Neurokinin-1 receptor antagonist compound

Abstract

Disclosed in the present invention is a neurokinin-1 receptor antagonist compound, specifically, a compound having a structure represented by the following formula (II), formula (III) or formula (IV), an isomer, or a pharmaceutically acceptable salt or acid thereof or a deuterated compound thereof. The compound of the present invention has suitable solubility, and can be rapidly converted into an active metabolite rolapitant in blood plasma and liver, such that the problem that rolapitant is difficult to develop into a conventional injection formulation due to poor solubility is solved; in addition, hemolysis can be avoided, and the injection risk can be reduced. Compared with an existing prodrug molecule (a compound of formula (I)), the compound of the present invention is converted in vivo to release the active metabolite rolapitant at a much faster rate, has higher in-vivo exposure of the active metabolite rolapitant, and exhibits superior pharmacokinetic properties.

Description

Neurokinin-1 receptor antagonist compounds Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a neurokinin-1 (NK1 or NK-1) receptor antagonist. Background Art

[0002] Neurokinins are central neurotransmitters involved in a variety of physiological activities in the human body. Neurokinins include various substances, such as substance P, neurokinin A, and neurokinin B. There are three types of neurokinin receptors: neurokinin receptor 1 (NK1R), neurokinin receptor 2 (NK2R), and neurokinin receptor 3 (NK3R). NK1R is the most important and widely distributed, present in neurons, brainstem, vascular endothelium, gastrointestinal tract, and urogenital system, with highest concentrations in the brain's vomiting center. Substance P is the most important neurotransmitter, widely distributed in the human central nervous system and gastrointestinal tract, and has the strongest binding affinity to NK1R. After binding to NK1R, substance P acts on calcium ion channels on the membrane through inositol triphosphate, causing membrane depolarization and changes in protein kinase activity. It participates in pain and stress signaling, triggering physiological responses such as vomiting, anxiety, and pain.

[0003] Neurokinin receptor antagonists and their uses include: US5760018 (1998) (pain, inflammation, migraine and vomiting), US5620989 (1997) (pain, inflammation and nociception), WO95 / 19344 (1995), WO94 / 13639 (1994) and WO94 / 10165 (1994). Other types of NK1 receptor antagonists include: WU et al., Tetrahedton 56, 3043-3051 (2000); Rombouts et al., Tetrahedton Letters 42, 7397-7399 (2001) and Rogiers et al., Tetrahedton 57, 8971-8981 (2001).

[0004] US7049320 provides a potent, selective NK1 antagonist (5S,8S)-8-(((1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy)-methyl)-8-phenyl-1,7-diazaspiro(4,5)decan-2-one (rolapitant) with beneficial therapeutic and pharmacological properties and good metabolic stability. The compound is in the form of a free base or a pharmaceutically acceptable salt, and is suitable for parenteral administration.

[0005] Rolapitant has poor solubility at physiological pH and is difficult to develop into a conventional injection. In order to solve this problem, researchers used a co-solvent-based preparation containing Captisol, propylene glycol and ethanol to significantly improve the solubility of rolapitant, but this preparation has a significant hemolytic effect after intravenous administration. The hemolytic nature of the drug is caused by the massive destruction of red blood cells caused by immune factors after the drug enters the human body, and clinically manifests as symptoms such as anemia, jaundice, and soy sauce urine. CN102573475 provides a series of prodrugs of rolapitant and an improved prescription containing polyethylene glycol 15-hydroxystearate and medium-chain triglycerides, but does not completely solve the hemolytic effect of the pharmaceutical composition. WO2020259675A1 discloses a series of rolapitant prodrug compounds, the solubility of the prodrug compound of the invention (Formula (I)) is significantly improved, and most of it can be converted into rolapitant in the body, which can avoid the hemolytic effect of the pharmaceutical composition and reduce side effects during administration. A prodrug is a compound that, after chemical structural modification of a drug (parent drug), is inactive or minimally active in vitro but releases the active drug in vivo through enzymatic or non-enzymatic conversion to exert its pharmacological effect. The prodrug design of rolapitant is primarily intended to improve its water solubility and facilitate the development of an injectable formulation. Such prodrugs are considered to possess ideal pharmacokinetic properties and are ideal rolapitant prodrugs because they rapidly convert to the active metabolite rolapitant in vivo and have high in vivo exposure to the active metabolite.

[0006] In view of this, more prodrug designs of rolapitant are provided, and it is found that the conversion and release of the active metabolite rolapitant in the body is faster, and the in vivo exposure of the active metabolite rolapitant is higher. The safer and more effective prodrug molecules have important clinical value.

[0007] Summary of the Invention

[0008] One of the objects of the present invention is to provide a neurokinin-1 (NK1 or NK-1) receptor antagonist, a compound having a structure represented by the following formula (II), formula (III) or formula (IV), an isomer, or a pharmaceutically acceptable salt or acid or deuterated product thereof:

[0009] in:

[0010] In formula (II),

[0011] L1 is selected from -[C(R4)(R5)] m -(A) q -、-[C(R4)(R5)] m -(A) p -C(O)-[C(R4)(R5)] n -(A)q -、-[C(R4)(R5)] m -C(O)-(A) p -[C(R4)(R5)] n -(A) q -、-[C(R4)(R5)] m -(A) p -B-(A) q -、-[C(R4)(R5)] m -C(O)-(A) p -B-(A) q -、-[C(R4)(R5)] m -(A) p -C(O)-B-(A) q -、-[C(R4)(R5)] m -(A) p -C(S)-B-(A) q -、-[C(R4)(R5)] m -C(S)-(A) p -B-(A) q -、-[C(R4)(R5)] m -B-(A) p -、-[C(R4)(R5)] m -B-C(O)-(A) p -、-[C(R4)(R5)] m -B-(A) p -C(O)-(A) q -、-[C(R4)(R5)] m -B-(A) p -C(S)-(A) q -、-[C(R4)(R5)] m -B-C(S)-(A) p -、-[C(R4)(R5)] m -(A) p -S(O) t -B-、-[C(R4)(R5)] m -S(O) t -(A) p -B-、-[C(R4)(R5)] m -S(O)=N-[C(R4)(R5)] n -、-[C(R4)(R5)] m -N=S(O)-[C(R4)(R5)] n -;

[0012] A is selected from O, S, N(R6);

[0013] B is selected from cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S, alkenyl or alkynyl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S is optionally substituted with one or more selected from alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, SH, halogen;

[0014] R1 is selected from

[0015] R2 is selected from hydrogen, hydroxy, SH, alkyl, haloalkyl, alkoxy, -[C(R4)(R5)] m -N(R7)3 + , cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S, alkenyl, alkynyl or nitrile group, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S is optionally substituted with one or more selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile group, halogen;

[0016] R3 is selected from hydrogen, SH, alkyl, haloalkyl, alkoxy, -[C(R4)(R5)] m -N(R7)3 +, cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S, alkenyl or alkynyl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S is optionally substituted with one or more selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen;

[0017] When L1 is -[C(R4)(R5)] m -(A) p -B-(A) q -、-[C(R4)(R5)] m -S(O)=N-[C(R4)(R5)] n -、-[C(R4)(R5)] m -N=S(O)-[C(R4)(R5)] n -, R1 can also be selected from

[0018] When L1 is -[C(R4)(R5)] m -(A) q -、-[C(R4)(R5)] m -S(O)=N-[C(R4)(R5)] n -、-[C(R4)(R5)] m -N=S(O)-[C(R4)(R5)] n -, R1 can also be

[0019] R4 and R5 are independently selected from hydrogen, hydroxy, SH, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, nitrile or halogen, wherein cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen;

[0020] R6 is selected from hydrogen, C 1-6 Alkyl, haloalkyl, C 1-8 Cycloalkyl, C 1-8Heterocyclyl, aryl, heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen;

[0021] R7 is selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile;

[0022] m is an integer from 0 to 6; n is an integer from 0 to 6; p is 0, 1 or 2; q is 0, 1 or 2; t is 1 or 2;

[0023] In formula (III),

[0024] R' is selected from H, Alkoxy, alkenyl, alkynyl, nitro, nitrile, halogen, acetyl, sulfonyl, C 1-6 Alkyl, haloalkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclic group, aryl group, heteroaryl group,

[0025] R" is selected from NH2, having a substituted or unsubstituted group selected from the following: 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S, -[C(R4)(R5)] m -N(R”')3 + 、C 2-7 Cyclic quaternary ammonium salts (such as: ), 5-12 membered heterospirocyclic quaternary ammonium salts containing N, O or S (for example: ), 5-12 membered hetero-bridged ring quaternary ammonium salts containing N, O or S (for example: ); substituents are selected from H, OH, SH, NH2, C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; R4 and R5 are as described above;

[0026] m is an integer from 0 to 6;

[0027] Or R' and R" together with the carbon atoms to which they are attached form a substituted or unsubstituted group: It has a 5-12 membered spiro ring selected from N, O or S, a 5-12 membered heterobridged ring containing N, O or S, or a 6-12 membered condensed ring containing N, O or S; and a substituent selected from H, OH, SH, NH2, C 1-6Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; x is an integer from 1 to 6;

[0028] R"' is selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile;

[0029] In formula (IV),

[0030] L2 is selected from -[C(R b )(R c )] x -、-[C(R b )(R c )] x -Z-[C(R d )(R e )] h -、-[C(R b )(R c )] x -AC(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -AC(S)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -AS(O)2-[C(R d )(R e )] h -、-[C(R b )(R c )] x -C(O)-A-[C(R d )(R e )] h -、-[C(R b )(R c )] x -C(S)-A-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S(O)2-A-[C(R d )(R e )] h -、-[C(R b )(R c )] x-vinyl-[C(R d )(R e )] h -、-[C(R b )(R c )] x -ethynyl-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S(O)(NR k )-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S(O)=N-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S(O) t -[C(R d )(R e )] h -;

[0031] R a Selected from -[C(R f )(R g )] n -R j 、 -Y-[C(R f )(R g )] n -R j 、-[C(R f )(R g )] n -N(R p )2 + -[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -AC(O)-[C(R h )(R i )] i -R j 、-[C(R f )(Rg )] n -A-C(S)-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -乙烯基-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -乙炔基-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O)(NR k )-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O)=N-[C(R h )(R i )] i -R j、 -[C(R f )(R g )] n -S(O) t -[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -C(O)-A-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -C(S)-A-[C(R h )(R i )] i -R j 、-[C(R f )(R g )]n -vinyl[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -ethynyl[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O)(NR k )-[C(R h )(R i )] i -R j 、[C(R f )(R g )] n -N=S(O)-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O) t -[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -N(R p )2 + -[C(R h )(R i )] i -R j ;

[0032] R b 、R c 、R d 、R e 、R f 、R g 、R h and R i Each is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, nitrile or halogen, wherein cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally replaced by one or more selected from alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen, acetyl, sulfonyl, replaced by;

[0033] or R b and R c 、R d and R e 、R f and R g 、R h and R i The following groups, taken together with the carbon atoms to which they are attached, are substituted or unsubstituted: cycloalkyl, heterocycloalkyl, 5-12 membered spirocyclic group containing N, O or S, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group containing N, O or S; the substituents are selected from H, OH, SH, NH2, C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen;

[0034] R j Selected from H, NH2, OH, SH, alkoxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen, C1-C6 alkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclic group, aryl group, heteroaryl group, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S, -N(R p )3 + 、C 2-7 Cyclic quaternary ammonium salts (such as: ), 5-12 membered heterospirocyclic quaternary ammonium salts containing N, O or S (for example: ), 5-12 membered hetero-bridged ring quaternary ammonium salts containing N, O or S (for example: ), wherein cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, amino, halogen, acetyl, sulfonyl, Replaced by; R2 is as described above;

[0035] R k Selected from hydrogen, C 1-6 Alkyl, haloalkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclyl, aryl, heteroaryl;

[0036] wherein cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, amino, SH, halogen;

[0037] R p Selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile;

[0038] A is selected from O, S, N(R k );

[0039] Y is selected from substituted or unsubstituted C 1-8 Cycloalkyl, C 1-8 Heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S,; substituents are selected from H, NH2, OH, SH, C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen;

[0040] Z is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, and halogen;

[0041] h is an integer of 0-10; i is an integer of 0-10; m is an integer of 0-6; n is an integer of 0-6; x is an integer of 1-6; and y is an integer of 0-10.

[0042] In some aspects, in formula (II) of the present invention:

[0043] In some embodiments, L1 is selected from -[C(R4)(R5)] m -(A) q -or-[C(R4)(R5)] m -(A) p -C(O)-[C(R4)(R5)] n -(A) q -; A is selected from O or S;

[0044] R1 is selected from

[0045] R2 is selected from hydrogen, hydroxy, SH, alkyl, C1-C6 alkyl, C1-C6 alkoxy;

[0046] R3 is selected from hydrogen, SH, alkyl, C1-C6 alkyl, C1-C6 alkoxy;

[0047] m is an integer of 0-6; n is an integer of 0-6; p is 0, 1 or 2; q is 0, 1 or 2; and t is 1 or 2.

[0048] In some more specific examples,

[0049] R1 is selected from

[0050] R2 is selected from hydrogen, hydroxy, SH, alkyl, C 1-6 Alkyl, C 1-6 Alkoxy; p is 0, 1 or 2.

[0051] In some aspects, in formula (III) of the present invention:

[0052] R' is selected from H, C 1-6 alkyl, C 1-6 Alkoxy, nitro, nitrile, halogen;

[0053] R" is selected from the following groups which are substituted or unsubstituted: 5-12 membered heterospirocyclic ring containing N, O or S, -[C(R4)(R5)] m -N(R”')3 + ; Substituents are selected from H, OH, SH, NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, nitro, nitrile, halogen; m is 0, 1, 2, 3, 4, 5 or 6; R4 and R5 are independently selected from hydrogen, hydroxy, SH, alkyl, C1-C4 alkyl;

[0054] Or R' and R" together with the carbon atoms to which they are attached form a substituted or unsubstituted group: It has a 5-12 membered spiro ring selected from N, O or S, a 5-12 membered heterobridged ring containing N, O or S, or a 6-12 membered condensed ring containing N, O or S; and a substituent selected from H, OH, SH, NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, nitro, nitrile, halogen; x is 1, 2, 3, 4, 5 or 6;

[0055] R"' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, alkenyl, alkynyl, nitrile.

[0056] In some more specific examples,

[0057] R' is selected from H, C 1-6 alkyl, C 1-4 Alkoxy, nitro, nitrile, halogen;

[0058] R" is selected from NH2, having a substituted or unsubstituted group selected from the following groups: -[C(R4)(R5)] m -N(R”')3 + ; Substituents are selected from H, OH, SH, NH2, C 1-4 Alkyl, C 1-4 haloalkyl, nitro, nitrile, halogen; m is 0, 1, 2, 3, 4, 5 or 6; R4 and R5 are independently selected from hydrogen, hydroxy, SH, alkyl, C1-C4 alkyl;

[0059] R"' is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, alkenyl, alkynyl, nitrile; preferably methyl, ethyl, propyl or isopropyl.

