °C for 3 hours. LC-MS showed that compound 12-11 was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC column chromatography to give compound 12-12 (210 mg, 81.0% yield, HPLC 100%) as a white solid.

[0471] ESI-MS m / z: 387.1 [M / 2+H] +

[0472] To a DCM solution (2.00 mL) of compound 12-12 (100 mg, 259 μmol, 1.00 eq), N-(2-hydroxyethyl)carbamate tert-butyl ester (83.4 mg, 517 μmol, 2.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (264 mg, 1.04 mmol, 4.00 eq) and triethylamine (209 mg, 2.07 mmol, 8.00 eq) were added. The mixture was stirred at 20 °C for 12 hours. LC-MS showed that compound 12-12 reacted completely. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give a brown oily compound 12-13 (200 mg, crude product).

[0473] ESI-MS m / z: 530.3 [M / 2+H] +

[0474] Trifluoroacetic acid (194 mg, 1.70 mmol, 6.00 eq) was added to a solution of compounds 12-13 (150 mg, 283 μmol, 1.00 eq) in dichloromethane (3.00 mL). The mixture was stirred at 20 °C for 1 hour. LC-MS showed that compounds 12-13 were completely consumed. The reaction mixture was concentrated under reduced pressure and purified by pre-HPLC column chromatography to give a pale yellow gel-like compound 12 (100 mg, 77.4% yield, HPLC 94.2%).

[0475] ESI-MS m / z: 430.2 [M / 2+H] +

[0476] 1 H NMR: (400MHz, MeOD) δ8.54-8.57(m,1H),8.00-8.07(m,2H),7.73(s,1H),7. 56-7.60(m,1H),7.45(d,J=1.2Hz,1H),7.29(s,1H),4.30-4.42(m,3H),3.2 5(t,J=5.2Hz,2H),3.19(t,J=7.6Hz,1H),3.01-3.13(m,2H),2.91-2.97(m, 2H),2.75-2.86(m,2H),2.60-2.67(m,1H),2.51(s,3H),2.16-2.27(m,2H).

[0477] Example 13

[0478] To a solution of compound 12-12 (200 mg, 517 μmol, 1.00 eq) in DCM (3.00 mL), 2-morpholinoethanol (102 mg, 776 μmol, 1.50 eq), 2-chloro-1-methylpyridin-1-onium iodide (529 mg, 2.07 mmol, 4.00 eq), and triethylamine (419 mg, 4.14 mmol, 8.00 eq) were added. The mixture was stirred at 20 °C for 1.5 h. LC-MS showed that compound 12-12 was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC column chromatography to give a yellow solid, compound 13 (120 mg, 46.0% yield, HPLC 99.0%).

[0479] ESI-MS m / z: 500.2 [M / 2+H] +

[0480] 1 H NMR: (400MHz, MeOD) δ8.49 (d, J = 4.8 Hz, 1H), 7.94-7.99 (m, 2H), 7.49-7.52 (m, 2H), 7.13 (s, 1H), 6.91 (s, 1H), 4.41 (t, J = 5. 2Hz,2H),4.08-5.12(m,1H),3.81(t,J=4.8Hz,4H),2.75-3.18(m,13H),2.62-2.68(m,1H),2.41(s,3H),2.03-2.21(m,2H).

[0481] Example 14

[0482] NIS (23.7 g, 105 mmol, 1.00 eq) was added to a solution of compound 12-1 (14.0 g, 105 mmol, 1.00 eq) in acetonitrile (120 mL). The mixture was stirred at 0 °C for 0.5 h. LC-MS showed that compound 12-1 had reacted completely. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give a brown oily compound 14-1 (13.0 g, 47.7% yield, HPLC 100%).

[0483] ESI-MS m / z: 259.8 [M+H] +

[0484] Compound 14-1 (13.0 g, 50.1 mmol, 1.00 eq) was dissolved in 100 mL of methanol, followed by the addition of TEA (18.3 g, 180 mmol, 3.60 eq) and Pd(dppf)Cl2 (3.67 g, 5.02 mmol, 0.10 eq). The mixture was degassed and purged three times with nitrogen. The mixture was then degassed again, purged three times with CO, and stirred at 80 °C under CO (50 PSI) for 16 hours. LC-MS showed that compound 14-1 was completely consumed. The mixture was concentrated under reduced pressure and then purified by column chromatography to give compound 14-2 (8.50 g, 82.9% yield, HPLC 93.6%) as a white solid.

[0485] ESI-MS m / z: 192.1 [M+H] +

[0486] Compound 14-2 (9.50 g, 49.7 mmol, 1.00 eq) was dissolved in methanol (76.0 mL) and H₂O (19.0 mL), followed by the addition of NaOH (3.97 g, 99.4 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 hours. TLC showed that compound 14-2 was completely consumed. The methanol was removed by concentration under reduced pressure. The pH was adjusted to 4 by adding 2 M HCl. The mixture was extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (40.0 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 14-3 (8.60 g, 93.5% yield, HPLC 95.7%).

[0487] ESI-MS m / z: 178.0 [M+H] +

[0488] A mixture of compound 14-3 (6.80 g, 38.4 mmol, 1.00 eq) and acetic anhydride (39.2 g, 384 mmol, 10.0 eq) was degassed and purged three times with nitrogen. The mixture was then stirred at 140 °C for 12 hours under nitrogen atmosphere. LC-MS showed that compound 14-3 was completely consumed. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give compound 14-4 (7.30 g, 35.6 mmol, 92.8% yield, HPLC 98.2%) as a pale yellow solid.

[0489] ESI-MS m / z: 201.9 [M+H] +

[0490] Under nitrogen protection, at -70 °C, i-PrMgCl·LiCl (1.3 M, 41.9 mL, 1.50 eq) was added to a THF (70.0 mL) solution of compound 14-4 (7.30 g, 36.3 mmol, 1.00 eq) and compound 14-5 (8.40 g, 43.5 mmol, 1.20 eq). The mixture was heated to 20 °C and stirred for 1 hour. LC-MS showed that compound 14-4 was completely consumed. The reaction was quenched with NH4Cl (70.0 mL) and extracted with EtOAc (70.0 mL × 3). The combined organic layers were washed with water (50.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography gave compound 14-6 (6.30 g, 43.4% yield) as a yellow solid.

[0491] ESI-MS m / z: 338.0 [M+Na] +

[0492] HCl (12M, 20.0mL, 12.0eq) was added to an ethanol (60.0mL) solution of compound 14-6 (6.30g, 20.0mmol, 1.00eq). The mixture was stirred at 100°C for 2 hours. LCMS showed that compound 14-6 was completely consumed. The reaction mixture was cooled to 0°C and the pH was adjusted to 10 with 2M NaOH (aqueous solution). The mixture was then diluted with ethyl acetate and extracted with ethyl acetate (30.0mL × 3). The combined organic layers were washed with brine (20.0mL × 2), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography to give a yellow solid, compound 14-7 (4.50g, 73.4% yield, HPLC 89.0%).

[0493] ESI-MS m / z: 273.9 [M+H] +

[0494] Compound 14-7 (4.50 g, 16.5 mmol, 1.00 eq) and compound 12-5 (7.58 g, 19.7 mmol, 1.20 eq) were mixed in dichloromethane (45.0 mL) at 20 °C, followed by the addition of DCC (4.08 g, 19.8 mmol, 1.20 eq). The solution was stirred at 20 °C for 12 h under a nitrogen atmosphere. Compound 14-7 was confirmed to be reacted completely by LCMS. The reaction mixture was quenched by the addition of water (70.0 mL) and then extracted with dichloromethane (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 14-8 (6.00 g, 52.9% yield, HPLC 92.7%) as a yellow solid.

[0495] ESI-MS m / z: 639.2 [M+H] +

[0496] Triethylamine (2.38 g, 23.5 mmol, 3.27 mL, 2.50 eq) was added to a solution of compound 14-8 (6.00 g, 9.39 mmol, 1.00 eq) in ACN (60.0 mL). The mixture was stirred at 40 °C for 12 hours. LC-MS showed that compound 14-8 was completely consumed. The solution was concentrated under reduced pressure to give compound 14-9 (4.00 g, crude product) as a yellow solid.

[0497] ESI-MS m / z: 417.1 [M+H] +

[0498] NH4OAc (1.48 g, 19.2 mmol, 2.00 eq) was added to a solution of compound 14-9 (4.00 g, 9.61 mmol, 1.00 eq) in AcOH (40.0 mL). The mixture was stirred at 50 °C for 12 hours. LC-MS showed that compound 14-9 was completely consumed. The mixture was purified by concentrated column chromatography under reduced pressure to give a yellow solid of compound 14-9 (1.24 g, 31.0% yield, HPLC 95.8%).

[0499] ESI-MS m / z: 399.1 [M+H] +

[0500] A mixture of sodium carbonate (910 mg, 8.58 mmol, 3.00 eq) and phosphorus pentasulfide (1.91 g, 8.58 mmol, 3.00 eq) in 1,2-dichloroethane (10.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 1 hour under a nitrogen atmosphere. A solution of compound 14-10 (1.14 g, 2.86 mmol, 1.00 eq) in 1,2-dichloroethane (10.00 mL) was then added. The mixture was stirred at 20 °C for 11 hours. LC-MS showed that compound 14-10 was completely consumed. The reaction mixture was quenched with 20.0 mL of water and then extracted with dichloromethane (20.00 mL × 3). The combined organic compounds were washed with brine (15.00 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give a yellow solid compound 14-11 (850 mg, 71.2% yield, HPLC 99.3%).

[0501] ESI-MS m / z: 415.0 [M+H] +

[0502] To a solution of compound 14-11 (630 mg, 1.52 mmol, 1.00 eq) in THF (3.00 mL), 2,2-dimethoxypropyl-1-amine (905 mg, 7.60 mmol, 5.00 eq) was added. The mixture was stirred at 70 °C for 12 hours. LC-MS showed that compound 14-11 reacted completely. The reaction mixture was concentrated under reduced pressure to give compound 14-12 (760 mg, crude product), a yellow oil.

[0503] ESI-MS m / z: 500.3 [M+H] +

[0504] To a MeOH solution of compound 14-12 (760 mg, 1.52 mmol, 1.00 eq) in 5.00 mL of MeOH, HCl / MeOH (2 M, 9.13 mL, 12.0 eq) was added. The mixture was stirred at 20 °C for 2 hours. LC-MS showed that compound 14-12 was completely consumed. The solvent was removed by concentration under reduced pressure. The solution was diluted with H₂O (5.00 mL) and the pH was adjusted to 10 with 2 M NaOH (aqueous solution). The residue was diluted with ethyl acetate (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid, compound 14-13 (630 mg, 95.1% yield).

[0505] ESI-MS m / z: 436.1 [M+H] +

[0506] Sodium hydroxide (116 mg, 2.89 mmol, 2.00 eq) was added to a methanol (4.00 mL) and water (1.00 mL) solution of compound 14-13 (630 mg, 1.45 mmol, 1.00 eq). The mixture was stirred at 40 °C for 3 hours. LC-MS showed that compound 14-13 was completely consumed. The solvent was removed by concentration under reduced pressure. The mixture was diluted with water (10.0 mL) and the pH was adjusted to 4 with 2 M HCl (aqueous solution). The reaction mixture was filtered, and the filter cake was washed with water. The filter cake was concentrated under reduced pressure to give a yellow solid, compound 14-14 (550 mg, 89.7% yield, HPLC 99.4%).

[0507] ESI-MS m / z: 422.2 [M+H] +

[0508] To a DCM solution of compound 14-14 (590 mg, 1.40 mmol, 1.00 eq) in 6.00 mL of DCM, 2-bromoethanol (210 mg, 1.68 mmol, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (1.07 g, 4.20 mmol, 3.00 eq), and triethylamine (850 mg, 8.40 mmol, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 hours. LCMS showed that compound 14-14 was completely consumed. The reaction mixture was quenched with 5.00 mL of H₂O, and then extracted with DCM (5.00 mL × 3). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give a yellow colloidal compound 14-15 (630 mg, 84.5% yield, HPLC 99.2%).

[0509] ESI-MS m / z: 528.1 [M+H] +

[0510] Sodium iodide (42.6 mg, 284 μmol, 1.50 eq) and potassium carbonate (131 mg, 946 μmol, 5.00 eq) were added to a solution of compounds 14-15 (100 mg, 189 μmol, 1.00 eq) in DMF (1.00 mL). The mixture was stirred at 20 °C for 12 h. LC-MS showed that compounds 14-15 were completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was pre-purified by high performance liquid chromatography to give compound 14 as a white solid (85.0 mg, 153 μmol, 80.9% yield, HPLC 98.8%).

[0511] ESI-MS m / z: 549.3 [M+H] +

[0512] 1 H NMR: (400MHz, MeOD) δ7.46-7.54(m,2H),7.17(s,1H),7.05(t,J=8.4Hz,2H),6.89(s,1H),4.38-4.42(m,2H),4.09-4.13(m,1H),3.91(s,1H),3. 33-3.43(m,4H),2.99-3.20(m,4H),2.90-2.95(m,2H),2.61-2.79(m,4H ),2.36(s,3H),2.12-2.21(m,2H),1.99-2.05(m,2H),1.74-1.84(m,2H).

[0513] Example 15

[0514] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 20 mL flask, add 5 mL of DCM and stir in an ice bath to dissolve. Then add 108.18 mg (1.2 eq) of EDCI and 12.70 mg (0.2 eq) of HOBt·H2O, followed by rinsing with 5 mL of DCM. Finally, weigh 102.36 mg (1.5 eq) of 3-(4-morpholino)-1-propanol and rinse the flask walls with 3.5 mL of DCM. After the reaction is complete as monitored by MS, wash three times with purified water (10 mL x 3). Concentrate the organic phase at 45 °C to obtain 15 (74.80 mg, 28.81% yield, HPLC 98.63%) solid.

[0515] ESI-MS m / z: 276.92 [M / 2+H] + .

[0516] 1 HNMR (600MHz, DMSO-d6) δ8.54 (ddd, J=4.9, 1.7, 0.9Hz, 1H), 8.10 (dt, J=8.0, 1.1Hz, 1H), 7. 94(td,J=7.7,1.8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3 Hz,1H),7.50(ddd,J=7.5,4.8,1.2Hz,1H),6.82(d,J=1.2Hz,1H),4.12–3.99(m,3H),3.53( t,J=4.7Hz,4H),2.50(p,J=1.9Hz,10H),2.30(d,J=1.1Hz,3H),1.68(dq,J=8.5,6.7Hz,2H).

[0517] Example 16

[0518] Weigh 400 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and 116.08 mg (2.2 eq) of ground KOH into a 100 mL single-necked flask. Add 10 mL of DCM and stir. Immediately add 2.5 mL of purified water and stir vigorously for 30 min. Weigh 382 mg (2.0 eq) of TMSCF2Br ((bromodifluoromethyl)trimethylsilane) into the flask and stir until the reaction is complete as monitored by MS. Add 10 mL of saturated NaCl solution to the reaction solution and stir for 10 min. Allow to stand and separate the phases. Extract the aqueous phase once with 10 mL of acetonitrile. Combine the acetonitrile phases, remove water with anhydrous sodium sulfate, and concentrate at 45 °C to obtain compound 16. The crude product was prepared and lyophilized to give compound 16 (brown solid, 53.68 mg, 13.50% yield). ESI-MS m / z: 475.22 [M+H] + .

[0519] Example 17

[0520] Weigh 300 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 15 mL of DCM and stir to dissolve. Under ice bath conditions, add 162.18 mg (1.2 eq) of EDCI·HCl, 114.31 mg (1.2 eq) of HOBt·H2O, and 451.62 mg (10 eq) of 2-fluoroethanol. Stir for 30 min and then move to room temperature to react. The reaction solution is pale yellow. After the reaction was completed under TLC monitoring (developing solvent: EA), 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a pale yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) yielded compound 17 (pale yellow solid, 276.1 mg, 83.09% yield, HPLC 95.51%).

[0521] ESI-MS m / z: 471.19 [M+H] + .

[0522] 1H NMR(500MHz,Chloroform-d)δ8.61–8.51(m,1H),8.17(d,J=7.9Hz,1H),7.79(td,J=7.3,1.5Hz,1H),7.71(dd,J=8.6,2.3Hz,1H),7.65(d,J=2.3Hz,1H ),7.38–7.25(m,3H),6.86(s,1H),4.56(dt,J=47.4,4.2Hz,2H),4.31(dt, J=28.6,4.2Hz,2H),4.05(d,J=8.0Hz,1H),2.94–2.73(m,4H),2.34(s,3H).

[0523] Example 18

[0524] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 28 mg (1.2 eq) of trifluoroethanol. Stir for 30 min and then move to room temperature to react. The reaction solution is a yellow transparent solution. After the reaction is completed by MS monitoring, add purified water (10 mL * 3) to the reaction solution and wash three times. Retain the organic phase, mix with silica gel, and concentrate at 45 °C to obtain a pale yellow silica gel powder. Automated column chromatography gradient purification is used to separate compound 18 (pale yellow solid, 60.3 mg, 50.55% yield, HPLC 93.44%).

[0525] ESI-MS m / z: 507.16 [M+H] + .

[0526] Example 19

[0527] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 268.06 mg (10.0 eq) of 1,1,1-trifluoroisopropanol. Stir for 30 min and then move to room temperature to react. The reaction solution is an orange-yellow transparent solution. After the reaction was completed under MS monitoring, purified water (10 mL * 3) was added to the reaction solution and the mixture was washed three times. The organic phase was retained, mixed with silica gel, and concentrated at 45 °C to obtain a pale yellow silica gel powder. The powder was purified and separated by column chromatography (developing solvent: EA:PE = 10:1) to give compound 19 (yellow oil, 32.60 mg, 26.61% yield, HPLC 90.71%). ESI-MS m / z: 521.23 [M+H] + .

[0528] Example 20

[0529] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 270.5 mg (1.2 eq) of EDCI·HCl, 190.68 mg (1.2 eq) of HOBt·H2O, and 1.976 g (10 eq) of hexafluoroisopropanol. Stir for 30 min and then move to room temperature to react. The reaction solution turns blue. After the reaction was complete under TLC monitoring (developing solvent: EA), 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a blue silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) yielded compound 20 (pale blue oily liquid, 639.3 mg, 94.57% yield, HPLC 94.22%). ESI-MS m / z: 575.07 [M+H] + .

[0530] 1HNMR(500MHz, CDCl3)δ1.65-1.73(m,2H),1.96-2.08(t,2H),2.35(s,3H),4.03-4.06(m,1H),5.75-5.80(m,1H),6.86(s,1H),7.3 0(d,J=5Hz,1H),7.35-7.37(m,1H),7.64(s,1H),7.72-7.74(m,1H),7.79-7.83(m,1H),8.15(d,J=10Hz,1H),8.57(d,J=5Hz,1H).

[0531] Example 21

[0532] Weigh 300 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 15 mL of DCM and stir to dissolve. Under ice bath conditions, add 162.18 mg (1.2 eq) of EDCI·HCl, 114.31 mg (1.2 eq) of HOBt·H2O, and 409.46 mg (10 eq) of cyclopropanol. Stir for 30 min and then move to room temperature to react. The reaction solution is pale yellow. After the reaction was completed under TLC monitoring (developing solvent: EA), 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a pale yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) yielded compound 21 (pale yellow solid, 223 mg, 67.93% yield, HPLC 99.00%).

[0533] ESI-MS m / z: 465.20 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ8.56(d,J=4.7Hz,1H),8.18(d,J=7.9Hz,1H),7.87–7.61(m,3H),7.31(dt,J= 24.7, 6.4Hz, 2H), 6.86 (s, 1H), 4.21–3.98 (m, 2H), 2.79 (d, J = 43.7Hz, 4H), 2.33 (s, 3H), 0.78–0.57 (m, 4H).

[0534] Example 22

[0535] Weigh 300 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 15 mL of DCM and stir to dissolve. Under ice bath conditions, add 162.18 mg (1.2 eq) of EDCI·HCl, 114.31 mg (1.2 eq) of HOBt·H2O, and 550.53 mg (10 eq) of 3-fluoropropanol. Stir for 30 min and then move to room temperature to react. The reaction solution is pale yellow. After the reaction was complete under TLC monitoring (developing solvent: EA), 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a blue silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) yielded compound 22 (blue solid, 260.5 mg, 76.13% yield, HPLC 94.02%). ESI-MS m / z: 485.19 [M+H] + .

[0536] 1 H NMR(500MHz,Chloroform-d)δ8.57(dd,J=4.9,1.6Hz,1H),8.17(d,J=7.9Hz,1H),7.79(td,J=7.8,1 .8Hz,1H),7.71(dd,J=8.7,2.3Hz,1H),7.65(d,J=2.3Hz,1H),7.34(dd,J=7.6,4.9Hz,1H),7.30(d,J =8.7Hz,1H),6.87(s,1H),4.53(t,J=5.8Hz,1H),4.44(t,J=5.8Hz,1H),4.20(t,J=6.3Hz,2H),4.08– 4.02(m,1H),2.90–2.73(m,4H),2.34(s,3H),2.04–1.93(m,2H),1.27(d,J=2.7Hz,1H),1.19(s,1H).

[0537] Example 23

[0538] Weigh 300 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 15 mL of DCM and stir to dissolve. Under ice bath conditions, add 162.18 mg (1.2 eq) of EDCI·HCl, 114.31 mg (1.2 eq) of HOBt·H2O, and 979.88 mg (10 eq) of 3-bromopropanol. Stir for 30 min and then move to room temperature to react. The reaction solution is sky blue. After the reaction was complete under TLC monitoring (developing solvent: EA), 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a sky-blue silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) yielded compound 23 (blue oily liquid, 138.7 mg, 36.02% yield). ESI-MS m / z: 547.03 [M+H] + .

[0539] 1 H NMR(500MHz,Chloroform-d)δ7.26(s,2H),7.13–7.07(m,1H),6.97(t,J=8.7Hz,1H),6.73(dd,J=18.2,8.1Hz,2H),6.55(dd,J=16 .3,8.2Hz,2H),4.59(dd,J=21.6,8.2Hz,1H),3.21(s,2H),3.13(s,2H),2.96(s,4H),2.39(d,J=6.6Hz,3H),1.27(d,J=9.0Hz,2H).

[0540] Example 24

[0541] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 25 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 305 mg (10 eq) of 3,3,3-trifluoropropane-1,2-diol. Stir for 30 min and then move to room temperature to react. After the reaction is complete, monitor by TLC (developing solvent: EA). Add 1 g of silica gel to the reaction solution, concentrate and stir at 45 °C to obtain a pale yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 1:1) gives compound 24 (pale yellow oily liquid, 124.5 mg, 98.54% yield). ESI-MS m / z: 537.16 [M+H] + .

[0542] 1 H NMR (600MHz, DMSO-d6) δ8.59–8.55(m,1H),8.11(dd,J=7.9,1.3Hz,1H),7.99(qd,J=8.2,2.0Hz,2H),7.83( d,J=8.7Hz,1H),7.76–7.69(m,1H),7.62–7.57(m,2H),7.55(ddd,J=7.7,4.8,1.2Hz,1H),7.46–7.37(m,1H) ,7.34–7.27(m,2H),6.61(s,1H),4.33(d,J=8.1Hz,1H),4.26(dq,J=12.3,4.7Hz,2H),4.15(td,J=8.2,7.3, 3.4Hz,1H),2.78(dqd,J=16.2,8.7,8.0,4.4Hz,1H),2.73–2.63(m,2H),2.50(p,J=1.9Hz,2H),2.38(s,3H).

[0543] Example 25

[0544] Weigh 250 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 135 mg (1.2 eq) of EDCI·HCl, 95 mg (1.2 eq) of HOBt·H2O, and 800 mg (10 eq) of 4,4-difluorocyclohexanol. Stir for 30 min and then move to room temperature to react. After the reaction was complete under TLC monitoring (developing solvent: EA), 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a pale yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) yielded compound 25 (yellow oily liquid, 129.6 mg, 40.56% yield, HPLC 98.56%). ESI-MS m / z: 543.23 [M+H] + .

[0545] 1H NMR (600MHz, DMSO-d6) δ8.58(d,J=4.8Hz,1H),8.13(d,J=7.9Hz,1H),8.06–7.96(m,2H),7.86(d,J=8 .8Hz,1H),7.75(d,J=2.3Hz,1H),7.56(dd,J=7.6,4.8Hz,1H),7.47(d,J=7.8Hz,2H),7.11(d,J=7.7Hz ,3H),4.91(dq,J=7.2,3.8Hz,1H),4.37(dd,J=9.3,4.9Hz,1H),3.69(td,J=7.6,3.8Hz,2H),2.80–2.5 9(m,2H),2.40(s,3H),2.29(s,3H),1.81(dqt,J=17.9,13.3,6.8Hz,4H),1.70(pd,J=7.7,4.2Hz,4H).

[0546] Example 26

[0547] Weigh 250 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 135 mg (1.2 eq) of EDCI·HCl, 95 mg (1.2 eq) of HOBt·H2O, and 1.0 g (10 eq) of 4-(trifluoromethyl)cyclohexanol. Stir for 30 min and then move to room temperature to react. After the reaction was complete under TLC monitoring (developing solvent: EA), 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a pale yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) yielded compound 26 (yellow oily liquid, 139.8 mg, 41.36% yield, HPLC 98.85%). ESI-MS m / z: 575.26 [M+H] + .

[0548] 1H NMR (600MHz, DMSO-d6) δ8.59(d,J=4.8Hz,1H),8.13(d,J=7.9Hz,1H),8.07–7.96(m,2H),7.86(d,J= 8.7Hz,1H),7.77(d,J=2.3Hz,1H),7.56(dd,J=7.6,4.8Hz,1H),7.47(d,J=7.7Hz,2H),7.11(d,J=7.7 Hz,3H),4.65(dt,J=10.7,5.4Hz,1H),4.36(dd,J=9.6,5.0Hz,1H),3.35(tt,J=10.6,4.3Hz,1H),2. 78–2.58(m,2H),2.40(s,3H),2.29(s,3H),1.94–1.84(m,4H),1.73–1.51(m,4H),1.40–1.33(m,2H).

[0549] Example 27

[0550] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 3-trifluoromethylcyclohexanol (395.17 mg, 10 eq). Stir for 30 min and then move to room temperature to react. The reaction solution is orange-yellow. After the reaction was completed under MS monitoring, 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a yellow silica gel powder. Rapid column chromatography (EA:n-heptane = 10:1) yielded compound 27 (yellow oil, 57.5 mg, 42.52% yield, HPLC 90.15%). ESI-MS m / z: 575.28 [M+H] + .

[0551] Example 28

[0552] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 169.45 mg (10 eq) of cyclobutanol. Stir for 30 min and then move to room temperature. The reaction solution is orange-yellow. After the reaction is completed by MS monitoring, add 1-2 g of silica gel to the reaction solution, concentrate and mix at 45 °C to obtain yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) gives compound 28 (yellow oil, 55.10 mg, 48.91% yield, HPLC 97.35%). ESI-MS m / z: 479.24 [M+H] + .

[0553] 1 H NMR (600MHz, DMSO-d6) δ8.54(ddd,J=4.8,1.7,0.9Hz,1H),8.10(dt,J=7.9,1.1Hz,1H),7.95(td,J =7.8,1.8Hz,1H),7.88(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.50(d dd,J=7.5,4.7,1.2Hz,1H),6.82(d,J=1.2Hz,1H),4.96–4.87(m,1H),4.09–4.00(m,1H),2.72–2.6 1(m,2H),2.50(p,J=1.9Hz,6H),2.30(d,J=1.1Hz,3H),1.95(dddt,J=20.1,12.1,10.1,5.1Hz,2H).

[0554] Example 29

[0555] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 254 mg (10 eq) of 3,3-difluorocyclobutanol. Stir for 30 min and then move to room temperature to react. After the reaction is complete as monitored by MS, add 1-2 g of silica gel to the reaction solution, concentrate and mix at 45 °C to obtain yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) gives compound 29 (yellow oil, 64.20 mg, 53.84% yield, HPLC 96.69%). ESI-MS m / z: 515.20 [M+H] + .

[0556] Example 30

[0557] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 72.03 mg (2.0 eq) of 2,2,3,3-tetrafluorocyclobutanol. Stir for 30 min and then move to room temperature to react. After the reaction was completed under MS monitoring, 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a yellow silica gel powder. Rapid column chromatography (EA:n-heptane = 10:1) yielded compound 30 (yellow oil, 74.70 mg, 57.66% yield, HPLC 92.50%). ESI-MS m / z: 551.16 [M+H] + .

[0558] Example 31

[0559] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 107.04 mg (2.0 eq) of 3,3,4,4,5,5,5-heptafluoropentan-2-ol. Stir for 30 min and then move to room temperature to react. After the reaction was completed under MS monitoring, 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a yellow silica gel powder. Rapid column chromatography (EA:n-heptane = 10:1) yielded compound 31 (yellow oil, 35.90 mg, 24.59% yield, HPLC 92.99%). ESI-MS m / z: 621.25 [M+H] + .

[0560] Example 32

[0561] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 71.06 mg (2.0 eq) of 1,1,1-trifluoro-3-methylbut-2-ol. Stir for 30 min and then move to room temperature to react. After the reaction was completed under MS monitoring, 1-2 g of silica gel was added to the reaction solution, and the mixture was concentrated and stirred at 45°C to obtain a yellow silica gel powder. Rapid column chromatography (EA:n-heptane = 10:1) yielded compound 32 (yellow oil, 23.00 mg, 17.81% yield, HPLC 91.36%). ESI-MS m / z: 549.28 [M+H] + .

[0562] Example 33

[0563] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 108 mg (1.2 eq) of EDCI·HCl, 76 mg (1.2 eq) of HOBt·H2O, and 44 mg (2.0 eq) of 3-fluorocyclobutanol. Stir for 30 min and then move to room temperature to react. After the reaction is complete as monitored by MS, add 1-2 g of silica gel to the reaction solution, concentrate and mix at 45 °C to obtain yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) gives compound 33 (yellow oil, 102.9 mg, 44.02% yield, HPLC 94.53%). ESI-MS m / z: 497.26 [M+H] + .

[0564] Example 34

[0565] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 108 mg (1.2 eq) of EDCI·HCl, 76 mg (1.2 eq) of HOBt·H2O, and 66 mg (2.0 eq) of 3-trifluoromethylcyclobutanol. Stir for 30 min and then move to room temperature to react. After the reaction is complete as monitored by MS, add 1-2 g of silica gel to the reaction solution, concentrate and mix at 45 °C to obtain yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) gives compound 34 (yellow oil, 139.20 mg, 54.10% yield, HPLC 92.93%). ESI-MS m / z: 547.25 [M+H] + .

[0566] Example 35

[0567] Weigh 100 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 50 mL single-necked flask, add 10 mL of DCM and stir to dissolve. Under ice bath conditions, add 54 mg (1.2 eq) of EDCI·HCl, 38 mg (1.2 eq) of HOBt·H2O, and 145.86 mg (10 eq) of ethylene glycol. Stir for 30 min and then move to room temperature. The reaction solution is orange-yellow. After the reaction is completed by MS monitoring, add 1-2 g of silica gel to the reaction solution, concentrate and mix at 45 °C to obtain yellow silica gel powder. Rapid column chromatography (EA: n-heptane = 10:1) gives compound 35 (white oil, 58.5 mg, 53.04% yield, HPLC 100%). ESI-MS m / z: 469.30 [M+H] + .

[0568] Example 36

[0569] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 20 mL single-necked flask, add 5 mL of DCM, stir to dissolve, and then add 108.18 mg (1.2 eq) of EDCI·HCl, 12.70 mg (0.2 eq) of HOBt·H2O, 227.42 mg (3.0 eq) of N-Boc-ethanolamine, and 3 drops of triethylamine (catalytic amount) in sequence under ice bath. After stirring for 30 min, the mixture was moved to room temperature and the reaction solution was orange-yellow. After the reaction was completed by MS monitoring, the solution was concentrated at 45 °C and subjected to rapid column chromatography (EA: n-heptane = 10:1) to give compound 36-1 (blue solid, 174.60 mg, 79.27% ​​yield). ESI-MS m / z: 568.42 [M+H] + .