[0060] In some aspects, in Formula (IV),

[0061] In some specific examples, L2 is selected from -[C(R b )(R c )] x -、-[C(R b )(R c )] x -Z-、-[C(R b )(R c )] x -OC(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -SC(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -OC(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -OC(S)-[C(R d )(R e )] h -;R b is H or methyl; R c is H or methyl; Z is C 5-10 aromatic ring or aromatic heterocyclic ring, more preferably Z is a benzene ring, a naphthalene ring or a thiophene ring; R d is methyl or ethyl; Re is H or methyl or ethyl; x is 1, 2, 3, 4, 5 or 6; h is an integer from 0 to 10.

[0062] In some more specific examples, L2 is selected from -CH2-, -CH(CH3)- or -C(CH3)2-; further, L2 is selected from -CH2-.

[0063] In other embodiments, L2 is selected from -CH2-OC(O)-(CH2) h -、-CH2-SC(O)-(CH2) h -、-CH2-OC(O)-[C(R d )(R e )] h -、-CH2-OC(S)-[C(R d )(R e )] h -;R d is methyl; R e is H or methyl; h is an integer of 0 or 10; more preferably h is an integer of 0-6; h is 0, 1, 2, 3 or 4.

[0064] In some instances, R a Selected from the following substituted or unsubstituted groups: C1-C 10 alkyl, -(CH2) h CHR x R y 、-(CH2) h NR m R n 、-(CH2) h N(R p )2 + -R j ; Substituents are selected from NH2, -OH, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carboxyalkyl;

[0065] h or y is an integer from 0 to 10;

[0066] R x Selected from H, -COOH, C1-C4 alkyl;

[0067] R y Selected from H, amino, C1-C4 alkyl;

[0068] R m 、R nIndependently selected from H, amino, -COOH, C1-C4 alkyl; or R m and R n Together with the nitrogen atom to which it is attached, it forms a 5- to 11-membered heterocyclic ring having 1 to 3 heteroatoms selected from N, O, or S;

[0069] R j Selected from H, C1-C6 alkyl;

[0070] R p Selected from H, C1-C6 alkyl.

[0071] In some more specific examples, R a Selected from the following substituted or unsubstituted groups: C1-C6 alkyl, -(CH2) h CHR x R y 、-(CH2) h NR m R n 、-(CH2) h N(R p )2 + -R j ; Substituents are selected from NH2, -OH, -COOH,

[0072] y is 1, 2, 3, 4, 5 or 6; h is 0, 1, 2, 3 or 4;

[0073] R x Selected from H, -COOH, methyl, ethyl, propyl, isopropyl;

[0074] R y Selected from H, amino, methyl, ethyl, propyl, isopropyl;

[0075] R m 、R n are independently selected from H, amino, -COOH, methyl, ethyl, propyl, isopropyl; or R m and R n Together with the nitrogen atom to which it is attached, it forms a 5- to 11-membered heterocyclic ring having 1 to 3 heteroatoms selected from N, O, or S;

[0076] R j Selected from H, methyl, ethyl, propyl, isopropyl;

[0077] R p Selected from H, methyl, ethyl, propyl, isopropyl.

[0078] In some specific examples, the present invention provides a compound having the following structure, an isomer, or a pharmaceutically acceptable salt or acid or a deuterated derivative thereof:

[0079] The present invention also provides a composition comprising the compound of the present invention, wherein the composition comprises the compound of the present invention and a pharmaceutically acceptable carrier.

[0080] The present invention also provides use of the above compound in preparing medicines for treating vomiting, nausea, asthma, anxiety, depression, cough or migraine.

[0081] Unless otherwise specified, the terms used in the present invention have the following definitions:

[0082] "Spirocyclic": When there are two rings in a molecule and these two rings share a carbon atom, this system is called a spirocyclic.

[0083] The "bridged ring" refers to a polycyclic hydrocarbon that shares two or more carbon atoms (bridgehead carbons), and is classified into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. according to the number of constituent rings.

[0084] "8-16 membered ring containing or not containing unsaturated bonds" means that the ring contains 8 to 16 atoms, wherein the 8-16 membered ring containing unsaturated bonds means that the ring has at least one carbon-carbon double bond or carbon-carbon triple bond, or both.

[0085] "Alkyl" refers to a saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, including straight-chain and branched groups (the numerical ranges mentioned in this application, such as "1-20", refer to the group, in this case an alkyl group, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, the alkyl group is a medium-sized alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, etc. C1-C8 alkyl refers to a straight-chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, etc. Alkyl groups containing 1 to 4 carbon atoms are called lower alkyl groups. When a lower alkyl group has no substituent, it is called an unsubstituted lower alkyl group. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, etc. The alkyl group may be substituted or unsubstituted, and the substituents may be plural.

[0086] "Haloalkyl" refers to a halogen-substituted alkyl group, preferably a halogen-substituted lower alkyl group as defined above, which is substituted by one or more halogen atoms, which may be the same or different, for example -CH2Cl, -CF3, -CH2CF3, -CH2CCl3, etc.

[0087] "Alkoxy" refers to -O-(unsubstituted alkyl) or -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0088] “C 1-6 The term "alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, and the like. A straight-chain or branched alkoxy group having 1 to 4 carbon atoms is preferred, with methoxy and ethoxy being particularly preferred.

[0089] "Cycloalkyl" means an all-carbon monocyclic or fused ring ("fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with every other ring in the system) group in which one or more rings does not have a completely connected pi electron system. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene.

[0090] "Heterocycle" means a saturated cyclic group of 3 to 8 ring atoms, one or two of which are selected from N, O or S(O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are C, wherein one or two C atoms may be optionally replaced by a carbonyl group. The ring of the heterocyclic group may be optionally substituted independently by one, two or three substituents selected from lower alkyl (optionally substituted by one or two substituents, the substituents being independently selected from carboxyl or ester groups), haloalkyl, cyanoalkyl, halogen, nitro, cyano, hydroxyl, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, heteroaralkyl and -COR (wherein R is an alkyl group). More specifically, the term heterocyclic includes, but is not limited to, tetrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, pyrrolidinyl, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4-ethoxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidinone, 2-pyrrolidone, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, and derivatives thereof. Preferably, the heterocyclic group is optionally substituted with one or two substituents independently selected from halogen, lower alkyl, lower alkyl substituted with carboxyl or ester, hydroxyl, mono- or dialkylamino.

[0091] The term "heterocyclyl" refers to a 3-12 membered aromatic or non-aromatic heterocyclic ring containing 1-4 heteroatoms selected from O, N and S, and includes bicyclic groups. "Heterocyclyl" therefore includes the above-mentioned heteroaryl groups, as well as their dihydrogenated and tetrahydrogenated analogs. Further examples of "heterocyclyl" include, but are not limited to, benzimidazolyl, benzofuranyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, dihydroindolinyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolyl pyridazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexallydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothiophenyl and N-oxides thereof. Attachment of the heterocyclic substituents may be through a carbon atom or through a heteroatom.

[0092] "Aryl" means an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms with a completely conjugated π electron system. Non-limiting examples of aryl groups include phenyl, naphthyl and anthracenyl. Aryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two, independently selected from lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, sulfhydryl, (lower alkyl) sulfenyl, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonylamino, S-sulfonylamino, R 10 S(O)-、R 10 S(O)2-、-C(O)OR 10 、R 10 C(O)O- and -NR10 R 11 The group composed of R 10 and R 11 Preferably, the aryl group is optionally substituted by one or two substituents independently selected from halogen, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-acylamino, mono- or dialkylamino, carboxyl or N-sulfonylamino.

[0093] "Heteroaryl" means a stable monocyclic ring of up to 3-10 atoms in the ring(s) or a bicyclic carbon ring of up to 3-10 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N, and S. Non-limiting examples of unsubstituted heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, indolyl, benzotriazolyl, benzothienyl, benzofuranyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, tetrazolyl, triazinyl, and carbazolyl. Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two, independently selected from the group consisting of lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, mercapto, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, nitro, N-sulfonylamino, S-sulfonylamino, R 10 S(O)-、R 10 S(O)2-、-C(O)OR 10 、R 10 C(O)O- and -NR 10 R 11 , where R 10 and R 11 Preferred heteroaryl groups are optionally substituted by one or two substituents independently selected from halogen, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-acylamino, mono- or dialkylamino, carboxyl or N-sulfonylamino.

[0094] "Acyl" means a -C(O)-R' group, wherein R' is selected from the group consisting of hydrogen, unsubstituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl, optionally substituted by one or more, preferably 1, 2 or 3, groups selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and -NR 10 R 11 The substituents of the group are substituted aryl groups, wherein R 10 and R 11As defined above, optionally substituted by one or more, preferably 1, 2 or 3, selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and -NR 10 R 11 The substituents of the group are heteroaryl (bonded via a ring carbon atom), and optionally substituted by one or more, preferably 1, 2 or 3, groups selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and -NR 10 R 11 The substituents of the group are substituted heteroalicyclic groups (bonded through a ring carbon atom), and representative acyl groups include but are not limited to acetyl, trifluoroacetyl, benzoyl, and the like.

[0095] "Sulfonyl" means a -S(O)2-R' group, wherein R' is selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl, optionally substituted by one or more, preferably 1, 2 or 3, groups selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and -NR 10 R 11 The substituents of the group are substituted aryl groups, wherein R 10 and R 11 As defined above, optionally substituted by one or more, preferably 1, 2 or 3, selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and -NR 10 R 11 The substituents of the group are heteroaryl (bonded via a ring carbon atom), and optionally substituted by one or more, preferably 1, 2 or 3, groups selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halogen and -NR 10 R 11 The substituents of the group are substituted heteroalicyclic groups (bonded through a ring carbon atom), and representative acyl groups include but are not limited to methylsulfonyl, trifluoromethylsulfonyl, phenylsulfonyl, and the like.

[0096] A "carbonyl group" is an organic functional group composed of carbon and oxygen atoms connected by a double bond (C=O).

[0097] "Quaternary ammonium salts" are compounds formed by replacing all four hydrogen atoms in an ammonium ion with hydrocarbon groups.

[0098] The compounds of the present invention possess suitable solubility and are rapidly converted into the active metabolite, rolapitant, in plasma and the liver. This addresses the poor solubility of rolapitant, which makes it difficult to develop conventional injectable formulations. Furthermore, they avoid hemolysis and reduce injection risks. Compared to existing prodrug molecules (compounds of formula (I)), the compounds of the present invention convert and release the active metabolite, rolapitant, more rapidly in the body and have a higher in vivo exposure of the active metabolite, rolapitant, exhibiting superior pharmacokinetic properties. DETAILED DESCRIPTION

[0099] The following examples are provided to facilitate a better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples, unless otherwise specified, are conventional methods. The test materials used in the following examples, unless otherwise specified, were purchased from conventional biochemical reagent stores.

[0100] Example 1

[0101] Under nitrogen protection, compound 1 (3.0 g, 6.0 mmol) was weighed and dissolved in dichloromethane (45 mL) in a 100 mL three-necked flask. Diisopropylethylamine (6.2 g, 48 mmol) was added, the mixture was cooled to -30°C, and trimethylsilyl chloride (1.69 g, 15.6 mmol) was added. The mixture was stirred at room temperature for 2 h. After cooling to -25°C, a solution of chloromethyl chloroformate (950 mg, 7.30 mmol) in dichloromethane was added dropwise. The temperature was maintained at -25°C to -5°C and stirred until the reaction was complete. The reaction mixture was poured into ice water, separated, extracted with dichloromethane, and then water and 1N dilute hydrochloric acid were added. The organic phase was washed sequentially with water, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain 3.0 g of intermediate I in an 83.3% yield. LC-MS [M+H] + :593.2.

[0102] Compound 2 (1.439 g, 12.6 mmol) was dissolved in water (4 mL) and passed through an ion exchange resin (Dowex 50WX-8, H + ), rinsed with pure water, cooled the receiving solution to 0°C in an ice bath, added tri-n-butylamine (2.34 g, 12.6 mmol), warmed to room temperature, stirred for 2 h, and lyophilized to obtain 3.0 g of compound 3 with a yield of 80.1%, which was directly used in the next reaction.

[0103] Under N2 protection, Intermediate I (200 mg, 0.336 mmol) was weighed and dissolved in acetonitrile (5 mL) in a 100 mL three-necked flask. Compound 3 (1.5 g, 5.04 mmol) was added and stirred at room temperature for 2 h. The reaction solution was subjected to preparative separation (Solution A: 0.05% aqueous ammonia, Solution B: acetonitrile) to obtain 3.6 mg of Example 1, a yield of 1.49%. LC-MS [M+H] + :670.1. 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.00(s,1H),7.95(s,2H),7.39-6.98(m ,9H),5.25-5.17(m,1H),5.11-5.02(m,1H),4.69-4.61(m,1H),4.09-3.97(m ,2H),3.53(d,J=13.6Hz,1H),3.41(d,J=13.8Hz,1H),2.45-2.30(m,3H),2.1 2-2.02(m,2H),1.96-1.88(m,1H),1.64-1.55(m,2H),1.36(d,J=6.4Hz,3H).

[0104] Example 2

[0105] Under N2 protection, tri(tetrabutylammonium) hydrogen pyrophosphate (567 mg, 1.36 mmol) was weighed and dissolved in acetonitrile (5 mL) in a 100 mL three-necked flask. A solution of intermediate I (400 mg, 0.68 mmol) in acetonitrile (5 mL) was added and stirred at room temperature for 3 hours. HPLC preparation was directly carried out (Preparation A solution: 0.1% HN 3. H2O, solution B: acetonitrile) to give 150 mg of Example 2 compound, yield 29.56%. LC-MS: 734.6 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.98(s,1H),7.94(s,2H),7.84-5.90(m,11H),5 .47-5.36(m,1H),5.26(d,J=6.8Hz,1H),4.62(s,1H),4.17(d,J=7.7Hz,1H),3.98(d,J =9.0Hz,1H),3.70(d,J=13.7Hz,1H),3.14(d,J=13.8Hz,1H),2.33(s,2H),2.19-2.05( m,2H),1.94(s,1H),1.65-1.55(m,2H),1.42(t,J=11.9Hz,1H),1.32(d,J=6.3Hz,3H).

[0106] Example 3

[0107] Compound 1 (200 mg, 1.36 mmol) was weighed and dissolved in 10 mL of water in a 100 mL round-bottom flask. Compound 2 (40% aqueous solution) was added and the pH of the solution was slowly adjusted to 8-9. The solution was lyophilized to obtain 240 mg of crude compound 3, which was used directly in the next reaction.

[0108] To a solution of Intermediate I (150 mg, 0.25 mmol) in anhydrous acetonitrile (3 mL) was added Compound 3 (240 mg). The resulting solution was stirred at room temperature for 1 hour, after which the solvent was removed in vacuo, and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 μm ACN-H2O, 0.1% NH4HCO3) to afford 6 mg of Example 3, a 3.25% yield. LC-MS: 733.1 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.91-7.81(m,3H),7.46-7.35(m,4H),7.32-7.25(m,1H),5.67- 5.60(m,1H),5.57-5.50(m,1H),4.64-4.54(m,1H),4.26-4.18(m,1H),4.18-4.09(m ,1H),4.00-3.94(m,1H),3.25-3.14(m,1H),2.53-2.32(m,4H),2.21(t,J=19.5Hz,2 H),2.09-1.98(m,1H),1.88-1.76(m,2H),1.74-1.65(m,1H),1.38(d,J=6.4Hz,3H).