[0570] Compound 36-1 (174.60 mg, 1.0 eq) was dissolved in DCM (3.4 mL), stirred in an ice bath, and trifluoroacetic acid (1.05 g, 30.0 eq) was added using a syringe. The reaction solution turned purple. The reaction was continued in an ice bath until MS monitoring showed completion, then concentrated at 45 °C. Methyl ether was repeatedly added, and the mixture was concentrated multiple times until the sample became a solid, yielding compound 36 (blue viscous solid, 259.5 mg, 98.35% yield, HPLC 94.76%). ESI-MS m / z: 468.43 [M-TFA+H] + .

[0571] 1H NMR (600MHz, DMSO-d6) δ8.57(dt,J=4.7,1.4Hz,1H),8.09–8.07(m,1H),7.99–7.92(m,2H),7.74(d,J=8.7Hz,1H),7.68(d,J=2.3Hz,1H),7.53(dd d,J=7.5,4.8,1.2Hz,1H),7.07(s,1H),4.27–4.18(m,3H),3.11(p,J=5.6 Hz,2H),2.74–2.60(m,2H),2.50(p,J=1.9Hz,4H),2.34(d,J=1.1Hz,3H).

[0572] Example 37

[0573] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 108.18 mg (1.2 eq) of EDCI·HCl, 12.70 mg (0.2 eq) of HOBt·H2O, and 247.21 mg (3.0 eq) of 1-(Boc-amino)-2-propanol. Stir for 30 min and then move to room temperature to react. After the reaction was completed under MS monitoring, it was concentrated at 45°C to give compound 37-1 (a blue oily substance). This was dissolved in DCM (5 mL), followed by the addition of trifluoroacetic acid (3.0 mL). The mixture was stirred and reacted. After the reaction was completed under MS monitoring, it was concentrated and separated by TLC to give compound 37 (a pale blue solid, 25.2 mg, 12% yield, HPLC 92.37%). ESI-MS m / z: 482.32 [M+H] + .

[0574] Example 38

[0575] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 108.18 mg (1.2 eq) of EDCI·HCl, 12.70 mg (0.2 eq) of HOBt·H2O, and 247.21 mg (3.0 eq) of N-Boc-N-methylaminoethanol. Stir for 30 min and then move to room temperature to react. After the reaction was completed under MS monitoring, it was concentrated at 45°C to give compound 38-1 (blue oil). This was dissolved in DCM (5 mL), followed by the addition of trifluoroacetic acid (3.0 mL). The mixture was stirred and reacted. After the reaction was completed under MS monitoring, it was concentrated and separated by TLC to give compound 38 (white oil, 9.8 mg, 4% yield, HPLC 93.86%). ESI-MS m / z: 241.82 [M / 2+1] + .

[0576] Example 39

[0577] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 108.18 mg (1.2 eq) of EDCI·HCl, 76.25 mg (1.2 eq) of HOBt·H2O, and 2-diethylaminoethanol hydrochloride (216.77 mg (3.0 eq) and stir for 30 min. Then, move the mixture to room temperature. After the reaction is complete as monitored by MS, concentrate at 45 °C and separate by TLC (developed with pure EA) to give compound 39 (pale blue oil, 6.2 mg, 2.5% yield, HPLC 94.32%).

[0578] ESI-MS m / z: 439.30 (Since the LC-MS system uses methanol as the mobile phase, the synthesized compound undergoes transesterification with methanol during the injection process, and is shown as the molecular weight of methyl ester (remazolam)).

[0579] Example 40

[0580] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 100 mL single-necked flask, add 20 mL of DCM and stir to dissolve. Under ice bath conditions, add 108.18 mg (1.2 eq) of EDCI·HCl, 76.25 mg (1.2 eq) of HOBt·H2O, and 177.19 mg (3.0 eq) of 2-dimethylaminoethanol hydrochloride. Stir for 30 min and then move to room temperature to react. After the reaction is completed by MS monitoring, concentrate at 45 °C and separate by TLC (developed with pure EA) to give compound 40 (pale blue oil, 2.7 mg, 1.2% yield, HPLC 96.53%).

[0581] ESI-MS m / z: 439.34 (Since the LC-MS system uses methanol as the mobile phase, the synthesized compound undergoes transesterification with methanol during the injection process, and is shown as the molecular weight of methyl ester (remazolam)).

[0582] Example 41

[0583] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.30 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir at room temperature to dissolve. Then weigh N-(2-hydroxyethyl)piperidine (91.08 mg, 1.5 eq) and rinse the vial wall with 3.5 mL of DCM. Finally, add DIPEA (182.24 mg, 3.0 eq). The reaction solution turns brown. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3). Concentrate the organic phase at 45 °C to obtain compound 41 (brown oil, 226.70 mg, 89.91% yield, HPLC 95.20%). ESI-MS m / z: 268.89 [M / 2+H] + .

[0584] 1H NMR(600MHz,DMSO-d6)δ9.16(s,1H),8.55(ddd,J=4.8,1.7,0.9Hz,1H),8.06(dt,J=8.0,1.1Hz,1H) ,7.96(td,J=7.7,1.8Hz,1H),7.89(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.63–7.55(m,3H) ,7.51(ddd,J=7.5,4.8,1.2Hz,1H),7.34–7.27(m,3H),6.82(d,J=1.3Hz,1H),4.36(s,2H),4.09(dd ,J=7.8,6.0Hz,1H),2.93(s,2H),2.84–2.70(m,2H),2.50(p,J=1.8Hz,12H),2.31(d,J=1.1Hz,3H).

[0585] Example 42

[0586] Weigh 100.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (78.05 mg, 1.3 eq) into a 20 mL vial. Add 3 mL of DCM and stir at room temperature to dissolve. Then weigh 50.50 mg (1.5 eq) of 2-(4-methylpiperidin-1-yl)ethane-1-ol and rinse the vial wall with 1.5 mL of DCM. Finally, add 91.12 mg (3.0 eq) of DIPEA. The reaction solution turns brown. After the reaction is completed by MS monitoring, concentrate and perform rapid column chromatography (EA: n-heptane = 10:1) to give compound 42 (brown solid, 51.70 mg, 39.96% yield). ESI-MS m / z: 275.90 [M / 2+H] + .

[0587] 1H NMR(600MHz,DMSO-d6)δ9.24(s,1H),8.56(dt,J=4.7,1.3Hz,1H),8.10–8.04(m,1H),7.96(td,J=7.8,1.8 Hz,1H),7.92(dd,J=8.7,2.3Hz,1H),7.70(d,J=8.8Hz,1H),7.64(d,J=2.3Hz,1H),7.61–7.57(m,2H),7.5 2(ddd,J=7.6,4.8,1.2Hz,1H),7.35–7.27(m,3H),6.95(s,1H),4.37(t,J=5.2Hz,2H),4.03(q,J=7.1Hz,1 H),3.01–2.86(m,2H),2.50(p,J=1.8Hz,12H),2.32(s,3H),1.17(t,J=7.1Hz,1H),0.89(d,J=6.5Hz,3H).

[0588] Example 43

[0589] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.30 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir at room temperature to dissolve. Then weigh 202.07 mg (3.0 eq) of 2-(1-methylpiperidin-4-yl)ethanol and rinse the vial wall with 3.5 mL of DCM. Finally, add 182.24 mg (3.0 eq) of DIPEA. The reaction solution turns brown. After the reaction is completed by MS monitoring, concentrate and perform rapid column chromatography (EA: n-heptane = 10:1) to give compound 43 (brown solid, 29.90 mg, 11.55% yield). ESI-MS m / z: 275.96 [M / 2+H] + .

[0590] 1H NMR (600MHz, DMSO-d6) δ9.08(s,1H),8.55(dt,J=4.8,1.3Hz,1H),8.08(d,J=7.9Hz,1H),7.95(td ,J=7.8,1.8Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.67(d,J=8.7Hz,1H),7.63–7.57(m,3H),7.50(d dd,J=7.5,4.8,1.2Hz,1H),7.34–7.26(m,3H),6.84(s,1H),4.08(td,J=6.2,3.0Hz,3H),2.90–2.8 2(m,2H),2.74–2.72(m,3H),2.50(p,J=1.9Hz,12H),2.31(d,J=1.1Hz,3H),1.11(d,J=2.6Hz,1H).

[0591] Example 44

[0592] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.30 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir at room temperature to dissolve. Then weigh 100.98 mg (1.5 eq) of (1-ethylpiperidin-4-yl)methanol and rinse the vial wall with 3.5 mL of DCM. Finally, add 182.24 mg (3.0 eq) of DIPEA. The reaction solution turns brown. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3). Concentrate the organic phase at 45 °C to obtain compound 44 (gray foamy solid, 200.00 mg, 77.29% yield, HPLC 96.62%). ESI-MS m / z: 275.94 [M / 2+H] + .

[0593] 1H NMR(600MHz,DMSO-d6)δ8.55(dt,J=4.7,1.4Hz,1H),8.10–8.05(m,1H),7.95(td,J=7.7,1.8Hz,1H), 7.89(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.63–7.58(m,3H),7.50(ddd,J=7.6,4.8,1.2Hz, 1H),7.34–7.27(m,3H),6.82(d,J=1.3Hz,1H),4.07(dd,J=7.8,5.9Hz,1H),3.99–3.88(m,2H),2.77– 2.67(m,2H),2.50(p,J=1.8Hz,12H),2.30(d,J=1.1Hz,3H),1.18(q,J=6.3,4.9Hz,3H),1.11(s,1H).

[0594] Example 45

[0595] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.30 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir at room temperature to dissolve. Then weigh 91.08 mg (1.5 eq) of 1-methyl-4-piperidinemethanol and rinse the vial wall with 3.5 mL of DCM. Finally, add 182.24 mg (3.0 eq) of DIPEA. The reaction solution turns brown. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3). Concentrate the organic phase at 45 °C to give compound 45 (blue foamy solid, 158.40 mg, 62.82% yield, HPLC 94.72%). ESI-MS m / z: 268.92 [M / 2+H] + .

[0596] 1H NMR(600MHz,DMSO-d6)δ9.07(s,1H),8.56(dt,J=4.7,1.4Hz,1H),8.11–8.06(m,1H),7.96(td,J=7.8,1 .8Hz,1H),7.92(dd,J=8.8,2.3Hz,1H),7.70(d,J=8.7Hz,1H),7.65(d,J=2.3Hz,1H),7.62–7.57(m,2H), 7.52(ddd,J=7.6,4.8,1.2Hz,1H),7.35–7.27(m,3H),6.97(s,1H),4.18–4.08(m,1H),3.94(d,J=6.0Hz ,2H),2.81–2.71(m,4H),2.50(p,J=1.9Hz,8H),2.32(s,3H),1.99(s,1H),1.83(dd,J=14.2,3.5Hz,3H).

[0597] Example 46

[0598] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.30 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir at room temperature to dissolve. Then weigh 81.19 mg (1.5 eq) of N-(2-hydroxyethyl)-pyrrolidine and rinse the vial wall with 3.5 mL of DCM. Finally, add 182.24 mg (3.0 eq) of DIPEA. The reaction solution turns brown. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3). Concentrate the organic phase at 45 °C to obtain compound 46 (dark green foamy solid, 178.90 mg, 72.86% yield, HPLC 95.73%). ESI-MS m / z: 261.91 [M / 2+H] + .

[0599] 1H NMR (600MHz, DMSO-d6) δ9.53(s,1H),8.56(dd,J=4.8,1.8Hz,1H),8.07(d,J=8.0Hz,1H),7.96(td, J=7.7,1.8Hz,1H),7.91(dd,J=8.7,2.4Hz,1H),7.68(d,J=8.7Hz,1H),7.63(d,J=2.3Hz,1H),7.60 –7.58(m,2H),7.53–7.50(m,1H),7.34–7.28(m,3H),6.96–6.79(m,1H),4.33(q,J=4.5Hz,2H),4.1 2(t,J=7.0Hz,1H),2.77(dddd,J=44.7,16.2,9.0,6.1Hz,2H),2.50(p,J=1.9Hz,12H),2.31(s,3H).

[0600] Example 47

[0601] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.30 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir at room temperature to dissolve. Then weigh 81.20 mg (1.5 eq) of 1-methyl-4-piperidinol and rinse the vial wall with 3.5 mL of DCM. Finally, add 182.24 mg (3.0 eq) of DIPEA. The reaction solution turns brown. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3). Concentrate the organic phase at 45 °C to give compound 47 (blue foamy solid, 145.60 mg, 59.29% yield, HPLC 94.18%). ESI-MS m / z: 261.92 [M / 2+H] + .

[0602] 1H NMR(600MHz, DMSO-d6)δ9.31(d,J=24.2Hz,1H),8.55(dd,J=4.7,1.5Hz,1H),8.10–8.03(m,1H),7.96( tt,J=7.8,1.4Hz,1H),7.90(dt,J=8.8,1.9Hz,1H),7.68(d,J=8.7Hz,1H),7.63(dd,J=8.1,2.4Hz,1H), 7.61–7.58(m,2H),7.51(ddd,J=7.6,4.8,1.2Hz,1H),7.35–7.25(m,3H),6.88(s,1H),5.01(p,J=3.3Hz ,1H),4.11(dt,J=13.6,6.7Hz,1H),2.78(dd,J=12.5,4.7Hz,3H),2.50(p,J=1.9Hz,12H),2.31(s,3H).

[0603] Example 48

[0604] Weigh 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid (300.00 mg, 1.0 eq) and CPMI (234.15 mg, 1.3 eq) into a 20 mL single-necked flask, add DCM (10 mL) and stir to dissolve. Then weigh N-(2-hydroxyethyl)morpholine (155.80 mg, 1.5 eq) and add it to the flask. Rinse with DCM (5 mL), and finally add DIPEA (273.36 mg, 3.0 eq). Stir the reaction at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with purified water (15 mL * 5), and concentrate at 45 °C to obtain compound 48 (brown oil, 377.00 mg, 96.38% yield, HPLC 90.87%). ESI-MS m / z: 277.90 [M / 2+H] + .

[0605] 1HNMR (600MHz, DMSO-d6) δ8.54 (dd, J=4.4, 1.7Hz, 1H), 8.09 (d, J=8.0Hz, 1H), 7.95 (td, J=7.7, 1.7Hz,1H),7.89(dd,J=8.8,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.62(d,J=2.3Hz,1H),7.50(d dd,J=7.7,4.7,1.3Hz,1H),6.82(d,J=1.5Hz,1H),4.12(tt,J=12.0,5.8Hz,2H),4.08–4.04(m ,1H),2.69(dt,J=14.3,8.5Hz,2H),2.64–2.58(m,4H),2.52–2.48(m,8H),2.34–2.27(m,3H).

[0606] Example 49

[0607] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid into a 20 mL flask, add 5 mL of DCM and stir in an ice bath to dissolve. Then add 108.18 mg (1.2 eq) of EDCI·HCl and 12.70 mg (0.2 eq) of HOBt·H2O, rinse with 5 mL of DCM, and finally weigh 88.10 mg (1.5 eq) of 2-bromoethanol and rinse the flask wall with 3.5 mL of DCM. After the reaction is completed by MS monitoring, wash three times with purified water (10 mL * 3), concentrate the organic phase at 45 °C to obtain compound 49-1 (blue solid, 156.30 mg, 62.48% yield, HPLC 90.78%). ESI-MS m / z: 531.29 [M+H] + .

[0608] 1H NMR(600MHz,DMSO-d6)δ8.59(dt,J=4.7,1.4Hz,1H),8.13(dt,J=8.0,1.1Hz,1H),8.04–7 .96(m,2H),7.86(d,J=8.8Hz,1H),7.76(d,J=2.3Hz,1H),7.61–7.58(m,2H),7.56(ddd,J= 7.6,4.8,1.2Hz,1H),7.53(s,1H),7.34–7.26(m,4H),4.41(dd,J=9.4,5.1Hz,1H),4.38(t d,J=5.3,1.9Hz,2H),3.67(t,J=5.5Hz,2H),2.50(p,J=1.9Hz,4H),2.40(d,J=1.2Hz,3H).

[0609] Compound 49-1 (50.00 mg, 1.0 eq) was weighed into a 20 mL single-necked flask, and acetonitrile (5 mL) was added and stirred to dissolve. The flask was placed in a parallel reactor at 40 °C, and triethylamine (19.02 mg, 2.0 eq), potassium carbonate (51.96 mg, 4.0 eq), and (S)-pyrrolidine-2-ylmethanol (28.51 mg, 3.0 eq) were added sequentially. The mixture was stirred until the reaction was complete as monitored by MS (conversion ≥90%). The mixture was then filtered through a 0.45 μm filter and washed three times with purified water (10 mL * 3) and once with saturated brine (10 mL) to obtain the acetonitrile phase. The acetonitrile phase was concentrated at 45 °C to obtain compound 49 (yellow oil, 51.70 mg, 99.55% yield, HPLC 90.13%). ESI-MS m / z: 276.86 [M / 2+H] + .

[0610] 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.9Hz,1H),8.09(d,J=7.9Hz,1H),7.95(td,J=7.7,1.8Hz,1H),7 .89(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.8Hz,1H),7.63–7.59(m,1H),7.50(dd,J=7.5,4.9Hz,1H),6 .82(s,1H),4.37(t,J=5.6Hz,1H),4.13(dt,J=12.0,6.3Hz,1H),4.08–4.01(m,2H),3.05–2.94(m,2 H),2.74–2.55(m,2H),2.51(p,J=1.8Hz,6H),2.44(h,J=5.3Hz,1H),2.30(s,3H),1.80–1.40(m,4H).

[0611] Example 50

[0612] Compound 49-1 (150.00 mg, 1.0 eq) was weighed into a 20 mL single-necked flask, and acetonitrile (7.5 mL) was added and stirred to dissolve. The flask was placed in a parallel reactor at 40 °C, and triethylamine (57.30 mg, 2.0 eq), potassium carbonate (155.79 mg, 4.0 eq), and (S)-pyrrolidine-3-methanol (85.52 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2.5 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥90%). The mixture was then filtered through a 0.45 μm filter and washed four times with saturated brine (10 mL * 4) to obtain the acetonitrile phase. The acetonitrile phase was concentrated at 45 °C to give compound 50 (pale yellow solid, 140.00 mg, 89.92% yield, HPLC 95.29%). ESI-MS m / z: 276.85 [M / 2+H] + .

[0613] 1 H NMR (600MHz, DMSO-d6) δ8.54(ddd,J=4.8,1.7,0.9Hz,1H),8.09(dt,J=8.0,1.1Hz,1H),7.94(td,J=7.7,1.8Hz,1 H),7.88(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(ddd,J=7.6,4.8,1.2Hz,1H), 6.82(d,J=1.3Hz,1H),4.55(s,1H),4.10(t,J=5.9Hz,2H),4.06(dd,J=8.0,5.8Hz,1H),3.24(q,J=10.0,8.5Hz,2 H),2.74–2.65(m,2H),2.62–2.47(m,8H),2.30(d,J=1.1Hz,3H),1.79–1.63(m,2H),1.30(dq,J=12.5,6.5Hz,1H).

[0614] Example 51

[0615] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL single-necked flask. Add 5 mL of DCM and stir at room temperature for 10 min to dissolve. Then weigh 102 mg (1.5 eq) of (1,4-dimethylpiperazin-2-yl)methanol and add it to the flask. Rinse with 3.5 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with 15 mL of purified water and concentrate the organic phase to obtain compound 51 (pink solid, 199.8 mg, 77.08% yield, UPLC 96.02%). ESI-MS m / z: 276.29 [M / 2+H] + .

[0616] 1 H NMR (600MHz, DMSO-d6) δ8.56–8.52(m,1H),8.10(dd,J=8.0,6.6Hz,1H),7.95(tt,J=7.8,1.5Hz,1H),7.88(ddd,J=8.7,2.4 ,1.1Hz,1H),7.66(dd,J=8.7,5.1Hz,1H),7.60(dd,J=19.7,2.3Hz,1H),7.50(ddd,J=7.6,4.8,1.2Hz,1H),6.83–6.79(m,1H ),4.12(ddd,J=18.0,11.4,3.9Hz,1H),4.06(dd,J=8.5,5.5Hz,1H),3.98(ddd,J=22.7,11.4,5.7Hz,1H),3.34(s,1H),2.7 0(q,J=7.5Hz,2H),2.63–2.55(m,2H),2.50(p,J=1.8Hz,2H),2.30(s,3H),2.12(d,J=5.0Hz,4H),2.08(s,3H),2.04(s,3H).

[0617] Example 52

[0618] Compound 49-1 (300 mg, 1.0 eq) was weighed and dissolved in acetonitrile (5 mL). The solution was heated and stirred in a parallel reactor at 40 °C. Triethylamine (114 mg, 2.0 eq), potassium carbonate (312 mg, 4.0 eq), and (R)-(morpholino-2-yl)methanol (198 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL) and stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered, washed (with 10 mL of purified water * 3), and concentrated to obtain crude compound 52. Compound 52-AcOH (white solid, 183.6 mg, 57.30% yield, UPLC 97.84%) was prepared, separated, and lyophilized. ESI-MS m / z: 284.80 [(M-AcOH) / 2+H] + .

[0619] 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.9Hz,1H),8.09(d,J=8.0Hz,1H),7.94(td,J=7.8,1.8Hz,1H),7.88(dd,J= 8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.51–7.47(m,1H),6.82(d,J=1.5Hz,1H),4.64( s,1H),4.13(hept,J=5.8Hz,2H),4.06(dd,J=7.9,5.9Hz,1H),3.69(ddd,J=11.1,3.3,1.6Hz,1H),3.40–3.29( m,4H),2.79–2.74(m,2H),2.72–2.65(m,2H),2.62(dd,J=11.7,9.2Hz,2H),2.50(p,J=1.9Hz,4H),2.30(s,3H).

[0620] Example 53

[0621] Compound 49-1 (300 mg, 1.0 eq) was weighed and dissolved in acetonitrile (5 mL). The solution was heated and stirred in a parallel reactor at 40 °C. Triethylamine (114 mg, 2.0 eq), potassium carbonate (468 mg, 6.0 eq), and (S)-morpholine-2-methanol hydrochloride (260 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL) and stirred until MS monitoring showed completion (conversion ≥90%). The mixture was then filtered, washed (with 10 mL of purified water * 3), and concentrated to obtain crude compound 53. Compound 53-AcOH (white solid, 146 mg, 45.57% yield, UPLC 97.64%) was prepared, separated, and lyophilized. ESI-MS m / z: 284.73 [(M-AcOH) / 2+H] + .

[0622] 1 H NMR (600MHz, DMSO-d6) δ8.56–8.52(m,1H),8.09(d,J=8.0Hz,1H),7.94(td,J=7.7,1.8Hz,1H),7.88( dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.53–7.46(m,1H),6.82(d,J=1.4 Hz,1H),4.63(s,1H),4.14(qt,J=11.5,5.8Hz,2H),4.06(dd,J=7.9,5.9Hz,1H),3.69(ddd,J=11.2,3. 2,1.6Hz,1H),3.33(s,4H),2.81–2.75(m,2H),2.71–2.58(m,4H),2.50(p,J=1.9Hz,4H),2.30(s,3H).

[0623] Example 54

[0624] Compound 49-1 (300 mg, 1.0 eq) was weighed and dissolved in acetonitrile (5 mL). The solution was heated and stirred in a parallel reactor at 40 °C. Triethylamine (114 mg, 2.0 eq), potassium carbonate (468 mg, 6.0 eq), and 4-methoxypiperidine hydrochloride (257 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL) and stirred until MS monitoring showed completion (conversion ≥90%). The mixture was then filtered, washed (with 10 mL of purified water * 3), and concentrated to obtain crude compound 54. Compound 54-AcOH (white solid, 204.90 mg, 64.17% yield, UPLC 99.51%) was prepared, separated, and lyophilized. ESI-MS m / z: 283.78 [(M-AcOH) / 2+H]+ .

[0625] 1 H NMR (600MHz, DMSO-d6) δ8.58–8.51(m,1H),8.09(d,J=8.0Hz,1H),7.94(td,J=7.8,1.8Hz,1H),7.88(dd,J=8 .7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.54–7.48(m,1H),6.82(d,J=1.4Hz,1H),4.13– 4.02(m,3H),3.18(s,3H),3.09(tt,J=8.7,4.0Hz,1H),2.68(q,J=6.9Hz,2H),2.61(dt,J=14.6,7.3Hz,2H), 2.50(p,J=1.8Hz,4H),2.30(s,3H),2.06(t,J=11.0Hz,2H),1.76–1.69(m,2H),1.32(tt,J=12.2,6.4Hz,2H).

[0626] Example 55

[0627] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL single-necked flask. Add 7 mL of DCM and stir at room temperature for 10 min to dissolve. Then weigh 106 mg (1.5 eq) of triethanolamine and add it to the flask. Rinse with 3 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with 15 mL of purified water. Concentrate the organic phase to obtain crude compound 55. Prepare, separate and freeze-dry to obtain compound 55-AcOH (white solid, 47.40 mg, 18.12% yield, UPLC 97.94%).

[0628] ESI-MS m / z:278.70[(M-AcOH) / 2+H] + .

[0629] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=7.9Hz,1H),7.94(td,J=7.7,1.8Hz ,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.4Hz,1H),7.49(dd,J= 7.6,4.9Hz,1H),6.81(s,1H),4.31(s,2H),4.05(q,J=5.9Hz,3H),3.37(t,J=6.3Hz,4H),2.7 3–2.66(m,2H),2.65–2.56(m,2H),2.54(t,J=6.3Hz,4H),2.50(p,J=1.9Hz,2H),2.30(s,3H).

[0630] Example 56

[0631] Compound 49-1 (300 mg, 1.0 eq) was weighed and dissolved in acetonitrile (5 mL). The solution was heated and stirred in a parallel reactor at 40 °C. Triethylamine (114 mg, 2.0 eq), potassium carbonate (468 mg, 6.0 eq), and 3-methoxyazacyclobutane (209 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL) and stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered, washed (with 10 mL of purified water * 3), and concentrated to obtain crude compound 56. Compound 56-AcOH (white solid, 166.80 mg, 54.96% yield, UPLC 94.35%) was prepared, separated, and lyophilized. ESI-MS m / z: 269.78 [(M-AcOH) / 2+H] + .

[0632] 1H NMR (600MHz, DMSO-d6) δ8.54(dd,J=5.0,1.8Hz,1H),8.09(d,J=8.0Hz,1H),7.94(td,J=7.8,1.8Hz,1H),7.89(d d,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.62(d,J=2.3Hz,1H),7.49(ddd,J=7.5,4.8,1.2Hz,1H),6.81(d,J= 1.4Hz,1H),4.05(dd,J=8.0,5.8Hz,1H),3.97(hept,J=5.7Hz,2H),3.87(p,J=5.8Hz,1H),3.45(q,J=6.5Hz,2H), 3.33(s,2H),3.10(s,3H),2.77(ddd,J=8.2,5.8,2.4Hz,2H),2.70–2.65(m,2H),2.62–2.53(m,2H),2.30(s,3H).

[0633] Example 57

[0634] Compound 49-1 (150 mg, 1.0 eq) was weighed and dissolved in acetonitrile (7.5 mL). The solution was heated and stirred in a parallel reactor at 40 °C. Triethylamine (57 mg, 2.0 eq), potassium carbonate (234 mg, 6.0 eq), and 7-oxa-2-azaspiro[3,5]nonane hydrochloride (138 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2.5 mL) and stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered, washed (with 10 mL of purified water * 3), and concentrated to obtain crude compound 57. Compound 57-AcOH (white solid, 5 mg, 3.07% yield, UPLC 98.07%) was prepared, separated, and lyophilized. ESI-MS m / z: 289.77[(M-AcOH) / 2+H] + .

[0635] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=7.9Hz,1H),7.94(td,J=7.8,1.8Hz,1H),7. 89(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(dd,J=7.5,4.8Hz,1H), 6.81(s,1H),4.06(dd,J=7.9,5.7Hz,1H),3.97(hept,J=5.7Hz,2H),3.42(t,J=5.3Hz,4H),2.93(s,4 H),2.67(q,J=7.1Hz,2H),2.65–2.58(m,2H),2.56(t,J=5.7Hz,2H),2.30(s,3H),1.59–1.54(m,4H).

[0636] Example 58

[0637] A mixture of compound 58-1 (3.00 g, 26.8 mmol, 1.00 eq) and morpholine (2.80 g, 32.1 mmol, 2.83 mL, 1.20 eq) was degassed and purged three times with nitrogen, then stirred at 20 °C for 12 h under a nitrogen atmosphere. LCMS showed detection of the desired m / z (Rt = 0.133 min, MS = 200.1, M+H). + The reaction mixture was concentrated under reduced pressure to give a colorless oily compound 58-2 (5.40 g, crude product).

[0638] ESI-MS m / z: 200.1 [M+H] +

[0639] At 0 °C, under nitrogen atmosphere, NaH (442 mg, 11.1 mmol, 60% purity, 1.10 eq) was added dropwise to a THF (20.0 mL) solution of compound 58-2 (2.00 g, 10.04 mmol, 1.00 eq). After addition, the mixture was stirred at 20 °C for 0.5 h, and then Cb2Cl (1.88 g, 11.0 mmol, 1.58 mL, 1.10 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. LCMS showed that compound 58-2 was completely consumed. A new peak was observed on LCMS, and the desired m / z (Rt = 0.331 min, MS = 334.2, M+H) was detected. +The reaction mixture was quenched with NH4Cl (20.0 mL) at 0 °C, then diluted with EtOAc (15.0 mL), and extracted with EtOAc (10.0 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to rapid silica gel chromatography (…). 6.00g Purification was performed by silica gel rapid column chromatography with a gradient elution of 0–8% ethyl acetate / petroleum ether at 40 mL / min, and by TLC (petroleum ether / ethyl acetate = 5:1, Rf = 0.32) to give a white solid compound 58-3 (2.62 g, 6.97 mmol, 69.4% yield, 88.7% purity). The residues were separated by chiral NP-HPLC (conditions: column: DAICL CHIRALCEL OJ (250 mm * 50 mm, 10 μm); mobile phase: [hexane-ethanol (0.1% IPAm)]; B%: 7%, isocratic elution mode), yielding a yellow oily compound 58-4 (retention time Rt = 1.631 min, 1.00 g, 2.99 mmol, 41.9% yield, 99.8% purity) and a yellow oily compound 59-1 (retention time Rt = 1.822 min, 1.10 g, 2.87 mmol, 39.9% yield, 87.0% purity). ESI-MS M / Z: 334.2 [M+H] +

[0640] Under a nitrogen atmosphere, Pd / C (351 mg, 330 μmol, 10% purity, 0.10 eq) was added to a MeOH (10.0 mL) solution of compound 58-4 (1.00 g, 2.99 mmol, 1.00 eq). The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 20 °C under hydrogen for 3 h. LCMS showed that compound 58-4 was completely consumed. A new peak was observed on LCMS, and the desired m / z (Rt = 0.094 min, MS = 199.7, M+H) was detected. + The reaction mixture was filtered and concentrated under reduced pressure to give a yellow oily compound 58-6 (550 mg, 2.76 mmol, 83.7% yield) ESI-MS m / z: 199.7 [M+H] +

[0641] 1 H NMR: (400MHz, CDCl3) δ4.15-4.21(m,1H),3.76-3.84(m,4H),2.70-2.80(m,4H),2.60-2.68(m,2H).

[0642] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.10 mg, 1.3 eq) into a 20 mL single-necked flask. Add 7 mL of DCM and stir at room temperature for 10 min to dissolve. Then weigh 140.40 mg (1.5 eq) of compound 58-6 and add it to the flask. Rinse with 3 mL of DCM. Finally, add 121.49 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with 15 mL of purified water and concentrate at 45 °C to obtain compound 58 (brown solid, 281.90 mg, 98.90% yield, HPLC 97.36%). ESI-MS m / z: 303.85 [M / 2+H] + .

[0643] 1 H NMR(600MHz,DMSO-d6)δ8.61(ddd,J=4.8,1.8,0.9Hz,1H),8.17(dt,J=8.1,1.2Hz,1H),8.01(t d,J=7.8,1.8Hz,1H),7.98–7.91(m,1H),7.72(dd,J=12.0,8.7Hz,1H),7.64(dd,J=11.6,2.3Hz ,1H),7.56(ddd,J=7.6,4.7,1.3Hz,1H),6.88(d,J=1.2Hz,1H),5.75–5.58(m,1H),4.22–4.08( m,1H),2.90(hept,J=9.0,8.5Hz,2H),2.75–2.59(m,4H),2.58–2.49(m,8H),2.39–2.35(m,3H).

[0644] Example 59

[0645] Under a nitrogen atmosphere, Pd / C (303 mg, 285 μmol, 10% purity, 0.10 eq) was added to a MeOH (10.0 mL) solution of compound 59-1 (950 mg, 2.85 mmol, 1.00 eq). The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 20 °C under hydrogen for 3 h. LCMS showed that compound 59-1 was completely consumed. A new peak was observed on LCMS, and the desired m / z (Rt = 0.423 min, MS = 199.7, M+H) was detected. +The reaction mixture was filtered and concentrated under reduced pressure to give a yellow oily compound 59-2 (560 mg, 2.81 mmol, 98.6% yield).

[0646] 1 H NMR: (400MHz, CDCl3) δ4.12-4.17(m,1H),3.74-3.83(m,4H),2.67-2.77(m,4H),2.57-2.64(m,2H).

[0647] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.10 mg, 1.3 eq) into a 20 mL single-necked flask. Add 7 mL of DCM and stir at room temperature for 10 min to dissolve. Then weigh 59-2 (140.40 mg, 1.5 eq) and add it to the flask. Rinse with 3 mL of DCM. Finally, add 121.49 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with purified water (15 mL * 5) and concentrate at 45 °C to obtain compound 59 (brown solid, 285.00 mg, 99.99% yield, HPLC 92.45%). ESI-MS m / z: 303.85 [M / 2+H] + .

[0648] 1 H NMR (600MHz, DMSO-d6) δ8.55(dd,J=4.8,1.9Hz,1H),8.10(dd,J=10.2,7.9Hz,1H),7.95(ddd, J=10.0,5.0,2.1Hz,1H),7.92–7.85(m,1H),7.66(dd,J=11.9,8.7Hz,1H),7.58(dd,J=11.6,2 .3Hz,1H),7.54–7.46(m,1H),6.83(d,J=1.4Hz,1H),5.61(q,J=6.8Hz,1H),4.17–4.02(m,1H) ,2.91–2.73(m,2H),2.62(dqd,J=27.6,13.1,7.1Hz,3H),2.50(p,J=1.8Hz,8H),2.31(s,3H).

[0649] Example 60

[0650] Weigh 100.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (78.05 mg, 1.3 eq) into a 20 mL single-necked flask. Add 5 mL of DCM and stir at room temperature for 10 min to dissolve. Then weigh 88.20 mg (1.5 eq) of 60-1 into the flask and rinse with 5 mL of DCM. Finally, add 91.12 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Then wash 5 times with purified water (15 mL * 5) and concentrate at 45 °C to obtain compound 60-2 (brown oil, 206.40 mg, HPLC 74.76%, no purification required for the next step).

[0651] ESI-MS m / z: 657.46 [M+H] + .

[0652] Compound 60-2 (206.40 mg, 1.0 eq) was dissolved in DCM (10 mL) in a 20 mL single-necked flask, and trifluoroacetic acid (0.5 mL) was added dropwise. The mixture was stirred at room temperature until the reaction was completed as monitored by MS (conversion ≥90%, trifluoroacetic acid can be added as needed). The mixture was then concentrated at 45 °C to obtain crude compound 60 (brown oil, 349.80 mg, HPLC 78.76%). The crude compound 60 was separated by rapid column chromatography (EA:PE = 10:1) to obtain compound 60 (pale yellow oil, 132.20 mg, 78.37% yield, UPLC 97.65%).

[0653] ESI-MS m / z: 537.36 [M+H] + .

[0654] 1 H NMR (600MHz, DMSO-d6) δ8.55(dd,J=4.7,1.6Hz,1H),8.09(d,J=8.0Hz,1H),7.95(td,J=7.8,1.7Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.67(d,J=8.7Hz,1H ),7.61(d,J=2.3Hz,1H),7.50(dd,J=7.5,4.8Hz,1H),6.87(s,1H),6.64(s,1 H),4.33–4.21(m,2H),4.18–4.05(m,2H),2.50(p,J=1.8Hz,4H),2.31(s,3H).

[0655] Example 61

[0656] Weigh 100.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (78.05 mg, 1.3 eq) into a 20 mL single-necked flask. Add 5 mL of DCM and stir at room temperature for 10 min to dissolve. Then weigh 88.20 mg (1.5 eq) of 61-1 into the flask and rinse with 5 mL of DCM. Finally, add 91.12 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with purified water (15 mL * 5) and concentrate at 45 °C to obtain compound 61-2 (brown oil, 184.60 mg, HPLC 79.32%, no purification required for the next step). ESI-MS m / z: 657.44 [M+H] + .

[0657] Compound 61-2 (184.60 mg, 1.0 eq) was dissolved in 10 mL of DCM in a 20 mL single-necked flask. Trifluoroacetic acid (0.5 mL) was added dropwise, and the mixture was stirred at room temperature until the reaction was complete as monitored by MS (conversion ≥90%, additional trifluoroacetic acid may be added as needed). The mixture was then concentrated at 45 °C to obtain crude compound 61 (brown oil, 248.90 mg, HPLC 81.07%). Rapid column chromatography (EA:PE = 10:1) was used to separate compound 61 (pale yellow oil, 94.70 mg, 62.77% yield, UPLC 95.54%). ESI-MS m / z: 537.37 [M+H] + .

[0658] 1 H NMR(600MHz,DMSO-d6)δ8.55(d,J=4.7Hz,1H),8.08(d,J=8.0Hz,1H),7.95(td, J=7.8,1.7Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.67(d,J=8.8Hz,1H),7.61(d,J =2.3Hz,1H),7.50(dd,J=7.5,4.9Hz,1H),6.86(s,1H),6.64(s,1H),4.25(ddd,J =15.9,11.8,5.1Hz,2H),4.18–3.97(m,2H),2.51(t,J=1.9Hz,4H),2.31(s,3H).

[0659] Example 62

[0660] Weigh 200.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156.00 mg, 1.3 eq) into a 20 mL single-necked flask. Add 8 mL of DCM and stir at room temperature for 10 min to dissolve. Then weigh 110.78 mg (1.5 eq) of compound 62-1 and add it to the flask. Rinse with 2 mL of DCM. Finally, add 182.00 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS (conversion ≥90%). Wash 5 times with purified water (15 mL * 5) and concentrate at 45 °C to obtain compound 62 (brown solid, 235.00 mg, 88.59% yield, HPLC 97.65%). ESI-MS m / z: 282.84 [M / 2+H] + .

[0661] 1 H NMR (600MHz, DMSO-d6) δ8.55 (ddd, J=4.8, 1.8, 0.9Hz, 1H), 8.10 (dt, J=7.9, 1.0Hz, 1H), 7.95 (td, J=7.8,1.8Hz,1H),7.89(dt,J=8.7,1.6Hz,1H),7.67(d,J=8.7Hz,1H),7.58(d,J=2.3Hz,1H),7.5 0(ddd,J=7.5,4.8,1.2Hz,1H),6.84–6.80(m,1H),5.54(dq,J=10.9,7.8,7.4Hz,1H),4.11–4.00( m,1H),2.90–2.75(m,2H),2.62(dt,J=13.8,8.3Hz,2H),2.54–2.49(m,6H),2.30(d,J=1.1Hz,3H).

[0662] Example 63

[0663] Compound 49-1 (150 mg, 1.0 eq) was weighed and dissolved in acetonitrile (7.5 mL). The solution was heated and stirred in a parallel reactor at 40 °C. Triethylamine (57 mg, 2.0 eq), potassium carbonate (234 mg, 6.0 eq), and 4-oxopiperidone hydrochloride (115 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2.5 mL) and stirred until MS monitoring showed completion (conversion ≥90%). The mixture was then filtered, washed (with 10 mL of purified water * 3), and concentrated to obtain crude compound 63. Compound 63-AcOH (white solid, 22.30 mg, 14.37% yield, UPLC 98.68%) was prepared, separated, and lyophilized. ESI-MS m / z: 275.69 [(M-AcOH) / 2+H] + .

[0664] 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=5.8Hz,1H),8.09(d,J=8.0Hz,1H),7.95(td,J=7.8,1.8H z,1H),7.88(dd,J=8.7,2.4Hz,1H),7.65(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(dd, J=7.6,4.9Hz,1H),6.81(s,1H),4.17(t,J=5.8Hz,2H),4.07(dd,J=7.9,5.9Hz,1H),2.70(q ,J=7.7,6.8Hz,6H),2.65(t,J=5.8Hz,2H),2.30(s,3H),2.27(t,J=6.1Hz,2H),1.90(s,4H).

[0665] Example 64

[0666] Weigh 100.00 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (78.05 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir to dissolve at room temperature. Then weigh 50.79 mg (1.5 eq) of compound 64-1 and rinse the vial wall with 5 mL of DCM. Finally, add 91.12 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL * 3). Concentrate the organic phase at 45 °C to obtain crude compound 64 (brown oil, 113.90 mg, HPLC). The compound was purified by rapid column chromatography (EA:PE = 10:1) to give compound 64 (pale yellow solid, 50.40 mg, 38.90% yield, HPLC 97.94%). ESI-MS m / z: 551.32 [M+H]. + .

[0667] 1 H NMR(600MHz,DMSO-d6)δ8.55(ddd,J=4.8,1.8,0.9Hz,1H),8.10(dq,J=7.9,1.2Hz,1H),7.95(t d,J=7.7,1.7Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.67(d,J=8.7Hz,1H),7.59(t,J=2.3Hz,1H), 7.50(ddd,J=7.5,4.8,1.2Hz,1H),6.83(d,J=1.3Hz,1H),5.69–5.48(m,1H),4.08(dt,J=8.1,5 .5Hz,1H),3.69–3.57(m,2H),3.24(d,J=12.1Hz,3H),2.50(p,J=1.8Hz,4H),2.33–2.26(m,3H).

[0668] Example 65

[0669] Compound 49-1 (150.00 mg, 1.0 eq) was weighed into a 20 mL single-necked flask, and acetonitrile (7.5 mL) was added and stirred to dissolve. The flask was placed in a parallel reactor at 40 °C, and triethylamine (57.03 mg, 2.0 eq), potassium carbonate (233.69 mg, 6.0 eq), and 4-hydroxypiperidine hydrochloride (116.42 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2.5 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥90%). The mixture was then filtered through a 0.45 μm filter and washed four times with saturated brine (10 mL * 4) to obtain the acetonitrile phase. The acetonitrile phase was concentrated at 45 °C to give compound 65 (yellow solid, 147.00 mg, 94.36% yield, HPLC 92.08%). ESI-MS m / z: 276.91 [M / 2+H] + .

[0670] 1 H NMR (600MHz, DMSO-d6) δ8.54(ddd,J=4.9,1.8,0.9Hz,1H),8.14–8.07(m,1H),7.95(td,J=7.7,1.8Hz,1H),7.88( dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(ddd,J=7.5,4.7,1.2Hz,1H),6.82(d,J= 1.3Hz,1H),4.53(d,J=4.2Hz,1H),4.08(dt,J=24.1,6.9Hz,3H),2.71–2.62(m,4H),2.50(p,J=1.8Hz,4H),2.44(t ,J=6.0Hz,2H),2.35–2.26(m,3H),2.08(s,1H),1.63(dd,J=12.5,3.8Hz,2H),1.31(dtd,J=12.8,9.6,4.8Hz,2H).

[0671] Example 66

[0672] Compound 49-1 (150.00 mg, 1.0 eq) was weighed into a 20 mL single-necked flask, and acetonitrile (7.5 mL) was added and stirred to dissolve. The flask was placed in a parallel reactor at 40 °C, and triethylamine (57.03 mg, 2.0 eq), potassium carbonate (155.79 mg, 4.0 eq), and (R)-3-(hydroxymethyl)pyrrolidine (85.57 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2.5 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥90%). The mixture was then filtered through a 0.45 μm filter and washed four times with saturated brine (10 mL * 4) to obtain the acetonitrile phase. The acetonitrile phase was concentrated at 45 °C to give compound 66 (pale yellow solid, 131.80 mg, 84.59% yield, HPLC 94.27%). ESI-MS m / z: 276.86 [M / 2+H] + .

[0673] 1 H NMR (600MHz, DMSO-d6) δ8.54(dt,J=4.6,1.4Hz,1H),8.09(dt,J=8.0,1.1Hz,1H),7.94(td,J=7.8,1.8Hz,1H),7.88 (dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(ddd,J=7.6,4.7,1.2Hz,1H),6.82(d,J= 1.3Hz,1H),4.55(s,1H),4.09(t,J=6.0Hz,2H),4.06(dd,J=7.9,5.9Hz,1H),3.25(q,J=9.0,7.8Hz,2H),2.73–2.66 (m,2H),2.57–2.46(m,8H),2.30(d,J=1.1Hz,3H),1.72(ddt,J=13.0,9.4,6.8Hz,2H),1.30(dq,J=12.7,6.7Hz,1H).

[0674] Example 67

[0675] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL vial. Add 5 mL of DCM and stir to dissolve at room temperature. Then weigh 84 mg (1.5 eq) of N-methyldiethanolamine and rinse the vial wall with 5 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL x 3). Concentrate the organic phase to give compound 67 (brown oil, 204.9 mg, 82.81% yield, UPLC 99.05%). ESI-MS m / z: 263.75 [M / 2+H] + .

[0676] 1 H NMR (600MHz, DMSO-d6) δ8.58–8.49(m,1H),8.09(d,J=8.0Hz,1H),7.94(td,J=7.7,1.8Hz,1H),7.88 (dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.49(ddd,J=7.5,4.8,1.2Hz,1 H),6.82(d,J=1.4Hz,1H),4.31(d,J=5.5Hz,1H),4.12–3.98(m,3H),3.44–3.37(m,2H),2.72–2.59(m ,2H),2.56(t,J=6.1Hz,2H),2.50(p,J=1.8Hz,2H),2.41(q,J=6.8Hz,2H),2.30(s,3H),2.16(s,3H).

[0677] Example 68

[0678] Compound 68-1 (249 mg, 1.0 eq) was weighed into a reaction flask, dissolved in 20 mL of methanol, and the pH was adjusted to 13–14 with 1 M sodium hydroxide solution. The mixture was stirred at room temperature until MS showed complete reaction of the starting material. The pH was then adjusted to 5–6 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate and water. The organic phase was concentrated to give compound 68-2 (white solid, 240 mg, 97.16% yield). ESI-MS m / z: 425.26 [M+H] + .

[0679] Compound 68-2 (244 mg, 1.0 eq) was dissolved in dichloromethane and placed in a 100 mL single-necked flask. 2-Chloro-1-methylpyridine iodide (190.59 mg, 1.3 eq) was added, followed by 2-ethanolmorpholine (113 mg, 1.5 eq). The flask walls were rinsed with DCM (2 mL), and finally DIPEA (223 mg, 3.0 eq) was added. The mixture was stirred at room temperature until the reaction was complete as monitored by MS. The solution was then concentrated to obtain crude compound 68. Compound 68 was then prepared and isolated (35 mg, 11.36% yield, UPLC 96.00%). ESI-MS m / z: 538.22 [M+H] + .

[0680] 1 H NMR (600MHz, DMSO-d6) δ8.00(d,J=8.7Hz,1H),7.89(dd,J=8.7,2.4Hz,1H),7.64(td,J=7.7,1.9Hz,1H ),7.57(tdd,J=7.6,5.1,1.9Hz,1H),7.39–7.32(m,2H),7.23(dd,J=10.8,8.3Hz,1H),4.24(dd,J=8.5, 5.3Hz,1H),4.14(hept,J=5.8Hz,2H),3.49(t,J=4.6Hz,4H),2.76–2.62(m,2H),2.62–2.48(m,4H),2.3 5(t,J=4.7Hz,4H),2.11(ddd,J=13.3,8.4,5.0Hz,1H),1.17(dt,J=9.1,6.2Hz,1H),1.04–0.90(m,3H).

[0681] Example 69

[0682] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL vial. Add 8 mL of DCM and stir to dissolve at room temperature. Then weigh 87 mg (1.5 eq) of 4-ethanolylpyridine and rinse the vial wall with 2 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL x 3). Concentrate the organic phase to give compound 69 (brown oil, 240.37 mg, 96.36% yield, UPLC 98.13%). ESI-MS m / z: 265.79 [M / 2+H] + .

[0683] 1 H NMR (600MHz, DMSO-d6) δ8.55–8.51(m,1H),8.43–8.40(m,2H),8.06(d,J=7.9Hz,1H),7.94(d,J= 1.8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.59(d,J=2.3Hz,1H),7.49(ddd, J=7.6,4.8,1.2Hz,1H),7.28–7.22(m,2H),6.81(d,J=1.4Hz,1H),4.29(td,J=6.6,3.2Hz,2H),4. 02–3.97(m,1H),2.89(t,J=6.6Hz,2H),2.70–2.59(m,2H),2.59–2.43(m,2H),2.31–2.28(m,3H).

[0684] Example 70

[0685] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL vial. Add 8 mL of DCM and stir to dissolve at room temperature. Then weigh 87 mg (1.5 eq) of 2-hydroxyethylpyridine and rinse the vial wall with 2 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL x 3). Concentrate the organic phase to give compound 70 (brown oil, 242.31 mg, 97.14% yield, UPLC 94.40%). ESI-MS m / z: 265.76 [M / 2+H] + .

[0686] 1H NMR (600MHz, DMSO-d6) δ8.57–8.52(m,1H),8.48–8.42(m,1H),8.07(d,J=7.9Hz,1H),7.94(td,J=7.7,1.8 Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.70–7.63(m,2H),7.60(d,J=2.3Hz,1H),7.49(ddd,J=7.6,4.8,1.2H z,1H),7.27(d,J=7.8Hz,1H),7.20(ddd,J=7.6,4.8,1.2Hz,1H),6.81(d,J=1.4Hz,1H),4.39(t,J=6.8Hz,2 H),4.02–3.98(m,1H),3.02(t,J=6.7Hz,2H),2.67–2.57(m,2H),2.50(p,J=1.8Hz,2H),2.33–2.27(m,3H).

[0687] Example 71

[0688] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL vial. Add 8 mL of DCM and stir at room temperature to dissolve. Then weigh 97 mg (1.5 eq) of 6-methyl-2-pyridinylethanol and rinse the vial wall with 2 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL x 3). Concentrate the organic phase to give compound 71 (brown solid, 232.9 mg, 90.96% yield, UPLC 90.10%). ESI-MS m / z: 272.75 [M / 2+H] + .

[0689] 1H NMR(600MHz,DMSO-d6)δ8.59–8.54(m,1H),8.28(s,1H),8.06(d,J=8.0Hz,1H),7.99– 7.93(m,1H),7.78–7.71(m,1H),7.69(dd,J=13.0,4.9Hz,1H),7.61–7.58(m,1H),7.5 3(dd,J=7.7,4.8Hz,1H),7.35–7.27(m,3H),4.44(t,J=6.3Hz,2H),4.18(s,1H),3.27 (t,J=6.3Hz,2H),2.67(s,3H),2.64–2.53(m,2H),2.50(p,J=1.8Hz,2H),2.35(s,3H).

[0690] Example 72

[0691] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL vial. Add 8 mL of DCM and stir to dissolve at room temperature. Then weigh 77 mg (1.5 eq) of 2-pyridinemethanol and rinse the vial wall with 2 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL x 3). Concentrate the organic phase to give compound 72 (brown oil, 237.79 mg, 97.92% yield, UPLC 93.11%). ESI-MS m / z: 258.75 [M / 2+H] + .

[0692] 1H NMR (600MHz, DMSO-d6) δ8.55–8.52(m,1H),8.49–8.45(m,1H),8.10(d,J=7.9Hz,1H),7.93(td,J=7.8, 1.8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.77(td,J=7.7,1.8Hz,1H),7.66(d,J=8.7Hz,1H),7.59(d,J= 2.3Hz,1H),7.49(ddd,J=7.6,4.8,1.2Hz,1H),7.36(d,J=7.8Hz,1H),7.33–7.28(m,1H),6.82(d,J=1. 3Hz,1H),5.17(s,2H),4.10(dd,J=8.1,5.9Hz,1H),2.86–2.75(m,2H),2.68–2.55(m,2H),2.30(s,3H).

[0693] Example 73

[0694] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL vial. Add 8 mL of DCM and stir to dissolve at room temperature. Then weigh 77 mg (1.5 eq) of 4-pyridinemethanol and rinse the vial wall with 2 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL x 3). Concentrate the organic phase to give compound 73 (brown oil, 238.3 mg, 98.13% yield, UPLC 98.56%). ESI-MS m / z: 258.74 [M / 2+H] + .

[0695] 1H NMR (600MHz, DMSO-d6) δ8.53 (ddd, J=12.4, 4.0, 1.4Hz, 3H), 8.09 (d, J=7.9Hz, 1H), 7.93 ( td,J=7.7,1.8Hz,1H),7.88(dd,J=8.7,2.4Hz,1H),7.65(d,J=8.7Hz,1H),7.59(d,J=2.3 Hz,1H),7.49(ddd,J=7.6,4.8,1.2Hz,1H),7.33–7.29(m,2H),6.82(d,J=1.4Hz,1H),5.1 6(s,2H),4.08(dd,J=8.1,5.8Hz,1H),2.89–2.77(m,2H),2.69–2.53(m,2H),2.30(s,3H).

[0696] Example 74

[0697] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CPMI (156 mg, 1.3 eq) into a 20 mL vial. Add 8 mL of DCM and stir at room temperature to dissolve. Then weigh 123 mg (1.5 eq) of N'N-bis(2-hydroxyethyl)piperazine and rinse the vial wall with 2 mL of DCM. Finally, add 182 mg (3.0 eq) of DIPEA and stir at room temperature until the reaction is complete as monitored by MS. Wash three times with purified water (10 mL * 3). Concentrate the organic phase to give compound 74 (brown oil, 115.1 mg, 42.09% yield, UPLC 93.02%). ESI-MS m / z: 291.30 [M / 2+H] + .

[0698] 1H NMR (600MHz, DMSO-d6) δ8.53(d,J=4.8Hz,1H),8.09(d,J=8.0Hz,1H),7.93(tt,J=7.7,2. 2Hz,1H),7.87(dd,J=8.7,2.4Hz,1H),7.65(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.48 (dd,J=7.5,4.9Hz,1H),6.81(s,1H),4.11–4.01(m,4H),3.33(s,2H),2.68(q,J=7.2Hz,2 H),2.60(dt,J=14.6,6.7Hz,2H),2.50(p,J=1.8Hz,10H),2.44–2.38(m,2H),2.29(s,3H).

[0699] Example 75

[0700] Compound 49-1 (200 mg, 1.0 eq) was weighed into a 20 mL single-necked flask, and acetonitrile (5 mL) was added. The mixture was heated and stirred at 40 °C. Then, triethylamine (76 mg, 2.0 eq), (3S,5S)-3,5-dimethylmorpholine hydrochloride (171 mg, 3.0 eq), and potassium carbonate (312 mg, 6.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL), and the reaction was stirred until the reaction was complete as monitored by MS. The mixture was then filtered and concentrated to obtain crude compound 75 (brown oil, 253 mg). This crude compound was then sent for preparative separation to obtain compound 75-AcOH (white solid, 8.4 mg, 3.6% yield, UPLC 98.55%). ESI-MS m / z: 283.73 [M / 2+H] + .

[0701] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.99–7.91(m,1H),7.88(dd,J=8.7,2.4Hz,1H),7.6 6(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(dd,J=7.5,4.8Hz,1H),6.82(s,1H),4.07(ddd,J=11.7,9.5,6.0Hz,2H),3. 98(dt,J=11.5,6.2Hz,1H),3.47(dd,J=10.8,3.0Hz,2H),3.14(dd,J=10.9,5.9Hz,2H),2.75(tt,J=8.6,6.6Hz,3H),2.72– 2.64(m,1H),2.64–2.58(m,1H),2.53(d,J=10.6Hz,2H),2.44(dt,J=13.1,6.1Hz,1H),2.30(s,3H),0.87(d,J=6.4Hz,6H).

[0702] Example 76

[0703] Compound 49-1 (200 mg, 1.0 eq) was weighed into a 20 mL single-necked flask, and acetonitrile (5 mL) was added. The mixture was heated and stirred at 40 °C. Then, triethylamine (76 mg, 2.0 eq), 3-methylmorpholine (114 mg, 3.0 eq), and potassium carbonate (208 mg, 4.0 eq) were added sequentially. After washing with acetonitrile (5 mL), the mixture was stirred until the reaction was complete as monitored by MS. The mixture was then filtered and concentrated to obtain crude compound 76 (light brown oil, 231 mg). This crude compound was then sent for preparative separation to obtain compound 76-AcOH (white solid, 22.6 mg, 9.8% yield, UPLC 93.64%). ESI-MS m / z: 276.74 [M / 2+H] + .

[0704] 1H NMR (600MHz, DMSO-d6) δ8.56–8.53(m,1H),8.09(d,J=7.9Hz,1H),7.95(td,J=7.8,1.8Hz,1H),7.88(dd,J=8.8,2.3Hz,1H ),7.66(dd,J=8.8,3.1Hz,1H),7.60(dd,J=5.2,2.3Hz,1H),7.50(dd,J=7.5,4.9Hz,1H),6.82(s,1H),4.14(ddd,J=22.3,1 1.8,6.1Hz,1H),4.10–4.03(m,2H),3.62–3.54(m,2H),3.54–3.46(m,1H),2.97(q,J=9.8,8.4Hz,1H),2.90–2.64(m,4H), 2.65–2.58(m,1H),2.52(s,2H),2.40–2.31(m,1H),2.30(s,3H),2.25(td,J=11.1,9.6,3.0Hz,1H),0.84(d,J=6.2Hz,3H).

[0705] Example 77

[0706] Compound 49-1 (1.0 g, 1.0 eq) was weighed into a 50 mL single-necked flask, and acetonitrile (15 mL) was added. The mixture was heated and stirred at 40 °C. Triethylamine (0.38 g, 2.0 eq), 2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride (0.76 g, 3.0 eq), and potassium carbonate (1.56 g, 6.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL), and the reaction was stirred until the reaction was complete as monitored by MS. The mixture was then filtered, concentrated, and washed three times with ethyl acetate and purified water. The organic phase was concentrated to give compound 77 (brown oil, 734.40 mg, 71.00% yield, UPLC 90.34%). ESI-MS m / z: 275.70 [M / 2+H] + .

[0707] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.97–7.92(m,1H),7.88(dd,J=8.8,2.3Hz,1H),7.66 (d,J=8.7Hz,1H),7.61(dd,J=7.7,2.3Hz,1H),7.50(dd,J=7.5,4.9Hz,1H),6.82(s,1H),4.25(d,J=16.2Hz,1H),4.05(t,J =6.0Hz,2H),3.74(t,J=7.5Hz,1H),3.47–3.39(m,2H),2.75(t,J=9.8Hz,1H),2.69(tt,J=11.2,6.4Hz,4H),2.60(dd,J=14 .0,6.9Hz,1H),2.52(s,2H),2.34(dd,J=10.0,5.6Hz,1H),2.30(s,3H),1.61(dt,J=9.4,2.8Hz,1H),1.51(t,J=7.5Hz,1H).

[0708] Example 78

[0709] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (180 mg, 1.5 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 90 mg (1.2 eq) of 2-methyl-2-morpholinopropane-1-ol and 243 mg (4.0 eq) sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Wash (10 mL * 3 of purified water) and concentrate to give compound 78 (brown oil, 188 mg, 70.60% yield, UPLC 91.06%). ESI-MS m / z: 283.77 [M / 2+H] + .

[0710] 1H NMR (600MHz, DMSO-d6) δ8.55(d,J=4.8Hz,1H),8.10(d,J=8.0Hz,1H),7.95(td,J=7.8,1.8Hz,1H),7.88 (dd,J=8.8,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.59(d,J=2.3Hz,1H),7.51–7.48(m,1H),6.82(d,J=1.5H z,1H),4.10(dd,J=8.3,5.8Hz,1H),3.98(d,J=11.3Hz,1H),3.89(d,J=11.4Hz,1H),3.41(t,J=5.6Hz,4 H),2.72(t,J=7.2Hz,2H),2.68–2.54(m,2H),2.42(q,J=4.1Hz,4H),2.30(s,3H),0.90(d,J=2.4Hz,6H).

[0711] Example 79

[0712] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (5 mL). The mixture was heated and stirred at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (312 mg, 6.0 eq), and 8-oxo-3-azabicyclo[3,2,1]octane hydrochloride (169 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL), and the reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 79 (yellow oil). TLC purification yielded compound 79 (pale yellow oil, 68.2 mg, 32.13% yield, UPLC 94.98%). ESI-MS m / z: 282.73 [M / 2+H] + .

[0713] 1H NMR (600MHz, DMSO-d6) δ8.54(dd,J=5.0,1.8Hz,1H),8.09(d,J=8.0Hz,1H),7.95(td,J=7.7,1.8Hz,1H),7.89(dd,J=8.7 ,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.50(ddd,J=7.6,4.8,1.2Hz,1H),6.82(d,J=1.5Hz,1H),4.1 5–4.10(m,4H),4.06(dd,J=8.1,5.9Hz,1H),2.69(q,J=7.1Hz,2H),2.61(p,J=7.1Hz,1H),2.57–2.52(m,1H),2.48(d,J= 11.3Hz,2H),2.43–2.39(m,2H),2.31–2.28(m,3H),2.14(d,J=10.7Hz,2H),1.69(d,J=7.7Hz,2H),1.59(t,J=5.2Hz,2H).

[0714] Example 80

[0715] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (180 mg, 1.5 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add N-(2-hydroxypropyl)morpholine (82 mg, 1.2 eq) and DIPEA (243 mg, 4.0 eq) sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Wash (10 mL * 3 of purified water) and concentrate to give compound 80 (blue-green solid, 173.70 mg, 66.89% yield, UPLC 93.45%). ESI-MS m / z: 276.74 [M / 2+H] + .

[0716] 1H NMR (600MHz, DMSO-d6) δ8.55(d,J=4.5Hz,1H),8.10(dd,J=8.0,5.0Hz,1H),7.95(td,J=7.8,1.8Hz,1H),7.88(d t,J=8.7,2.8Hz,1H),7.66(dd,J=8.7,6.8Hz,1H),7.60(dd,J=8.8,2.3Hz,1H),7.52–7.48(m,1H),6.82(d,J=1.4 Hz,1H),5.06–4.96(m,1H),4.12–3.97(m,1H),3.47–3.38(m,4H),2.67(dd,J=6.9,2.6Hz,1H),2.50(p,J=1.9Hz, 6H), 2.36 (ddd, J=14.1, 9.1, 4.6Hz, 2H), 2.30 (s, 3H), 2.26 (dt, J=12.8, 4.6Hz, 1H), 1.12 (dd, J=9.5, 6.4Hz, 3H).

[0717] Example 81

[0718] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (180 mg, 1.5 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 70 mg (1.2 eq) of 2-hydroxyethylpyrazine and 4.0 eq of DIPEA sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Wash (10 mL * 3 of purified water) and concentrate to give compound 81 (brown oil, 227 mg, 90.87% yield, UPLC 95.60%). ESI-MS m / z: 531.22 [M+H] + .

[0719] 1H NMR(600MHz,DMSO-d6)δ8.57(d,J=1.5Hz,1H),8.55–8.52(m,2H),8.47(d,J=2.5Hz,1H),8.06(d, J=7.9Hz,1H),7.94(td,J=7.7,1.8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.6 1(d,J=2.3Hz,1H),7.49(dd,J=7.5,4.9Hz,1H),6.81(s,1H),4.42(t,J=6.5Hz,2H),4.07–3.95(m ,1H),3.09(t,J=6.6Hz,2H),2.60(tdd,J=28.9,15.0,8.6Hz,2H),2.49–2.42(m,2H),2.30(s,3H).

[0720] Example 82

[0721] Compound 82-1 (700 mg, 1.0 eq) was weighed into a reaction flask, dissolved in 10 mL of methanol, and then 10 mL of purified water was added. The pH was adjusted to 13–14 with 1 M sodium hydroxide solution. The mixture was stirred at room temperature until MS showed complete reaction of the starting material. The pH was adjusted to 5–6 with dilute hydrochloric acid. Most of the methanol was removed by rotary evaporation. The mixture was extracted three times with ethyl acetate and water. The organic phase was concentrated to give compound 82-2 (white solid, 480 mg, 98.25% yield). ESI-MS m / z: 398.23 [M+H] + .