[0109] Example 4

[0110] Compound 1 (200 mg, 0.66 mmol) was dissolved in 5 mL of anhydrous dichloromethane, to which compound 2 (75 mg, 0.67 mmol) and 4-dimethylaminopyridine (8.6 mg, 0.066 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was then removed in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 5) to obtain 200 mg of compound 3 in a yield of 72.6%. 1 H NMR (400MHz, MeOD) δ5.12 (t, J = 23.1Hz, 1H), 4.30-4.12 (m, 8H), 2.44-2.34 (m, 4H), 2.00-1.85 (m, 2H), 1.43-1.33 (m, 12H).

[0111] Compound 3 (100 mg, 0.168 mmol), intermediate I (140 mg, 0.336 mmol), sodium iodide (50.43 mg, 0.336 mmol) and potassium bicarbonate (33.66 mg, 0.336 mmol) were dissolved in anhydrous dimethylformamide (3 mL) and the solution was stirred at 25° C. under nitrogen for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC (Gemini-C18 150×21.2 mm, 5 μm ACN-H 2 O, 0.1% NH 4 HCO 3 ) to give 65 mg of compound 4 in a yield of 39.62%. LC-MS: 974.3 [M+H] + .

[0112] To a solution of compound 4 (20 mg, 0.021 mmol) in anhydrous dichloromethane (2 mL) was added trimethylsilyl bromide (31 mg, 0.205 mmol). The solution was stirred at -10°C for 16 hours. The solvent was then removed in vacuo, and the residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% NH4HCO3) to afford 2 mg of Example 4 in an 11.22% yield. LC-MS: 861.6 [M+H] + . 1H NMR(400MHz,D2O)δ7.94(s,1H),7.84(s,2H),7.34-7.18(m,3H),7.16-7.01(m,2H),5.64-5.48(m,1H),5.33-5.19(m,1H),4.59-4. 51(m,1H),4.30(t,J=19.1Hz,1H),4.07-3.96(m,2H),3.74-3.58(m,2H),2.54-2.13(m,8H),1.88-1.58(m,6H),1.50-1.40(m,3H).

[0113] Example 5

[0114] Compound 1 (5 g, 25.7 mmol) was dissolved in 40 mL of anhydrous acetonitrile, and sodium hydride (1.54 g, 38.5 mmol) was added thereto at 0°C. The reaction solution was stirred at room temperature under nitrogen for 30 minutes, and then iodomethane (5.47 g, 38.5 mmol) was slowly added and stirred overnight at ambient temperature. After the reaction was complete, 1 mL of water was added to quench the reaction, and the mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 4.74 g of compound 2 in a yield of 88.7%. 1 H NMR (400MHz, DMSO-d6) δ1.42 (s, 18H), 1.32 (d, J = 17.2Hz, 3H).

[0115] Compound 2 (3.6g, 17.3mmol) is dissolved in 60mL anhydrous tetrahydrofuran, and the temperature is lowered to 78 degrees Celsius below zero under nitrogen protection. Diisopropylamine lithium (17.3mL, 34.6mmol, 2.0M / L) is slowly added dropwise, and the reaction solution is stirred at this temperature for 30 minutes. Then a tetrahydrofuran (35mL) solution of compound 3 (4.62g, 17.3mmol) is added. The reactant is stirred and heated to room temperature overnight. The reaction is quenched with saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate (200mL). The organic phase merged is washed with saturated common salt water and dried over anhydrous sodium sulfate, filtered and concentrated filtrate. By silica gel column chromatography purification (petroleum ether / ethyl acetate=20 / 1+1% triethylamine), 1.9g compound 4 is obtained, and yield is 24.28%. 1 HNMR (400MHz, CDCl3) δ3.42-3.32(m,4H),2.10(dd,J=20.7,1.3Hz,2H),1.50(s,18H),1.19-1.14(m,24H).

[0116] 4,5-Dicyanoimidazole (300 mg, 2.6 mmol, 1 eq) was slowly added to a mixture of compound 4 (1.9 g, 4.3 mmol) and tert-butyl alcohol (320 mg, 4.3 mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature for 4 hours and then concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 + 1% triethylamine) to give 900 mg of compound 5 in a yield of 51.16%. 1 HNMR (400MHz, CDCl3) δ3.60-3.38(m,2H),2.21-2.07(m,1H),1.92-1.81(m,1 H),1.50(s,18H),1.30(s,9H),1.17(d,J=6.6Hz,6H),1.10(d,J=6.7Hz,6H).

[0117] To a mixed solution of compound 5 (300 mg, 0.73 mmol) and compound 6 (122 mg, 0.73 mmol) in dimethylformamide (2 mL) was added tetrazole (204 mg, 2.92 mmol), and the mixture was reacted at room temperature for 2 hours. Hydrogen peroxide solution (165 mg, 30%) was then added dropwise at 0°C. After stirring for 16 hours, the reaction was quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed sequentially with water and saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 92 / 8) to obtain 150 mg of compound 7 in a yield of 41.70%. 1 H NMR (400MHz, MeOD) δ7.44-7.33(m,5H),5.27-5.18(m,2H),4.79-4.65(m,2H),2.67-2.49(m,J=22.2,20.8Hz,2H),1.57-1.51(m,27H).

[0118] Compound 7 (100 mg, 0.203 mmol) was dissolved in ethyl acetate (3 mL), and Pd / C (100 mg) was added to the solution. The resulting solution was stirred with hydrogen at room temperature for 4 hours. The solid was filtered out, and the filtrate was concentrated under vacuum to obtain 70 mg of compound 8 in a yield of 85.88%. 1 H NMR (400MHz, CD3OD) δ4.66-4.49(m,2H),2.63-2.49(m,2H),1.55-1.50(m,27H).

[0119] A mixture of compound 8 (176 mg, 0.437 mmol), intermediate I (130 mg, 0.219 mmol), sodium iodide (65.55 mg, 0.437 mmol) and potassium bicarbonate (43.75 mg, 0.437 mmol) in anhydrous dimethylformamide (5 mL) was stirred at 25° C. under nitrogen for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC (solution A: 0.1% NH 4 HCO 3 , solution B: acetonitrile) to afford 70 mg of compound 9 in a yield of 33.36%. LC-MS: 981.2 [M+Na] + .

[0120] Compound 9 (25 mg, 0.026 mmol) was dissolved in anhydrous dichloromethane (2 mL). Phosphoric acid (0.1 mL) was added at -10°C. The resulting solution was stirred at -10°C for 1 hour, after which the solvent was removed in vacuo. The residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 μm ACN-H2O, 0.1% NH4HCO3) to afford 1 mg of Example 5 in a 4.85% yield. LC-MS: 790.6 [M+H] + .

[0121] Example 6

[0122] Compound 1 (12.8 g, 0.0444 mol) was added dropwise to a suspension of sodium hydride (5.33 g, 0.1332 mol) in N,N-dimethylformamide (30 mL) under an ice bath. The reaction mixture was stirred at 25°C under nitrogen for 1 hour. A solution of compound 2 (12.88 g, 0.1332 mol) in N,N-dimethylformamide (10 mL) was slowly added dropwise to the reaction mixture and stirred at 65°C for 16 hours. Saturated aqueous ammonium chloride (500 mL) was added to the reaction system, and the aqueous phase was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3) to obtain 13.8 g of crude compound 3, a yield of 35.98%, which was used directly in the next reaction. LC-MS: 882.6.[2M+Na] + .

[0123] To a solution of compound 3 (2.4 g, 5.6 mmol) in methanol (10 mL) was added p-toluenesulfonic acid (0.19 g, 1.1 mmol) at room temperature. The reaction mixture was stirred at 25°C under nitrogen for 16 h. Saturated aqueous sodium bicarbonate was added to the reaction system to adjust the pH to 8-9. The resulting solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 96:4) to obtain 0.8 g of compound 4 in a 37.50% yield. LC-MS: 346.9 [M+H] + .

[0124] To a solution of compound 4 (1.2 g, 3.5 mmol) in DMF (20 mL) at room temperature was added PDC (13.17 g, 35 mmol). The reaction mixture was stirred at 25°C under nitrogen for 16 h. The reaction system was diluted with water (300 mL), and the pH of the solution was adjusted to 8.0 by adding 1 M aqueous sodium hydroxide. The resulting solution was cooled to 0°C, and then 6.1 wt% aqueous Na₂SO₃ (30 mL) was slowly added. The mixture was stirred at 0°C for 30 min, and the aqueous phase was washed with diethyl ether (30 mL). The aqueous layer was acidified to pH 3-4 with concentrated hydrochloric acid and extracted three times with a mixture of chloroform / isopropanol (4:1) (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10 to 85 / 15) to obtain 0.35 g of compound 5 in a yield of 22.86%. LC-MS: 361.1[M+H] + .

[0125] Compound 5 (227 mg, 0.63 mmol), intermediate I (150 mg, 0.25 mmol), sodium iodide (76 mg, 0.63 mmol) and potassium bicarbonate (50 mg, 0.50 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). The solution was stirred at 30°C under nitrogen for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel column (dichloromethane / methanol = 96 / 4) to obtain 160 mg of compound 6 with a yield of 62.16%. LC-MS: 917.2 [M+H] + .

[0126] To a solution of compound 6 (30 mg, 0.032 mmol) in anhydrous dichloromethane (2 mL) was added trimethylsilyl bromide (175 mg, 1.144 mmol). The solution was stirred at -10°C for 16 hours. The solvent was then removed in vacuo, and the residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O (0.1% TFA) to afford 2 mg of Example 6 compound - in a 7.8% yield. LC-MS: 804.6 [M+H] + .

[0127] Example 7

[0128] Under nitrogen protection, compound 1 (20 mg, 0.031 mmol) was weighed and dissolved in dimethylformamide (1 mL) in a 25 mL three-necked flask. A solution of (2-bromoethyl)trimethylammonium bromide (38 mg, 0.155 mmol) and 4A molecular sieves (20 mg) in dimethylformamide (1 mL) was added. Finally, a solution of diisopropylethylamine (80 mg, 0.62 mmol) in dimethylformamide (1 mL) was added. The mixture was stirred at 55°C for 3 hours. After filtration, the product was directly purified by HPLC (Solution A: 0.1% NH4HCO3, Solution B: acetonitrile) to afford 5 mg of Example 7, compound -, in a yield of 20.35%. LC-MS: 740.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.80 (s, 2H), 7.28 (t, J = 7.5Hz, 2H), 7.23-7.15 (m ,3H),5.17(dd,J=9.7,5.3Hz,1H),4.01(s,2H),3.88(s,1H),3.78-3.53(m,3H),3.42- 3.27(m,3H),3.12-3.01(m,3H),2.95(s,9H),2.40-2.26(m,3H),2.02-1.93(m,2H),1. 79-1.69(m,2H),1.55(t,J=11.4Hz,1H),1.38(d,J=6.4Hz,3H),1.20(d,J=6.6Hz,8H).

[0129] Example 8

[0130] Compound 1 (300 mg, 1.66 mmol), compound 2 (396 mg, 1.99 mmol, 1.2 eq) and potassium carbonate (458 mg, 3.31 mmol, 2 eq) were dissolved in anhydrous tetrahydrofuran (10 mL) and stirred at 25°C under nitrogen for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain 260 mg of compound 3, which was used directly in the next reaction without purification. LC-MS: 299.2 [M+H] + .

[0131] Compound 3 (190 mg) was dissolved in 5 mL of dimethylformamide, and intermediate I (113 mg, 0.19 mmol) and sodium iodide (57 mg, 0.38 mmol) were added. The solution was stirred at room temperature under nitrogen for 16 hours. The residue was concentrated and purified by preparative HPLC (Solution A: 0.1% NH4HCO3, Solution B: acetonitrile) to obtain 75 mg of compound 4 in a yield of 15.62%. LC-MS: 855.4 [M+H] + .

[0132] Compound 4 (80 mg, 0.09 mmol) was dissolved in 4 mL of anhydrous dichloromethane. 1 mL of trifluoroacetic acid was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) and lyophilized to obtain 15 mg of Example 8, a yield of 21.20%. LC-MS: 755.0 [M+H] + . 1 H NMR(400MHz,D2O)δ7.93(s,1H),7.82(s,2H),7.35-7.19(m,3H),7.18-7.07(m,2H),5.8 3-5.72(m,1H),5.61-5.51(m,1H),4.60-4.53(m,1H),4.50-4.34(m,3H),4.30(s,4H),4 .16-4.02(m,2H),3.91-3.83(m,1H),3.72-3.62(m,1H),3.39-3.22(m,2H),2.45-2.26( m,3H),2.13-1.77(m,5H),1.63-1.59(m,1H),1.41(d,J=6.4Hz,3H),1.01-0.65(m,6H).

[0133] Example 9

[0134] Example 8 compound (50 mg, 0.066 mmol) was dissolved in 3 mL of methanol, and sodium cyanoborohydride (8.31 mg, 0.132 mmol) and paraformaldehyde (9.92 mg, 0.331 mmol) were added at zero degrees Celsius. The reaction solution was stirred at room temperature for 16 hours, then filtered, concentrated, and the residue was purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) and lyophilized to obtain 8 mg of Example 9 compound in a yield of 15.73%. LC-MS: 768.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.85-10.52(m,1H),9.95-9.78(m,1H),8.24-8.13(m,1H),8.09-7. 92(m,3H),7.37-7.14(m,5H),5.95-5.77(m,1H),5.68-5.54(m,1H),4.72-4.64(m,1H),4.52- 4.26(m,5H),4.16-3.92(m,6H),3.60-3.37(m,3H),2.85-2.75(m,3H),2.28-2.13(m,2H),2. 10-1.83(m,3H),1.80-1.61(m,2H),1.51-1.33(m,4H),1.07-0.91(m,3H),0.91-0.72(m,3H).

[0135] Example 10

[0136] Compound 1 (300 mg, 1.51 mmol), compound 2 (441 mg, 1.81 mmol) and potassium carbonate (416 mg, 3.01 mmol) were dissolved in anhydrous acetonitrile (10 mL) and stirred at 60°C under nitrogen for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to obtain 500 mg of compound 3, which was used directly in the next step without purification. LC-MS: 361.2 [M+H] + .

[0137] Compound 3 (500 mg) was dissolved in 10 mL of ethyl acetate, and Pd / C (500 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The mixture was filtered and the filtrate was concentrated to dryness to obtain 400 mg of compound 4, which was used in the next step without purification. LC-MS: 271.1 [M+H] + .

[0138] Intermediate I (300 mg, 0.50 mmol) was dissolved in 5 mL of anhydrous dimethylformamide, and sodium iodide (151 mg, 1.0 mmol), potassium bicarbonate (101 mg, 1.0 mmol) and compound 4 (273.6 mg, 1.008 mmol) were added thereto. The reaction solution was stirred at room temperature under nitrogen for 2 hours, then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel separation (petroleum ether / ethyl acetate = 1 / 1) to obtain 150 mg of compound 5 in a yield of 35.86%. LC-MS: 827.3 [M+H] + .