[0722] Compound 82-2 (470 mg, 1.0 eq) was dissolved in dichloromethane and placed in a 100 mL single-necked flask. 2-Chloro-1-methylpyridine iodide (392 mg, 1.3 eq) was added, followed by 2-ethanolmorpholine (232 mg, 1.5 eq). The flask walls were rinsed with DCM (2 mL), and finally DIPEA (458 mg, 3.0 eq) was added. The mixture was stirred at room temperature until the reaction was complete as monitored by MS. The solution was then concentrated to obtain crude compound 82. Compound 82 (130 mg, 21.55% yield) was then prepared and isolated. ESI-MS m / z: 511.24 [M+H] + .

[0723] 1H NMR(600MHz,DMSO-d6)δ7.78(d,J=3.0Hz,2H),7.62(td,J=7.7,1.8Hz,1H),7.56( qd,J=8.8,7.4,5.2Hz,1H),7.35–7.31(m,2H),7.21(dd,J=10.8,8.3Hz,1H),6.84 (s,1H),4.13(hept,J=5.8Hz,2H),4.00(dd,J=8.2,5.8Hz,1H),3.49(t,J=4.6Hz, 4H),2.69–2.59(m,2H),2.50(t,J=2.0Hz,6H),2.47(t,J=5.9Hz,2H),2.32(s,3H).

[0724] Example 83

[0725] Compound 83-6 (yellow oil, 41.9 mg, 29.30% yield, HPLC 90.39%) was prepared using the same method as in Example 12. ESI-MS m / z: 409.29 [M+H] + .

[0726] Compound 83-7 (1.1 g, 1.0 eq) was weighed into a reaction flask, dissolved in 20 mL of methanol, and then 20 mL of purified water was added. The pH was adjusted to 13–14 with 1 M sodium hydroxide solution. The mixture was stirred at room temperature until MS showed complete reaction of the starting material. The pH was adjusted to 5–6 with dilute hydrochloric acid. Most of the methanol was removed by rotary evaporation. The mixture was extracted three times with ethyl acetate and water. The organic phase was concentrated to give compound 83-8 (yellow oily liquid, 510 mg, 66.58% yield). ESI-MS m / z: 395.24 [M+H] + ;

[0727] Compound 83-8 (501 mg, 1.0 eq) was dissolved in dichloromethane and placed in a 100 mL single-necked flask. 2-Chloro-1-methylpyridine iodide (427 mg, 1.3 eq) was added, followed by 2-ethanolmorpholine (249 mg, 1.5 eq). The flask walls were rinsed with DCM (2 mL), and finally DIPEA (492 mg, 3.0 eq) was added. The mixture was stirred at room temperature until the reaction was complete as monitored by MS. The solution was then concentrated to obtain crude compound 83. Compound 83 (300 mg, 47.00% yield) was then prepared and isolated. ESI-MS m / z: 254.88 [M / 2+H] + .

[0728] 1H NMR (600MHz, DMSO-d6) δ8.53(d,J=4.8Hz,1H),8.08(d,J=8.0Hz,1H),7.94(t,J=7.8Hz,1H),7.70(s,1H),7.49(dd,J=7.6,4.8Hz,1H),7.45(s,1H),6 .81(s,1H),4.13(t,J=5.8Hz,2H),4.04(t,J=7.0Hz,1H),3.47(t,J=4.6Hz ,4H),2.68(q,J=6.8Hz,2H),2.62–2.47(m,8H),2.34(s,3H),2.32(s,3H).

[0729] Example 84

[0730] The preparation method was the same as in Example 83, yielding compound 84 (60 mg, 34.04% yield). ESI-MS m / z: 276.75 [M / 2+H] + .

[0731] 1 H NMR(600MHz, DMSO-d6)δ8.54(dd,J=4.8,1.7Hz,1H),8.08(d,J=8.0Hz,1H),7.94(t d,J=7.8,1.8Hz,1H),7.70(s,1H),7.60(s,1H),7.49(dd,J=7.6,4.7Hz,1H),6.81(s ,1H),4.13(t,J=5.8Hz,2H),4.04(dd,J=8.0,5.9Hz,1H),3.47(t,J=4.7Hz,4H),2.7 4–2.56(m,2H),2.50(q,J=2.1Hz,6H),2.47(t,J=5.8Hz,2H),2.33(d,J=5.5Hz,6H).

[0732] Example 85

[0733] The preparation method was the same as in Example 83, yielding compound 85. ESI-MS m / z: 246.81 [M / 2+H] + .

[0734] 1H NMR (600MHz, DMSO-d6) δ8.53(d,J=4.7Hz,1H),8.07(d,J=8.0Hz,1H),7.93(td,J=7. 8,1.8Hz,1H),7.64(d,J=6.6Hz,1H),7.48(dd,J=7.5,4.7Hz,1H),7.21(d,J=9.9Hz,1 H),6.80(s,1H),4.13(t,J=5.8Hz,2H),4.05–4.00(m,1H),3.47(t,J=4.7Hz,4H),2. 71–2.66(m,2H),2.62–2.49(m,6H),2.47(t,J=5.8Hz,2H),2.40(s,3H),2.31(s,3H).

[0735] Example 86

[0736] The preparation method was the same as in Example 83, yielding compound 86. ESI-MS m / z: 246.82 [M / 2+H] + .

[0737] 1 H NMR (600MHz, DMSO-d6) δ8.52(dd,J=5.1,1.7Hz,1H),8.06(d,J=7.9Hz,1H),7.93(td,J=7.7,1 .8Hz,1H),7.59(d,J=10.5Hz,1H),7.48(dd,J=7.6,4.9Hz,1H),7.35(d,J=8.2Hz,1H),6.80(d ,J=1.5Hz,1H),4.13(td,J=5.7,2.8Hz,2H),4.02(dd,J=8.0,5.9Hz,1H),3.47(t,J=4.6Hz,4H ),2.68(q,J=7.1Hz,2H),2.62–2.49(m,6H),2.47(t,J=5.9Hz,2H),2.32(s,3H),2.27(s,3H).

[0738] Example 87

[0739] Compound 87-1 (830 mg, 1.0 eq) was weighed into a reaction flask, dissolved in 10 mL of methanol, and then 10 mL of purified water was added. The pH was adjusted to 13–14 with 1 M sodium hydroxide solution. The mixture was stirred at room temperature until MS showed complete reaction of the starting material. Most of the methanol was removed by rotary evaporation, and the pH was adjusted to 5–6 with dilute hydrochloric acid. Water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was collected and concentrated to give compound 87-2 (yellow solid, 450 mg, 62.50% yield). ESI-MS m / z: 412.17 [M+H] + .

[0740] Compound 87-2 (500 mg, 1.0 eq) was dissolved in acetonitrile and placed in a 100 mL single-necked flask. Under ice bath conditions, HATU (696 mg, 1.5 eq) was added, followed by 2-ethanolmorpholine (242 mg, 1.5 eq), and the flask walls were rinsed with DCM (2 mL). Finally, triethylamine (12 mg, 0.1 eq) was added. The reaction was stirred at room temperature until MS monitoring showed completion, and then concentrated to obtain crude compound 87. Compound 87 (123 mg, 19.30% yield) was prepared and isolated. ESI-MS m / z: 525.15 [M+H] + .

[0741] 1 H NMR(600MHz,DMSO-d6)δ9.23(s,1H),8.52(d,J=4.8Hz,1H),8.08(d,J=8.0Hz,1H ),8.02–7.94(m,2H),7.82(d,J=8.7Hz,1H),7.62(d,J=2.3Hz,1H),7.51(dd,J=7. 5,4.8Hz,1H),4.40(dd,J=8.0,5.5Hz,1H),4.16(q,J=6.1Hz,2H),3.48(t,J=4.6 Hz,4H),2.72(ddt,J=39.5,24.7,7.6Hz,2H),2.51(s,4H),2.36(t,J=4.7Hz,4H).

[0742] Example 88

[0743] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (9 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (312 mg, 6.0 eq), and bicyclic [3,2,1]octane hydrochloride (169 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (1 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 88 (yellow oil). Compound 88 was separated by TLC (brown oil, 108 mg, 51.43% yield, UPLC 90.57%). ESI-MS m / z: 282.75 [M / 2+H] + .

[0744] 1 H NMR (600MHz, DMSO-d6) δ8.58–8.51(m,1H),8.09(d,J=7.9Hz,1H),7.95(td,J=7.7,1.8Hz,1H),7.88(dd ,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(dd,J=7.5,4.9Hz,1H),6.82(s, 1H),4.09(qt,J=10.6,6.0Hz,3H),3.35–3.30(m,4H),3.02–2.96(m,2H),2.70(p,J=7.8,7.0Hz,2H),2. 63–2.52(m,2H),2.38(t,J=6.1Hz,2H),2.30(s,3H),1.75(dd,J=8.6,4.1Hz,2H),1.66(t,J=6.5Hz,2H).

[0745] Example 89

[0746] Compound 87-2 (500 mg, 1.0 eq) was dissolved in acetonitrile and placed in a 100 mL single-necked flask. 2-chloro-1-methylpyridine iodide (CMPI) (740 mg, 3.0 eq) was added, followed by 3-(4-morpholino)-1-propanol (422 mg, 3.0 eq), and finally DIPEA (375 mg, 3.0 eq). The mixture was stirred at room temperature until the reaction was complete as monitored by MS. The solution was then concentrated to give crude compound 89. Compound 89 was then prepared and isolated as a grayish-white solid (69 mg, 13.19% yield, UPLC 95.00%). ESI-MS m / z: 270.23 [M / 2+H] + .

[0747] 1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.67(d,J=4.6Hz,1H),7.19(s,1H),7.14(s,1H),7.11(s,1H ),6.97(d,J=8.7Hz,1H),6.78(d,J=2.3Hz,1H),6.66(dd,J=7.5,4.9Hz,1H),3.57(t,J=6.7Hz,1H) ,3.28(t,J=6.3Hz,2H),3.13(d,J=13.0Hz,2H),2.76(t,J=12.3Hz,2H),2.58(d,J=12.6Hz,2H),2. 35–2.31(m,2H),2.20(d,J=11.4Hz,2H),2.01–1.87(m,2H),1.83–1.75(m,2H),1.17–1.13(m,2H).

[0748] Example 90

[0749] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (9 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (312 mg, 6.0 eq), and (R)-2-methylmorpholine hydrochloride (155 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (1 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 90 (yellow oil). Compound 90 was separated by TLC (pale yellow oil, 124.80 mg, 60.08% yield, UPLC 91.47%). ESI-MS m / z: 276.77 [M / 2+H] + .

[0750] 1H NMR (600MHz, DMSO-d6) δ8.54(dq,J=4.3,1.4Hz,1H),8.12–8.08(m,1H),7.95(tt,J=7.7,1.6Hz,1H),7.89(dt,J=8.8,2.0Hz, 1H),7.66(dd,J=8.7,1.5Hz,1H),7.60(t,J=1.9Hz,1H),7.52–7.48(m,1H),6.84–6.80(m,1H),4.13(tp,J=10.1,5.5Hz,2H),4 .06(dd,J=8.0,5.8Hz,1H),3.65(ddd,J=11.3,3.3,1.7Hz,1H),3.36(d,J=1.5Hz,2H),2.69(td,J=9.4,7.7,4.0Hz,3H),2.65– 2.55(m,2H),2.54–2.50(m,2H),2.48–2.43(m,2H),2.30(t,J=1.3Hz,3H),2.08(d,J=1.5Hz,1H),0.97(dd,J=6.3,1.5Hz,3H).

[0751] Example 91

[0752] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (9 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (208 mg, 4.0 eq), and (S)-2-methylmorpholine (114 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (1 mL). The reaction was stirred until MS monitoring showed that the reaction was complete (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 91 (yellow oil). Compound 91 was separated by TLC (pale yellow oil, 112.50 mg, 54.16% yield, UPLC 92.44%). ESI-MS m / z: 276.74 [M / 2+H] + .

[0753] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=7.9Hz,1H),7.95(dd,J=8.7,6.8Hz,1H),7.89(dt,J=8.7, 1.8Hz,1H),7.68–7.62(m,1H),7.60(q,J=2.8,1.8Hz,1H),7.52–7.46(m,1H),6.82(s,1H),4.13(t,J=5.7Hz,2H),4 .06(t,J=6.9Hz,1H),3.68–3.63(m,1H),3.36(d,J=1.5Hz,2H),2.70(dq,J=15.2,7.8Hz,3H),2.62(dq,J=14.6,7.7 Hz,2H),2.51(dt,J=3.7,1.8Hz,2H),2.46(d,J=5.9Hz,2H),2.30(s,3H),2.08(d,J=1.5Hz,1H),1.01–0.96(m,3H).

[0754] Example 92

[0755] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (9 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (208 mg, 4.0 eq), and (2R,6R)-dimethylmorpholine (130 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (1 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 92 (yellow oil). Compound 92 was separated by TLC (pale yellow oil, 133.00 mg, 62.44% yield, UPLC 98.68%). ESI-MS m / z: 283.74 [M / 2+H] + .

[0756] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.6Hz,1H),8.08(d,J=7.9Hz,1H),7.95(tt,J=7.7,1.6Hz,1H),7.89(dt,J=8.7,1. 9Hz,1H),7.66(dd,J=8.7,1.4Hz,1H),7.60(t,J=1.9Hz,1H),7.53–7.48(m,1H),6.81(d,J=1.8Hz,1H),4.16(dt,J=11 .9, 6.0Hz, 1H), 4.10 (q, J=5.8Hz, 1H), 4.06 (dd, J=8.0, 6.0Hz, 1H), 3.79 (td, J=6.3, 3.5Hz, 2H), 2.73–2.65 (m, 2H), 2. 65–2.52(m,1H),2.44(dt,J=12.3,5.9Hz,1H),2.40–2.34(m,2H),2.30(s,3H),2.11–2.02(m,4H),1.08–1.01(m,6H).

[0757] Example 93

[0758] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (9 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (208 mg, 4.0 eq), and (2S,6S)-dimethylmorpholine (130 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (1 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 93 (yellow oil). Compound 93 was separated by TLC (pale yellow oil, 96.3 mg, 45.21% yield, UPLC 99.42%). ESI-MS m / z: 283.74 [M / 2+H] + .

[0759] 1H NMR(600MHz,DMSO-d6)δ8.57–8.51(m,1H),8.11–8.05(m,1H),7.94(tt,J=7.8,1.5Hz,1H),7.91–7.87(m,1H), 7.69–7.63(m,1H),7.60(dd,J=2.3,1.2Hz,1H),7.52–7.47(m,1H),6.81(d,J=1.7Hz,1H),4.13(dp,J=16.0,5. 9Hz, 2H), 4.06 (dd, J=7.9, 6.0Hz, 1H), 3.80 (tt, J=9.3, 4.5Hz, 2H), 2.68 (q, J=7.3Hz, 2H), 2.61 (dq, J=14.8, 7. 3Hz,1H),2.43(dt,J=12.2,5.9Hz,1H),2.40–2.35(m,2H),2.30(s,3H),2.10–2.03(m,4H),1.08–1.03(m,6H).

[0760] Example 94

[0761] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (9 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (312 mg, 6.0 eq), and 2-trifluoromethyl-morpholine hydrochloride (216 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (1 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 94 (yellow oil). Compound 94 was separated by TLC (pale yellow oil, 62.40 mg, 27.37% yield, UPLC 99.10%). ESI-MS m / z: 303.75 [M / 2+H] + .

[0762] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.94(tt,J=7.8,1.7Hz,1H),7.88(d,J=8.7 Hz,1H),7.66(d,J=8.8Hz,1H),7.60(q,J=2.0Hz,1H),7.52–7.47(m,1H),6.81(s,1H),4.17(q,J=5.8,4.6Hz,2H), 4.06(dt,J=13.6,6.6Hz,2H),3.86(d,J=11.3Hz,1H),3.55–3.47(m,1H),2.93(d,J=11.0Hz,1H),2.70(ddd,J=20 .1,11.4,4.7Hz,3H),2.60(qd,J=13.6,12.8,6.3Hz,3H),2.30(s,3H),2.14(t,J=11.7Hz,1H),2.11–2.04(m,2H).

[0763] Example 95

[0764] Weigh 1 g (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (780 mg, 1.3 eq) and dissolve them in dichloromethane (40 mL). Stir, then add 540 mg (1.5 eq) of 4-bromo-1-butanol and 1.22 g (4.0 eq) of DIPEA sequentially. Wash with DCM (10 mL) and stir until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate, add EA (50 mL) and wash with purified water (50 mL each of purified water), and concentrate to give compound 95-1 (brown oil, 1.28 g, 97.44% yield). ESI-MS m / z: 559.18 [M+H] + ;

[0765] Compound 95-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (72 mg, 2.0 eq), potassium carbonate (197 mg, 4.0 eq), and morpholine (93 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 95 (brown oil). Compound 95 was separated by TLC (pale yellow oil, 70 mg, 34.62% yield, UPLC 95.07%). ESI-MS m / z: 283.71 [M / 2+H]+ .

[0766] 1 H NMR(600MHz,DMSO-d6)δ8.59–8.51(m,1H),8.09(dd,J=8.0,1.5Hz,1H),7.95(tt,J=7.8,1.6Hz,1H),7 .89(dt,J=8.8,1.8Hz,1H),7.66(dd,J=8.7,1.3Hz,1H),7.60(t,J=1.8Hz,1H),7.50(ddd,J=7.5,4.6, 1.3Hz,1H),6.82(t,J=1.3Hz,1H),4.08–3.98(m,3H),3.52(t,J=4.7Hz,4H),2.68(p,J=7.5,6.8Hz,2H ),2.30(s,3H),2.29–2.25(m,6H),2.21(t,J=7.3Hz,2H),1.54(p,J=6.9Hz,2H),1.40(p,J=7.4Hz,2H).

[0767] Example 96

[0768] Weigh 1 g (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (780 mg, 1.3 eq) and dissolve them in 40 mL of dichloromethane. Stir, then add 0.59 g (1.5 eq) of 4-bromo-1-butanol and 1.22 g (4.0 eq) of DIPEA sequentially. Wash with 10 mL of DCM and stir until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate, add 50 mL of EA and wash with purified water (50 mL each of purified water), and concentrate to obtain compound 96-1 (brown oily substance, 1.5 g). ESI-MS m / z: 573.19 [M+H] + ;

[0769] Compound 96-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.19 g, 4.0 eq), and morpholine (0.09 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 96 (brown oil). Compound 96 was separated by TLC (pale yellow oil, 90 mg, 44.55% yield, UPLC 97.12%). ESI-MS m / z: 290.74 [M / 2+H]+ .

[0770] 1 H NMR(600MHz,DMSO-d6)δ8.54(s,1H),8.10(d,J=8.7Hz,1H),7.94(d,J=7.5Hz,1 H),7.89(d,J=9.1Hz,1H),7.66(d,J=8.6Hz,1H),7.60(s,1H),7.50(s,1H),6.8 1(s,1H),4.03(d,J=20.6Hz,3H),3.54(d,J=14.7Hz,4H),2.67(s,2H),2.29(d, J=17.4Hz,9H),2.18(s,2H),1.58–1.47(m,2H),1.45–1.34(m,2H),1.26(s,2H).

[0771] Example 97

[0772] Weigh 1 g (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (780 mg, 1.3 eq) and dissolve them in dichloromethane (40 mL). Stir, then add 490 mg (1.5 eq) of 3-bromo-1-propanol and 1.22 g (4.0 eq) of DIPEA sequentially. Wash with DCM (10 mL) and stir until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate, add EA (50 mL) and wash with purified water (50 mL * 5), and concentrate to obtain compound 97-1 (brown oil, 1.47 g). ESI-MS m / z: 545.16 [M+H] + ;

[0773] Compound 97-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.30 g, 6.0 eq), and (R)-2-methylmorpholine hydrochloride (0.15 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed that the reaction was complete (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 97 (brown oil). Compound 97 was separated by TLC (brown oil, 90.10 mg, 42.90% yield, UPLC 95.70%). ESI-MS m / z: 283.76 [M / 2+H] + .

[0774] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.10(dd,J=8.0,1.6Hz,1H),7.94(tt,J=7.7,1.6Hz,1H),7.88(dt,J=8. 8,1.9Hz,1H),7.66(dd,J=8.7,1.3Hz,1H),7.61(t,J=1.9Hz,1H),7.52–7.46(m,1H),6.82(t,J=1.3Hz,1H),4.05(qd,J= 7.5,3.5Hz,3H),3.74–3.65(m,1H),3.44–3.40(m,2H),2.68(q,J=7.0Hz,2H),2.61(dd,J=20.7,11.9Hz,5H),2.30(s,3H ), 2.25(t,J=7.2Hz,2H), 1.87(ddd,J=13.5,11.1,3.1Hz,1H), 1.69(td,J=8.1,4.2Hz,2H), 0.99(dd,J=6.3,1.4Hz,3H).

[0775] Example 98

[0776] Compound 97-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.20 g, 4.0 eq), and (S)-2-methylmorpholine hydrochloride (0.11 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 98 (brown oil). Compound 98 was separated by TLC (brown oil, 104.2 mg, 50.26% yield, UPLC 95.65%). ESI-MS m / z: 283.80 [M / 2+H] + .

[0777] 1H NMR (600MHz, DMSO-d6) δ8.55(dd,J=4.2,2.4Hz,1H),8.09(dd,J=8.0,1.5Hz,1H),7.94(tt,J=7.7,1.6Hz,1H),7. 88(dt,J=8.7,1.9Hz,1H),7.66(dd,J=8.8,1.4Hz,1H),7.61(t,J=1.9Hz,1H),7.50(ddt,J=7.5,6.0,1.3Hz,1H), 6.81(t,J=1.4Hz,1H),4.10–3.99(m,2H),3.75–3.64(m,1H),3.50–3.38(m,3H),2.75–2.53(m,5H),2.30(s,3H), 2.25(t,J=7.1Hz,2H),1.93–1.83(m,1H),1.68(q,J=7.0Hz,2H),1.64–1.52(m,2H),1.01(dd,J=6.4,1.4Hz,3H).

[0778] Example 99

[0779] Compound 97-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.20 g, 4.0 eq), and (2R,6R)-dimethylmorpholine (0.13 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 99 (brown oil). Compound 99 was separated by TLC (brown oil, 96.9 mg, 45.60% yield, UPLC 96.76%). ESI-MS m / z: 290.76 [M / 2+H] + .

[0780] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.95(td,J=7.7,1.7Hz,1H),7.89(dd,J=8.8,2.1 Hz,1H),7.66(dd,J=8.7,1.4Hz,1H),7.60(q,J=2.0Hz,1H),7.53–7.47(m,1H),6.82(s,1H),4.06(qd,J=11.7,10.2,5. 5Hz,3H),3.84(qd,J=12.2,6.2Hz,2H),2.68(p,J=8.0,7.0Hz,2H),2.61(td,J=14.8,12.7,5.9Hz,2H),2.30(s,5H),2. 23(dt,J=13.6,7.3Hz,1H),2.18(q,J=6.3,5.6Hz,1H),2.06–1.95(m,3H),1.68(p,J=7.0Hz,2H),1.08(d,J=6.4Hz,6H).

[0781] Example 100

[0782] Compound 97-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.20 g, 4.0 eq), and (2S,6S)-dimethylmorpholine (0.13 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed that the reaction was complete (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 100 (brown oil). Compound 100 was separated by TLC (brown oil, 103.9 mg, 48.89% yield, UPLC 96.16%).

[0783] ESI-MS m / z: 290.79 [M / 2+H] + .

[0784] 1H NMR (600MHz, DMSO-d6) δ8.56–8.52(m,1H),8.09(dd,J=8.0,1.7Hz,1H),7.94(tt,J=7.7,1.6Hz,1H),7.88(dt,J=8.8 ,1.9Hz,1H),7.66(dd,J=8.7,1.4Hz,1H),7.60(t,J=2.1Hz,1H),7.54–7.48(m,1H),6.82(t,J=1.3Hz,1H),4.12–4.0 1(m,3H),3.85(dp,J=16.2,6.4Hz,2H),2.68(q,J=7.7Hz,2H),2.61(td,J=14.7,13.7,7.2Hz,2H),2.30(s,5H),2.23 (q,J=7.2,6.5Hz,1H),2.17(q,J=6.4,5.7Hz,1H),2.02–1.96(m,2H),1.71–1.65(m,2H),1.08(dd,J=6.5,1.5Hz,6H).

[0785] Example 101

[0786] Compound 97-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.30 g, 6.0 eq), and 2-trifluoromethyl-morpholine hydrochloride (0.21 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 101 (brown oil). Compound 101 was separated by TLC (brown oil, 75.80 mg, 33.38% yield, UPLC 90.66%). ESI-MS m / z: 310.77 [M / 2+H] + .

[0787] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.6Hz,1H),8.09(d,J=7.9Hz,1H),7.94(td,J=7.7,1.7Hz,1H),7.88(ddt,J=9.0,2 .7,1.3Hz,1H),7.66(dt,J=8.7,1.4Hz,1H),7.60(t,J=1.8Hz,1H),7.50(ddd,J=8.8,4.3,2.9Hz,1H),6.84–6.79(m,1 H),4.08–4.02(m,3H),3.91–3.86(m,1H),3.61–3.52(m,1H),3.46–3.38(m,1H),2.92–2.82(m,1H),2.67(qd,J=22.0, 20.1,14.5Hz,5H),2.42–2.33(m,2H),2.30(s,3H),1.99(dtd,J=32.6,11.4,10.6,4.5Hz,2H),1.73(h,J=6.8Hz,2H).

[0788] Example 102

[0789] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (156 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 92 mg (1.5 eq) of 2-tetrahydropyran-4-ethanol and 4.0 eq of DIPEA sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5), and concentrate to give compound 102 (light brown foamy solid, 226.2 mg, 89.55% yield, UPLC 97.57%). ESI-MS m / z: 537.20 [M+H] + .

[0790] 1H NMR (600MHz, DMSO-d6) δ8.55(dd,J=4.0,2.4Hz,1H),8.09(dd,J=8.0,1.6Hz,1H),7.95(tt,J=7.7,1.6Hz,1H),7.89(dt,J=8 .7,1.8Hz,1H),7.66(dd,J=8.7,1.4Hz,1H),7.60(t,J=1.8Hz,1H),7.50(ddd,J=7.5,4.6,1.3Hz,1H),6.82(t,J=1.3Hz,1H) ,4.12–4.01(m,3H),3.77(td,J=11.6,4.1Hz,2H),3.19(qd,J=10.9,9.9,1.9Hz,2H),2.68(q,J=6.9Hz,2H),2.61(tt,J=14. 8,6.6Hz,2H),2.30(d,J=1.5Hz,3H),1.51(tt,J=11.1,5.4Hz,3H),1.46(q,J=6.9Hz,2H),1.11(dq,J=12.4,7.3,6.6Hz,2H).

[0791] Example 103

[0792] Compound 97-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.30 g, 6.0 eq), and 4-hydroxypiperidine hydrochloride (0.15 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 103. Compound 103 was separated by TLC (brown oil, 57 mg, 27.50% yield, UPLC 94.99%). ESI-MS m / z: 283.74 [M / 2+H] + .

[0793] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.10(d,J=7.9Hz,1H),7.95(td,J=7.8,3.9Hz,1H),7.88(dt,J=8.7,1.9Hz ,1H),7.66(dd,J=8.7,1.5Hz,1H),7.61(t,J=1.9Hz,1H),7.50(dt,J=7.9,3.2Hz,1H),6.82(d,J=1.7Hz,1H),4.53(d,J=4 .3Hz,1H),4.03(dq,J=10.5,5.9,4.6Hz,3H),3.44–3.39(m,1H),2.68(p,J=7.8Hz,2H),2.61(dt,J=14.2,7.0Hz,2H),2.5 1(p,J=1.8Hz,2H),2.30(s,3H),2.22(t,J=7.2Hz,2H),1.90(t,J=10.7Hz,2H),1.66(q,J=6.5Hz,4H),1.35–1.27(m,2H).

[0794] Example 104

[0795] Weigh 185 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (145 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 100 mg (1.5 eq) of 3-bromo-2-methylpropane-1-ol and 225 mg (4.0 eq) of DIPEA sequentially. Stir the reaction until MS monitoring shows the reaction is complete (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5), and concentrate to obtain compound 104-1 (brown oil, 287.10 mg). ESI-MS m / z: 559.13 [M+H] + ;

[0796] Compound 104-1 (245 mg, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (88 mg, 2.0 eq), potassium carbonate (242 mg, 4.0 eq), and morpholine (114 mg, 3.0 eq) were then added sequentially. The mixture was washed with acetonitrile (5 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 104 (brown oil). Compound 104 was separated by TLC (pale yellow oil, 204 mg, 82.39% yield, UPLC 97.94%). ESI-MS m / z: 283.71 [M / 2+H] + .

[0797] 1 H NMR (600MHz, DMSO-d6) δ8.55(d,J=4.7Hz,1H),8.10(d,J=8.0Hz,1H),7.95(tt,J=7.7,1.6Hz,1H),7.89(dt,J= 8.7,1.9Hz,1H),7.66(dd,J=8.7,1.5Hz,1H),7.59(q,J=2.0Hz,1H),7.50(t,J=6.2Hz,1H),6.82(d,J=1.8Hz,1 H),4.12–4.01(m,3H),3.57–3.49(m,4H),2.70(p,J=8.1,7.4Hz,2H),2.61(h,J=7.7Hz,2H),2.56–2.50(m,4H) ,2.30(s,3H),2.23(q,J=7.3,6.7Hz,1H),2.18–2.11(m,1H),2.03(dd,J=12.1,7.0Hz,1H),0.84–0.79(m,3H).

[0798] Example 105

[0799] Weigh 463 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (362 mg, 1.3 eq) and dissolve them in 20 mL of dichloromethane. Stir, then add 250 mg (1.5 eq) of 3-bromobutane-1-ol and 4.0 eq of DIPEA sequentially. Stir the reaction until MS monitoring shows the reaction is complete (conversion ≥90%). Concentrate, add 20 mL of EA and wash with purified water (20 mL * 5), and concentrate to obtain compound 105-1 (brown oil, 668 mg). ESI-MS m / z: 559.11 [M+H] + .

[0800] Compound 105-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 40 °C. Triethylamine (72 mg, 2.0 eq), potassium carbonate (197 mg, 4.0 eq), and morpholine (93 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 105 (yellow oil). Compound 105 was separated by TLC (yellow oil, 25 mg, 12.5% ​​yield, UPLC 91.35%). ESI-MS m / z: 283.71 [M / 2+H] + .

[0801] 1 H NMR (600MHz, DMSO-d6) δ8.48(d,J=4.7Hz,1H),8.02(d,J=8.0Hz,1H),7.91–7.85(m,1H),7.82(dt,J=8.7,2.0 Hz,1H),7.59(dd,J=8.8,1.6Hz,1H),7.53(q,J=2.2Hz,1H),7.46–7.39(m,1H),6.75(s,1H),3.99(dt,J=21.3 ,7.0Hz,3H),3.52–3.38(m,5H),2.61(p,J=8.2,7.7Hz,2H),2.57–2.47(m,2H),2.35(dd,J=11.3,6.0Hz,2H), 2.23(s,3H),2.21(s,2H),1.70–1.52(m,1H),1.41(dt,J=13.0,6.3Hz,1H),0.81(ddd,J=8.5,6.6,1.5Hz,3H).

[0802] Example 106

[0803] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (312 mg, 6.0 eq), and (S)-bridged morpholine hydrochloride (153 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 106 (yellow oil). Compound 106 was separated by TLC (yellow oil, 128.20 mg, 61.93% yield, UPLC 93.97%). ESI-MS m / z: 275.70 [M / 2+H] + .

[0804] 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.6Hz,1H),8.09(d,J=7.9Hz,1H),7.95(tt,J=7.7,1.7Hz,1H),7.88( dt,J=8.8,1.9Hz,1H),7.66(dd,J=8.7,1.5Hz,1H),7.61(t,J=1.9Hz,1H),7.52–7.48(m,1H),6.82(s,1H ),4.26(s,1H),4.05(t,J=6.3Hz,3H),3.74(d,J=7.6Hz,1H),3.44(dt,J=7.6,1.7Hz,1H),2.79–2.65(m, 4H),2.63–2.51(m,4H),2.35(d,J=9.9Hz,1H),2.30(s,3H),1.62(d,J=9.6Hz,1H),1.52(d,J=9.5Hz,1H).

[0805] Example 107

[0806] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (312 mg, 6.0 eq), and (1R,4R)-2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride (153 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 107 (yellow oil). Compound 107 was separated by TLC (yellow foamy solid, 106.7 mg, 51.55% yield, UPLC 94.34%). ESI-MS m / z: 275.75 [M / 2+H] + .

[0807] 1H NMR(600MHz,DMSO-d6)δ8.54(d,J=4.7Hz,1H),8.14–8.02(m,1H),7.95(tt,J=7.8,1.6Hz,1H),7.88(dt,J=8.8,1.8H z,1H),7.66(dd,J=8.7,1.4Hz,1H),7.63–7.58(m,1H),7.50(ddd,J=7.7,4.8,1.5Hz,1H),6.82(d,J=1.4Hz,1H),4.2 3(d,J=2.6Hz,1H),4.11–3.99(m,3H),3.75(d,J=7.6Hz,1H),3.48–3.43(m,1H),2.76(dd,J=9.9,1.8Hz,1H),2.68(q ,J=8.0,7.4Hz,3H),2.63–2.52(m,4H),2.34(d,J=9.9Hz,1H),2.30(s,3H),1.61(d,J=9.5Hz,1H),1.55–1.48(m,1H).

[0808] Example 108

[0809] Compound 97-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 40 °C. Triethylamine (74 mg, 2.0 eq), potassium carbonate (304 mg, 6.0 eq), and (S)-bridged morpholine hydrochloride (149 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL). The reaction was stirred until MS monitoring showed that the reaction was complete (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 108 (pale yellow oil). Compound 108 was separated by TLC (pale yellow foaming solid, 77.00 mg, 37.27% yield, UPLC 93.08%). ESI-MS m / z: 282.71 [M / 2+H] + .

[0810] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.10(d,J=7.9Hz,1H),7.98–7.91(m,1H),7.88(dt,J=8 .7,2.0Hz,1H),7.66(dd,J=8.8,1.6Hz,1H),7.61(dt,J=4.1,2.0Hz,1H),7.52–7.47(m,1H),6.82(s,1 H),4.28(s,1H),4.06(p,J=7.1,6.4Hz,3H),3.76(t,J=7.5Hz,1H),3.44(dt,J=7.4,2.2Hz,1H),2.76– 2.63(m,4H),2.62–2.53(m,4H),2.46–2.42(m,1H),2.30(s,3H),1.70–1.59(m,3H),1.56–1.48(m,1H).

[0811] Example 109

[0812] Compound 97-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 40 °C. Triethylamine (74 mg, 2.0 eq), potassium carbonate (304 mg, 6.0 eq), and (1R,4R)-2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride (149 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL). The reaction was stirred until MS monitoring showed that the reaction was complete (conversion ≥90%). The mixture was then filtered and concentrated to obtain crude compound 109 (pale yellow oil). Compound 109 was separated by TLC (yellow foamy solid, 83.50 mg, 40.42% yield, UPLC 93.34%).

[0813] ESI-MS m / z: 282.73 [M / 2+H] + .

[0814] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.10(d,J=7.9Hz,1H),7.99–7.92(m,1H),7.92–7.87(m,1H ),7.66(d,J=8.7Hz,1H),7.62(dt,J=3.7,1.7Hz,1H),7.50(dd,J=7.5,4.9Hz,1H),6.82(s,1H),4.28(s,1 H),4.06(p,J=7.1,6.7Hz,3H),3.76(t,J=7.5Hz,1H),3.44(d,J=6.9Hz,1H),2.69(dq,J=14.6,7.6Hz,4H) ,2.63–2.53(m,4H),2.44(dt,J=12.4,7.2Hz,1H),2.30(s,3H),1.69–1.58(m,3H),1.52(d,J=9.7Hz,1H).

[0815] Example 110

[0816] Compound 97-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 60 °C. Triethylamine (74 mg, 2.0 eq), potassium carbonate (304 mg, 6.0 eq), and 3-oxa-6-azabicyclo[3,3,1]heptane hydrochloride (50 mg, 1.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 110 (pale yellow oil). Compound 110 was separated by TLC (pale yellow foaming solid, 25 mg, 12.10% yield, UPLC 98.25%). ESI-MS m / z: 282.78 [M / 2+H] + .

[0817] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.94(td,J=7.8,4.0Hz,1H),7.88(dt,J=8.9,2.0Hz,1 H),7.66(dd,J=8.8,1.6Hz,1H),7.62(t,J=2.0Hz,1H),7.49(t,J=6.2Hz,1H),6.81(s,1H),4.07(tdd,J=12.7,9.7,6.3Hz,3H ),4.02(d,J=10.7Hz,2H),3.52(d,J=10.8Hz,2H),3.30(t,J=4.5Hz,2H),2.69(dq,J=16.1,7.7Hz,2H),2.60(td,J=16.2,15 .4,8.7Hz,2H),2.55(t,J=7.3Hz,2H),2.40(q,J=6.6,5.7Hz,1H),2.30(s,3H),1.66(d,J=8.0Hz,1H),1.57(p,J=7.0Hz,2H).

[0818] Example 111

[0819] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (390 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 134 mg (1.5 eq) of ethylene glycol methyl ether and 608 mg (4.0 eq) of DIPEA sequentially. Stir the reaction until MS monitoring shows the reaction is complete (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5), and concentrate to obtain compound 111 (light brown foamy solid, 483.00 mg, 84.98% yield, UPLC 98.64%). ESI-MS m / z: 483.14 [M+H] + .

[0820] 1H NMR(600MHz,DMSO-d6)δ8.56–8.51(m,1H),8.12–8.05(m,1H),7.94(tt,J=7.7,1.7Hz,1H) ,7.88(dt,J=8.8,2.0Hz,1H),7.66(dd,J=8.7,1.6Hz,1H),7.61(t,J=1.9Hz,1H),7.54–7. 45(m,1H),6.82(t,J=1.5Hz,1H),4.16–4.12(m,2H),4.06(ddd,J=7.6,5.8,1.5Hz,1H),3. 51–3.46(m,2H),3.21(d,J=1.6Hz,3H),2.75–2.64(m,2H),2.63–2.53(m,2H),2.30(s,3H).

[0821] Example 112

[0822] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (390 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 2-cyclohexylethanol (226 mg, 1.5 eq) and DIPEA (608 mg, 4.0 eq) sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate, add EA (10 mL) and wash with purified water (10 mL * 5), and concentrate to give compound 112 (brown oil, 720.3 mg, 99.93% yield, UPLC 96.77%). ESI-MS m / z: 535.19 [M+H] + .

[0823] 1H NMR (600MHz, DMSO-d6) δ8.56–8.52(m,1H),8.09(d,J=8.0Hz,1H),7.94(tt,J=7.8,1.6Hz ,1H),7.88(dt,J=8.8,1.9Hz,1H),7.66(dd,J=8.7,1.4Hz,1H),7.59(t,J=1.9Hz,1H),7. 52–7.46(m,1H),6.82(d,J=1.8Hz,1H),4.29(td,J=5.1,1.4Hz,1H),4.07–4.01(m,2H),2 .67(q,J=6.6,6.1Hz,2H),2.60(dq,J=14.7,7.3Hz,2H),2.30(s,3H),1.69–1.53(m,13H).

[0824] Example 113

[0825] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 60 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (312 mg, 6.0 eq), and 3-oxa-6-azabicyclo[3,3,1]heptane hydrochloride (51 mg, 1.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 113 (yellow oil). Compound 113 was separated by TLC (yellow solid, 40.10 mg, 19.37% yield, UPLC 90.09%). ESI-MS m / z: 275.80 [M / 2+H] + .

[0826] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.95(tt,J=7.8,1.7Hz,1H),7.88(d t,J=8.7,1.9Hz,1H),7.66(dd,J=8.7,1.4Hz,1H),7.61(t,J=1.9Hz,1H),7.53–7.48(m,1H),6.81(s,1H),4 .07–4.01(m,5H),3.54(dd,J=10.7,4.8Hz,2H),3.34(s,2H),2.74(t,J=5.7Hz,2H),2.66(dq,J=13.4,7.3 ,6.7Hz,2H),2.59(dq,J=21.8,7.5,6.9Hz,2H),2.38(q,J=6.6Hz,1H),2.30(s,3H),1.63(d,J=8.0Hz,1H).

[0827] Example 114

[0828] Compound 97-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (8 mL). The solution was heated and stirred in an oil bath at 60 °C. Triethylamine (74 mg, 2.0 eq), potassium carbonate (304 mg, 6.0 eq), and 4,4-difluoropiperidine hydrochloride (173 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (2 mL). The mixture was stirred until the reaction was complete as monitored by MS (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 114 (pink oil). Compound 114 was separated by TLC (pink oil, 81.40 mg, 37.91% yield, UPLC 93.75%).

[0829] ESI-MS m / z: 293.76 [M / 2+H] + .

[0830] 1H NMR(600MHz,DMSO-d6)δ8.54(d,J=4.6Hz,1H),8.12–8.07(m,1H),7.94(tt,J=7.7,1.7Hz,1H),7.88( dt,J=8.8,1.9Hz,1H),7.66(dd,J=8.7,1.5Hz,1H),7.61(t,J=1.9Hz,1H),7.52–7.43(m,1H),6.81(t ,J=1.4Hz,1H),4.05(q,J=6.2Hz,3H),2.68(h,J=9.0Hz,2H),2.61(td,J=14.7,13.8,7.0Hz,2H),2.4 0(s,4H),2.38–2.32(m,2H),2.30(s,3H),1.90(td,J=13.8,13.2,6.0Hz,4H),1.69(p,J=7.0Hz,2H).

[0831] Example 115

[0832] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (390 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 388 mg (3.0 eq) of 2-pyrimidinemethanol and 608 mg (4.0 eq) of DIPEA sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5), and concentrate to give compound 115 (brown foamy solid, 468.50 mg, 77.01% yield, UPLC 96.29%). ESI-MS m / z: 517.12 [M+H] + .

[0833] 1H NMR(600MHz,DMSO-d6)δ8.66(dd,J=4.9,1.5Hz,2H),8.58–8.51(m,1H),8.11(dd,J=7.9,1.6Hz,1H),7 .95(tt,J=7.7,1.7Hz,1H),7.89(dt,J=8.8,1.9Hz,1H),7.68(dd,J=8.7,1.5Hz,1H),7.61(t,J=1.9Hz ,1H),7.50(ddd,J=8.0,3.8,1.4Hz,1H),7.43–7.34(m,1H),6.83(d,J=1.8Hz,1H),5.25(d,J=1.8Hz,2 H), 4.17 (dd, J=8.0, 6.1Hz, 1H), 2.89–2.76 (m, 2H), 2.63 (ddq, J=27.4, 13.9, 7.2Hz, 2H), 2.31 (s, 3H).

[0834] Example 116

[0835] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (390 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 484 mg (3.0 eq) of 2-pyridinylpropanol and 608 mg (4.0 eq) of DIPEA sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5), and concentrate to give compound 116 (orange oil, 604.50 mg, 94.41% yield, UPLC 94.56%). ESI-MS m / z: 272.75 [M / 2+H] + .

[0836] 1H NMR(600MHz,DMSO-d6)δ8.54(d,J=4.5Hz,1H),8.49–8.42(m,1H),8.09(dd,J=8.1,1.6Hz,1H), 7.93(tt,J=7.8,1.7Hz,1H),7.86(dt,J=8.7,1.9Hz,1H),7.69–7.62(m,2H),7.60(t,J=1.9Hz,1 H),7.52–7.47(m,1H),7.22–7.14(m,2H),6.82(d,J=1.8Hz,1H),4.09–4.01(m,3H),2.74(t,J=7 .6Hz,2H),2.67(td,J=9.2,8.8,4.7Hz,2H),2.64–2.51(m,2H),2.30(s,3H),1.99–1.94(m,2H).

[0837] Example 117

[0838] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (390 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 533 mg (3.0 eq) of 4-(2-pyridinyl)-1-butanol and 608 mg (4.0 eq) of DIPEA in sequence. Stir the reaction until MS monitoring shows that the reaction is complete (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5 of purified water), and concentrate to obtain compound 117 (orange oil, 566.00 mg, 86.18% yield, UPLC 97.94%). ESI-MS m / z: 279.76 [M / 2+H] + .

[0839] 1H NMR(600MHz,DMSO-d6)δ8.54(d,J=4.6Hz,1H),8.45–8.41(m,1H),8.08(dd,J=7.8,1.6Hz,1H),7.93( tt,J=7.7,1.6Hz,1H),7.87(dt,J=8.8,1.9Hz,1H),7.71–7.63(m,2H),7.60(t,J=1.9Hz,1H),7.52–7. 46(m,1H),7.22(t,J=7.3Hz,1H),7.19–7.14(m,1H),6.81(t,J=1.4Hz,1H),4.07–4.01(m,3H),2.73–2 .65(m,5H),2.60(dq,J=21.8,7.3,6.8Hz,1H),2.30(s,3H),1.68–1.65(m,2H),1.56(t,J=7.4Hz,2H).

[0840] Example 118

[0841] To a solution of 2-bromopyridine (2.96 g, 18.7 mmol, 1.79 mL, 2.00 eq) in toluene (50.0 mL) was added at -60 °C. Butyllithium (2.50 M, 8.24 mL, 2.20 eq) was then added. Compound 118-1 (1.50 g, 9.36 mmol, 1.00 eq) was added, and the temperature was maintained at -60 °C. The mixture was stirred at -60 °C for 2 hours. LC-MS showed that compound 118-1 was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was quenched at 0 °C with NH4Cl (50.0 mL), and then diluted with ethyl acetate (50.0 mL). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 118-2 (3.30 g, crude) as a yellow solid. ESI-MS M / Z: 241.1 [M+H] +

[0842] DCC (2.06 g, 9.15 mmol, 1.00 eq) was added to a DCM (50.0 mL) solution of compound 118-2 (2.30 g, 9.15 mmol, 1.00 eq) and compound 118-11 (3.86 g, 10.1 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed that 118-2 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with 50.0 mL H₂O and then diluted with ethyl acetate (50.0 mL). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 118-3 (5.89 g, crude product) as a yellow solid. ESI-MS M / Z: 606.0 [M+H] +

[0843] TEA (4.92 g, 48.6 mmol, 6.77 mL, 5.00 eq) was added to a solution of 118-3 (5.89 g, 9.73 mmol, 1.00 eq) in 100 mL of ACN. The mixture was stirred at 25 °C for 12 h. LC-MS showed that 118-3 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with 50.0 mL of H₂O, diluted with 5.00 mL of ethyl acetate, and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 118-4 (6.71 g, crude product) as a yellow gel. ESI-MS M / Z: 384.1 [M+H] +

[0844] NH4OAc (2.36 g, 30.6 mmol, 2.00 eq) was added to a solution of 118-4 (5.86 g, 15.3 mmol, 1.00 eq) in AcOH (50.0 mL). The mixture was stirred at 25 °C for 1 hour. LCMS showed that 118-4 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with H2O (25.0 mL) and then diluted with ethyl acetate (25.0 mL). The combined organic layers were washed with brine (25.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 118-5 (3.86 g, 10.4 mmol, 67.8% yield, 98.1% purity) as a yellow solid. ESI-MS M / Z: 366.1 [M+H] +

[0845] P2S5 (5.47 g, 24.6 mmol, 2.62 mL, 3.00 eq) was added to a solution of 118-5 (3.00 g, 8.21 mmol, 1.00 eq) and Na2CO3 (3.48 g, 32.8 mmol, 4.00 eq) in toluene (50.0 mL). The mixture was stirred at 80 °C for 12 h. LC-MS showed that 118-5 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched at 0 °C by adding H2O (25.0 mL), diluted with ethyl acetate (25.0 mL), and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 118-6 (3.87 g, crude) as a yellow solid. ESI-MS M / Z: 382.1 [M+H] +

[0846] A solution of 118-6 (3.80 g, 9.96 mmol, 1.00 eq) in 10.0 mL of THF was stirred for 30 min at 0 °C. Then, 2,2-dimethoxypropyl-1-amine (11.9 g, 99.6 mmol, 10.0 eq) was added, and the mixture was stirred at 80 °C for 3.5 h. LCMS showed that 118-6 was completely consumed, and the molecular weight of the target product was detected. The cooled mixture was diluted with ethyl acetate and washed successively with brine (20.0 mL × 2). The aqueous layer was extracted with ethyl acetate (20.0 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 118-7 (8.30 g, crude product), a brown gel. ESI-MS M / Z: 467.2 [M+H] +

[0847] To a methanol (1.00 mL) solution of 118-7 (180 mg, 386 μmol, 1.00 eq), HCl / MeOH (2.00 M, 1.93 mL, 10.0 eq) was added. The mixture was stirred at 25 °C for 2 hours. LCMS showed that 118-7 was completely consumed, and the molecular weight of the target product was detected. The mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC to give 118-8 (75.0 mg, 183.94 μmol, 47.7% yield, 98.7% purity) as a yellow solid. ESI-MS M / Z: 403.1 [M+H] +

[0848] 1H NMR: (MeOD, 400MHz) δ8.47-8.50(m,1H),7.93-8.02(m,2H),7.47-7.53(m,1H),7.12(s,1H),6.99(s,1H),6.82(d,J =0.8Hz,1H),4.65-4.78(m,2H),4.02-4.08(m,1H),3.65(s,3H),3.15-3.28(m,2H),2.60-2.80(m,4H),2.38(s,3H).

[0849] To a methanol (0.50 mL) solution of 118-8 (401 mg, 996 μmol, 1.00 eq), NaOH (79.7 mg, 1.99 mmol, 2.00 eq) and purified water (0.5 mL) were added. The mixture was stirred at 45 °C for 4 hours. LC-MS showed that 118-8 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with 5.00 mL HCl, diluted with 5.00 mL EtOAc, and extracted with 5.00 mL (5.00 mL × 2) EtOAc. The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 118-9 (378 mg, crude) as a red solid. ESI-MS M / Z: 389.2 [M+H] +

[0850] A solution of 118-9 (100 mg, 257 μmol, 1.00 eq), N-(2-hydroxyethyl)carbamate tert-butyl ester (83.0 mg, 515 μmol, 79.7 μL, 2.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (263 mg, 1.03 mmol, 4.00 eq), and TEA (209 mg, 2.06 mmol, 287 μL, 8.00 eq) in DCM (1.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. LCMS showed that 118-9 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (2.00 mL), diluted with EtOAc (2.00 mL), and extracted with EtOAc (2.00 mL x 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to 118-10 (83.0 mg, 153 μmol, 59.6% yield, 98.2% purity) as a pale yellow solid. ESI-MS M / Z: 532.1 [M+H] +

[0851] To a solution of 118-10 (113 mg, 213 μmol, 1.00 eq) in 1.00 mL of ACN, benzenesulfonic acid (33.6 mg, 213 μmol, 1.00 eq) was added. The mixture was stirred at 0 °C for 2 hours. LC-MS showed that 118-10 was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to 118 (81.0 mg, 188 μmol, 88.3% yield, 100% purity) as a yellow oil. ESI-MS M / Z: 432.1 [M+H] +

[0852] 1 H NMR: (DMSO-d6,400MHz)δ8.50-8.54(m,1H),7.97-8.02(m,1H),7.88-7.94( m,1H),7.43-7.49(m,1H),7.19(s,1H),7.06(s,1H),6.76(d,J=1.20Hz,1H), 4.60-4.71(m,2H),4.07-4.13(m,2H),3.95-4.00(m,1H),3.07-3.22(m,4H) ,2.92(t,J=6.00Hz,2H),2.65-2.78(m,2H),2.52-2.64(m,2H),2.28(s,3H).

[0853] Example 119

[0854] The mixture of 118-8 (200 mg, 5151 μmol, 1.00 eq), N-(2-hydroxyethyl)-N-methyl-tert-butyl carbamate (90.2 mg, 515 μmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (526 mg, 2.06 mmol, 4.00 eq), and TEA (417 mg, 4.12 mmol, 573 μL, 8.00 eq) was degassed in a DCM solution (1.00 mL) and purged three times with nitrogen. The mixture was then stirred at 20 °C for 1 hour under a nitrogen atmosphere. LCMS showed that 118-8 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to 119-2 (170 mg, 312 μmol, 60.5% yield, 100% purity) as a blue solid. ESI-MS M / Z: 546.3 [M+H]+

[0855] To a solution of 119-2 (160 mg, 293 μmol, 1.00 eq) in 2.00 mL of ACN, benzenesulfonic acid (46.4 mg, 293 μmol, 1.00 eq) was added. The mixture was stirred at 0 °C for 2 hours. LC-MS showed that 119-2 was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to 119 (108 mg, 240 μmol, 81.8% yield, 99.0% purity) as a purple solid. ESI-MS M / Z: 446.2 [M+H] +

[0856] 1 H NMR: (CDCl3, 400MHz) δ8.56-8.59(m,1H),8.13-8.18(m,1H),7.83-7.86(m,2H),7.33(s,1H),7.02(s,1H),6.83(s,1H),4.68-4.79(m,2H),4.4 7-4.53(m,2H),4.19(t,J=7.00Hz,1H),3.31-3.42(m,3H),3.18-3.28( m,1H),2.95-3.10(m,2H),2.77-2.87(m,3H),2.74(s,3H),2.37(s,3H).

[0857] Example 120

[0858] A solution of 118-8 (200 mg, 514.91 μmol, 1.00 eq), N-(2-hydroxypropyl)carbamate tert-butyl ester (180 mg, 1.03 mmol, 2.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (526 mg, 2.06 mmol, 4.00 eq), and TEA (417 mg, 4.12 mmol, 573 μL, 8.00 eq) in DCM (2.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 1 hour under a nitrogen atmosphere. LCMS showed complete consumption of 118-8 and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to 120-2 (163 mg, 299 μmol, 58.0% yield, 100% purity), as a grayish-white solid. ESI-MS M / Z: 546.3 [M+H] +

[0859] To a solution of 120-2 (153 mg, 280 μmol, 1.00 eq) in 2.00 mL of ACN, benzenesulfonic acid (44.4 mg, 280 μmol, 1.00 eq) was added. The mixture was stirred at 0 °C for 2 hours. LC-MS showed that 120-2 was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to 120 (117 mg, 261 μmol, 93.0% yield, 99.3% purity) as a yellow solid. ESI-MS M / Z: 446.2 [M+H] +

[0860] 1 H NMR:(MeOD,400MHz)δ8.90-8.95(m,1H),8.60-8.67(m,1H),8.13-8.26(m,2H ),7.60(s,1H),7.40-7.42(m,1H),7.28-7.31(m,1H),5.10-5.21(m,1H),4.76 -4.86(m,1H),4.56-4.63(m,1H),4.40-3.52(m,1H),3.37(s,2H),3.05-3.30( m,3H),2.85-3.00(m,2H),2.65-2.82(m,1H),2.48(s,3H),1.30-1.34(m,3H).

[0861] Example 121

[0862] To a DCM (2.00 mL) solution of compound 12-12 (100 mg, 259 μmol, 1.00 eq), tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (90.7 mg, 517 μmol, 2.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (264 mg, 1.04 mmol, 4.00 eq) and TEA (209 mg, 2.07 mmol, 288 μL, 8.00 eq) were added. The mixture was stirred at 20 °C for 12 h. LC-MS showed the residue of compound 12-12 and detected the molecular weight of the target product. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give a yellow solid compound 121-1 (100 mg, 183 μmol, 70.9% yield, 99.7% purity).

[0863] ESI-MS M / Z: 544.3 [M+H] +

[0864] TFA (126 mg, 1.10 mmol, 82.0 μL, 6.00 eq) was added to a DCM (2.00 mL) solution of compound 121-1 (100 mg, 183 μmol, 1.00 eq). The mixture was stirred at 20 °C for 2 h. LCMS showed that compound 121-1 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high performance liquid chromatography to give a pink colloidal compound 121 (150 mg, 250 μmol, 90.6% yield, 92.9% purity).

[0865] 1 H NMR: (400MHz, MeOD) δ8.55 (d, J=4.8Hz, 1H), 7.99-8.06 (m, 2H), 7.72 (s, 1H), 7 .56-8.59(m,1H),7.44(d,J=1.2Hz,1H),7.29(s,1H),4.34-4.43(m,3H),3.31 -3.35(m,2H),3.16-3.23(m,1H),3.01-3.13(m,2H),2.90-2.99(m,2H),2.76- 2.85(m,2H),2.76(s,1H),2.59-2.66(m,1H),2.53(s,3H),2.16-2.27(m,2H).

[0866] Example 122

[0867] To a DCM (2.00 mL) solution of compound 12-12 (100 mg, 259 μmol, 1.00 eq), N-(2-hydroxypropyl)carbamate tert-butyl ester (90.7 mg, 517.7 μmol, 2.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (264 mg, 1.04 mmol, 4.00 eq) and TEA (209 mg, 2.07 mmol, 288 μL, 8.00 eq) were added. The mixture was stirred at 20 °C for 12 h. LCMS showed that compound 12-12 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give a yellow solid compound 122-1 (88.0 mg, 158 μmol, 60.9% yield, 97.4% purity).

[0868] ESI-MS M / Z: 544.3 [M+H] +

[0869] TFA (110 mg, 971 μmol, 72.1 μL, 6.00 eq) was added to a DCM (1.00 mL) solution of compound 122-1 (88.0 mg, 162 μmol, 1.00 eq). The mixture was stirred at 20 °C for 2 h. LCMS showed that compound 122-1 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high performance liquid chromatography to give a yellow gel-like compound 122 (150 mg, 220 μmol, 90.6% yield, 98.5% purity).

[0870] ESI-MS M / Z: 444.2 [M+H] +

[0871] 1 H NMR: (400MHz, MeOD) δ8.56 (dd, J = 4.8, 1.2 Hz, 1H), 8.01-8.08 (m, 2H), 7.73 (s, 1H), 7.57-7.61 (m, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 5.12-5.1 6(m,1H),4.38-4.42(m,1H),3.07-3.19(m,7H),2.82-2.97(m,2H),2.52-2.79(m,1H),2.52(s,3H),2.15-2.27(m,2H),1.26-1.33(m,3H).

[0872] Example 123

[0873] NaH (967 mg, 24.2 mmol, 60% purity, 1.20 eq) was added to a THF (30.0 mL) solution of 123-1 (2.40 g, 20.1 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, 123-2 (4.43 g, 20.1 mmol, 1.00 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2.5 h. LCMS showed that 123-1 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched at 10 °C by adding ammonium chloride (50.0 mL), diluted with ethyl acetate (20.0 mL), and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue as 123-3 (6.67 g, crude product) as a purple solid. ESI-MS M / Z: 321.0 [M+H] +

[0874] To a solution of 123-3 (6.17 g, 19.3 mmol, 1.00 eq) in DCM (60.0 mL), m-CPBA (5.89 g, 29.0 mmol, 85% purity, 1.50 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS showed that 123-3 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched at 10 °C by adding Na₂SO₃ (100 mL), then diluted with 40.0 mL of ethyl acetate, and extracted with 40.0 mL of ethyl acetate (40.0 mL × 2). The combined organic layers were washed with brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 123-4 (3.73 g, 12.1 mmol, 62.6% yield, 100% purity) as a yellow solid. ESI-MS M / Z: 309.8 [M+H] +

[0875] A solution of 123-4 (2.06 g, 6.69 mmol, 1.00 eq), Fe (1.87 g, 33.43 mmol, 5.00 eq), ammonium chloride (3.58 g, 66.9 mmol, 10.0 eq), and purified water (4.00 mL) in ethanol (16.0 mL) was degassed, purged three times with nitrogen, and then stirred at 80 °C for 3 hours under a nitrogen atmosphere. LC-MS showed complete consumption of 123-4, and the molecular weight of the target product was detected. The cooled mixture was diluted with ethyl acetate and washed successively with ethyl acetate (100 mL x 2) and brine (100 mL x 2). The aqueous layer was extracted with sodium sulfate, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography to 123-5 (1.83 g, 6.31 mmol, 94.4% yield, 95.9% purity) as a yellow solid. ESI-MS M / Z: 280.0 [M+H] +

[0876] At 0 °C, 123-5 (1.10 g, 2.27 mmol, 1.00 eq) and methyl rac-(4S)-5-chloro-4-(9H-fluorene-9-methoxycarbonylamino)-5-oxovalerate (911 mg, 2.27 mmol, 1.00 eq) were added to DCM (20.0 mL). The mixture was stirred at 20 °C for 12 h. LCMS showed that 123-5 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched at 0 °C by adding purified water (50.0 mL), then diluted with ethyl acetate (50.0 mL), and the combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to obtain 123-6 (580 mg, crude) as a yellow solid. ESI-MS M / Z: 643.1 [M+H] +

[0877] To a solution of 123-6 (900 mg, 1.40 mmol, 1.00 eq) in DCM (10.0 mL), piperidine (238 mg, 2.80 mmol, 276 μL, 2.00 eq) was added. The mixture was stirred at 20 °C for 6 hours. LC-MS showed that 123-6 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (50.0 mL) and then diluted with ethyl acetate (50.0 mL). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to obtain 123-7 (5.89 g, crude product) as a yellow solid. ESI-MS M / Z: 403.0 [M+H] +

[0878] P2S5 (331 mg, 1.49 mmol, 158 μL, 1.50 eq) and Na2CO3 (315 mg, 2.98 mmol, 3.00 eq) were added to a DCE (20.0 mL) solution of 123-7 (400 mg, 992 μmol, 1.00 eq). The mixture was stirred at 30 °C for 12 h. LCMS showed that 123-7 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (2.00 mL), diluted with ethyl acetate (5.00 mL), and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to obtain 123-8 (250 mg, 594 μmol, 59.9% yield, 99.7% purity) as a yellow solid. ESI-MS M / Z: 421.0 [M+H] +

[0879] A solution of 123-8 (200 mg, 477 μmol, 1.00 eq) and 2,2-dimethoxypropyl-1-amine (284 mg, 2.38 mmol, 5.00 eq) in THF (2.00 mL) was stirred at 80 °C for 12 h. LC-MS showed that 123-8 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (2.00 mL) and then diluted with ethyl acetate (2.00 mL). The combined organic layers were washed with brine (2.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 123-9 (298 mg, crude product), a brown gel. ESI-MS M / Z: 506.0 [M+H] +

[0880] To a methanol (1.00 mL) solution of 123-9 (298 mg, 591 μmol, 1.00 eq), HCl / MeOH (2 M, 295 μL, 1.00 eq) was added. The mixture was stirred at 20 °C for 3 h. LC-MS showed that 123-9 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched at 0 °C by adding purified water (25.0 mL), diluted with ethyl acetate (25.0 mL), and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 123-10 (356 mg, crude), a brown gel. ESI-MS M / Z: 440.1 [M+H] +

[0881] To a solution of 123-10 (56.0 mg, 127 μmol, 1.00 eq) in methanol (0.1 mL) and tetrahydrofuran (0.100 mL), LiOH·H₂O (10.7 mg, 254 μmol, 2.00 eq) and purified water (0.05 mL) were added. The mixture was stirred at 40 °C for 2 hours. LCMS showed that 123-10 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with 1.00 mL of ice water, then extracted with ethyl acetate (2.00 mL x 3), washed with brine (2.00 mL x 2), filtered, and the filtrate was concentrated under reduced pressure to obtain 123-11 (48.0 mg, crude), as a brown solid. ESI-MS M / Z: 428.0 [M+H] +

[0882] A solution of 123-11 (45.0 mg, 105 μmol, 1.00 eq), 2-thiomorpholine ethanol (15.5 mg, 105 μmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (108 mg, 422 μmol, 4.00 eq), and TEA (85.4 mg, 845 μmol, 117 μL, 8.00 eq) in DCM (1.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 12 hours under a nitrogen atmosphere. LCMS showed that 123-11 was completely consumed, and the molecular weight of the target product was detected. The mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to 123 (52.0 mg, 90.6 μmol, 85.8% yield, 96.8% purity) as a yellow solid. ESI-MS M / Z: 557.1 [M+H] +

[0883] 1 H NMR: (MeOD, 400MHz) δ8.47-8.51(m,1H),8.24-8.28(m,1H),7.95-7.99(m,1H),7.48-7.53(m,1H),7.13(s,1H),7.00(s,1H),6.83-6.85(m,1H),4 .65-4.79(m,2H),4.22-4.27(m,2H),4.06-4.12(m,1H),3.18-3.28(m,1H ),2.85-2.89(m,4H),2.74-2.79(m,4H),2.59-2.63(m,3H),2.39(s,3H).