[0139] Compound 5 (50 mg, 0.0603 mmol) was dissolved in 3 mL of dichloromethane. 1 mL of trifluoroacetic acid was added under nitrogen at zero temperature. The reaction solution was stirred at room temperature for 1 hour, then concentrated and the residue was purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) and lyophilized to obtain 10 mg of Example 10, in a yield of 22.72%. LC-MS: 727.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.89(s,3H),7.44-7.36(m,2H),7.36-7.28(m,3H),5.99-5.69(m,2H),4.58-4.25(m,11H),4.22-4.14(m,1H),4.10-4.05 (m,1H),3.95-3.82(m,1H),2.49-2.34(m,4H),2.02-1.92(m,1H),1.91 -1.82(m,2H),1.80-1.72(m,1H),1.52-1.46(m,3H),1.44-1.39(m,3H).

[0140] Example 11

[0141] Compound 1 (115 mg, 0.50 mmol) and sodium iodide (101 mg, 0.67 mmol) were added to DMF (2 mL), followed by potassium bicarbonate (67.3 mg, 0.67 mmol). The mixture was stirred at room temperature for half an hour. Intermediate I (200 mg, 0.34 mmol) dissolved in 10 mL of dimethylformamide was then added dropwise to the reaction system. The reaction was allowed to react overnight, and water (50 mL) was added to quench the reaction. The mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 200 mg of compound 2 in a yield of 75.6%. LC-MS [M+H] + :784.3.

[0142] Compound 2 (200 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) was added under ice-cooling. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated and the crude product was separated by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to give 47.4 mg of Example 11, a yield of 26.6%. LC-MS [M+H] + :684.3. 1 H NMR(400MHz,D2O)δ7.62-7.38(m,3H),7.16-6.78(m,5H),5.85-5.13(m,2H),4.36-3.99(m,5H),3.94-3.50(m,3H), 3.11-2.49(m,1H),2.42-1.98(m,3H),1.95-1.71(m,2H),1.65-1.41(m,2H),1.40-1.25(m,2H),1.23-0.62(m,5H).

[0143] Example 12

[0144] Under N2 protection, intermediate I (150 mg, 0.25 mmol) and compound 1 (115 mg, 0.5 mmol) were weighed into a 25 mL three-necked flask and dissolved in dimethylformamide (3 mL). Sodium iodide (76 mg, 0.5 mmol) and potassium bicarbonate (76 mg, 0.75 mmol) were added and stirred at room temperature for 5 hours. Water (10 mL) was added and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 3 / 1) to obtain 160 mg of compound 2 in a yield of 70.96%. LC / MS: 806.2 [M+Na] + .

[0145] Compound 2 (160 mg, 0.2 mmol) was weighed into a 25 mL three-necked flask and dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure and purified by C18 column chromatography (Solution A: 0.1% TFA, Solution B: acetonitrile) to provide 60 mg of Example 12, with a yield of 42.99%. LC-MS: 684.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.88(s,2H),7.85(s,1H),7.32(d,J=6.6Hz,2H),7.25(s,3H),5.69(s,2H),4.57(s,1H),4.13(s,1H),4.00(d,J =7.8Hz,1H),3.77(s,1H),3.50(s,4H),2.65-2.06(m,7H),2.00(s,1H),1.81(d,J=11.6Hz,2H),1.69(d,J=12.7Hz,2H),1.41(s,3H).

[0146] Example 13

[0147] In a 25 mL three-necked flask, the compound of Example 12 (20 mg, 0.03 mmol) was dissolved in methanol (5 mL). Paraformaldehyde (3.5 mg, 0.12 mmol) was added and stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.7 mg, 0.06 mmol) was added and stirred at room temperature for another 2 hours. The mixture was filtered, concentrated under reduced pressure, and purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to afford 2.5 mg of the compound of Example 13 in a 12.24% yield. LC-MS: 698.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.87(s,2H),7.85(s,1H),7.33(t,J=7.3Hz,2H),7.25(t,J=7 .1Hz,3H),5.68(s,2H),4.57(s,1H),4.13(s,1H),3.99(d,J=8.7Hz,1H),3.79(dd ,J=11.4,6.5Hz,3H),3.44(d,J=11.4Hz,2H),2.92(s,3H),2.58-2.11(m,7H),1.9 6(s,1H),1.81(dd,J=10.0,4.1Hz,3H),1.73-1.61(m,1H),1.41(d,J=5.2Hz,3H).

[0148] Example 14

[0149] Compound 1 (109.53 mg, 0.504 mmol), sodium iodide (100.83 mg, 0.672 mmol), and potassium bicarbonate (67.3 mg, 0.672 mmol) were weighed into a 50 mL three-necked flask and dissolved in N,N-dimethylformamide (2 mL). The reaction solution was stirred at 25°C for 0.5 hours, followed by the addition of a solution of intermediate I (200 mg, 0.361 mmol) in N,N-dimethylformamide (5 mL). The reaction solution was stirred at room temperature for 18 hours. Water (20 mL) was added to quench the reaction, and the resulting solution was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column separation (petroleum ether / ethyl acetate = 80:20) to obtain 200 mg of compound 2 with a yield of 76.63%. LC-MS: 796.4 [M+Na] + .

[0150] Compound 2 (200 mg, 0.258 mmol) was weighed into a 50 mL single-necked flask and dissolved in anhydrous dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was separated and purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 μm ACN-H2O, 0.1% TFA) to obtain 23.10 mg of Example 14, a yield of 13.27%. LC-MS: 674.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.29(s,1H),7.71(s,1H),7.60(s,2H),7.37(t,J=7.3Hz,2H),7.33-7.26(m,3H),6 .20(s,1H),5.62(d,J=5.5Hz,1H),4.26(q,J=6.2Hz,1H),4.16(d,J=9.1Hz,1H),4.03(d,J=9.4Hz,1H),3 .96(d,J=13.9Hz,1H),3.82(d,J=4.6Hz,1H),2.73(d,J=14.0Hz,1H),2.53(d,J=14.9Hz,1H),2.46-2.28 (m,4H),1.86(d,J=14.0Hz,1H),1.74-1.70(m,3H),1.24(d,J=6.3Hz,3H),1.06(dd,J=11.5,6.9Hz,6H).

[0151] Example 15

[0152] Intermediate I (200 mg, 0.336 mmol), compound 1 (69 mg, 0.672 mmol), sodium iodide (101 mg, 0.672 mmol) and potassium bicarbonate (67 mg, 0.672 mmol) were dissolved in anhydrous dimethylformamide (6 mL), and the solution was stirred at 25 ° C under nitrogen protection for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine, dried over sodium sulfate, filtered, concentrated and the residue was purified by reverse phase chromatography (ACN-H2O, 0.1% NH4HCO3) to obtain 150 mg of compound 2 with a yield of 67.45%. LC-MS: 659.8 [M+H] + .

[0153] Compound 2 (150 mg, 0.227 mmol) was dissolved in 5 mL of anhydrous toluene, and iodomethane (644 mg, 4.53 mmol) was added. The solution was stirred at 50°C under nitrogen for 16 hours. The solvent was then removed in vacuo, and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 μm ACN-H2O, 0.1% FA) to afford 8.46 mg of Example 15, a 5.51% yield. LC-MS: 674.3 [M+H] + . 1 H NMR(400MHz,D2O)δ8.07-7.72(m,3H),7.44-7.14(m,5H),5.49-5.14(m,1H),4.61-4.45(m,1H),4.38-4.0 0(m,2H),3.92-3.49(m,6H),3.30-3.00(m,4H),2.79-2.14(m,8H),2.04-1.64(m,4H),1.54-1.32(m,3H).

[0154] Example 16

[0155] Compound 2 (109 mg, 0.504 mmol) and sodium iodide (101 mg, 0.672 mmol) were added to DMF (2 mL), followed by potassium bicarbonate (67.3 mg, 0.672 mmol). The mixture was stirred at room temperature for half an hour. Intermediate I (200 mg, 0.336 mmol) dissolved in 10 mL of dimethylformamide was then added dropwise to the reaction system. The reaction was allowed to react overnight, then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed sequentially with water and saturated brine, dried over sodium sulfate, filtered, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 210 mg of compound 2. The yield was 80.4%. LC-MS [M+H] + :774.4.

[0156] Compound 2 (210 mg, 0.271 mmol) was dissolved in dichloromethane (6 mL). 1.5 mL of trifluoroacetic acid was added dropwise under ice-cooling. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was concentrated and the residue was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 150 mg of compound 3 in an 82% yield. LC-MS [M+H] + :674.4.

[0157] Compound 3 (50 mg, 0.074 mmol) and ethyl acetate (5 mL) were added to a 100 mL three-necked flask. Palladium on carbon (50 mg) and paraformaldehyde (88.9 mg, 2.96 mmol) were added with stirring at room temperature. The atmosphere was replaced with hydrogen three times and stirred at room temperature for 24 h. The mixture was filtered and concentrated to obtain 50 mg of compound 4. LC-MS [M+H] + :702.2.

[0158] Compound 4 (50 mg, 0.0711 mmol, 1 eq) was weighed and dissolved in anhydrous toluene (5 mL) in a 100 mL single-necked flask. Methyl iodide (404 mg, 2.844 mmol) was added and stirred at 50°C for 24 h. The reaction solution was concentrated and separated by preparative HPLC (Solution A: 0.1% FA, Solution B: acetonitrile) to afford 5.16 mg of Example 16, a 10.1% yield. LC-MS [M+H] + :716.0. 1HNMR(400MHz,D2O)δ7.94-7.60(m,3H),7.30-7.00(m,5H),5.91-5.50(m,2H),4.6 2-4.28(m,1H),4.09-3.81(m,2H),3.70-3.58(m,1H),3.50-3.24(m,1H),3.12(s, 10H),2.55-2.20(m,4H),2.08-1.82(m,2H),1.81-1.72(m,1H),1.65-1.51(m,1H) ,1.38(d,J=5.0Hz,3H),1.25-1.12(m,1H),1.10-0.92(m,3H),0.87-0.61(m,3H).

[0159] Example 17

[0160] Intermediate I (100 mg, 0.168 mmol) was dissolved in anhydrous dimethylformamide (3 mL), and sodium iodide (50.42 mg, 0.336 mmol), potassium bicarbonate (33.65 mg, 0.336 mmol), and compound 1 (54.37 mg, 0.336 mmol) were added. The mixture was stirred at room temperature under nitrogen for 18 hours, then quenched with water (3 mL) and extracted three times with ethyl acetate (3 mL). The aqueous phase was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm x 21.2 mm 5 μm ACN-H2O, 0.1% FA) and lyophilized to obtain 3.3 mg of Example 17 compound in a yield of 2.72%. LC-MS: 718.4 [M+H] + . 1 H NMR(400MHz,D2O)δ8.33(s,2H),7.92(s,1H),7.81(s,2H),7.36-7.06(m,5H) ,5.60-5.52(m,2H),4.59-4.50(m,3H),4.12-3.87(m,4H),3.82-3.42(m,3H) ,3.40-3.19(m,3H),3.10-3.04(m,6H),2.64-2.51(m,1H),2.46-2.29(m,3H) ,2.15-2.08(m,1H),1.86-1.71(m,2H),1.66-1.54(m,1H),1.49-1.36(m,3H).

[0161] Example 18

[0162] According to the method of Example 17, intermediate I was reacted with stachydrine hydrochloride to obtain the compound of Example 18. LC-MS [M+H] + :700.4.

[0163] Example 19

[0164] According to the method of Example 17, intermediate I was reacted with ergothioneine to obtain the compound of Example 19. LC-MS [M+H] + :786.3. 1 H NMR(400MHz,D2O)δ8.09-7.73(m,3H),7.41-7.07(m,6H),5.47-5.28(m,3H),4.01-3.96(m,1H),3.65-3.59(m,1H),3.35-2.9 2(m,12H),2.49-2.21(m,2H),1.95-1.73(m,3H),1.58-1.36(m,1H),1.36-1.26(m,3H),1.24-1.01(m,3H),0.79-0.61(m,1H).

[0165] Example 20

[0166] Intermediate I (200 mg, 0.336 mmol) was dissolved in anhydrous DMF (5 mL), and sodium iodide (100.84 mg, 0.672 mmol), potassium bicarbonate (67.3 mg, 0.672 mmol) and compound 1 (79.03 mg, 0.672 mmol) were added thereto. The reaction solution was stirred under nitrogen protection at room temperature for 18 hours, then quenched with water (30 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 150 mg of compound 2 in a yield of 66.02%. LC-MS: 674.2 [M+H] + .

[0167] Compound 2 (150 mg, 0.223 mmol) was dissolved in anhydrous toluene (5 mL), and iodomethane (630.21 mg, 4.44 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours under nitrogen. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% FA) to afford 30 mg of Example 20, a yield of 19.56%. LC-MS: 688.3 [M+H]+ . 1 H NMR(400MHz,D2O)δ7.67-7.44(m,3H),7.24-6.80(m,5H),5.72-5.45(m,1H),5.20-4.83(m,1H),4.38-4.05(m,2H),4.00-3.6 0(m,3H),3.56-3.38(m,2H),3.23-2.88(m,6H),2.82-2.43(m,2H),2.40-1.84(m,4H),1.75-1.14(m,7H),1.12-0.61(m,3H).

[0168] Example 21

[0169] Intermediate I (150 mg, 0.25 mmol), compound 1 (59 mg, 0.50 mmol), and sodium iodide (75.6 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (2 mL). Potassium bicarbonate (50.5 mg, 0.50 mmol) was added and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was poured into water, separated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 3) to afford 80 mg of compound 2 in a 46.9% yield. LC-MS [M+H]+: 674.3.

[0170] Compound 2 (80 mg, 0.118 mmol, 1 eq) was dissolved in toluene (2 mL), and iodomethane (84 mg, 0.592 mmol, 5 eq) was added. The temperature was raised to 50°C and stirred for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by preparative HPLC to obtain 11 mg of Example 21, with a yield of 13.4%. LC-MS [M+H] + :688.3. 1 H NMR(400MHz,D2O)δ8.01-7.73(m,3H),7.41-7.07(m,5H),5.38-5.11(m,2H),4.57 -4.41(m,1H),4.25-4.04(m,2H),4.01-3.85(m,1H),3.77-3.58(m,3H),3.54-3.3 4(m,2H),3.25-2.91(m,4H),2.71-2.63(m,1H),2.55-2.48(m,1H),2.45-2.15(m, 4H),1.99-1.64(m,4H),1.61-1.52(m,1H),1.49-1.32(m,3H),1.24-0.98(m,2H).

[0171] Example 22

[0172] According to the method of Example 20, 4-(dimethylamino)butyric acid was used instead of N,N-dimethyl-D-alanine to synthesize the compound of Example 22. LC-MS [M+H] + :701.7. 1 H NMR(400MHz,D2O)δ8.38(s,1H),8.00-7.87(m,3H),7.37-7.26(m,5H),5.21-5.10(m,2H),4.58-4.52(m,1H) ),4.26-4.11(m,4H),3.63(s,3H),3.33-3.22(m,2H),3.08-2.99(m,3H),2.59-1.71(m,15H),1.47(s,3H).

[0173] Example 23

[0174] Under nitrogen, a solution of 4-mercaptobenzoic acid (2.5 g, 16.2 mol) in tetrahydrofuran (30 mL) was slowly added dropwise to a suspension of lithium aluminum hydride (1.84 g, 48.6 mmol) in tetrahydrofuran (30 mL). Stirring was continued for 3 hours after the addition was complete. 1N aqueous hydrochloric acid (500 mL) was added dropwise to the reaction solution, and the resulting solution was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to obtain 2.2 g of compound 2, with a yield of 97.04%. LC-MS [M+H] + :141.2.

[0175] Compound 3 (6.92 g, 31.4 mmol) was added to a solution of compound 2 (2.2 g, 15.7 mmol) in dichloromethane (50 mL) at room temperature, and the mixture was stirred at 25°C under nitrogen for 16 hours. After the reaction, the solvent was removed by vacuum concentration, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 2.0 g of compound 4 in a yield of 45.86%. LC-MS [M+H] + :250.1.

[0176] Compound 4 (400 mg, 1.60 mmol) and N,N-diisopropylethylamine (207 mg, 1.60 mmol) were dissolved in dichloromethane (10 mL) under an ice bath. The reaction system was protected by nitrogen and triphosgene (476 mg, 1.60 mmol) was slowly added. The reaction mixture was stirred at 0°C for 0.5 hours, then warmed to 25°C and stirred for 2 hours. Ice water (10 mL) was added to the reaction mixture to quench the reaction. The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude compound 5 was used directly in the next step. LC-MS [M+H] + :312.0.

[0177] Compound 6 (200 mg, 0.39 mmol) and anhydrous potassium carbonate (440 mg, 3.18 mmol) were dissolved in anhydrous acetonitrile (10 mL) under an ice bath. A solution of compound 5 (372 mg, 1.19 mmol) in ethyl acetate (5 mL) was slowly added to the reaction system under nitrogen. The reaction mixture was stirred at 50°C for 16 h. Ice water (10 mL) was added, and the resulting solution was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (dichloromethane / methanol = 100 / 2) to obtain 50 mg of compound 7 in a yield of 12.9%. LC-MS [M+H] + :776.1.

[0178] At room temperature, compound 7 (30 mg, 0.04 mmol) and compound 8 (13 mg, 0.08 mmol) were dissolved in anhydrous dichloromethane (2 mL). The reaction system was protected by nitrogen and stirred at 25°C for 16 h. After vacuum concentration, the crude product of compound 9 was used directly in the next step. LC-MS [M+H] + :842.2.

[0179] Compound 9 (30 mg, 0.03 mmol) was dissolved in anhydrous dichloromethane (2 mL) under an ice bath. Trifluoroacetic acid (0.5 mL) was slowly added to the reaction system under nitrogen protection and stirred at 25°C for 30 minutes. The solvent was removed by vacuum concentration, and the residue was separated and purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to obtain 30 mg of Example 23, a yield of 14.65%. LC-MS [M+H] + :742.1. 1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.00(s,1H),7.94(s,2H),7.84(s,2H),7.42(s,2H),7.32- 7.28(m,2H),7.24-7.19(m,3H),4.89-4.83(m,2H),4.64(q,J=6.3Hz,1H), 4.10(d,J=8.9Hz,1H),4.00-3.98(m,1H),3.54(s,2H),3.10-3.07(m,2H),2 .95-2.91(m,2H),2.27-2.07(m,2H),2.08-1.94(m,2H),1.92-1.82(m,1H) ,1.78-1.59(m,2H),1.47-1.39(m,1H),1.40(d,J=6.4Hz,3H),1.23(s,2H).

[0180] Example 24

[0181] Under nitrogen, intermediate I (50.0 mg, 0.08 mmol) was weighed and dissolved in N,N-dimethylformamide (1 mL) in a 50 mL three-necked flask. Compound 2 (53.0 mg, 0.30 mmol), sodium iodide (25.2 mg, 0.17 mmol), and potassium bicarbonate (16.8 mg, 0.17 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was separated and purified by preparative HPLC (Solution A: 0.1% formic acid, Solution B: acetonitrile) to obtain 1.99 mg of Example 24, a yield of 2.98%. LC-MS [M+H] + :766.5. 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),8.01(s,1H),7.96(s,2H),7.32(m,2H),7.25-7.20(m ,3H),5.55(s,2H),4.66(d,J=5.7Hz,1H),4.07(d,J=9.1Hz,1H),4.01-3.99(m,1H),3.51(d ,J=12.6Hz,1H),3.34(s,1H),2.86-2.84(m,4H),2.59(t,J=6.9Hz,2H),2.52-2.50(m,2H) ,2.23-2.11(m,2H),2.02-1.95(m,2H),1.70-1.60(m,2H),1.42(s,1H),1.40-1.38(m,4H).

[0182] Example 25

[0183] According to the method of Example 24, 4,4'-dithiodibutyric acid was used instead of 3,3'-dithiodipropionic acid to synthesize the compound of Example 25. LC-MS [M+H] + :794.5. 1 H NMR(400MHz,DMSO-d6)δ 12.09(s,1H),8.12(s,1H),8.02(s,1H),7.96(s,2H),7.34-7.30(m,2H),7.25-7.18(m ,3H),5.52(s,2H),4.59-4.66(m,1H),4.08(d,J=8.9Hz,1H),4.01-3.95(m,1H),3.50-3 .45(m,2H),2.71-2.66(m,4H),2.47-2.42(m,2H),2.33-2.29(m,4H),2.19-2.15(m,2H) ,2.04-1.95(m,2H),1.87-1.80(m,4H),1.68-1.63(m,2H),1.41-1.40(d,J=6.3Hz,3H).

[0184] Example 26

[0185] Compound 1 (100 mg, 0.37 mmol), compound 2 (40 mg, 0.37 mmol), copper chloride (5 mg, 0.037 mmol) and N, N, N', N'-tetramethylethylenediamine (173 mg, 1.49 mmol) were dissolved in methanol (3 mL) and stirred at room temperature for 3 hours under nitrogen protection. The solid was filtered out. The filtrate was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to give 60 mg of compound 3 with a yield of 43.24%. LC-MS: 373.1 [M+H] + .

[0186] Intermediate I (60 mg, 0.10 mmol), compound 3 (75 mg, 0.20 mmol), sodium iodide (30 mg, 0.20 mmol), and potassium bicarbonate (20 mg, 0.20 mmol) were dissolved in dimethylformamide (3 mL), and the solution was stirred at room temperature under nitrogen for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% TFA) to give 10 mg of Example 26 in a yield of 10.62%. LC-MS: 928.9 [M+H] + .

[0187] Example 27

[0188] Compound 1 (500 mg, 1.0 mmol) was placed in a 25 mL three-necked flask, and 10 mL of anhydrous dichloromethane was added. The atmosphere was replaced with nitrogen three times, and diisopropylethylamine (1032 mg, 8 mmol) was added. The mixture was cooled to -30°C, and trimethylsilyl chloride (283 mg, 2.6 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was then cooled to -30°C, and a solution of compound 2 (175 mg, 1.23 mmol) in anhydrous dichloromethane (2 mL) was added dropwise. The reaction temperature was controlled between -20°C and -5°C until the reaction was complete. The reaction solution was poured into 10 mL of ice water and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 300 mg of compound 3 with a yield of 62%. LC-MS: 620.6 [M+H] + .

[0189] Compound 3 (200 mg, 0.322 mmol) and sodium iodide (484 mg, 3.22 mmol) were placed in a 25 mL three-necked flask. 5 mL of anhydrous acetonitrile was added, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 80°C for 2 days. The reaction solution was concentrated to dryness, and the residue was purified using a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 120 mg of compound 4 in a 52% yield. LC-MS: 712.5 [M+H] + .

[0190] Compound 4 (120 mg, 0.1685 mmol) and compound 5 (76 mg, 0.3371 mmol) were placed in a 25 mL three-necked flask. 5 mL of anhydrous acetonitrile was added, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C for 3 hours, then stirred at room temperature overnight. The reaction solution was concentrated to dryness, the residue was diluted with water (10 mL), and the resulting solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 70 mg of compound 6, with a yield of 52%. LC-MS: 772.5 [M+H] + .

[0191] Compound 6 (70 mg, 0.09 mmol) and triethylamine (18 mg, 0.18 mmol) were placed in a 25 mL three-necked flask, 4 mL of anhydrous dichloromethane was added, and the atmosphere was replaced with N2 three times. The temperature was lowered to -40°C, and a dichloromethane (1 mL) solution of compound 7 (15.8 mg, 0.09 mmol, 1 eq) was added dropwise. After the addition was complete, the mixture was reacted at -40°C for 1 h. The reaction solution was poured into 10 mL of ice water, and the resulting solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 10 mg of compound 8 with a yield of 14%. LC-MS: 794.1 [M+H] + .

[0192] Compound 8 (10 mg, 0.0126 mmol) was dissolved in a mixture of 2 mL of dichloromethane and 0.5 mL of trifluoroacetic acid at 0°C and stirred for 0.5 h. The reaction solution was concentrated to dryness, and the resulting crude product was purified using a C18 column (ACN-H2O (0.1% TFA) gradient: 30-60) to obtain 2.32 mg of Example 27, a 27% yield. LC-MS: 693.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.12(s,1H),8.03(s,1H),7.96(s,2H),7.75(s,3H) ,7.35-7.28(m,2H),7.21(t,J=7.6Hz,3H),4.72-4.68(m,1H),4.10(d,J=8.8 Hz,2H),3.98(s,2H),3.83(s,2H),3.44(d,J=12.7Hz,2H),3.04-3.02(m,2H) ,2.78-2.77(m,2H),2.30-2.05(m,5H),1.73-1.64(m,4H),1.47-1.42(m,4H).

[0193] Example 28

[0194] Compound 1 (200 mg, 0.4 mmol) was placed in a 25 mL three-necked flask, and 5 mL of anhydrous dichloromethane was added. The atmosphere was replaced with nitrogen three times, and diisopropylethylamine (413 mg, 3.2 mmol) was added. The mixture was cooled to -30°C, and trimethylsilyl chloride (113 mg, 1.04 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was then cooled to -30°C, and a solution of compound 2 (70 mg, 0.492 mmol) in anhydrous dichloromethane (2 mL) was added dropwise. The reaction temperature was controlled between -20°C and -5°C until the reaction was complete. The reaction solution was poured into 10 mL of ice water, and the resulting solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 150 mg of compound 3 with a yield of 62%. LC-MS: 606.7 [M+H] + .

[0195] Compound 3 (120 mg, 0.198 mmol) and compound 4 (90 mg, 0.396 mmol) were placed in a 5 mL microwave tube, 3 mL of anhydrous acetonitrile was added, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C for 6 h. The reaction solution was concentrated to dryness, the residue was diluted with water (10 mL), and the resulting solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 80 mg of compound 5, with a yield of 53%. LC-MS: 758.6 [M+H] + .

[0196] Compound 5 (40 mg, 0.0528 mmol) and triethylamine (10.5 mg, 0.1055 mmol) were placed in a 25 mL three-necked flask, 4 mL of anhydrous dichloromethane was added, and the atmosphere was replaced with N2 three times. The temperature was lowered to -40°C, and a dichloromethane (1 mL) solution of compound 6 (9.3 mg, 0.0528 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -40°C for 1 h. The reaction solution was poured into 10 mL of ice water and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 12 mg of compound 7 with a yield of 29%. LC-MS: 779.6 [M+H] + .

[0197] Compound 7 (12 mg, 0.0154 mmol) was dissolved in a mixture of 2 mL of dichloromethane and 0.5 mL of trifluoroacetic acid at 0°C and stirred for 0.5 h. The reaction solution was concentrated to dryness, and the residue was purified using a C18 column (ACN-H2O (0.1% TFA), gradient: 30-70%) to obtain 5.3 mg of Example 28, in a 50% yield. LC-MS: 679.6 [M+H] + . 1 H NMR (400MHz, D2O): δ8.08(s,1H),7.96(s,2H),7.50-7.23(m,5H),4.72-4.69(m,1H),4.20-4.08(m,3H),3.77(s,1H),3. 57(s,1H),3.29(s,3H),2.87(s,3H),2.52-2.49(m,4H),2.20(s,1H),2.05-1.94(m,3H),1.75-1.68(m,1H),1.54(s,3H).

[0198] Example 29

[0199] The compound of Example 29 was synthesized according to the third and fourth steps of Example 28, using N-tert-butyloxycarbonyl-L-cysteine ​​instead of 2-tert-butyloxycarbonylaminoethanethiol. LC-MS [M+H] + :723.8. 1 HNMR (400MHz, DMSO-d6): δ8.13(s,1H),8.02(s,1H),7.96(s,2H),7.35-7.28(m,2H),7. 25-7.19(m,3H),4.66(q,J=6.2Hz,1H),4.17-3.92(m,5H),3.49(s,2H),3.21(d,J=14.5 Hz,2H),3.05-2.99(m,1H),2.80(br,1H),2.45(s,1H),2.30-2.23(m,1H),2.17-2.11(m ,1H),2.08-2.03(m,1H),1.87(d,J=14.0Hz,1H),1.75-1.60(m,2H),1.45-1.39(m,4H).

[0200] Example 30

[0201] Intermediate I (100 mg, 0.1686 mmol) and compound 1 (76 mg, 0.3372 mmol) were placed in a 25 mL three-necked flask, anhydrous acetonitrile (5 mL) was added, the atmosphere was replaced with N2 three times, and the mixture was stirred at 100°C for 3 h, then stirred at room temperature overnight. The reaction solution was concentrated, the residue was diluted with water (10 mL), and the resulting solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 40 mg of Intermediate II with a yield of 32%. LC-MS: 744.5 [M+H] + .

[0202] Intermediate II (40 mg, 0.05376 mmol) and triethylamine (10.75 mg, 0.1075 mmol) were placed in a 25 mL three-necked flask, anhydrous dichloromethane (4 mL) was added, and the atmosphere was replaced with N2 three times. The temperature was lowered to -40 ° C, and a dichloromethane (1 mL) solution of compound 2 (9.5 mg, 0.05376 mmol) was added dropwise. After the addition was complete, the mixture was reacted at -40 ° C for 1 hour. The reaction solution was poured into ice water (10 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26 mg of white solid compound 3 with a yield of 50.5%. LC-MS: 788.1 [M+Na] + .

[0203] Compound 3 (26 mg, 0.02715 mmol) was dissolved in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) at 0°C and stirred for 1 hour. The reaction solution was concentrated to dryness, and the residue was purified using a C18 column (ACN-H2O (0.1% TFA) gradient: 25-60) to obtain 10 mg of Example 30, in a 55% yield. LC-MS [M+H] + :665.7. 1 H NMR (400MHz, MeOD): δ7.92(s,2H),7.89(s,1H),7.42-7.26(m,5H),5.35-5.30(m, 2H),4.64-4.59(m,1H),4.22(d,J=9.3Hz,1H),4.04(d,J=9.0Hz,1H),3.86(d,J=1 2.6Hz,1H),3.25-3.21(m,3H),2.97(s,2H),2.55-2.36(m,3H),2.31-2.25(m,1H) ,2.12-2.05(m,1H),1.91-1.85(m,2H),1.75-1.67(m,1H),1.46(d,J=6.4Hz,3H).

[0204] Example 31

[0205] To a solution of compound 1 (2 g, 19.2 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (10.48 g, 48 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction was then quenched with water (100 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated to give 2.2 g of compound 2 in a yield of 37.50%. LC-MS: 305.3 [M+H] + .