[0884] Example 124

[0885] A solution of 118-8 (100 mg, 257 μmol, 1.00 eq), 2-morpholinoethanol (33.8 mg, 257 μmol, 31.5 μL, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (263 mg, 1.03 mmol, 4.00 eq), and TEA (208 mg, 2.06 mmol, 287 μL, 8.00 eq) in DCM (1.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. LC-MS showed complete consumption of 118-8 and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase HPLC to 124 (81.0 mg, 156 μmol, 60.5% yield, 96.5% purity) as a yellow solid. ESI-MS M / Z: 502.3 [M+H] +

[0886] 1 H NMR: (MeOD, 400MHz) δ8.48-8.51(m,1H),7.94-8.03(m,2H),7.48-7.53(m,1H ),7.13(s,1H),6.99(s,1H),6.83(d,J=0.80Hz,1H),4.65-4.79(m,2H),4.21 -4.26(m,2H),4.06-4.11(m,1H),3.60(t,J=4.80Hz,4H),3.15-3.28(m,2H), 2.71-2.77(m,3H),2.61-2.68(m,2H),2.48-2.53(m,4H),2.38-2.40(m,3H).

[0887] Example 125

[0888] A solution of 118-8 (100 mg, 257 μmol, 1.00 eq), 2-thiomorpholine ethanol (37.9 mg, 257 μmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (263 mg, 1.03 mmol, 4.00 eq), and TEA (208 mg, 2.06 mmol, 287 μL, 8.00 eq) in DCM (2.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. LC-MS showed complete consumption of 118-8 and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to obtain 125 (96.0 mg, 182 μmol, 71.0% yield, 98.5% purity), which was a yellow solid.

[0889] ESI-MS M / Z: 518.3 [M+H] +

[0890] 1 H NMR: (D2O, 400MHz) δ8.46 (d, J = 4.80Hz, 1H), 7.72-7.77 (m, 2H), 7.52-7.5 7(m,1H),7.16(s,1H),7.09(s,1H),7.06(s,1H),4.65-4.72(m,2H),4.44 (t,J=0.80Hz,2H),4.19-4.27(m,1H),4.41-4.53(m,6H),3.09-3.29(m,2 H),2.83-2.89(m,4H),2.68-2.81(m,3H),2.50-2.65(m,1H),2.36(s,3H).

[0891] Example 126

[0892] A solution of 118-8 (100 mg, 257 μmol, 1.00 eq), 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (46.2 mg, 257 μmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (263 mg, 1.03 mmol, 4.00 eq), and TEA (208 mg, 2.06 mmol, 287 μL, 8.00 eq) in DCM (2.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. LCMS showed complete consumption of 118-8 and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 126 (98.0 mg) as a yellow solid.

[0893] ESI-MS M / Z: 550.2 [M+H] +

[0894] 1 H NMR: (D2O, 400MHz) δ8.46 (d, J = 4.80Hz, 1H), 7.97 (t, J = 7.60Hz, 1H), 7.81-7.87 ( m,1H),7.51-7.58(m,1H),7.18(s,1H),7.07(s,2H),4.65-4.72(m,2H),4.21(t,J =4.80Hz,3H),3.16-3.30(m,2H),3.10-3.15(m,4H),2.90-3.06(m,4H),2.79-2. 83(m,2H),2.74-2.78(m,2H),2.66-2.74(m,1H),2.55-2.65(m,1H),2.36(s,3H).

[0895] Example 127

[0896] A solution of 118-8 (100 mg, 257 μmol, 1.00 eq), 2-(4-methylpiperazin-1-yl)ethanol (37.1 mg, 257 μmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (263 mg, 1.03 mmol, 4.00 eq), and TEA (208 mg, 2.06 mmol, 287 μL, 8.00 eq) in DCM (2.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. LCMS showed that 118-8 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue of 127 (113 mg) as a yellow solid. ESI-MS M / Z: 515.3 [M+H] +

[0897] 1 H NMR: (D2O, 400MHz) δ8.47 (d, J = 4.00Hz, 1H), 8.36 (s, 1H), 7.95-8.02 (m, 1H), 7.82-7.87(m,1H),7.17-7.23(m,2H),7.12(s,1H),4.77-4.79(m,2H),4.67- 4.72(m,1H),4.31-4.36(m,1H),4.21-4.28(m,2H),3.10-3.40(m,6H),2.83( s,3H),2.77-2.82(m,4H),2.68-2.76(m,2H),2.53-2.65(m,1H),2.39(s,3H).

[0898] Example 128

[0899] A solution of 118-8 (100 mg, 257 μmol, 1.00 eq), 2-pyrrolidone-1-ylethanol (29.7 mg, 257 μmol, 30.10 μL, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (263 mg, 1.03 mmol, 4.00 eq), and TEA (208 mg, 2.06 mmol, 287 μL, 8.00 eq) in DCM (1.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. LCMS showed that 118-8 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase HPLC to obtain 128 (82.0 mg, 166 μmol, 64.6% yield, 98.5% purity) as a yellow solid.

[0900] ESI-MS M / Z: 486.2 [M+H] +

[0901] 1 H NMR: (D2O, 400MHz) δ8.42-8.46(m,1H),7.90-7.97(m,1H),7.76(d,J=8.00 Hz,2H),7.10(s,1H),6.96(s,1H),6.83-6.85(m,1H),4.78-4.77(m,1H),4. 63-4.72(m,2H),4.39(t,J=4.80Hz,2H),4.02-4.07(m,1H),3.46-3.51(m, 2H),3.00-3.35(m,5H),2.55-2.85(m,4H),2.31(s,3H),2.38-2.40(m,3H).

[0902] Example 129

[0903] A solution of 118-8 (100 mg, 257 μmol, 1.00 eq), 2-bromoethanol (32.2 mg, 257 μmol, 18.3 μL, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (263 mg, 1.03 mmol, 4.00 eq), and TEA (208 mg, 2.06 mmol, 287 μL, 8.00 eq) in DCM (1.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 1 hour under a nitrogen atmosphere. LCMS showed that 118-8 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with purified water (5.00 mL), diluted with EtOAc (5.00 mL), and extracted with EtOAc (5.00 mL × 2). The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC to give 129-1 (45.0 mg, 89.5 μmol, 34.8% yield, 98.5% purity) as a blue solid.

[0904] ESI-MS M / Z: 497.1 [M+H] +

[0905] 129-1 (45.0 mg, 90.8 μmol, 1.00 eq), pyrrolidine-2-ylmethanol (23.0 mg, 227 μmol, 2.50 eq), and DIEA (23.48 mg, 182 μmol, 31.7 μL, 2.00 eq) were dissolved in ACN (1.00 mL). The mixture was degassed and purged three times with nitrogen, and then stirred at 20 °C for 1 hour under a nitrogen atmosphere. LC-MS showed that 129-1 was completely consumed, and the molecular weight of the target product was detected. The mixture was concentrated under reduced pressure to obtain the residue. 129 (45.0 mg, 87.2 μmol, 96.0% yield, 99.9% purity) was purified by reversed-phase HPLC as a white solid.

[0906] ESI-MS M / Z: 516.3 [M+H] +

[0907] 1H NMR: (MeOD,400MHz)δ8.48-8.53(m,1H),7.95-8.00(m,2H),7.48-7.54(m,1H),7.12(s,1H),6.99 (s,1H),6.83(d,J=0.80Hz,1H),4.65-4.80(m,2H),4.25-4.40(m,2H),4.05-4.12(m,1H),3.55-3. 70(m,2H),3.40-3.50(m,2H),3.12-3.28(m,3H),2.98-3.10(m,1H),2.79-2.87(m,1H),2.72-2.77 (m,3H),2.63-2.71(m,1H),2.39(s,3H),2.00-2.10(m,1H),1.82-1.97(m,2H),1.70-1.80(m,1H).

[0908] Example 130

[0909] 129-1 (200 mg, 404 μmol, 1.00 eq), pyrrolidine-3-ylmethanol (102 mg, 1.01 mmol, 2.50 eq), and DIEA (104 mg, 807 μmol, 141 μL, 2.00 eq) were dissolved in ACN (2.00 mL). The mixture was degassed and purged three times with nitrogen, and then stirred at 20 °C for 1 hour under a nitrogen atmosphere. LC-MS showed that 129-1 was completely consumed, and the molecular weight of the target product was detected. The mixture was concentrated under reduced pressure to obtain the residue. Reversed-phase HPLC purification gave 130 (58.0 mg, 111 μmol, 48.0% yield, 99.3% purity) as a green solid.

[0910] ESI-MS M / Z: 516.3 [M+H] +

[0911] 1H NMR: (MeOD, 400MHz) δ8.49-8.52(m,1H),7.94-7.99(m,2H),7.48-7.54(m,1H),7.12(s,1H),6 .99(s,1H),6.83(d,J=1.20Hz,1H),4.65-4.80(m,2H),4.37(t,J=5.20Hz,2H),4.05-4.12(m,1 H),3.48-3.60(m,2H),3.33-3.41(m,3H),3.17-3.29(m,4H),3.01-3.11(m,1H),2.72-2.85(m, 3H),2.63-2.72(m,1H),2.50-2.60(m,1H),2.39(s,3H),2.07-2.20(m,1H),1.74-1.87(m,1H).

[0912] Example 131

[0913] 129-1 (200 mg, 404 μmol, 1.00 eq), piperidine-4-ol (102 mg, 1.01 mmol, 2.50 eq), and DIEA (104 mg, 807 μmol, 141 μL, 2.00 eq) were dissolved in ACN (2.00 mL). The mixture was degassed and purged three times with nitrogen, and then stirred at 20 °C for 1 hour under a nitrogen atmosphere. LC-MS showed that 129-1 was completely consumed, and the molecular weight of the target product was detected. The mixture was concentrated under reduced pressure to obtain the residue. 131 (63.0 mg, 122 μmol, 52.4% yield, 99.8% purity) was purified by reversed-phase HPLC as a purple solid.

[0914] ESI-MS M / Z: 516.3 [M+H] +

[0915] 1H NMR: (MeOD, 400MHz) δ8.49-8.52(m,1H),7.95-7.99(m,2H),7.48-7.55(m,1H),7.12 (s,1H),7.00(s,1H),6.83(d,J=0.80Hz,1H),4.65-4.79(m,2H),4.38(t,J=5.20Hz,2 H),4.06-4.12(m,1H),3.77-3.88(m,1H),3.17-3.29(m,5H),2.90-3.05(m,2H),2.73 -2.86(m,3H),2.61-2.71(m,1H),2.39(s,3H),1.89-2.01(m,2H),1.64-1.78(m,2H).

[0916] Example 132

[0917] To a DCM (2.00 mL) solution of compound 12-12 (200 mg, 518 μmol, 1.00 eq), 2-thiomorpholinoethanol (114 mg, 776 μmol, 1.50 eq), 2-chloro-1-methylpyridin-1-onium iodide (397 mg, 1.55 mmol, 3.00 eq) and triethylamine (314 mg, 3.11 mmol, 432 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LCMS showed that compound 12-12 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC to give compound 132 (90.0 mg, 77.3 μmol, 27.0% yield, 99.7% purity) as a gray solid.

[0918] ESI-MS M / Z: 516.2 [M+H] +

[0919] 1 H NMR: (400MHz, MeOD) δ8.49(dt,J=4.4,1.2Hz,1H),7.94-8.00(m,2H),7.49-7.52(m,2H),7.13(s,1H),6.86(d,J=1.2Hz,1H),4.31(t,J=5. 6Hz,2H),4.07-5.11(m,1H),3.09-3.15(m,5H),3.02-3.06(m,3H),2.89-3.00(m,2H),2.62-2.80(m,8H),2.40(s,3H),2.13-2.23(m,2H).

[0920] Example 133

[0921] To a DCM (2.00 mL) solution of compound 12-12 (200 mg, 518 μmol, 1.00 eq), 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (111 mg, 621 μmol, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (397 mg, 1.55 mmol, 3.00 eq), and triethylamine (314 mg, 3.11 mmol, 432 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LCMS showed complete consumption of compound 12-12, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 133 (103 mg, 187 μmol, 36.2% yield, 99.6% purity) as a gray solid.

[0922] ESI-MS M / Z: 548.2 [M+H] +

[0923] 1 H NMR: (400MHz, MeOD) δ8.49(d,J=5.2Hz,1H),7.95-8.04(m,2H),7.49-7.54(m,2H),7.16(s,1H),6.91(d,J=0.8Hz,1H),4.20(t,J=5.2Hz ,2H),4.09-4.13(m,1H),3.00-3.14(m,2H),2.91-2.97(m,10H),2.74-2.80(m,5H),2.63-2.70(m,1H),2.41(s,3H),2.15-2.23(m,2H).

[0924] Example 134

[0925] To a DCM (2.00 mL) solution of compound 12-12 (200 mg, 518 μmol, 1.00 eq), 2-(4-methylpiperazin-1-yl)ethanol (89.6 mg, 621 μmol, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (397 mg, 1.55 mmol, 3.00 eq), and triethylamine (3147 mg, 3.11 mmol, 4327 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LC-MS showed complete consumption of compound 12-12, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC to give compound 134 as a yellow solid (101 mg, 193 μmol, 37.3% yield, 98.1% purity). ESI-MS M / Z: 513.3 [M+H] +

[0926] 1 H NMR: (400MHz, MeOD) δ8.49(dt,J=4.8,1.2Hz,1H),7.95-8.00(m,2H),7.49-7.53(m,2H),7.13(s,1H),6.86(d,J=1.2Hz,1H),4.24( t,J=5.6Hz,2H),4.04-4.08(m,1H),2.95-3.25(m,10H),2.83(s,3H),2.61-2.80(m,8H),2.41(d,J=0.8Hz,3H),2.14-2.23(m,2H).

[0927] Example 135

[0928] To a DCM solution of compound 12-12 (200 mg, 518 μmol, 1.00 eq) in 2.00 mL, 2-pyrrolidone-1-ylethanol (71.5 mg, 621 μmol, 72.6 μL, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (397 mg, 1.55 mmol, 3.00 eq), and triethylamine (314 mg, 3.11 mmol, 432 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LC-MS showed complete consumption of compound 12-12, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 135 (110 mg, 227 μmol, 44.0% yield, 100% purity) as a yellow solid. ESI-MS M / Z: 484.2 [M+H] +

[0929] 1 H NMR: (400MHz, MeOD) δ8.49 (dt, J=4.8, 1.2Hz, 1H), 7.96-8.00 (m, 2H), 7.49-7.5 2(m,2H),7.12(s,1H),6.86(d,J=1.2Hz,1H),4.40(t,J=4.8Hz,2H),4.05-4.09 (m,1H),3.50-3.53(m,2H),3.41(s,4H),2.91-3.16(m,4H),2.75-2.82(m,3H), 2.64-2.70(m,1H),2.40(d,J=0.4Hz,3H),2.12-2.24(m,2H),2.05-2.09(m,4H).

[0930] Example 136

[0931] To a DCM solution (3.00 mL) of compound 12-12 (300 mg, 776 μmol, 1.00 eq), 2-bromoethanol (116 mg, 931 μmol, 66.0 μL, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (595 mg, 2.33 mmol, 3.00 eq) and triethylamine (471 mg, 4.66 mmol, 648 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LC-MS showed that compound 12-12 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give a grayish-white solid compound 136-1 (270 mg, 506 μmol, 65.2% yield, 95.9% purity). ESI-MS M / Z: 495.1 [M+H] +

[0932] To a DMF (1.00 mL) solution of compound 136-1 (50.0 mg, 101 μmol, 1.00 eq) and pyrrolidine-2-ylmethanol (15.4 mg, 152 μmol, 1.50 eq), NaI (22.8 mg, 152 μmol, 1.50 eq) and K₂CO₃ (70.0 mg, 507 μmol, 5.00 eq) were added. The mixture was stirred at 20 °C for 12 h. LC-MS showed that compound 136-1 was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 136 (40.0 mg, 77.9 μmol, 76.9% yield, 100% purity) as a purple solid. ESI-MS M / Z: 514.3 [M+H] +

[0933] 1 H NMR: (400MHz, MeOD) δ8.49 (d, J=4.8Hz, 1H), 7.96-8.00 (m, 2H), 7.48-7.52 (m, 2H), 7.12 (s,1H),6.85(s,1H),4.40-7.42(m,2H),4.05-4.09(m,1H),3.80-3.85(m,1H),3.62-3.7 2(m,3H),3.53-3.60(m,1H),3.33-3.39(m,1H),2.85-3.20(m,5H),2.75-2.82(m,3H),2 .65-2.70(m,1H),2.40(s,3H),2.10-2.24(m,3H),1.95-2.08(m,2H),1.82-1.89(m,1H).

[0934] Example 137

[0935] To a DMF (1.00 mL) solution of compound 136-1 (100 mg, 203 μmol, 1.00 eq), pyrrolidine-3-ylmethanol (30.8 mg, 304 μmol, 1.50 eq), NaI (45.6 mg, 304 μmol, 1.50 eq) and potassium carbonate (140 mg, 1.01 mmol, 5.00 eq) were added. The mixture was stirred at 20 °C for 12 h. LCMS showed that compound 136-1 was completely consumed. A new peak was observed on LCMS, and the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high performance liquid chromatography (column: CD01 Phenomenex luna C18 150*25*10um; mobile phase: [water (FA)-ACN]; gradient: 10%-33% B, duration 10 min) to give a pale yellow solid compound 137 (50.0 mg, 97.3 μmol, 48.0% yield, 100% purity).

[0936] ESI-MS m / z: 514.3 [M+H] +

[0937] 1H NMR: (400MHz, MeOD) δ8.49 (d, J=4.8Hz, 1H), 7.93-7.97 (m, 2H), 7.48-7.52 (m,2H),7.12(s,1H),6.86(s,1H),4.40(t,J=4.8Hz,2H),4.05-4.09(m,1H) ,3.40-3.62(m,7H),3.20-3.3.27(m,1H),2.85-3.17(m,4H),2.74-2.82(m, 3H),2.58-2.70(m,2H),2.40(s,3H),2.12-2.24(m,3H),1.86-1.94(m,2H).

[0938] Example 138

[0939] To a DCM (1.00 mL) solution of compound 136-1 (53.0 mg, 107 μmol, 1.00 eq), DIPEA (55.5 mg, 429 μmol, 74.8 μL, 4.00 eq) and piperidine-4-ol (32.6 mg, 322 μmol, 3.00 eq) were added. The mixture was stirred at 40 °C for 12 h. LC-MS showed that compound 136-1 was re-ground and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 138 (35.0 mg, 68.1 μmol, 63.4% yield, 100% purity) as a purple solid. ESI-MS M / Z: 514.3 [M+H] +

[0940] 1 H NMR: (400MHz, MeOD) δ8.49(d,J=4.8Hz,1H),7.97(d,J=3.6Hz,2H),7.48-7.53( m,2H),7.12(s,1H),6.86(s,1H),4.42(t,J=5.2Hz,2H),4.05-4.09(m,1H),3.8 9(s,1H),3.39-3.45(m,4H),3.17-3.3.21(m,2H),2.74-3.15(m,7H),2.62-2.6 9(m,1H),2.41(s,3H),2.13-2.23(m,2H),1.95-2.03(m,2H),1.71-1.82(m,2H).

[0941] Example 139

[0942] To a DCM (1.00 mL) solution of compound 14-14 (100 mg, 237 μmol, 1.00 eq), 2-morpholinoethanol (46.7 mg, 356 μmol, 43.6 μL, 1.50 eq), TEA (192 mg, 1.90 mmol, 264 μL, 8.00 eq), and 2-chloro-1-methylpyridin-1-onium iodide (242 mg, 949 μmol, 4.00 eq) were added. The mixture was stirred at 20 °C for 12 h. LC-MS showed complete consumption of compound 14-14, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 139 (50.0 mg, 92.97 μmol, 39.2% yield, 99.4% purity), a pale yellow solid. ESI-MS M / Z: 535.2 [M+H] +

[0943] 1 H NMR: (400MHz, MeOD) δ7.48-7.52(m,2H),7.17(s,1H),7.05(t,J=8.0Hz,2H),6.90(t,J=1.2Hz,1H),4.35(t,J=4.8Hz,2H),4.09-4.13 (m,1H),3.79(t,J=4.8Hz,4H),2.99-3.16(m,8H),2.93(d,J=7.6Hz,2H),2.63-2.75(m,4H),2.36(d,J=0.8Hz,3H),2.13-2.20(m,2H).

[0944] Example 140

[0945] To a DCM (1.00 mL) solution of compound 14-14 (100 mg, 237 μmol, 1.00 eq), 2-thiomorpholine ethanol (52.4 mg, 356 μmol, 1.50 eq), 2-chloro-1-methylpyridin-1-onium iodide (182 mg, 712 μmol, 3.00 eq) and TEA (144 mg, 1.42 mmol, 198 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LC-MS showed complete consumption of compound 14-14, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give a yellow solid, compound 140 (70.0 mg, 127 μmol, 44.6% yield, 100% purity). ESI-MS M / Z: 551.2 [M+H] +

[0946] 1 H NMR: (400MHz, MeOD) δ7.48-7.54(m,2H),7.17(s,1H),7.05(t,J=8.4Hz,2H),6.89(d,J=1.2Hz,1H),4.29(t,J=5.2Hz,2H),4.09-4.14 (m,1H),3.05-3.15(m,6H),3.01(t,J=5.2Hz,2H),2.93(t,J=7.2Hz,2H),2.60-2.79(m,8H),2.36(d,J=0.8Hz,3H),2.12-2.22(m,2H).

[0947] Example 141

[0948] To a DCM (2.00 mL) solution of compound 14-14 (100 mg, 237 μmol, 1.00 eq), 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (51.0 mg, 285 μmol, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (182 mg, 712 μmol, 3.00 eq), and TEA (144 mg, 1.42 mmol, 198 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LCMS showed that compound 14-14 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give a yellow solid, compound 141 (93.0 mg, 158 μmol, 66.4% yield, 98.7% purity). ESI-MS M / Z: 583.2 [M+H] + .

[0949] 1 H NMR: (400MHz, MeOD) δ7.48-7.54(m,2H),7.19(s,1H),7.05(t,J=8.8Hz,2H),6.91(s,1H),4.16-4.21(m,2H),4.11-4. 15(m,1H),3.02-3.15(m,2H),2.99(s,8H),2.94(t,J=7.6Hz,2H),2.61-2.76(m,6H),2.37(s,3H),2.12-2.22(m,2H).

[0950] Example 142

[0951] To a DCM (2.00 mL) solution of compound 14-14 (100 mg, 237 μmol, 1.00 eq), 2-(4-methylpiperazin-1-yl)ethanol (41.0 mg, 285 μmol, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (182 mg, 712 μmol, 3.00 eq), and TEA (144 mg, 1.42 mmol, 198 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LCMS showed that compound 14-14 was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 142 (113 mg, 203 μmol, 85.6% yield, 98.4% purity) as a yellow solid. ESI-MS M / Z: 548.3 [M+H] +

[0952] 1 H NMR: (400MHz, MeOD) δ7.48-7.52(m,2H),7.17(s,1H),7.05(t,J=8.0Hz,2H),6.94(d,J=1.2Hz,1H),4.18-4.24(m,2H),4. 07-4.11(m,1H),3.01-3.20(m,6H),2.92(t,J=7.2Hz,2H),2.61-2.86(m,13H),2.36(d,J=0.8Hz,3H),2.13-2.21(m,2H).

[0953] Example 143

[0954] To a DCM (2.00 mL) solution of compound 14-14 (100 mg, 237 μmol, 1.00 eq), 2-pyrrolidone-1-ylethanol (32.8 mg, 285 μmol, 33.3 μL, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (182 mg, 712 μmol, 3.00 eq), and TEA (144 mg, 1.42 mmol, 198 μL, 6.00 eq) were added. The mixture was stirred at 20 °C for 2 h. LCMS showed that compound 14-14 was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 143 (89.0 mg, 168 μmol, 71.0% yield, 98.2% purity) as a yellow solid. ESI-MS M / Z: 519.3 [M+H] +

[0955] 1H NMR: (400MHz, MeOD) δ7.48-7.54(m,2H),7.17(s,1H),7.05(t,J=8.8Hz,2H),6.89(d,J=0.8Hz,1H),4.37-4.41(m,2H),4.08-4.12(m, 1H),3.47-3.51(m,2H),3.36-3.43(m,3H),2.90-3.15(m,5H),2.61-2.78(m,4H),2.36(s,3H),2.13-2.23(m,3H),2.06-2.10(m,3H).

[0956] Example 144

[0957] To a DMF (1.00 mL) solution of compounds 14-15 (100 mg, 189 μmol, 1.00 eq) and pyrrolidine-2-ylmethanol (28.7 mg, 284 μmol, 1.50 eq), NaI (42.6 mg, 284 μmol, 1.50 eq) and K₂CO₃ (131 mg, 946 μmol, 5.00 eq) were added. The mixture was stirred at 20 °C for 12 h. LC-MS showed that compounds 14-15 were completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give compound 144 (55.0 mg, 99.4 μmol, 52.5% yield, 99.1% purity) as a white solid. ESI-MS M / Z: 549.3 [M+H] +

[0958] 1 H NMR: (400MHz, MeOD) δ7.48-7.52(m,2H),7.17(s,1H),7.05(t,J=8.4Hz,2H),6.89(s,1H), 4.38-4.42(m,2H),4.08-4.12(m,1H),3.83-3.89(m,1H),3.66-3.76(m,3H),3.57-2.63(m, 1H),3.35-3.42(m,1H),3.01-2.32(m,3H),2.90-2.95(m,2H),2.63-2.79(m,4H),2.90-2. 95(m,2H),2.36(d,J=0.8Hz,3H),2.07-2.22(m,4H),1.96-2.05(m,1H),1.84-1.92(m,1H).

[0959] Example 145

[0960] To a DMF (2.00 mL) solution of compounds 14-15 (80.0 mg, 151 μmol, 1.00 eq) and pyrrolidine-3-ylmethanol (23.0 mg, 227 μmol, 1.50 eq), NaI (34.0 mg, 223 μmol, 1.5 eq) and K₂CO₃ (105 mg, 757 μmol, 5.00 eq) were added. The mixture was stirred at 20 °C for 12 h. LC-MS showed that compounds 14-15 were completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative high-performance liquid chromatography to give a yellow solid, compound 145 (68.0 mg, 117 μmol, 77.5% yield, 94.7% purity). ESI-MS M / Z: 549.3 [M+H] +

[0961] 1 H NMR: (400MHz, MeOD) δ7.46-7.54(m,2H),7.17(s,1H),7.05(t,J=8.4Hz,2H ),6.89(s,1H),4.37(t,J=4.4Hz,2H),4.08-4.12(m,1H),3.52-3.63(m,2H ),3.39-3.48(m,3H),3.34-3.37(m,2H),2.99-3.17(m,3H),2.90-2.93(m, 2H),2.53-2.80(m,5H),2.36(s,3H),2.12-2.19(m,3H),1.83-1.90(m,1H).

[0962] Example 146

[0963] To a solution of 49-1 (375 mg, 705 μmol, 1.00 eq) and piperazine-2-one (70.5 mg, 705 μmol, 1.00 eq) in ACN (5.00 mL), K₂CO₃ (195 mg, 1.41 mmol, 2.00 eq) and NaI (211 mg, 1.41 mol, 2.00 eq) were added. The mixture was stirred at 25 °C for 12 h. LC-MS showed that 49-1 was completely consumed and the molecular weight of the target product was detected. The reaction mixture was quenched with 1.00 mL of ice water, then extracted with ethyl acetate (2.00 mL × 3), washed with brine (2.00 mL × 2), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase high-performance liquid chromatography to give 146 (110 mg, 191 μmol, 27.2% yield, 95.9% purity) as a yellow solid. ESI-MS M / Z: 551.2 [M+H] +

[0964] 1 H NMR: (MeOD, 400MHz) δ8.49-8.52(m,1H),8.08-8.13(m,1H),7.98(td,J1=8.0 Hz,J2=1.6Hz,1H),7.87(dd,J1=8.8Hz,J2=2.4Hz,1H),7.59(d,J=9.6Hz,1H) ,7.49-7.54(m,2H),6.85(d,J=1.2Hz,1H),4.24(t,J=5.4Hz,2H),4.10-4.15 (m,1H),3.24(t,J=5.4Hz,2H),3.11(s,2H),2.60-2.85(m,8H),2.40(s,3H).

[0965] Example 147

[0966] A solution of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid (200 mg, 470 μmol, 1.00 eq), 147-1 (74.4 mg, 470 μmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (481 mg, 1.88 mmol, 4.00 eq), and TEA (381 mg, 3.76 mmol, 524 μL, 8.00 eq) in DCM (5.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with 1.00 mL of ice water, extracted with ethyl acetate (2.00 mL × 3), washed with brine (2.00 mL × 2), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) to obtain 147 (93.0 mg, 161 μmol, 34.2% yield, 95.3% purity), as a red solid. ESI-MS M / Z: 565.2 [M+H] +

[0967] 1H NMR: (MeOD, 400MHz) δ 8.49-8.53 (m, 1H), 8.09-8.13 (m, 1H), 7.98 (td, J1=8.0Hz, J2=1. 6Hz,1H),7.87(dd,J1=8.8Hz,J2=2.4Hz,1H),7.60(d,J=9.6Hz,1H),7.49-7.54(m,2H), 6.86(d,J=1.2Hz,1H),4.23(t,J=5.4Hz,2H),4.09-4.15(m,1H),3.29(s,1H),3.13(s,2 H),2.91(s,3H),2.78-2.84(m,2H),2.71-2.77(m,3H),2.62-2.70(m,3H),2.40(s,3H).

[0968] Example 148

[0969] A solution of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid (498 mg, 1.17 mmol, 1.00 eq), 148-1 (300 mg, 1.17 mmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (1.20 g, 4.68 mmol, 4.00 eq), and TEA (474 ​​mg, 4.68 mmol / L, 652 μL, 4.00 eq) in DCM (5.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to give 148-2 (318 mg, crude product) as a yellow solid. ESI-MS M / Z: 663.0 [M+H] +

[0970] A solution of 148-2 (190 mg, 286 μmol, 1.00 eq) and TFA (32.65 mg, 286 μmol, 21.27 μL, 1.00 eq.) in DCM (2.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to give 148-3 (218 mg, crude product) as a yellow solid. ESI-MS M / Z: 563.1 [M+H] +

[0971] 148-3 (325 mg, 577 μmol, 1.00 eq), NaBH3CN (109 mg, 1.73 mmol, 3.00 eq), AcOH (104 mg, 1.71 mmol, 99.0 μL, 3.00 eq) and (CH2O) were added.n The solution of 17.3 mg (576 μmol, 15.9 μL, 1.00 eq) in MeOH (5.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under nitrogen atmosphere. The mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to obtain 148 (58.0 mg, 98.5 μmol, 17.1% yield, 98.1% purity) as a yellow solid. ESI-MS M / Z: 581.2 [M+H] +

[0972] 1 H NMR: (MeOD, 400MHz) δ8.46-8.57(m,1H),8.11(s,1H),7.85-8.05(m,1H),7.70(dd,J1=8.4H z,J2=1.6Hz,1H),7.41-7.48(m,2H),6.97(s,1H),6.50-6.80(m,1H),4.30-4.40(m,1H),4. 20-4.28(m,1H),4.00-4.18(m,1H),3.84-3.98(m,1H),3.70-3.80(m,3H),3.52-3.64(m,2H ),2.65-2.85(m,1H),2.43-2.55(m,2H),2.25-2.42(m,5H),2.13(s,3H),1.75-2.00(m,1H).