[0206] To a solution of N-chlorosuccinimide (240 mg, 1.8 mmol) in anhydrous tetrahydrofuran (5 mL) was added triphenylphosphine (471 mg, 1.8 mmol). The resulting solution was stirred at room temperature for 20 minutes. Then, under nitrogen protection, compound 2 (500 mg, 1.63 mmol) was added in batches at zero degrees Celsius. The resulting solution was stirred for 11 hours and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (dichloromethane / methanol=60:40) to obtain 200 mg of compound 3 in a yield of 37.73%. LC-MS: 323.1 [M+H] + .

[0207] Compound 3 (100 mg, 0.31 mmol) was dissolved in anhydrous dimethylformamide (3 mL), and potassium thioacetate (47 mg, 0.42 mmol) was added thereto under nitrogen protection. The mixture was then heated to 90 ° C and stirred for 12 hours. Water (20 mL) was added and the resulting solution was extracted with ethyl acetate (25 ml). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in methanol (5 mL) at room temperature and nitrogen, and potassium carbonate (128 mg, 0.92 mmol) was added. After stirring at room temperature for 1 hour, the pH was adjusted to 8 to 9 with 1M dilute hydrochloric acid. Water (25 mL) was added thereto and extracted with dichloromethane (25 mL). The organic phase was washed twice with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 60:40) to obtain 60 mg of white solid compound 4, with a yield of 60.46%. LC-MS: 321.2 [M+H] + .

[0208] At -40 ° C, triethylamine (16 mg, 0.16 mmol) and compound 4 (31 mg, 0.096 mmol) were added to a solution of intermediate II (60 mg, 0.08 mmol) in anhydrous dichloromethane (3 mL). The solution was stirred at -40 ° C under nitrogen protection for 30 minutes. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 50 mg of compound 5 in a yield of 68.24%. LC-MS: 931.3 [M+Na] + .

[0209] Compound 5 (50 mg, 0.055 mmol) was weighed into a 50 mL single-necked flask and dissolved in 5 mL of anhydrous dichloromethane. Trifluoroacetic acid (1 mL) was added to the reaction solution. The reaction solution was stirred at room temperature for 2 h, then concentrated and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 μm ACN-H2O, 0.1% TFA) to obtain 1.5 mg of Example 31, a yield of 3.85%. LC-MS: 708.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.87(s,3H),8.18(s,1H),8.02(s,1H),7.96(s,2H),7.3 6-7.29(m,2H),7.28-7.19(m,3H),5.25-5.15(m,2H),4.65(d,J=6.1Hz,1H),4.0 5(dd,J=24.7,8.8Hz,2H),3.56(d,J=13.0Hz,2H),3.31-3.04(m,7H),2.98(s,2H ),2.30-2.15(m,2H),),2.05-1.99(m,2H),1.73-1.66(m,2H),1.45-1.39(m,4H).

[0210] Example 32

[0211] Compound 1 (2 g, 8.04 mmol) and compound 2 (1.22 g, 16.08 mmol) were weighed into a 50 mL three-necked flask and dissolved in methanol (20 mL). The reaction solution was stirred at 50°C for 2 hours, and then a solution of sodium hydroxide (487 mg, 6.695 mmol) in water (5 mL) was added. The reaction solution was stirred at 50°C for 1 hour. The reaction solution was concentrated, the residue was diluted with water (30 mL), and the resulting solution was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.5 g of compound 3, with a yield of 87.80%. LC-MS: 246.9 [M+H] + .

[0212] Intermediate II (200 mg, 0.269 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (8 mL). Triethylamine (52.24 mg, 0.538 mmol) and compound 3 (132.32 mg, 0.538 mmol) were added at -40 ° C under nitrogen protection. The reaction solution was stirred at this temperature for 0.5 hours, then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 200 mg of compound 4 with a yield of 89.20%. LC-MS: 835.3 [M+H] + .

[0213] Compound 4 (200 mg, 0.269 mmol) was weighed into a 50 mL three-necked flask and dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, and the residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% TFA) to obtain 29.12 mg of Example 32, a yield of 16.54%. LC-MS: 734.6 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.01(s,1H),7.96(s,2H),7.34-7.31(t ,2H),7.27-7.21(m,3H),5.22-5.12(m,2H),4.69-4.64(m,1H),4.09-4.02(m ,3H),3.55-3.45(m,2H),3.12(s,4H),2.95-2.64(m,9H),2.33-2.15(m,2H), 2.07-1.98(m,1H),1.94-1.90(m,1H),1.75-1.65(m,2H),1.45-1.40(m,4H).

[0214] Example 33

[0215] Intermediate II (80 mg, 0.107 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (5 mL). Triethylamine (21.67 mg, 0.214 mmol) and compound 1 (56.84 mg, 0.536 mmol) were added at -40°C under nitrogen protection. The reaction solution was stirred at this temperature for 30 minutes, then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% FA) to obtain 25.73 mg of Example 33, with a yield of 34.48%. LC-MS: 694.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),8.02(s,1H),7.96(s,2H),7.36-7.30(m,2H) ,7.25-7.23(m,3H),5.22-5.08(m,2H),4.67-4.64(m,1H),4.04(dd,J=21.3,8.9Hz ,2H),3.57(d,J=13.3Hz,1H),3.42-3.39(m,2H),2.89-2.80(m,2H),2.56-2.51(m ,2H),2.34-2.10(m,2H),2.02-1.98(m,2H),1.74-1.62(m,2H),1.44-1.38(m,4H).

[0216] Example 34

[0217] Under nitrogen, Intermediate II (50.0 mg, 0.07 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous tetrahydrofuran (1 mL). Compound 1 (10.1 mg, 0.07 mmol) and triethylamine (13.6 mg, 0.13 mmol) were added and stirred at -40°C for 0.5 hours. The reaction solution was poured into ice water (10 mL) and the resulting solution was extracted three times with dichloromethane (10 mL). The combined organic phases were washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Preparative separation (Solution A: 0.05% aqueous ammonia, Solution B: acetonitrile) afforded 4.00 mg of Example 34, a yield of 7.61%. LC-MS [M+H] + :738.5. 1 H NMR(400MHz,D2O)δ7.93(s,1H),7.83(s,2H),7.34-7.30(m,2H),7.25-7. 19(m,3H),4.99(s,1H),4.58-4.50(m,3H),4.04-3.98(m,3H),3.72-3.60 (m,2H),3.40-3.35(m,1H),2.50-2.43(m,1H),2.35-2.30(m,2H),2.05-1 .98(m,2H),1.78-1.74(m,2H),1.60-1.55(m,1H),1.42(d,J=6.5Hz,3H).

[0218] Example 35

[0219] To a solution of compound 1 (1 g, 4.1 mmol) in 1,2-dibromoethane (10 mL) was added diisopropylethylamine (1.59 g, 12.3 mmol). The resulting solution was stirred at 80 ° C for 50 hours. The reaction was quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 7:3) to obtain 600 mg of compound 3 with a yield of 41.46%. LC-MS: 352.1 [M+H] + .

[0220] Thiourea (226.9 mg, 2.98 mmol) was added to a solution of compound 3 (350 mg, 0.99 mmol) in ethanol (6 mL). The resulting solution was stirred at 80°C for 16 hours, and then ethylenediamine (1.492 g, 24.84 mmol) was added dropwise at 0°C under nitrogen protection. The solution was stirred at 0°C for 24 hours. The solvent was then removed in vacuo to obtain 250 mg of compound 4 with a yield of 82.38%. LC-MS: 306.1 [M+H] + .

[0221] Intermediate II (200 mg, 0.268 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (5 mL). Triethylamine (81.3 mg, 0.804 mmol) and compound 4 (164 mg, 0.536 mmol) were added at -40°C under nitrogen protection. The reaction solution was stirred at this temperature for 30 minutes, then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain 200 mg of compound 5 with a yield of 83.31%. LC-MS: 893.6 [M+H] + .

[0222] Compound 5 (200 mg, 0.224 mmol) was weighed into a 50 mL single-necked flask and dissolved in anhydrous dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness, and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 μm ACN-H2O, 0.1% TFA) to obtain 15 mg of Example 35, with a yield of 8.58%. LC-MS: 781.5 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.01(s,1H),7.96(s,2H),7.37-7.30(m,2H),7.27-7.21(m ,3H),5.24(s,1H),5.09(d,J=10.9Hz,1H),4.66-4.59(m,2H),4.08(d,J=8.8Hz,1H),4.01(d,J= 8.9Hz,1H),3.70(s,4H),3.55(d,J=13.7Hz,1H),3.45(d,J=13.7Hz,1H),3.11(s,2H),2.93(s,2 H),2.29-2.13(m,2H),2.06-1.91(m,2H),1.69(dd,J=25.5,12.6Hz,2H),1.41(t,J=12.1Hz,4H).

[0223] Example 36

[0224] Under nitrogen protection, Intermediate II (130.0 mg, 0.17 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (3 mL). Triethylamine (35.2 mg, 0.34 mmol) and Compound 1 (16.0 mg, 0.17 mmol) were added. After stirring at -40°C for 1 hour, the reaction solution was poured into ice water (10 mL). The resulting solution was extracted three times with dichloromethane (10 mL). The combined organic phases were washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Preparative separation (Solution A: 0.1% formic acid, Solution B: acetonitrile) afforded 30.00 mg of Example 36, a 25.0% yield. LC-MS [M+H] +: 680.6. 1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.15(s,1H),8.01(s,1H),7.96(s,2H),7.36-7.28( m,2H),7.26-7.20(m,3H),5.26(s,1H),5.16(d,J=11.0Hz,1H),4.67-4.64(m,1H),4.09-4. 00(m,2H),3.65-3.50(m,3H),3.48-3.43(m,1H),2.36-2.21(m,2H),2.20-2.10(m,1H),2. 04-2.01(m,1H),1.95-1.91(m,1H),1.70-1.63(m,2H),1.44(s,1H),1.39(d,J=6.4Hz,3H).

[0225] Example 37

[0226] Intermediate II (60 mg, 0.0806 mmol) and triethylamine (16.1 mg, 0.1613 mmol) were placed in a 25 mL three-necked flask, anhydrous dichloromethane (4 mL) was added, and N2 was replaced three times. The temperature was lowered to -40 ° C, and a dichloromethane (1 mL) solution of compound 1 (17.8 mg, 0.0806 mmol) was added dropwise. After the addition was complete, the reaction was carried out at -40 ° C for 1 hour. The reaction solution was poured into ice water (10 mL), and the resulting solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 30 mg of compound 2 with a yield of 46%. LC-MS: 809.5 [M+H] + .

[0227] Compound 2 (10 mg, 0.037 mmol) was dissolved in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) at 0°C and stirred for 0.5 hours. The reaction solution was concentrated to dryness, and the residue was purified by reverse phase preparative purification (ACN-H2O, 0.1% TFA) to obtain 10 mg of Example 37 in a 38% yield. LC-MS: 709.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.39(s,3H),8.16(s,1H),8.02(s,1H),7.96(s,2H),7.36-7 .29(m,2H),7.27-7.21(m,3H),5.18(d,J=11.3Hz,1H),4.65(q,J=6.1Hz,1H),4.17(s ,1H),4.07(d,J=8.8Hz,1H),4.00(d,J=8.9Hz,1H),3.57(d,J=12.8Hz,2H),3.30-3.2 0(m,3H),2.31-2.13(m,2H),2.03-1.94(m,2H),1.74-1.65(m,2H),1.45-1.38(m,4H).

[0228] Example 38

[0229] Under N2 protection, intermediate II (400.0 mg, 0.53 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (10 mL). Triethylamine (108.4 mg, 1.06 mmol) and compound 1 (41.8 mg, 0.53 mmol) were added. After stirring at -40°C for 10 minutes, the reaction solution was poured into ice water (20 mL). The resulting solution was extracted three times with dichloromethane (20 mL). The combined organic phases were washed once with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 320 mg of compound 2, with a yield of 56.7%. It was used directly in the next reaction without purification. LC-MS: 666.6 [M+H] + .

[0230] Compound 2 (100 mg, 0.150 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (5 mL). Chlorosulfonic acid (20.97 mg, 0.180 mmol) was added under nitrogen protection at zero degrees. The reaction solution was stirred at this temperature for 10 min and then concentrated to dryness. The residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% ammonia water) to obtain 70.12 mg of Example 38, with a yield of 62.60%. LC-MS: 744.5 [MH] - . 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),8.01(s,1H),7.97(s,2H),7.39-7.31(m,2H),7.26-7.23(m,3 H),7.20(s,1H),7.07(s,1H),6.95(s,1H),5.25-5.09(m,2H),4.66(d,J=6.4Hz,1H),4.09(d,J=8. 9Hz,1H),4.01(d,J=9.1Hz,1H),3.94-3.86(m,2H),3.59(d,J=14.0Hz,1H),3.38(s,1H),2.90(s,2 H),2.34-2.24(m,1H),2.18-2.09(m,1H),2.07-1.93(m,2H),1.71-1.62(m,2H),1.44-1.38(m,4H).

[0231] Example 39

[0232] According to the method of Example 38, 3-mercapto-1-propanol was used instead of 2-mercaptoethanol to synthesize the compound of Example 39 through two steps. LC-MS [MH] - :758.6.1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.01(s,1H),7.97(s,2H),7.36-7.31(m,2H),7 .27-7.22(m,3H),7.20(s,1H),7.07(s,1H),6.95(s,1H),5.21(s,1H),5.08(s,2H), 4.69-4.65(m,1H),4.10(d,J=9.3Hz,1H),4.01(d,J=8.9Hz,2H),3.75(t,J=6.1Hz,2 H),3.57(d,J=13.0Hz,2H),3.44(s,2H),2.25-2.20(m,2H),2.18-2.15(m,1H),2.01 -1.95(m,1H),1.81(s,2H),1.69-1.63(m,2H),1.39(d,J=6.3Hz,3H).

[0233] Example 40

[0234] Following the method of Example 38, 2-mercaptopropanol was substituted for 2-mercaptoethanol to obtain the compound of Example 40 through a two-step reaction. LC-MS: 758.7 [MH] - . 1 H NMR(400MHz,D2O)δ7.54(d,J=0.5Hz,3H),7.00-6.89(m,5H),5.03-4.93(m,1H),4.30-4.25(m,1H),3.94-3.81(m,3H ),3.71-3.62(m,2H),3.05-2.85(m,2H),2.35-2.14(m,3H),1.91-1.87(m,2H),1.61-1.35(m,3H),1.10-1.03(m,7H).

[0235] Example 41

[0236] Following the method of Example 38, the compound of Example 41 was synthesized in two steps using mercapto-PEG4-ol instead of 2-mercaptoethanol. LC-MS: 876.7 [MH] - . 1H NMR(400MHz,D2O)δ7.50-7.43(m,3H),6.98-6.89(m,5H),5.03(s,1H),4.23(s,1H),4.00(d,J=2.9 Hz,3H),3.58-3.39(m,15H),3.02-2.91(m,3H),2.29-2.15(m,3H),1.92-1.28(m,5H),1.04(s,3H).

[0237] Example 42

[0238] Intermediate II (100 mg, 0.150 mmol) was weighed and dissolved in anhydrous dichloromethane (5 mL) in a 50 mL three-necked flask. Compound 1 (26.45 mg, 0.180 mmol) and triethylamine (40.65 mg, 0.450 mmol) were added at -40°C under nitrogen. The reaction mixture was stirred at this temperature for 30 minutes and then concentrated to dryness. The residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% aqueous ammonia) to obtain 25 mg of Example 42, a yield of 25.48%. LC-MS: 728.6 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.00(s,1H),7.96(s,2H),7.34(t,J=7.6Hz,2H),7.27-7.22(m ,3H),7.07(s,3H),5.25(s,1H),5.03-5.00(m,1H),4.67-4.64(m,1H),4.11(d,J=8.9Hz,1H),4.01( d,J=9.0Hz,1H),3.59(d,J=13.7Hz,1H),3.39(d,J=13.5Hz,1H),2.93-2.89(m,2H),2.71-2.65(m,2 H),2.29-2.30(m,2H),2.20-2.08(m,1H),2.02-1.95(m,2H),1.72-1.59(m,2H),1.42-4.38(m,4H).

[0239] Example 43

[0240] Intermediate II (200 mg, 0.2688 mmol) and triethylamine (53.7 mg, 0.5376 mmol) were placed in a 25 mL three-necked flask, anhydrous dichloromethane (8 mL) was added, and the atmosphere was replaced with N2 three times. The temperature was lowered to -40°C, and a solution of compound 1 (28.2 mg, 0.2688 mmol) in dichloromethane (2 mL) was added dropwise. After the addition was complete, the mixture was reacted at -40°C for 0.5 hours. The reaction solution was poured into ice water (10 mL), and the resulting solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase preparative purification (ACN-H2O (0.1% TFA) gradient: 30-60) to obtain 20 mg of Example 43, with a yield of 11%. LC-MS: 693.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ9.43(s,1H),8.16(s,1H),8.02(s,1H),7.96(s,2H),7.38-7.29(m,2H),7 .25-7.23(m,3H),5.25-5.15(m,2H),4.66(q,J=6.4Hz,1H),4.09-4.01(m,2H),3.55(d,J=12.8Hz, 2H),3.33(s,3H),3.06(s,2H),2.79(s,6H),2.35-2.12(m,2H),2.09-1.82(m,2H),1.75-1.65(m,2H),1.45-1.39(m,4H).

[0241] Example 44

[0242] Example 43 (20 mg, 0.02886 mmol, 1 eq) was placed in a 25 mL three-necked flask. 2 mL of anhydrous dichloromethane was added and the atmosphere was replaced with nitrogen three times. 0.1 mL of iodomethane (excess) was added to the reaction system and stirred at room temperature overnight. The reaction solution was directly concentrated to obtain the crude product, which was then purified by reverse phase preparative purification (ACN-H2O (0.1% TFA) gradient: 30-60) to obtain Example 44 in a 21% yield. LC-MS: 707.6 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ8.15(s,1H),8.02(s,1H),7.96(s,2H),7.36-7.29( m,2H),7.25-7.22(m,3H),5.31-5.07(m,2H),4.66(q,J=6.3Hz,1H),4.10-4.0 1(m,2H),3.55(d,J=13.2Hz,5H),3.18(s,2H),3.06(s,9H),2.29-2.15(m,2H) ,2.08-1.98(m,1H),1.94-1.86(m,1H),1.78-1.63(m,2H),1.45-1.40(m,4H).

[0243] Example 45

[0244] Under N2 protection, Example 43 compound (20.0 mg, 0.03 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (4 mL). Tert-butyl bromoacetate (16.8 mg, 0.09 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was poured into ice water (10 mL). The resulting solution was extracted three times with dichloromethane (10 mL). The combined organic phases were washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 20.0 mg of crude compound 2, with a yield of 67.9%. The product was directly carried on to the next step without purification. LC-MS [M+H] + :807.6.

[0245] Under N₂ protection, compound 2 (20.0 mg, 0.01 mmol) was weighed into a 25 mL single-necked flask and dissolved in a mixture of dichloromethane (4 mL) and trifluoroacetic acid (1 mL). After stirring at room temperature for 16 hours, the reaction solution was concentrated to dryness, and the residue was purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to provide 4.0 mg of Example 45, in a yield of 41.5%. LC-MS [M+H]⁺: 751.9. 1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.02(s,1H),7.97(s,2H),7.39-7.30(m,2H),7.2 8-7.21(m,3H),5.34-5.19(m,1H),5.15(d,J=11.0Hz,1H),4.67(q,J=6.2Hz,1H),4.33( s,2H),4.05-4.01(m,2H),3.78(d,J=7.1Hz,2H),3.56-3.50(m,4H),3.20(s,6H),2.34- 2.10(m,3H),2.01-1.93(m,2H),1.75-1.62(m,2H),1.46(s,1H),1.41(d,J=6.4Hz,3H).

[0246] Example 46

[0247] Intermediate II (30 mg, 0.042 mmol) was weighed into a 50 mL three-necked flask and dissolved in water (2 mL). Triethylamine (8.14 mg, 0.08 mmol) and compound 1 (30 mg, 0.042 mmol) were added at -40°C under nitrogen. The reaction solution was stirred at this temperature for 30 minutes, then quenched with water (5 mL). The resulting solution was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed sequentially with water and saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to obtain 8.66 mg of Example 46, a yield of 25.12%. LC-MS: 857.3 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.93(s,2H),7.89(s,1H),7.41-7.34(m,2H),7.33-7.23(m,3H),5.36(s,1H),5.21-5.14(m,1 H),4.69-4.62(m,1H),4.27-4.20(m,1H),4.08-4.00(m,1H),3.84-3.78(m,1H),3.75-3.67(m,2H),3.63(s,12H), 3.56-3.52(m,2H),3.40-3.35(m,3H),2.99-2.81(m,3H),2.61-2.44(m,3H),2.43-2.35 (m,1H),2.22-2.11(m,2H),1.90-1.81(m,2H),1.73-1.60(m,2H),1.49(d,J=6.3Hz,3H).

[0248] Example 47

[0249] Following the method of Example 46, 3,6,9,12,15-pentaoxahexadecan-1-thiol was replaced with mercapto-triethylene glycol-carboxylic acid and reacted with Intermediate II to obtain Example 47. LC-MS: 827.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.93(s,2H),7.88(s,1H),7.40-7.34(m,2H),7.34-7.25(m,3H),5.40-5.10(m,2H ),4.70-4.60(m,1H),4.26-4.17(m,1H),4.09-4.00(m,1H),3.86-3.78(m,1H),3.77-3.66(m,4H),3.6 5-3.58(m,8H),3.55-3.44(m,1H),3.02-2.79(m,2H),2.61-2.51(m,3H),2.51-2.44(m,1H),2.44-2.3 4(m,1H),2.20(dd,J=19.5,11.7Hz,2H),1.91-1.80(m,2H),1.74-1.61(m,1H),1.48(d,J=6.5Hz,3H).

[0250] Example 48

[0251] Intermediate II (100 mg, 0.107 mmol, 1 eq) was weighed into a 50 mL three-necked flask and dissolved in 5 mL of anhydrous dichloromethane. Triethylamine (21.67 mg, 0.214 mmol, 2 eq) and compound 1 (98.54 mg, 0.161 mmol, 1.5 eq) were added at -40°C under N2 protection. The reaction solution was stirred at this temperature for 30 min, then quenched with water (50 mL) and extracted three times with DCM (50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 μm ACN-H2O (0.1% TFA), gradient: 50-70) to obtain 25 mg of Example 48 in a yield of 17.63%. LC-MS [M+H] + :1046.8. 1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.13(s,1H),8.01(s,1H),7.96(s,2H),7.35-7.30(m ,2H),7.25-7.20(m,3H),5.21-5.10(m,2H),4.66(q,J=6.2Hz,1H),4.05(dd,J=19.2,8.9Hz ,2H),3.59(dd,J=12.3,6.0Hz,5H),3.49-3.47(m,10H),3.36(s,20H),2.89(s,2H),2.43(t ,J=6.3Hz,2H),2.28-2.14(m,2H),2.04-1.91(m,2H),1.71-1.64(m,2H),1.44-1.39(m,4H).

[0252] Example 49

[0253] Under N2 protection, intermediate II (200.0 mg, 0.27 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (10 mL). Triethylamine (81.3 mg, 0.80 mmol) and compound 1 (113.6 mg, 0.32 mmol) were added. After stirring at -40°C for 10 minutes, the reaction solution was poured into ice water (20 mL). The resulting solution was extracted three times with dichloromethane (20 mL). The combined organic phases were washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 200 mg of compound 2, with a yield of 71.2%. The product was directly processed into the next step without purification. LC-MS [M+H] + :941.5.

[0254] Under N2 protection, compound 2 (200.0 mg, 0.2 mmol) was weighed into a 25 mL single-necked flask and dissolved in a mixture of dichloromethane (4 mL) and trifluoroacetic acid (1 mL). After stirring at room temperature for 0.5 hours, the reaction solution was concentrated to dryness, and the residue was separated and purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to obtain 30.0 mg of Example 49, a yield of 16.0%. LC-MS [M+H] + :841.6. 1H NMR(400 MHz,DMSO-d6)δ8.15(s,1H),8.02(s,1H),7.96(s,2H),7.75(s,2H),7.35-7.29(m,2H),7 .25-7.21(m,3H),5.21(s,1H),5.12(d,J=10.6Hz,2H),4.66(q,J=6.4Hz,2H),4.08-4.05 (m,2H),3.60-3.54(m,8H),3.52-3.50(m,8H),2.97-2.95(m,2H),2.90(s,2H),2.33-2.1 1(m,4H),2.01-1.98(m,1H),1.92-1.86(m,1H),1.74-1.66(m,2H),1.40(d,J=6.3Hz,3H).

[0255] Example 50

[0256] Compound 1 (1.1 g, 2.19 mmol) was dissolved in dichloromethane (15 mL), the solution was cooled to -30 ° C, diisopropylethylamine (2.26 g, 17.52 mmol) and trimethylsilyl chloride (618 mg, 5.69 mmol) were added thereto under nitrogen protection and stirred at room temperature for 2 hours. Compound 2 (385 mg, 2.69 mmol) was then added dropwise at -5 ° C under nitrogen protection, and the solution was stirred at -5 ° C for 2 hours. The reaction was then quenched with water (200 mL), and the resulting solution was extracted three times with dichloromethane (200 mg). The combined organic phases were washed with water and brine in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 700 mg of compound 3 in a yield of 52.51%. LC-MS: 606.9 [M+H] + .

[0257] Compound 4 (167 mg, 0.74 mmol) was added to a solution of compound 3 (300 mg, 0.49 mmol) in anhydrous acetonitrile (5 mL). The resulting solution was stirred at 100°C for 3 hours. The solvent was then removed in vacuo to afford 300 mg of compound 5 in a yield of 80.04%. LC-MS: 759.2 [M+H] + .

[0258] Compound 5 (100 mg, 0.131 mmol) was weighed into a 50 mL three-necked flask and dissolved in anhydrous dichloromethane (5 mL). Triethylamine (39.89 mg, 0.393 mmol) and 3-mercaptopropionic acid (41.84 mg, 0.393 mmol) were added at 0°C under nitrogen protection. The reaction solution was stirred at this temperature for 30 minutes. The reaction solution was concentrated to dryness, and the residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5 μm ACN-H2O, 0.1% FA) to obtain 5 mg of Example 50 in a yield of 4.8%. LC-MS: 731.1 [M+Na] + . 1 H NMR(400MHz,DMSO)δ8.12(s,1H),8.03-7.92(m,3H),7.35-7.30(m,2H),7.27-7 .21(m,3H),5.69(s,1H),4.66-4.64(m,1H),4.12(d,J=8.6Hz,1H),4.01(d,J=9 .0Hz,1H),3.57-3.33(m,2H),2.90-2.69(m,2H),2.61-2.52(m,2H),2.44(s,1H ),2.31-2.11(m,2H),2.08-1.97(m,2H),1.75-1.59(m,2H),1.46-1.39(m,7H).

[0259] Test Example 1: Plasma stability test

[0260] 1.1 Test plasma

[0261] Human plasma (Vendor: AoNeng Biotech).

[0262] 1.2 Preparation of compound solution

[0263] A certain amount of the example compound was weighed and DMSO was added to prepare a 10 mM stock solution; a certain volume of the 10 mM stock solution was diluted with DMSO to a stock solution with a concentration of 1600 μM; and a certain volume of the 1600 μM stock solution was diluted with 45% methanol to a working solution with a concentration of 16 μM.

[0264] 1.3 Experimental steps

[0265] 1) Pre-incubate plasma in a 37°C water bath for 5 minutes.

[0266] 2) Take 4 μL of 16 μM working solution of the example compound and add it to 60 μL of plasma to make the final concentration of the compound 1 μM, and mix well.

[0267] 3) The samples were incubated at each time point (0, 15, 30, 60, and 120 min). After the incubation, 192 μL of acetonitrile containing the internal standard was added, followed by shaking for 1 min and centrifugation at 3700 rpm at 4°C for 20 min. The supernatant was collected for LC-MS analysis.

[0268] 2. Results

[0269] The conversion of the present invention examples in human plasma is as follows, and the data are shown in Table 1:

[0270] Table 1

[0271] Note: The parent drug in the table refers to rolapitant.

[0272] Conclusion: The compound of formula (I) is not substantially converted into the active metabolite rolapitant in plasma. Nearly half or more of the compounds of Examples 17, 25, 38, 39, and 42 are converted into the active metabolite rolapitant in plasma.

[0273] Test Example 2: Liver S9 Stability Test

[0274] 1.1 Liver S9

[0275] Human mixed liver S9 (Vendor: Xenotech) was thawed in a 37°C water bath before use.

[0276] 1.2 Preparation of compound solution

[0277] A certain amount of the example compound was weighed and DMSO was added to prepare a 10 mM stock solution. A certain volume of the stock solution was taken and diluted with DMSO to prepare a working solution with a concentration of 200 μM.

[0278] 1.3 Sample incubation

[0279] Take 1.5 μL of a 200 μM working solution of the example compound and add it to 238.5 μL of liver S9 working solution. Preincubate in a 37°C water bath for 5 minutes. Then, add 60 μL of NADPH working solution to initiate the reaction and mix thoroughly by inverting. At time 0, add the mixture to the quenching solution and mix thoroughly. At time points 5, 15, 30, and 60 minutes, add the mixture to the quenching solution and DMSO and mix thoroughly. Vortex vigorously for 1 minute and centrifuge at 3700 rpm at 4°C for 15 minutes. Collect the supernatant and analyze it by LC-MS.

[0280] 2. Results

[0281] The conversion of the compounds of the present invention in human liver S9 is as follows, and the data are shown in Table 2:

[0282] Table 2

[0283] Note: The parent drug in the table refers to rolapitant.

[0284] Conclusion: When incubated in human liver S9 for 30 minutes, Examples 2, 30, 32, 37, 38, 39, 42, 44, 45, and 46 were converted to the active metabolite rolapitant to a relatively high degree and at a relatively fast conversion rate. Among them, the conversion rates and degrees of 25, 33, 36, 38, 39, 42, 44, 45, and 47 were comparable to or better than those of the compound of formula (I).

[0285] Test Example 3: Thermodynamic Solubility

[0286] 1.1 Reagent preparation

[0287] 100 mM phosphate buffer solution: Dissolve 7.94 g K2HPO4.3H2O and 2.07 g KH2PO4 in 500 mL of ultrapure water. Adjust the pH of the solution to 7.4 with 1 N NaOH and filter.