[0973] Example 149

[0974] Compound 149-1 (19.0 g, 77.5 mmol, 1.00 eq) was degassed in NMP (190 mL) and purged three times with nitrogen. Zn (1.11 g, 17.0 mmol, 2.19 e⁻¹ eq), Zn(CN)₂ (18.0 g, 153 mmol, 9.72 mL, 1.98 eq), and Pd(t-Bu₃P)₂ (3.96 g, 7.75 mmol, 0.10 eq) were added. The mixture was stirred at 90 °C for 3 hours. LC-MS showed the molecular weight of the target product. The mixture was poured into ice water (100 mL) and extracted with EtOAc (100 mL × 2). The combined orange phases were then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid compound 149-2 (6.68 g, 46.3 mmol, 59.8% yield). ESI-MS M / Z: 145.2 [M+H] +

[0975] Add to a toluene solution of compound 149-2 (5.97 g, 41.4 mmol, 1.00 eq) and compound 149-3 (13.1 g, 82.8 mmol, 7.90 mL, 2.00 eq). Add n-butyllithium (2.5 M, 36.4 mL, 2.20 eq) at -65°C for 1 hour. Stir the resulting mixture at 0°C for 1 hour. LCMS showed the molecular weight of the target product. Pour the mixture into ice water (150 mL) and extract with EtOAc (150 mL × 2). Then wash the combined orange phases with brine (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by rapid silica gel chromatography to give a yellow oily compound 149-4 (4.80 g, 19.2 mmol, 46.2% yield, 89.5% purity). ESI-MS M / Z: 225.1 [M+H] +

[0976] A solution of compound 149-4 (4.80 g, 21.4 mmol, 1.00 eq), compound 149-5 (8.21 g, 21.40 mmol, 1.00 eq), and DCC (5.30 g, 25.7 mmol, 5.20 mL, 1.20 eq) in DCM (150 mL) was degassed and purged three times with nitrogen, then stirred at 20 °C for 12 h under nitrogen atmosphere. LCMS showed the molecular weight of the target product. The reaction mixture was quenched with 50.0 mL H₂O, diluted with 50.0 mL EtOAc, and extracted with 50.0 mL × 2 EtOAc. The combined organic layers were washed with brine (50.0 mL × 2), dried, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give compound 149-6 (10.3 g, 17.5 mmol, 73.8% yield) as a yellow solid. ESI-MS M / Z: 590.3 [M+H] +

[0977] A solution of compound 149-6 (10.0 g, 17.0 mmol, 1.00 eq) and TEA (17.2 g, 170 mmol, 23.6 mL, 10.0 eq) in ACN (150 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 40 °C for 12 hours under a nitrogen atmosphere. LC-MS showed the molecular weight of the target product. The reaction mixture was filtered through diatomaceous earth under a nitrogen atmosphere, and the filtrate was washed with saturated NaHCO3 aqueous solution (400 mL × 2). The combined organic solutions were washed with brine (400 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography to give compound 149-7 (15.0 g, crude) as a yellow oil. ESI-MS M / Z: 368.2 [M+H] +

[0978] NH4OAc (4.20 g, 54.4 mmol, 2.00 eq) was added to a solution of compound 149-7 (10.0 g, 27.2 mmol, 1.00 eq) in AcOH (100 mL). The mixture was stirred at 20 °C for 2 hours. LCMS showed the molecular weight of the target product. The mixture was poured into ice water (40.0 mL) and extracted with EtOAc (40.0 mL × 2). The combined orange phases were then washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow oily compound 149-8 (4.90 g, 14.0 mmol, 51.5% yield). ESI-MS M / Z: 350.1 [M+H] +

[0979] A solution of compound 149-8 (2.50 g, 7.16 mmol, 1.00 eq), P2S5 (3.18 g, 14.3 mmol, 1.52 mL, 2.00 eq), and Na2CO3 (3.03 g, 28.7 mmol, 4.00 eq) in toluene (50.0 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 25 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 11 hours. The molecular weight of the target product was detected by LCMS. The reaction mixture was diluted with H2O (100 mL). After separation, the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined EtOAc layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give compound 149-9 (2.60 g, 7.11 mmol, 51.8% yield) as a yellow solid. ESI-MS M / Z: 366.1 [M+H] +

[0980] A solution of compound 149-9 (2.60 g, 7.11 mmol, 1.00 eq) and 2,2-dimethoxypropyl-1-amine (1.70 g, 14.2 mmol, 2.00 eq) in THF (30.0 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 80 °C for 12 hours under nitrogen atmosphere. LC-MS showed the molecular weight of the target product. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography to give compound 149-10 (7.00 g, crude), a yellow oil. ESI-MS M / Z: 451.3 [M+H] +

[0981] A solution of compound 149-10 (3.50 g, 7.77 mmol, 1.00 eq) and TFA (4.43 g, 38.8 mmol, 2.89 mL, 5.00 eq) in DCM (50.0 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 3 hours under a nitrogen atmosphere. LC-MS showed the molecular weight of the target product. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving compound 149-11 (1.69 g, 4.37 mmol, 56.3% yield) as a yellow solid. ESI-MS M / Z: 387.1 [M+H] +

[0982] 1 H NMR: (CDCl3, 400MHz) δ8.57-8.59(m,1H),8.14-8.16(m,1H),7.83(s,1H),7.81-7.82(m,1H),7.14-7.27(m,2H),7.06(s,1H) ),4.10-4.13(m,1H),3.35(s,3H),3.25-3.30(m,2H),2.90-2.98(m,2H),2.78-2.80(m,1H),2.76-2.78(m,3H),2.36(s,3H).

[0983] A solution of compound 149-11 (1.60 g, 4.14 mmol, 1.00 eq), LiOH·H₂O (347 mg, 8.28 mmol, 2.00 eq) in THF (10.0 mL), MeOH (2.50 mL), and H₂O (2.50 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 50 °C for 2 hours under nitrogen atmosphere. LC-MS showed the molecular weight of the target product. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography to give compound 149-12 (1.52 g, 4.08 mmol, 98.6% yield) as a yellow solid. ESI-MS M / Z: 373.2 [M+H] +

[0984] A solution of compound 149-12 (150 mg, 403 μmol, 1.00 eq), ethanol (37.1 mg, 806 μmol, 2.00 eq), TEA (163 mg, 1.61 mmol, 224 μL, 4.00 eq), and 2-chloro-1-methylpyridin-1-onium iodide (412 mg, 1.61 mmol, 4.00 eq) in DCM (10.0 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 2 hours under a nitrogen atmosphere. LC-MS showed the molecular weight of the target product. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to give compound 149 (140 mg, 350 μmol, 86.8% yield) as a yellow solid. ESI-MS M / Z: 401.2 [M+H] +

[0985] 1 H NMR: (CDCl3, 400MHz) δ8.56-8.57(m,1H),7.79-8.12(m,1H),7.75-7.77(m,1H),7.31-7.32(m,1H),7.29(s,2H),7.10(s,1H),4. 10-4.15(m,2H),4.02-4.03(m,1H),3.29-3.36(m,3H),3.00-3.23(m,1H),2.78-2.89(m,5H),2.34(s,3H),1.23(d,J=7.2Hz,3H).

[0986] Example 150

[0987] A solution of compound 149-12 (300 mg, 806 μmol, 1.00 eq), compound 150-1 (106 mg, 806 μmol, 98.6 μL, 2.00 eq), TEA (326 mg, 3.22 mmol, 448 μL, 4.00 eq), and CMPI (823 mg, 3.22 mmol, 4.00 eq) in DCM (10.0 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 2 hours under a nitrogen atmosphere. LCMS showed the molecular weight of the target product. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to give compound 150 (150 mg, 309 μmol, 76.7% yield) as a white solid. ESI-MS M / Z: 486.3 [M+H] +

[0988] 1H NMR: (400MHz, CDCl3) δ8.58-8.59(m,1H),8.14(d,J=8.0Hz,1H),7.81-7.82(m,1H),7.35-7.36(m,1H),7.11-7.13(m,2H),6.94(s,1 H),4.01-4.32(m,2H),3.75-3.76(m,1H),3.35-3.38(m,4H),2.83-2.87(m,5H),2.83-2.85(m,3H),2.74-2.79(m,8H),2.73(s,3H).

[0989] Example 151

[0990] A solution of compound 149-12 (300 mg, 806 μmol, 1.00 eq), compound 151-1 (289 mg, 1.61 mmol, 2.00 eq), and TEA (326 mg, 3.22 mmol, 448 μL, 4.00 eq) in DCM (10.0 mL) was degassed and purged three times with nitrogen, then stirred at 20 °C for 2 h under a nitrogen atmosphere. The molecular weight of the target product was detected by LC-MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to give compound 151 (150 mg, 281 μmol, 76.5% yield) as a white solid. ESI-MS M / Z: 534.3 [M+H] +

[0991] 1 H NMR: (400MHz, CDCl3) δ8.57-8.59(m,1H),8.14(d,J=8.0Hz,1H),7.76-7.78(m,1H),7.30-7.34(m,1H),7.12-7.13(m,2H),6.94(s,1 H),4.16-4.22(m,2H),4.01-4.04(m,1H),3.02-3.37(m,2H),3.00-3.01(m,2H),2.81-3.01(m,8H),2.75-2.86(m,6H),2.34(s,3H).

[0992] Example 152

[0993] To a solution of compound 152-1 (4.80 g, 13.4 mmol, 1.00 eq) in ACN (50.0 mL), (Me3Si)2O (3.93 g, 24.2 mmol, 5.15 mL, 1.80 eq) and P2S5 (1.50 g, 6.73 mmol, 715 μL, 0.50 eq) were added. The mixture was stirred at 60 °C for 12 h. LC-MS showed that compound 152-1 was completely consumed and the molecular weight of the target product was detected. The mixture was quenched by adding 50.0 mL of H2O and extracted with EtOAc (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography to give a yellow solid compound 152-2 (3.50 g, crude). ESI-MS M / Z: 373.1 [M+H] +

[0994] To a solution of compound 152-2 (3.00 g, 8.05 mmol, 1.00 eq) in acetone (30.0 mL), K₂CO₃ (2.22 g, 16.0 mmol, 2.00 eq) and CH₃I (1.37 g, 9.65 mmol, 601 μL, 1.20 eq) were added. The mixture was stirred at 25 °C for 8 hours. LC-MS showed that compound 152-2 was completely consumed, and the molecular weight of the target product was detected. The mixture was quenched by adding 30.0 mL of H₂O and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 152-3 (2.41 g, crude) as a yellow solid. ESI-MS M / Z: 387.5 [M+H] +

[0995] Acetylhydrazine (919 mg, 12.4 mmol, 2.00 eq) was added to a solution of compound 152-3 (2.40 g, 6.20 mmol, 1.00 eq) in AcOH (20.0 mL). The mixture was stirred at 80 °C for 2 hours. LC-MS showed that compound 152-3 was completely consumed and the molecular weight of the target product was detected. The pH of the mixture was adjusted to >7 with Na2CO3 solution, and the mixture was extracted with EtOAc (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 152-4 (2.10 g, crude) as a yellow solid. ESI-MS M / Z: 395.1 [M+H] +

[0996] 1H NMR: (400MHz, DMSO-d6) δ7.86-7.89(m,2H),7.48-7.55(m,3H),7.39-7.46(m,3H),4.13-4.19(m,1H),3.62(s,3H),2.61-2.77(m,4H),2.56(s,3H).

[0997] LiOH·H2O (42.1 mg, 1.01 mmol, 2.00 eq) was added to a solution of compound 152-4 (200 mg, 506 μmol, 1.00 eq) in THF (2.00 mL) and H2O (2.00 mL). The mixture was stirred at 25 °C for 2 hours. LCMS showed that compound 152-4 was completely consumed and the molecular weight of the target product was detected. The mixture was quenched by adding 2.00 mL of H2O, the pH was adjusted to 1 with HCl (6 M), and extracted with EtOAc (2.00 mL × 3). The combined organic layers were washed with brine (2.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 152-5 (150 mg, crude) as a yellow oil. ESI-MS M / Z: 381.1 [M+H] +

[0998] A solution of compound 152-5 (200 mg, 525 μmol, 1.00 eq), compound 152-6 (103 mg, 787 μmol, 96.3 μL, 1.20 eq), 2-chloro-1-methylpyridin-1-onium iodide (221 mg, 867 μmol, 4.00 eq), and TEA (87.7 mg, 867 mol, 120 μL, 4.00 eq) in DCM (3.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 20 °C for 1 hour under a nitrogen atmosphere. LCMS showed that compound 152-5 was completely consumed, and the molecular weight of the target product was detected. The mixture was quenched by adding 3.0 mL of H2O and extracted with DCM (2.00 mL × 3). The combined organic layers were washed with brine (2.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase HPLC to give a yellow solid compound 152 (150 mg, 297 μmol, 73.4% yield, 97.9% purity). ESI-MS M / Z: 494.2 [M+H] +

[0999] 1H NMR: (400MHz, DMSO-d6) δ8.12-8.15(m,1H),7.86-7.89(m,2H),7.58-7.61(m,1H),7.49-7.55(m,3H),7.39-7.46(m,3 H),7.26-7.35(m,2H),4.24-4.40(m,2H),4.16-4.22(m,1H),3.54-3.77(m,4H),2.60-2.86(m,6H),2.51-2.59(m,7H).

[1000] Example 153

[1001] To a solution of compound 153-1 (1.60 g, 3.88 mmol, 1.00 eq) in THF (2.00 mL) and H₂O (2.00 mL), LiOH·H₂O (243 mg, 5.81 mmol, 1.50 eq) was added. The mixture was stirred at 50 °C for 2 h. LC-MS showed that compound 153-1 was completely consumed and the molecular weight of the target product was detected. The mixture was quenched by adding 2.00 mL of H₂O, the pH was adjusted to 1 with HCl (6 M), and extracted with EtOAc (2.00 mL × 3). The combined organic layers were washed with brine (2.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily compound 153-2 (1.02 g, 2.56 mmol, 65.9% yield). ESI-MS M / Z: 399.0 [M+H] +

[1002] A solution of compound 153-2 (300 mg, 752 μmol, 1.00 eq), compound 153-3 (148 mg, 1.13 mmol, 138 μL, 1.50 eq), EDCI (288 mg, 1.50 mmol, 2.00 eq), and DMAP (9.19 mg, 75.2 μmol, 0.10 eq) in DCM (3.00 mL) was degassed and purged three times with nitrogen, then stirred at 20 °C for 12 h under a nitrogen atmosphere. LCMS showed that compound 153-2 was completely consumed, and the molecular weight of the target product was detected. The mixture was quenched by adding 3.00 mL of H2O and extracted with DCM (2.00 mL × 3). The combined organic layers were washed with brine (2.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase HPLC to give a yellow solid compound 153 (220 mg, 314 μmol, 67.1% yield, 95.9% purity). ESI-MS M / Z: 512.2 [M+H] +

[1003] 1 H NMR: (400MHz, DMSO-d6) δ8.22(s,1H),7.86-7.90(m,2H),7.58-7.60(m,2H),7.32-7.34(m,2H),7.22-7.24(m,1H), 4.23-4.24(m,1H),4.13-4.15(m,1H),3.47-3.50(m,4H),2.54-2.67(m,4H),2.50-2.53(m,5H),2.35-2.47(m,4H).

[1004] Example 154

[1005] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (160 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 91 mg (1.2 eq) of 2-bromoethanol-D4 and 4.0 eq of DIPEA sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Wash (10 mL * 3 of purified water) and concentrate to obtain 154-1 (brown oil, 215 mg, 85.32% yield, UPLC 88.84%). ESI-MS m / z: 537.10 [M+H] + ;

[1006] Weigh 154-1 (215 mg, 1.0 eq) and dissolve it in acetonitrile (15 mL). Heat and stir in a parallel reactor at 40 °C. Then, add triethylamine (81 mg, 2.0 eq), potassium carbonate (333 mg, 6.0 eq), and morpholine-D8 hydrochloride (158 mg, 3.0 eq) sequentially. Wash with acetonitrile (5 mL). Stir until the reaction is complete as monitored by MS (conversion ≥90%). Filter, wash, and concentrate to obtain crude 154 (yellow oil). Separate compound 154 by TLC (yellow oil, 75.10 mg, 34.01% yield, UPLC 92.42%). ESI-MS m / z: 275.78 [M / 2+H] + .

[1007] 1H NMR (600MHz, DMSO-d6) δ8.54(dd,J=4.6,1.8Hz,1H),8.11–8.07(m,1H),7.95(td,J=7.8,1.8Hz,1H),7.90–7.86(m,1H),7.66(d,J =8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.51–7.47(m,1H),6.82(t,J=1.3Hz,1H),4.16–3.97(m,1H),2.76–2.53(m,4H),2.30(s,3H).

[1008] Example 155

[1009] To a solution of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazaphen-4-yl)propionic acid (200 mg, 470 μmol, 1.00 eq) and 2-(4H-1,2,4-triazol-4-yl)ethyl-1-ol (79.8 mg, 705 μmol, 1.50 eq) in DCM (5.00 mL), CMPI (240 mg, 941 μmol, 2.00 eq) and TEA (143 mg, 1.41 mmol, 196 μL, 3.00 eq) were added. The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated to give a residue. The residue was purified by reversed-phase HPLC to give a yellow solid 155 (140 mg, 269 μmol, 57.2% yield). ESI-MS M / Z: 520.1 [M+H] +

[1010] 1 H NMR: (400MHz, DMSO-d6) δ8.56-8.52(m,1H),8.49(s,2H),8.07(d,J=8.0Hz,1H ),7.94(dt,J=1.6,7.6Hz,1H),7.87(dd,J=2.4,8.8Hz,1H),7.67-7.61(m,2H) ,7.49(ddd,J=1.2,4.8,7.6Hz,1H),6.81(d,J=1.2Hz,1H),4.32(s,4H),4.04( dd,J=6.0,7.6Hz,1H),2.77-2.64(m,2H),2.55(d,J=6.4Hz,2H),2.30(s,3H).

[1011] Example 156

[1012] To a solution of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazaphen-4-yl)propionic acid (300 mg, 705 μmol, 1.00 eq) and (2,2-dimethyl-1,3-dioxolane-4-yl)methanol (186 mg, 1.41 mmol, 174 μL, 2.00 eq) in DCM (7.00 mL), CMPI (360 mg, 1.41 mmol, 2.00 eq) and TEA (285 mg, 2.82 mmol, 392 μL, 4.00 eq) were added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with 10 mL of purified water and extracted with 50 mL (10 mL x 5) of DCM / MeOH (10 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give 156-1 (350 mg, 649 μmol, 92.0% yield) as an orange oil. ESI-MS M / Z: 539.2 [M+H] +

[1013] 1 H NMR: (400MHz, DMSO-d6) δ8.57-8.51(m,1H),8.09(d,J=8.0Hz,1H),7.97-7.92(m,1H) ,7.88(dd,J=2.4,8.8Hz,1H),7.70-7.67(m,1H),7.61(d,J=2.4Hz,1H),7.40(s,1H),6 .82(s,1H),4.23(dd,J=1.6,6.0Hz,1H),4.14(s,1H),4.08-3.99(m,2H),3.99-3.94(m ,1H),3.64(d,J=6.4Hz,1H),2.77-2.53(m,4H),2.31(s,3H),1.29(s,3H),1.25(s,3H)

[1014] Prepare a solution of purified water (3.00 mL) in HCl (12.0 M, 0.50 mL, 11.5 eq), and add methyl (2,2-dimethyl-1,3-dioxolane-4-yl)3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazaphen-4-yl)propionate (0.28 g, 519 μmol, 1.00 eq). Stir the mixture at 25 °C for 0.5 h. Adjust the pH to 8 with an aqueous solution of NaHCO3. Purify the residue by preparative high-performance liquid chromatography (HPLC) to give 156 (150 mg, 300 μmol, 57.8% yield) as a white solid. ESI-MS M / Z: 499.1 [M+H] +

[1015] 1 H NMR: (400MHz, DMSO-d6) δ8.55 (dd, J=0.4, 4.8Hz, 1H), 8.10 (d, J=8.0Hz, 1H), 7.95 (dt, J=1.6, 7.6Hz, 1H),7.88(dd,J=2.4,8.8Hz,1H),7.66(d,J=8.8Hz,1H),7.62(d,J=2.4Hz,1H),7.50(ddd,J=1.2,4.8, 7.6Hz,1H),6.82(d,J=1.2Hz,1H),4.91-4.81(m,1H),4.67-4.59(m,1H),4.08(td,J=4.0,11.2Hz,2H ),3.93(ddd,J=3.2,6.4,11.2Hz,1H),3.68-3.59(m,1H),3.54-3.39(m,1H),2.55(s,5H),2.31(s,3H)

[1016] Example 157

[1017] To a solution of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazaphen-4-yl)propionic acid (200 mg, 470 μmol, 1.00 eq) and 2-(oxecyclobutan-3-yl)ethyl-1-ol (72.1 mg, 705 μmol, 1.50 eq) in DCM (5.00 mL), CMPI (240 mg, 941 μmol, 2.00 eq) and TEA (143 mg, 1.41 mmol, 196 μL, 3.00 eq) were added. The mixture was stirred at 20 °C for 12 hours. The mixture was concentrated to give a residue. The residue was purified by reversed-phase high-performance liquid chromatography to give a white solid compound 157 (150 mg, 294 μmol, 62.6% yield). ESI-MS M / Z: 509.1 [M+H] +

[1018] 1 H NMR: (400MHz, DMSO-d6) δ8.54(d,J=4.8Hz,1H),8.08(d,J=8.0Hz,1H),7.94(dt,J=1.6,7.6Hz,1H ),7.88(dd,J=2.4,8.8Hz,1H),7.66(d,J=8.4Hz,1H),7.61(d,J=2.4Hz,1H),7.52-7.47(m,1H),6. 81(d,J=1.2Hz,1H),4.57(ddd,J=2.0,5.6,7.8Hz,2H),4.24(dt,J=1.6,6.4Hz,2H),4.06-3.96(m, 3H),3.01-2.90(m,1H),2.72-2.61(m,3H),2.34-2.31(m,1H),2.30(s,3H),1.89(q,J=6.4Hz,2H).

[1019] Example 158

[1020] To a DCM (3.00 mL) solution of compound 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid (150 mg, 352 μmol, 1.00 eq) and (2-oxaspiro[3.3]heptane-6-yl)methanol (67.8 mg, 529 μmol, 1.50 eq), CMPI (180 mg, 705 μmol, 2.00 eq) and TEA (142 mg, 1.41 mmol, 196 μL, 4.00 eq) were added. The mixture was stirred at 25 °C for 16 hours. The mixture was filtered to obtain the filtrate. The filtrate was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) to give a white solid, compound 158 (144 mg, 266 μmol, 75.34% yield, 98.8% purity). ESI-MS M / Z: 535.1 [M+H] +

[1021] 1 H NMR: (400MHz, DMSO-d6)δ8.56(d,J=4.4Hz,1H),8.11(d,J=8.0Hz,1H),7.97(t,J=7.6Hz, 2H),7.82-7.75(m,1H),7.72-7.67(m,1H),7.59(dd,J=2.0,7.6Hz,1H),7.56-7.50(m,1H ),7.35-7.26(m,2H),4.51(s,2H),4.43(s,2H),4.29-4.17(m,1H),3.94(d,J=6.4Hz,2H) ,2.79-2.53(m,4H),2.38-2.28(m,4H),2.25-2.17(m,2H),1.87(dd,J=6.4,12.8Hz,2H).

[1022] Example 159

[1023] Weigh 200 mg (1.0 eq) of 97-1 and dissolve it in acetonitrile (8 mL). Heat and stir in an oil bath at 60 °C. Then, add triethylamine (74 mg, 2.0 eq), potassium carbonate (202 mg, 4.0 eq), and (9aS)-octahydropyrazino[2,1-c][1,4]oxazine (52 mg, 1.0 eq) sequentially. Wash with acetonitrile (2 mL). Stir the reaction until MS monitoring shows the reaction is complete (conversion ≥90%). Filter and concentrate to obtain crude product 159 (yellow oil). Separate 159 by TLC (yellow oil, 58.4 mg, 21.01% yield, UPLC 96.91%). ESI-MS m / z: 304.29 [M / 2+H] + .

[1024] 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.94(tt,J=7.7,1.7Hz,1H),7.88(dt,J=8.8 ,2.0Hz,1H),7.66(dd,J=8.8,1.6Hz,1H),7.61(t,J=2.0Hz,1H),7.52–7.45(m,1H),6.81(s,1H),4.09–3.98(m,3H ),3.75–3.65(m,1H),3.53(dd,J=10.8,2.8Hz,1H),3.49–3.38(m,2H),2.77–2.51(m,7H),2.30(s,3H),2.24(t,J= 7.2Hz,2H),2.15–2.09(m,2H),2.08(d,J=1.6Hz,1H),2.04–1.94(m,2H),1.66(p,J=6.8Hz,2H),1.57–1.45(m,2H).

[1025] Example 160

[1026] Weigh 200 mg (1.0 eq) of 97-1 and dissolve it in acetonitrile (8 mL). Heat and stir in an oil bath at 40 °C. Then, add triethylamine (74 mg, 2.0 eq), potassium carbonate (202 mg, 4.0 eq), and 1,4-dioxa-8-azaspiro[4,5]decane (0.16 g, 3.0 eq) sequentially. Wash with acetonitrile (2 mL) and stir until the reaction is complete as monitored by MS (conversion ≥ 90%). Filter and concentrate to obtain crude product 160 (yellow oily substance). Separate by TLC to obtain 160 (yellow foamy solid, 138.10 mg, 62.01% yield, UPLC 91.20%). ESI-MS m / z: 304.76 [M / 2+H] + .

[1027] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.6Hz,1H),8.10(d,J=8.0Hz,1H),7.94(td,J=7.8,3.9Hz,1H),7.8 8(dt,J=8.8,1.9Hz,1H),7.66(dd,J=8.7,1.5Hz,1H),7.62(t,J=1.9Hz,1H),7.52–7.47(m,1H),6.81( s,1H),4.04(hept,J=4.5Hz,3H),3.84(dd,J=6.8,1.5Hz,4H),2.68(p,J=7.5Hz,2H),2.64–2.52(m,2H ),2.36–2.31(m,4H),2.30(s,3H),2.27(t,J=7.2Hz,2H),1.66(p,J=7.1Hz,2H),1.55(t,J=5.7Hz,4H).

[1028] Example 161

[1029] A solution of compound 149-12 (300 mg, 806 μmol, 1.00 eq), compound 161-1 (106 mg, 806 μmol, 98.6 μL, 2.00 eq), TEA (326 mg, 3.22 mmol, 448 μL, 4.00 eq), and compound A (823 mg, 3.22 mol, 4.00 eq) in DCM (10.0 mL) was degassed and purged three times with nitrogen, then stirred at 20 °C for 2 h under a nitrogen atmosphere. The molecular weight of the target product was detected by LC-MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to give compound 161 (186 mg, 309 μmol, 76.7% yield) as a white solid. ESI-MS M / Z: 430.2 [M+H] +

[1030] 1 H NMR: (400MHz, CDCl3) δ8.48-8.49(m,1H),8.00-8.01(m,1H),7.99-8.00( m,1H),7.97-7.99(m,1H),7.52-7.54(m,1H),7.50-7.52(m,1H),7.43-7. 44(m,1H),7.43(s,2H),6.98(s,2H),4.16-4.18(m,2H),3.32-3.36(m,2H ),3.30-3.31(m,2H),2.84-2.86(m,3H),2.82-2.83(m,1H),2.42(s,3H).

[1031] Example 162

[1032] A solution of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid (200 mg, 470 μmol, 1.00 eq), 2-hydroxyacetamide (35.3 mg, 470 μmol, 1.00 eq), 2-chloro-1-methylpyridin-1-onium iodide (480 mg, 1.88 mmol, 4.00 eq), and TEA (190 mg, 1.88 mmol, 262 μL, 4.00 eq) in DCM (2.00 mL) was degassed and purged three times with nitrogen. The mixture was stirred at 25 °C for 1 hour under nitrogen atmosphere. The mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase high-performance liquid chromatography to obtain compound 162 (76.0 mg, 154 μmol, 32.8% yield, 97.9% purity), as a pink solid. ESI-MS M / Z: 482.0 [M+H] +

[1033] 1 H NMR(DMSO-d6,400MHz)δ8.52-8.56(m,1H),8.07-8.12(m,1H),7.94(td,J1=8.0Hz,J 2=1.6Hz,1H),7.88(dd,J1=8.8Hz,J2=2.4Hz,1H),7.66(d,J=9.6Hz,1H),7.61(d,J=2 .4Hz,1H),7.47-7.52(m,1H),7.44(s,1H),7.21(s,1H),6.81(d,J=1.2Hz,1H),4.37 -4.47(m,2H),4.06-4.12(m,1H),2.70-2.85(m,2H),2.53-2.68(m,2H),2.30(s,3H).

[1034] Example 163

[1035] Compound 49-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (76 mg, 2.0 eq), potassium carbonate (208 mg, 4.0 eq), and N-methyltetrahydro-2H-pyran-4-amine (130 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL). The reaction was stirred until MS monitoring showed completion (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 163 (yellow oil). Compound 163 was separated by TLC (yellow oil, 56.80 mg, 26.67% yield, UPLC 90.00%). ESI-MS m / z: 283.75 [M / 2+H] + .

[1036] 1 H NMR (600MHz, DMSO-d6) δ8.54(dd,J=4.8,2.1Hz,1H),8.11–8.07(m,1H),7.94(tt,J=7.7,1.7Hz,1H),7.89(dt,J=8 .8,2.0Hz,1H),7.66(dd,J=8.7,1.6Hz,1H),7.60(t,J=1.9Hz,1H),7.52–7.47(m,1H),6.81(t,J=1.5Hz,1H),4.06( dtd,J=8.7,6.4,5.2,3.2Hz,3H),3.85–3.80(m,2H),3.20(ddd,J=13.8,10.8,2.1Hz,2H),2.73–2.59(m,3H),2.57( t,J=6.2Hz,2H),2.49–2.42(m,2H),2.30(s,3H),2.14(d,J=1.6Hz,3H),1.57–1.49(m,2H),1.33(t,J=12.0Hz,2H).

[1037] Example 164

[1038] Weigh 414 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (323 mg, 1.3 eq) and dissolve them in 20 mL of dichloromethane. Stir the mixture and then add 250 mg (1.5 eq) of (1-(morpholinomethyl)cyclopropyl)methanol and 503 mg (4.0 eq) of DIPEA. Stir the mixture until the reaction is complete as monitored by MS (conversion ≥90%). Concentrate the mixture and wash it with 20 mL of EA and purified water (20 mL * 5) to obtain compound 164 (pink foaming solid, 446.50 mg, 79.32% yield, UPLC 90.49%). ESI-MS m / z: 289.80 [M / 2+H] + .

[1039] 1 H NMR (600MHz, DMSO-d6) δ8.55(d,J=4.7Hz,1H),8.10(d,J=7.9Hz,1H),7.98–7.92(m,1H),7.89(dt, J=8.8,2.0Hz,1H),7.66(dd,J=8.7,1.7Hz,1H),7.60(t,J=2.1Hz,1H),7.50(t,J=6.3Hz,1H),6.82( s,1H),4.09–3.99(m,1H),3.95(d,J=2.2Hz,2H),3.50(t,J=4.7Hz,4H),2.69(q,J=7.1Hz,2H),2.6 5–2.53(m,2H),2.29(d,J=9.6Hz,7H),2.16–2.06(m,2H),0.51–0.43(m,2H),0.27(t,J=9.4Hz,2H).

[1040] Example 165

[1041] Weigh 200 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (180 mg, 1.5 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 99 mg (1.2 eq) of 4-[2-(2-hydroxyethoxy)ethyl]morpholine and 243 mg (4.0 eq) sequentially. Stir until the reaction is complete as monitored by MS (conversion ≥90%). Wash (10 mL * 3 of purified water) and concentrate to give compound 165 (brown oil, 176.20 mg, 64.35% yield, UPLC 90.48%). ESI-MS m / z: 291.82 [M / 2+H] + .

[1042] 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.8Hz,1H),8.09(d,J=8.0Hz,1H),7.94(td,J=7.7,1.7Hz,1H) ,7.88(dd,J=8.8,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.4Hz,1H),7.53–7.45(m,1H),6. 82(s,1H),4.17–4.10(m,2H),4.09–4.00(m,1H),3.55(t,J=4.8Hz,2H),3.52(t,J=4.6Hz,4H),3. 48(t,J=5.8Hz,2H),2.71–2.59(m,2H),2.50(p,J=1.7Hz,6H),2.41(t,J=5.9Hz,2H),2.30(s,3H).

[1043] Example 166

[1044] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (390 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 0.51 g (3.0 eq) of 2-morpholin-4-yl-2-one ethanol and 608 mg (4.0 eq) of DIPEA in sequence. Stir the reaction until MS monitoring shows that the reaction is complete (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5 of purified water), and concentrate to obtain compound 166 (light brown foamy solid, 425.20 mg, 65.45% yield, UPLC 99.53%). ESI-MS m / z: 552.12 [M+H] + .

[1045] 1 H NMR (600MHz, DMSO-d6) δ8.57–8.52(m,1H),8.13–8.07(m,1H),7.95(tt,J=7.7,1.6Hz,1H) ,7.87(dt,J=8.7,1.8Hz,1H),7.65(dd,J=8.7,1.3Hz,1H),7.59(t,J=1.9Hz,1H),7.51–7. 46(m,1H),6.82(t,J=1.3Hz,1H),4.79(s,2H),4.19(dd,J=8.1,6.0Hz,1H),3.54(dt,J=13 .8,4.6Hz,8H),2.76(hept,J=7.8,7.3Hz,2H),2.59(dq,J=34.0,7.1Hz,2H),2.30(s,3H).

[1046] Example 167

[1047] Weigh 500 mg (1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and CMPI (390 mg, 1.3 eq) and dissolve them in 10 mL of dichloromethane. Stir, then add 0.42 g (3.0 eq) of diethylene glycol monomethyl ether and 608 mg (4.0 eq) of DIPEA sequentially. Stir the reaction until MS monitoring shows the reaction is complete (conversion ≥90%). Concentrate, add 10 mL of EA and wash with purified water (10 mL * 5), and concentrate to give compound 167 (orange viscous solid, 463.80 mg, 74.78% yield, UPLC 99.08%). ESI-MS m / z: 527.14 [M+H]+ .

[1048] 1 H NMR (600MHz, DMSO-d6) δ8.54(dd,J=3.9,2.5Hz,1H),8.09(dd,J=7.9,1.6Hz,1H),7.94(tt,J=7.7,1.7Hz,1H) ,7.88(dt,J=8.8,1.9Hz,1H),7.66(dd,J=8.7,1.5Hz,1H),7.61(t,J=1.9Hz,1H),7.50(ddd,J=7.6,4.7,1.4H z,1H),6.82(t,J=1.4Hz,1H),4.16–4.12(m,2H),4.07(dd,J=8.0,5.9Hz,1H),3.59–3.54(m,2H),3.49(td,J= 4.6, 2.1Hz, 2H), 3.42–3.37 (m, 2H), 3.21 (d, J = 1.5Hz, 3H), 2.76–2.65 (m, 2H), 2.64–2.53 (m, 2H), 2.30 (s, 3H).

[1049] Example 168

[1050] Compound 97-1 (200 mg, 1.0 eq) was weighed and dissolved in acetonitrile (6 mL). The solution was heated and stirred in an oil bath at 60 °C. Triethylamine (74 mg, 2.0 eq) and methyl 4-piperidincarnate (157 mg, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (4 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 168 (yellow oil). Compound 168 was separated by TLC (yellow oil, 113 mg, 50.74% yield, UPLC 94.73%). ESI-MS m / z: 304.53 [M / 2+H] +

[1051] 1H NMR (600MHz, DMSO-d6) δ8.55 (dd, J=5.0, 1.7Hz, 1H), 8.08 (d, J=7.9Hz, 1H), 7.95 (td, J=7. 7,1.8Hz,1H),7.89(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.7Hz,1H),7.63–7.58(m,1H),7.51( dd,J=7.5,4.8Hz,1H),6.82(s,1H),4.08(dt,J=11.4,6.9Hz,3H),3.64(d,J=7.0Hz,3H),2. 78–2.53(m,4H),2.51(p,J=1.8Hz,6H),2.31(s,3H),2.05–1.88(m,4H),1.80–1.63(m,3H).

[1052] Example 169

[1053] A solution of compound 162 (180 mg, 373.19 μmol, 1.00 eq), Zn(CN)2 (87.6 mg, 746 μmol, 47.4 μL, 2.00 eq), Pd(t-Bu3P)2 (19.1 mg, 37.3 μmol, 0.10 eq), and Zn (2.44 mg, 37.3 μmol, 0.10 eq) in 1-methylpyrrolidone-2-one (2.00 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 90 °C for 3 hours under nitrogen atmosphere. The cooled mixture was diluted with ethyl acetate and washed successively with ethyl acetate (1.00 mL x 2) and brine (2.00 mL x 2). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried and concentrated. The crude product was purified by reversed-phase high-performance liquid chromatography to obtain compound 169 (51.0 mg, 114 μmol, 30.6% yield, 95.8% purity), as a yellow solid. ESI-MS M / Z: 429.1 [M+H] +

[1054] 1H NMR: (MeOD, 400MHz) δ8.49-8.53(m,1H),8.09-8.12(m,1H),7.98(td,J1=8.0Hz,J2=1.6Hz,1H),7.87(dd,J1=8.8Hz,J2=2.0Hz,1H),7.59(d,J=8.8Hz ,1H),7.51(td,J1=6.0Hz,J2=1.2Hz,1H),6.86(d,J=1.2Hz,1H),4.55(s,2 H),4.12-4.19(m,1H),2.77-2.87(m,3H),2.65-2.72(m,1H),2.41(s,3H).

[1055] Example 170

[1056] Compound 97-1 (0.2 g, 1.0 eq) was weighed and dissolved in acetonitrile (10 mL). The solution was heated and stirred in a water bath at 40 °C. Triethylamine (0.07 g, 2.0 eq), potassium carbonate (0.20 g, 4.0 eq), and (S)-methylmorpholine-3 carboxylic acid ester (0.16 g, 3.0 eq) were added sequentially. The mixture was washed with acetonitrile (5 mL) and stirred until the reaction was complete as monitored by MS (conversion ≥ 90%). The mixture was then filtered and concentrated to obtain crude compound 170 (orange oil). Compound 170 was separated by TLC (orange oil, 70.40 mg, 32% yield, UPLC 91.03%). ESI-MS m / z: 305.83 [M / 2+H] + .

[1057] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=4.7Hz,1H),8.09(d,J=8.0Hz,1H),7.95(dt,J=7.8,1.7Hz,1H),7.88(dt,J=8.8,1.9Hz,1H),7.66(dd ,J=8.7,1.5Hz,1H),7.61(p,J=1.4Hz,1H),7.50(dd,J=7.4,5.0Hz,1H),6.81(d,J=1.9Hz,1H),4.39(qd,J=5.4,1.5Hz,1H),4.05(t,J=6 .8Hz,3H),3.75(td,J=11.9,11.5,4.8Hz,1H),3.68–3.62(m,2H),3.61(d,J=1.7Hz,3H),3.27(dd,J=16.7,3.9Hz,1H),2.97(ddd,J=19. 8,11.4,5.5Hz,2H),2.67(dt,J=19.3,7.9Hz,2H),2.63–2.57(m,2H),2.44(dt,J=12.9,6.9Hz,2H),2.30(s,3H),1.66(q,J=7.2Hz,2H).

[1058] Example 171

[1059] The preparation method was the same as in Example 150, yielding compound 171. ESI-MS M / Z: 496.3 [M+H] +

[1060] 1 H NMR: (400MHz, DMSO-d6) δ8.53-8.49(m,1H),8.13(s,1H),7.95-7.88(m,1H),7.48 -7.44(m,1H),7.38(s,1H),7.02(s,1H),6.77(d,J=1.1Hz,1H),4.14(br s,2H),4.03-3.81(m,5H),3.29-3.20(m,5H),3.18-3.11(m,1H),2.76-2.54(m,4H),2.28(s,3H),2.12(br t,J=7.6Hz,4H),1.78-1.68(m,2H).

[1061] Example 172

[1062] The preparation method was the same as in Example 150, yielding compound 172. ESI-MS M / Z: 498.2 [M+H] +

[1063] 1 H NMR: (400MHz, DMSO-d6) δ8.50(d,J=4.0Hz,1H),8.14(s,1H),7.96-7.88(m,1H),7.47-7.44(m,1H),7.33-7.27(m,1H),7.02(s, 1H),6.80-6.74(m,1H),4.55(s,4H),4.01-3.91(m,3H),3.33-3.14(m,9H),2.70-2.64(m,2H),2.63-2.55(m,3H),2.28(s,3H).

[1064] Example 173

[1065] A solution of compound 173-1 (500 mg, 1.40 mmol, 1.00 eq) in THF (5.00 mL) was degassed, purged three times with nitrogen, and then potassium hexamethyldisilamide (1.00 M, 2.10 mL, 1.50 eq) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour. Then, CH3I (397 mg, 2.80 mmol, 174 μL, 2.00 eq) was added at 0 °C. The mixture was stirred at 20 °C for 11 hours. The reaction mixture was quenched by adding 5.00 mL of H2O and extracted with 5.00 mL × 3 EtOAc. The combined organic layers were washed with brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 173-2 (550 mg, crude) as a yellow solid. ESI-MS M / Z: 371.3 [M+H] +

[1066] 1 H NMR: (400MHz, DMSO-d6) δ7.73 (dd, J=8.8, 2.6Hz, 1H), 7.61-7.65 (m, 1H), 7.50-7.56 (m, 3H), 7.44-7.49 (m, 2H), 7.24-7.26 (m, 1H), 3 .59-3.64(m,1H),3.57-3.59(m,3H),3.33-3.34(m,3H),2.52-2.58(m,1H),2.42-2.49(m,1H),2.29-2.38(m,1H),2.17-2.27(m,1H).

[1067] LiOH·H2O (56.5 mg, 1.35 mmol, 2.00 eq) was added to a solution of compound 173-2 (250 mg, 674 μmol, 1.00 eq) in THF (2.00 mL) and H2O (2.00 mL). The mixture was stirred at 25 °C for 2 h. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that compound 173-2 was completely consumed, forming a new main spot. The mixture was quenched by adding 2.00 mL of H2O, the pH was adjusted to 1 with HCl (6 M), and the mixture was extracted with EtOAc (2.00 mL × 3). The combined organic layers were washed with brine (2.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 173-3 (220 mg, crude) as a yellow oil.

[1068] A solution of compound 173-3 (200 mg, 560 μmol, 1.00 eq), compound 173-4 (147 mg, 1.12 mmol, 137 μL, 2.00 eq), 4-dimethylaminopyridine (6.85 mg, 56.0 μmol, 0.10 eq), and EDCI (214 mg, 1.12 mmol, 2.00 eq) in DCM (3.00 mL) was degassed and purged three times with nitrogen, then stirred at 20 °C for 2 hours under nitrogen atmosphere. The mixture was quenched by adding 3.00 mL of H2O and extracted with DCM (2.00 mL × 3). The combined organic layers were washed with brine (2.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase HPLC to give a yellow solid, compound 173 (150 mg, 31...

Claims

1. A compound of Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof; in, X1 and X2 are independently N or CR 6 ; R 6 Independently for H and C 1-6 Alkyl, hydroxyl, or halogen; L2 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylenes may be optionally oxidized by one or more deuterium, halogen, hydroxyl, or C. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R 4 R 5 R 8 and R 9 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; Or, R 4 and R 5 Together with the C atoms attached thereto, they form a 4-6 membered carbon ring or a 4-6 membered heterocycle, wherein the 4-6 membered carbon ring and the 4-6 membered heterocycle are optionally separated by one or more R atoms. b replace; R b Independently hydroxyl, oxo, halogen, C 1-6 Alkyl, C 1-6 alkoxy or -NR b-1 R b-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may optionally be replaced by one or more hydroxyl groups or halogens; R b-1 and R b-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens; for X4 is hydrogen or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens; or, for X3 is either N or CH; R 7 Independently, it is H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkyl or C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace; R 7-1 Independently for C 1-6 Alkoxy, C 1-6 Alkyl, halogen, or hydroxyl; R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl; X5 is L1 is the connection key, C 1-6 Alkylene, C 1-6 Alkylene-NR L-1 -、C 1-6 Alkylene-OR L-2 -、C 1-6 alkylene-CO-, wherein the C 1- 6-alkylene groups are optionally reacted with one or more deuterium, halogen, hydroxyl, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl substitution; R L-1 It is hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens; R L-2 For single bond or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens; R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, 4-10 membered heterocyclic, 4-6 membered heteroaryl or -NR 2 R 3 The 3-7 membered cycloalkyl, 4-10 membered heterocyclic and 4-6 membered heteroaryl groups are optionally surrounded by one or more R groups. a replace; R 2 and R 3 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens; R a Independently deuterium, hydroxyl group, oxo group, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a-1 R a-2 or -COOR a-3 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may optionally be replaced by one or more hydroxyl groups or halogens; R a-1 R a-2 and R a-3 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more hydroxyl groups or halogens; R 11 and R 12 It is attached to an N atom to form a 4-10 membered heterocyclic group or a 4-6 membered heteroaryl group; wherein the 4-10 membered heterocyclic group and the 4-6 membered heteroaryl group are optionally connected to one or more R atoms. d replace; R d Independently deuterium, hydroxyl group, oxo group, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a-4 R a-5 or -COOR a-6 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may optionally be replaced by one or more hydroxyl groups or halogens; R a-4 R a-5 and R a-6 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens; When L1 is the connector, X1 is N, X2 is CH, X3 is CH, and R... 4 For H, R 5 For Br, R 7 When it is methyl, R 1 Not cyclohexane; when for At that time, R 1 It is a 6-membered heterocyclic group, wherein the 6-membered heterocyclic group is optionally converted by one or more R a Substitution; the heteroatom of the 6-membered heterocyclic group is one or more of O, N and S, the number of heteroatoms is 1, 2 or 3, and it contains at least one N; The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-10 member heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-6 membered heteroaryl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

2. The compound of Formula I as claimed in claim 1, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by Formula I is any of the following schemes: Option 1: The compound of formula I is: X1 and X2 are independently N or CR 6 ; X3 is either N or CH; R 6 Independently for H and C 1-6 Alkyl, hydroxyl, or halogen; L2 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene is optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution; Hal is a halogen; R 10 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The alkyl group is a haloalkoxy group, a 3-7 membered cycloalkyl group, a 4-10 membered heterocyclic group (preferably a 4-9 membered heterocyclic group), or a 4-6 membered heteroaryl group, wherein the 3-7 membered cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-6 membered heteroaryl group are optionally surrounded by one or more R groups. c replace; R c Independently hydroxyl, oxo, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkyl groups are optionally surrounded by one or more R groups. c-1 Replace; R c-1 Independently hydroxyl or halogen; R 4 R 5 R 8 and R 9 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; Or, R 4 and R 5 Together with the C atoms attached thereto, they form a 4-6 membered carbon ring or a 4-6 membered heterocycle, wherein the 4-6 membered carbon ring and the 4-6 membered heterocycle are optionally separated by one or more R atoms. b replace; R b Independently hydroxyl, oxo, halogen, C 1-6 Alkyl, C 1-6 alkoxy or -NR b-1 R b-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; R b-1 and R b-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens; R 7 Independently, it is H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkyl or C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace; R 7-1 Independently for C 1-6 Alkoxy, C 1-6 Alkyl, halogen, or hydroxyl; R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl; The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-9 membered heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatom of the 4-6 membered heteroaryl group is one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; Option 2: The compound of formula I is: in, X1 and X2 are independently N or CR 6 ; X3 is either N or CH; R 6 Independently for H and C 1-6 Alkyl, hydroxyl, or halogen; L1 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene is optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution; R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, 4-10 membered heterocyclic (preferably 4-9 membered heterocyclic), 4-6 membered heteroaryl or -NR 2 R 3 The 3-7 membered cycloalkyl, 4-10 membered heterocyclic and 4-6 membered heteroaryl groups are optionally surrounded by one or more R groups. a replace; R 2 and R 3 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens; R a Independently hydroxyl, oxo, halogen, C 1-6 Alkyl, C 1-6 alkoxy or -NR a-1 R a-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; R a-1 and R a-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens; R 4 and R 5 Independently, H, halogen, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; Or, R 4 and R 5 Together with the C atoms attached thereto, they form a 4-6 membered carbon ring or a 4-6 membered heterocycle, wherein the 4-6 membered carbon ring and the 4-6 membered heterocycle are optionally separated by one or more R atoms. b replace; R b Independently hydroxyl, oxo, halogen, C 1-6 Alkyl, C 1-6 alkoxy or -NR b-1 R b-2 Wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; R b-1 and R b-2 Independently hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens; R 7 Independently H, halogen, cyano, ethynyl, 3-7 membered cycloalkyl, surrounded by one or more R 7-1 Substituted 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, with one or more R 7-2 Substituted 3-7 membered heterocyclic alkyl groups, C 1-6 Alkyl group, with one or more R 7-3 Replacement C 1-6 Alkyl, C 1-6 alkoxy or surrounded by one or more R 7-4 Replacement C 1-6 alkoxy, wherein the 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally surrounded by one or more R 7-1 Instead, the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 7-2 replace; R 7-1 Independently for C 1-6 Alkoxy, C 1-6 Alkyl, halogen, or hydroxyl; R 7-2 Independently deuterium, halogen, hydroxyl, C 1-6 alkoxy or -NR 7-2-1 R 7-2-2 ;R 7-2-1 and R 7-2-2 Independently H or C 1-6 alkyl; When L1 is the connector, X1 is N, X2 is CH, X3 is CH, and R... 4 For H, R 5 For Br, R 7 When it is methyl, R 1 Not cyclohexane; The heteroatoms of the 3-7 membered heterocyclic alkyl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-9 membered heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-6 membered heteroaryl group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

3. The compound of formula I as described in claim 1 or 2, characterized in that, It meets one or more of the following conditions: (1) The C 1-6 The alkylene group is methylene, ethylene, n-propylene, or isopropylene; (2) The halogen is independently fluorine, chlorine, bromine or iodine; (3) The C 1-6 The alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl; (4) The C 1-6 Haloalkyl is a C that is substituted with one or more halogens. 1-3 Alkyl groups, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3; (5) The C 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy; (6) The 3-7 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; (7) The 4-9 member heterocyclic group is a single ring or a multi-ring, and the multi-ring is a fused ring, a helical ring or a bridged ring; (8) The 4-6 heteroaryl group is pyridyl, for example (9) The optional substitution by one or more substituents to be unsubstituted or to be substituted by one or more substituents, wherein the substituents are the same or different, and there are multiple substituents, such as 2, 3, 4, 5 or 6; (10) The 4-6 membered carbon ring is a 4-6 membered cyclic alkenyl group containing a carbon-carbon double bond, with the carbon-carbon double bond side forming a fused ring with a phenyl group, for example... (11) The 4-6 membered heterocycle is a 4-6 membered heterocyclic alkenyl group containing a carbon-carbon double bond, the heteroatom being N, O, or S, and the carbon-carbon double bond side forming a fused ring with a phenyl group, for example... (12) The 3-7 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group, and the heteroatom can be N, O or S, and the number of heteroatoms is 1 or 2, such as oxocyclic butyl alkyl; (13) The 4-10 membered heterocyclic group is a 4-10 membered heterocyclic alkyl group or a 4-10 membered heterocyclic alkenyl group, such as a 4-9 membered heterocyclic group, including bridged rings, fused rings, and spirocyclic rings, such as piperazine, morpholino, piperidinyl, azacyclic butyl, tetrahydropyrrole, thiomorpholino, etc. For example The 4-9 membered heterocyclic alkenyl group, for example For example 4. The compound of formula I as described in claim 1 or 2, characterized in that, It meets one or more of the following conditions: (1) L1 is a connection key or C 1-3 Alkylene, the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl substitution; (2)R 1 Halogen, hydroxyl, -C(O)NH2, C 1-3 Haloalkyl, C 1-3 alkoxy, pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group or -NR2R3, wherein the pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace; (3)R 2 R 3 Each independently can be either hydrogen or C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens; and (4)R a Each is independently hydrogen, hydroxyl, Halogen, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens.

5. The compound of formula I as described in claim 1 or 2, characterized in that, It meets one or more of the following conditions: (1) X1 and X2 are independently N or CR 6 R 6 Independently H or halogen; (2) X3 is CH; (3) L1 is a linker, not substituted, or is occupied by one or more Rs. L1 Replacement C 1-6 Alkylene, R L1 Independently halogen or C 1-6 Haloalkyl, such as L1, is an unsubstituted C. 1-6 Alkylene; (4)R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, 4-9 membered heterocyclic group, 4-6 membered heteroaryl group or -NR 2 R 3 The 4-9 membered heterocyclic group and the 4-6 membered heteroaryl group are optionally surrounded by one or more R a Replacement; preferably, R 1 Halogen, hydroxyl, C 1-6 Halogenated alkyl, unsubstituted or with one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 For example, R 1 For not replaced or by one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 ; (5)R 2 and R 3 Independently hydrogen, unsubstituted or by one or more R 2-1 Replacement C 1-6 Alkyl groups, such as hydrogen; (6)R 2-1 It is a hydroxyl group; (7)R a Independently hydroxyl, oxo, halogen, unsubstituted, or modified by one or more R groups a-3 Replacement C 1-6 Alkyl, unsubstituted or with one or more R a-4 Replacement C 1-6 alkoxy or -NR a-1 R a-2 For example, R a Independently an oxo group, hydroxyl group, or C 1-6 alkyl; (8)R a-3 and R a-4 Independently hydroxyl or halogen; (9)R a-1 and R a-2 Independently hydrogen or C 1-6 alkyl; (10)R 4 and R 5 Independently H or halogen, such as R 4 For H, R 5 It is a halogen; (11)R 4 and R 5 Together with the C atoms it is attached to, they form 4-6 membered carbon rings, for example and (12)R 7 C 1-6 alkyl.

6. The compound of formula I as described in claim 1 or 2, characterized in that, It meets one or more of the following conditions: (1) X1 is N or CR 6 ; (2) X2 is CH; (3) X3 is N; (4)R 6 Halogens, such as fluorine; (5) L2 is C 1-6 Alkylene, preferably C 1-3 Alkyl groups, such as methylene groups; (6) Hal is F; (7)R 10 For H; (8)R 4 R 5 R 8 and R 9 Independently H, halogen, or nitro, such as R 4 R 8 and R 9 For H, R 5 It is halogenated or nitro; (9) The C 1-6 A haloalkoxy group is independently a C- group substituted with one or more halogens. 1-6 Alkoxy groups, preferably C groups substituted with one or more halogens. 1-3 Alkoxy, more preferably C substituted with one or more fluorine atoms. 1-3 Alkyl groups, such as -OCH2F, -OCH2Cl, -OCHF2, -OCHCl2, -OCCl3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3 or -OCF2CF3; (10) The compound shown in Formula I is not any of the following compounds; 7. The compound of formula I as described in claim 1 or 2, characterized in that, It meets one or two of the following conditions: (1) L1 is the connection key. Where end a and R 1 Connected; (2)R 1 The compounds are fluorine, methoxy, bromine, trifluoromethyl, hydroxyl, -C(O)NH2, and amino(-NH2). (3)R 4 H, methyl, or F; R 5 It can be -NO2, Br, Cl or F; (4)R 4 and R 5 It forms together with the C atoms it is attached to. (5)R 7 It is methyl, cyclopropyl, or H; and (6) for 8. The compound of formula I as described in claim 1 or 2, characterized in that, The compound represented by Formula I satisfies one of the following schemes: Option 1: L1 is the connection key or C 1-3 alkylene, wherein the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl substitution; R 1 Halogen, hydroxyl, -C(O)NH2, C 1-3 Haloalkyl, C 1-3 alkoxy, pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group or -NR2R3, wherein the pyridine, 3-7 membered cycloalkyl, 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace; R 2 R 3 Each independently can be either hydrogen or C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens; R a Each independently is a hydroxyl group, Halogen, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl and C 1-3 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; When L1 is the connection key, R 1 Not cyclohexane; Option 2: L1 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution; R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 alkoxy or -NR 2 R 3 ; R 2 R 3 Each independently can be either hydrogen or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens; When L1 is the connection key, R 1 Not cyclohexane; Option 3: R 1 Halogen or C 1-3 Halogenated alkyl; preferably, R 1 Fluorine or C 1-3 Fluorinated alkyl groups; Option 4: L1 is C 1-3 alkylene, wherein the C 1-3 Alkylene oxides are reacted with one or more halogens or C 1-6 Halogenated alkyl substitution; R 1 It is a hydroxyl group; Option 5: L1 is the connection key or C 1-6 alkylene, wherein the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution; R 1 It is a 3-7-membered cycloalkyl, a 4-9-membered heterocyclic, or a 4-6-membered heteroaryl, wherein the 3-7-membered cycloalkyl, 4-9-membered heterocyclic, and 4-6-membered heteroaryl are optionally surrounded by one or more R a replace; R a Each independently is a hydroxyl group, Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; When L1 is the connection key, R 1 Not cyclohexane; The heteroatoms of the 4-9 membered heterocyclic groups are O, N or S, and the number of heteroatoms is 1, 2 or 3; The heteroatom of the 4-6 membered heteroaryl group is O, N or S, and the number of heteroatoms is 1, 2 or 3; Option Six: R 1 It is a 4-9 membered heterocyclic group, wherein the 4-9 membered heterocyclic group is optionally surrounded by one or more R a replace; R a Each independently is a hydroxyl group, Halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; The heteroatoms of the 4-9 membered heterocyclic groups are O, N or S, and the number of heteroatoms is 1, 2 or 3; Preferably, the heteroatom of the 4-9 membered heterocyclic group is nitrogen, and the number of heteroatoms is 1 or 2; Option Seven: R 1 The morpholino group is optionally surrounded by one or more R groups. a replace; R a Halogen and C are independently distinguished. 1-6 Alkyl or C 1-6 Alkoxy; Option 8: X1 and X2 are independently N or CR 6 ; X3 is CH; R 6 Independently H or halogen; L1 is a linker key, not replaced, or occupied by one or more R keys. L1 Replacement C 1-6 Alkylene, R L1 Independent of halogen, C 1-6 Alkyl or C 1- 6-Hydroalkyl; R 1 Halogen, hydroxyl, -C(O)NH2, C 1-6 Haloalkyl, C 1-6 Alkoxy, unsubstituted, or substituted with one or more R a Substituted 3-7 membered cycloalkyl, unsubstituted or with one or more R a Substituted 4-9 membered heterocyclic groups, unsubstituted or substituted with one or more R groups a Substituted 4-6 aryl or -NR 2 R 3 ; R 2 and R 3 Independently hydrogen, unsubstituted or by one or more R 2-1 Replacement C 1-6 Alkyl, R 2-1 It is a hydroxyl group; R a Independently hydroxyl, oxo, halogen, unsubstituted, or modified by one or more R groups a-3 Replacement C 1-6 Alkyl, unsubstituted or with one or more R a-4 Replacement C 1-6 alkoxy or -NR a-1 R a-2 R a-3 and R a-4 Independently hydroxyl or halogen; R a-1 and R a-2 Independently hydrogen or C 1-6 alkyl; R 4 and R 5 Independently H or halogen; Or, R 4 and R 5 Together with the C atoms attached to it, it forms a 4-6 membered carbon ring or a 4-6 membered heterocycle; R 7 C 1-6 alkyl; When L1 is the connector, X1 is N, X2 is CH, X3 is CH, and R... 4 For H, R 5 For Br, R 7 When it is methyl, R 1 Not cyclohexane; The heteroatoms of the 4-6 membered heterocycles are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms of the 4-9 membered heterocyclic group are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; The heteroatom of the 4-6 membered heteroaryl group is one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3; Option Nine: X1 and X2 are independently N or CR 6 ; X3 is CH; R 6 Independently H or halogen; L1 is a linker key, not replaced, or occupied by one or more R keys. L1 Replacement C 1-6 Alkylene, R L1 Independently halogen or C 1-6 Halogenated alkyl groups; R 1 Halogen, hydroxyl, C 1-6 Halogenated alkyl, unsubstituted or with one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 ; R 2 and R 3 Independently hydrogen; R a Independently an oxo group, hydroxyl group, or C 1-6 alkyl; R 4 and R 5 Independently H or halogen; Or, R 4 and R 5 Together with the C atoms attached to it, they form 4-6 membered carbon rings; R 7 C 1-6 alkyl; The heteroatoms of the 4-9 membered heterocyclic groups are one or more of O, N and S, and the number of heteroatoms is 1, 2 or 3.

9. The compound of formula I as described in claim 1 or 2, characterized in that, The compound represented by Formula I satisfies one of the following schemes: Option 1: The compound shown in Formula I is the same as the compound shown in Formula II; Where L1 is C 1-6 Alkylene, the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution; R 4a R 5a Independently, they are hydrogen and C respectively. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens; Or, R 4a and R 5a Together with the N atom it is attached to, a 4-9 membered heterocyclic group is formed, wherein the 4-9 membered heterocyclic group is optionally bonded by one or more R atoms. a replace; R a Each independently is a hydroxyl group, Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; Option 2: The compound shown in Formula I is the same as the compound shown in Formula II; Where L1 is C 1-3 Alkylene, the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl substitution; R 4a R 5a Independently, they are hydrogen and C respectively. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted with one or more hydroxyl groups or halogens; Or, R 4a and R 5a Together with the N atom it is attached to, a 4-9 membered heterocyclic group is formed, wherein the 4-9 membered heterocyclic group is optionally bonded by one or more R atoms. a replace; R a Each independently is a hydroxyl group, Halogen, C 1-3 Alkyl, C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3 The alkoxy group may be optionally replaced by one or more hydroxyl groups or halogens; Option 3: The compound shown in Formula I is the same as the compound shown in Formula III; Where L1 is C 1-6 Alkylene, the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution; Selected from single or double bonds; R 6a It is hydrogen, halogen, hydroxyl or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more halogens or hydroxyl groups; Option 4: The compound shown in Formula I is the same as the compound shown in Formula III; Where L1 is C 1-3 Alkylene, the C 1-3 Alkylene optionally coated with one or more halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl substitution; Selected from single or double bonds; R 6a It is hydrogen, halogen, hydroxyl or C 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted with one or more halogens or hydroxyl groups; Option 5: The compound shown in Formula I is the same as the compound shown in Formula IV; M1, M2 and M3 are independently NH, O, S, CH2 or C(O); Alternatively, M2 is a connecting bond, and M1 and M3 are independently NH, O, S, CH2 or C(O); X1, X2, L1, and R 1 As described in claim 1 or 2; Preferably, M1, M2 and M3 are CH2; X1 and X2 are independently N or CR 6 ; R 6 Independently H or halogen; L1 is C 1-6 Alkylene; R 1 For not replaced or by one or more R a Substituted 4-9 membered heterocyclic groups or -NR 2 R 3 ; R 2 and R 3 Independently hydrogen; R a It is a hydroxyl group; Option Six: The compound shown in Formula I is the same as the compound shown in Formula V; Among them, L 2 X1, X3, R 5 and R 10 Independently as described in claim 1 or 2.

10. The compound of formula I as described in claim 1 or 2, characterized in that, The compound represented by Formula I satisfies one of the following schemes: Option 1: The compound shown in Formula I is the same as the compound shown in Formula II; Where L1 is C 1-6 Alkylene, the C 1-6 Alkylene optionally coated with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl substitution; R 4a R 5a Independently, they are hydrogen and C respectively. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with one or more hydrogens, hydroxyl groups, or halogens; Or, R 4a and R 5a Together with the N atom it is attached to, a 4-10 membered heterocyclic group is formed, wherein the 4-10 membered heterocyclic group is optionally surrounded by one or more R atoms. a Replace; R a As described in claim 1 or 2; Option 2: R 1 for Where R 1a For O or NR 1f ; R 1b R 1c R 1d and R 1e Independently deuterium, hydroxyl group, oxo group, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a-1 R a-2 or -COOR a- 3 R 1f Independently H or C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally substituted with one or more hydroxyl groups or halogens, R a-1 R a-2 and R a-3 As described in claim 1 or 2; Or, R 1b and R 1d The links form bridge rings, with one or two bridge atoms; Or, R 1c and R 1d The links form a bridge ring, with one or two bridge atoms.

11. The compound of formula I as described in claim 1 or 2, characterized in that, The compound represented by Formula I is any of the following compounds:

12. A method for preparing the compound of Formula I according to any one of claims 1-11, comprising the following steps: esterifying 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-A][1,4]diazaphen-4-yl)propionic acid and compound Ia to obtain the compound of Formula I; in, L1 and R 1 As described in any one of claims 1-11.

13. A compound represented by formula Ic; in, R 1 ' is a hydroxyl group, a halogen, or an amino group substituted with an amino protecting group; M1, M2, M3, L1, X1, and X2 are independently as described in any one of claims 1-11; Preferably, the compound represented by formula Ic is 14. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1-11, a stereoisomer thereof, a deuterated form thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

15. The use of a compound of Formula I as claimed in any one of claims 1-11, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 14 in the preparation of an anesthetic and sedative medicament.

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