[0288] 1.2 Test Method

[0289] Accurately weigh an appropriate amount of Example compound and add it to 100 mM phosphate buffer in small amounts to a final concentration of 20 mg / mL. Shake at room temperature for 16 hours, then let stand for 30 minutes. Filter the supernatant and dilute with DMSO. Add the diluted Example sample solution to the quenching buffer, mix thoroughly, and analyze by LC / MS. See Table 3 for data.

[0290] 2. Results

[0291] Table 3

[0292] Test Example 4: In vitro human hemolysis test

[0293] 1.1 Test samples

[0294] Examples 38, 39, and 42.

[0295] 1.2 Whole blood test

[0296] Fresh whole human blood.

[0297] 1.3 Preparation of cell resuspension

[0298] Collect whole blood, store in a 250ml conical flask, and shake at 500rpm for 10 minutes to remove fibrinogen and make defibrillated blood. Add normal saline (blood volume: normal saline volume = 1:4) for washing. Centrifuge the blood / normal saline mixture at 2500rpm for 15 minutes (4°C), remove the supernatant, and wash the precipitated red blood cells with normal saline (blood volume: normal saline volume = 1:4) several times and centrifuge at 2500rpm for 15 minutes until the supernatant no longer appears red. Prepare a suspension of the obtained red blood cells with normal saline at a ratio of 1:49 (blood cell volume: normal saline volume) and store at 4°C for use.

[0299] 1.4 Preparation of working solution

[0300] Examples 38, 39, and 42 were prepared with DMSO to concentrations of 200, 80, and 20 μM, respectively, for later use.

[0301] 1.5 Experimental steps

[0302] 1) Add the working solution of the example compound to the red blood cell suspension and mix gently.

[0303] 2) Incubate the mixture in a CO2 incubator at 37±0.5°C for 45 minutes. Observe for aggregation every 15 minutes.

[0304] 3) The resulting solution was centrifuged at 4000 rpm for 15 minutes (4°C), 100 μL was transferred and the absorbance was measured at 540 nm to calculate the hemolysis rate (%).

[0305] 2. Results

[0306] The compounds of Examples 38, 39 and 42 showed no hemolytic effect at concentrations as high as 200 μM.

[0307] Test Example 5: Pharmacokinetics test in rats

[0308] The drug concentrations in whole blood of rats at different times after tail vein injection of the compound of formula (I) and the compounds of Examples 38, 39, and 42 were determined by LC / MS / MS. The pharmacokinetic behavior of the compounds in rats was studied and their pharmacokinetic characteristics were evaluated.

[0309] 1.1 Drug preparation

[0310] A certain amount of the compound of formula (I) and the compounds of Examples 38, 39, and 42 were weighed and prepared into pH 4.0 solutions respectively with 20 mmol / L sodium dihydrogen phosphate for later use.

[0311] 1.2 Administration

[0312] Intravenous push injection, push injection time is about 5 minutes, the dosage is 2 mg / kg, the dosage concentration is 0.4 mg / mL, and the dosage volume is 5 mL / kg.

[0313] 1.3 Operation

[0314] Blood was collected via jugular sinus puncture before dosing and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, and 48 hours after dosing. Blood was anticoagulated with sodium heparin. Protein was immediately precipitated with methanol:acetonitrile (1:1) and the supernatant was removed for LC / MS / MS analysis.

[0315] 1.3 Pharmacokinetic parameter results are shown in Table 4.

[0316] Table 4

[0317] Note: a) Pharmacokinetic parameters of the compound in Example 1 in rats; b) Pharmacokinetic parameters of the compound in Example 1 metabolized to rolapitant in rats

[0318] Conclusion: Examples 38, 39, and 42 were rapidly converted into the active metabolite rolapitant in rats after injection. AUC last 、C max and T max The data show that Examples 38 and 39 have comparable pharmacokinetic properties of Rolapitant to the compound of formula (I); 1 / 2 The data showed that Example 42 was converted into rolapitant at a faster rate after administration, and the AUC last 、C max The data showed that the in vivo exposure level of rolapitant after conversion was higher, showing better pharmacokinetic properties than the compound of formula (I).

[0319] Test Example 6: Pharmacokinetic test of the compound in cynomolgus monkeys

[0320] The drug concentrations in whole blood of cynomolgus monkeys at different times after intravenous administration of the compound of formula (I) and the compound of Example 42 were determined by LC / MS / MS. The pharmacokinetic behavior of the compounds in cynomolgus monkeys was studied and their pharmacokinetic characteristics were evaluated.

[0321] 1.1 Drug preparation

[0322] A certain amount of the compound of formula (I) and the compound of Example 42 were weighed and solutions were prepared with 5% DMSO / 20% PEG400 / H2O for later use.

[0323] 1.2 Administration

[0324] Intravenous infusion, infusion time 30min, dosage 2mg / kg, dosage concentration 0.4mg / mL, dosage volume 5mL / kg.

[0325] 1.3 Operation

[0326] Blood was collected from the forelimb vein before dosing and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 36, 48, and 72 hours after the start of dosing, and anticoagulated with sodium heparin. Immediately after whole blood collection, protein was precipitated with methanol:acetonitrile (1:1), and the supernatant was removed for LC / MS / MS analysis.

[0327] 1.3 Pharmacokinetic parameters are shown in Table 5

[0328] Table 5

[0329] Note: a) Pharmacokinetic parameters of the compound in Example 1 in cynomolgus monkeys; b) Pharmacokinetic parameters of the compound in Example 1 metabolized to rolapitant in cynomolgus monkeys

[0330] Conclusion: The compound of formula (I) and Example 42 were rapidly converted into the active metabolite rolapitant in cynomolgus monkeys after intravenous infusion. Identification of plasma metabolites showed that rolapitant was the major metabolite of Example 42, with approximately 98% of Example 42 converted into the active metabolite rolapitant. 1 / 2 The data showed that Example 42 was converted into rolapitant at a faster rate after administration, and the AUC last 、C max The data showed that the exposure of rolapitant converted by the compound of Example 42 was significantly higher than that of the compound of formula (I), showing better pharmacokinetic properties than the compound of formula (I).

Claims

1. A compound having a structure represented by the following formula (II), formula (III) or formula (IV), an isomer, or a pharmaceutically acceptable salt or acid or a deuterated product thereof: in: In formula (II), L1 is selected from -[C(R4)(R5)] m -(A) q -、-[C(R4)(R5)] m -(A) p -C(O)-[C(R4)(R5)] n -(A) q -、-[C(R4)(R5)] m -C(O)-(A) p -[C(R4)(R5)] n -(A) q -、-[C(R4)(R5)] m -(A) p -B-(A) q -、-[C(R4)(R5)] m -C(O)-(A) p -B-(A) q -、-[C(R4)(R5)] m -(A) p -C(O)-B-(A) q -、-[C(R4)(R5)] m -(A) p -C(S)-B-(A) q -、-[C(R4)(R5)] m -C(S)-(A) p -B-(A) q -、-[C(R4)(R5)] m -B-(A) p -、-[C(R4)(R5)] m -B-C(O)-(A) p -、-[C(R4)(R5)] m -B-(A) p -C(O)-(A) q -、-[C(R4)(R5)] m -B-(A) p -C(S)-(A) q -、-[C(R4)(R5)] m -B-C(S)-(A) p -、-[C(R4)(R5)] m -(A) p -S(O) t -B-、-[C(R4)(R5)] m -S(O) t -(A) p -B-、-[C(R4)(R5)] m -S(O)=N-[C(R4)(R5)] n -、-[C(R4)(R5)] m -N=S(O)-[C(R4)(R5)] n -; A is selected from O, S, N(R6); B is selected from cycloalkyl, heterocyclic, aryl, heteroaryl, 5-12-membered spirocyclic, 5-12-membered heterospirocyclic, 5-12-membered bridged ring, 5-12-membered heterobridged ring, 6-12-membered fused ring, 6-12-membered fused ring containing N, O or S, alkenyl or alkynyl, wherein cycloalkyl, heterocyclic, aryl, heteroaryl, 5-12-membered spirocyclic, 5-12-membered heterospirocyclic, 5-12-membered bridged ring, 5-12-membered heterobridged ring, 6-12-membered fused ring, 6-12-membered fused ring containing N, O or S, alkenyl or alkynyl, wherein cycloalkyl, heterocyclic, aryl, heteroaryl, 5-12-membered spirocyclic, 5-12-membered heterospirocyclic, 5-12-membered bridged ring, 5-12-membered heterobridged ring, 6-12-membered fused ring, 6-12-membered fused ring containing N, O or S is optionally replaced by one or more selected from alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl substituted by alkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, SH, or halogen; R1 is selected from R2 is selected from hydrogen, hydroxy, SH, alkyl, haloalkyl, alkoxy, -[C(R4)(R5)] m -N(R7)3 + , cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12-membered spirocyclic group, 5-12-membered heterospirocyclic group containing N, O or S, 5-12-membered bridged ring group, 5-12-membered heterobridged ring group containing N, O or S, 6-12-membered fused ring group, 6-12-membered fused ring group containing N, O or S, alkenyl, alkynyl or nitrile group, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12-membered spirocyclic group, 5-12-membered heterospirocyclic group containing N, O or S, 5-12-membered bridged ring group, 5-12-membered heterobridged ring group containing N, O or S, 6-12-membered fused ring group, 6-12-membered fused ring group containing N, O or S is optionally substituted by one or more selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile group, halogen; R3 is selected from hydrogen, SH, alkyl, haloalkyl, alkoxy, -[C(R4)(R5)] m -N(R7)3 + , cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12-membered spirocyclic group, 5-12-membered heterospirocyclic group containing N, O or S, 5-12-membered bridged ring group, 5-12-membered heterobridged ring group containing N, O or S, 6-12-membered fused ring group, 6-12-membered fused ring group containing N, O or S, alkenyl or alkynyl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, 5-12-membered spirocyclic group, 5-12-membered heterospirocyclic group containing N, O or S, 5-12-membered bridged ring group, 5-12-membered heterobridged ring group containing N, O or S, 6-12-membered fused ring group, 6-12-membered fused ring group containing N, O or S is optionally substituted by one or more selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; When L1 is -[C(R4)(R5)] m -(A) p -B-(A) q -、-[C(R4)(R5)] m -S(O)=N-[C(R4)(R5)] n -、-[C(R4)(R5)] m -N=S(O)-[C(R4)(R5)] n -, R1 can also be selected from When L1 is -[C(R4)(R5)] m -(A) q -、-[C(R4)(R5)] m -S(O)=N-[C(R4)(R5)] n -、-[C(R4)(R5)] m -N=S(O)-[C(R4)(R5)] n -, R1 can also be R4 and R5 are independently selected from hydrogen, hydroxy, SH, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, nitrile or halogen, wherein cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; R6 is selected from hydrogen, C 1-6 Alkyl, haloalkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclyl, aryl, heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; R7 is selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile; m is an integer from 0 to 6; n is an integer from 0 to 6; p is 0, 1 or 2; q is 0, 1 or 2; t is 1 or 2; In formula (III), R' is selected from H, Alkoxy, alkenyl, alkynyl, nitro, nitrile, halogen, acetyl, sulfonyl, C 1-6 Alkyl, haloalkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclic group, aryl group, heteroaryl group, R" is selected from NH2, having a substituted or unsubstituted group selected from the following: 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterospirocyclic group containing N, O or S 6- to 12-membered hetero-bridged ring group, 6- to 12-membered fused ring group, 6- to 12-membered fused ring group containing N, O or S, -[C(R4)(R5)] m -N(R”')3 + , C 2-7 Cyclic quaternary ammonium salts (such as: ), 5-12 membered spirocyclic quaternary ammonium salts containing N, O or S (for example: ), 5-12 membered hetero-bridged quaternary ammonium salts containing N, O or S (for example: ); the substituent is selected from H, OH, SH, NH2, C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; R4 and R5 are as described above; m is an integer from 0 to 6; Or R' and R" together with the carbon atom to which they are attached form a substituted or unsubstituted group: It has a 5-12 membered spiro ring selected from N, O or S, a 5-12 membered heterobridged ring containing N, O or S, or a 6-12 membered condensed ring containing N, O or S; the substituent is selected from H, OH, SH, NH2, C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; x is an integer of 1-6; R"' is selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile; In formula (IV), L2 is selected from -[C(R b )(R c )] x -, -[C(R b )(R c )] x -Z-[C(R d )(R e )] h -, -[C(R b )(R c )] x -A-C(O)-[C(R d )(R e )] h -, -[C(R b )(R c )] x -A-C(S)-[C(R d )(R e )] h -, -[C(R b )(R c )] x -A-S(O)2-[C(R d )(R e )] h -, -[C(R b )(R c )] x -C(O)-A-[C(R d )(R e )] h -, -[C(R b )(R c )] x -C(S)-A-[C(R d )(R e )] h -, -[C(R b )(R c )] x -S(O)2-A-[C(R d )(R e )] h -, -[C(R b )(R c )] x -vinyl-[C(R d )(R e )] h -, -[C(R b )(R c )] x -ethynyl-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S(O)(NR k )-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S(O)=N-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S(O) t -[C(R d )(R e )] h -; R a Selected from -[C(R f )(R g )] n -R j , -Y-[C(R f )(R g )] n -R j 、-[C(R f )(R g )] n -N(R p )2 + -[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -A-C(O)-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -A-C(S)-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -Vinyl-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -Ethynyl-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O)(NR k )-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O)=N-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O) t -[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -C(O)-A-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -C(S)-A-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -vinyl[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -ethynyl[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O)(NR k )-[C(R h )(R i )] i -R j 、[C(R f )(R g )] n -N=S(O)-[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -S(O) t -[C(R h )(R i )] i -R j 、-[C(R f )(R g )] n -N(R p )2 + -[C(R h )(R i )] i -R j ; R b , R c , R d , R e , R f , R g , R h and R i Each is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, nitrile or halogen, wherein cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more selected from alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen, acetyl, sulfonyl, replaced by; or R b and R c , R d and R e , R f and R g , R h and R i The following groups, together with the carbon atoms to which they are attached, are substituted or unsubstituted: cycloalkyl, heterocycloalkyl, 5-12-membered spirocyclic group selected from N, O or S, 5-12-membered heterobridged ring group containing N, O or S, 6-12-membered fused ring group containing N, O or S; the substituents are selected from H, OH, SH, NH2, C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; R j is selected from H, NH2, OH, SH, alkoxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen, C1-C6 alkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclic group, aryl group, heteroaryl group, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S Cyclic group, -N(R p )3 + , C 2-7 Cyclic quaternary ammonium salts (such as: ), 5-12 membered spirocyclic quaternary ammonium salts containing N, O or S (for example: ), 5-12 membered hetero-bridged quaternary ammonium salts containing N, O or S (for example: )、 wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, amino, halogen, acetyl, sulfonyl, Replaced by; R2 is as described above; R k Selected from hydrogen, C 1-6 Alkyl, haloalkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclyl, aryl, heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more selected from alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, amino, SH, halogen; R p Selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile; A is selected from O, S, N (R k ); Y is selected from substituted or unsubstituted C 1-8 Cycloalkyl, C 1-8 Heterocyclic group, aryl, heteroaryl, 5-12 membered spirocyclic group, 5-12 membered heterospirocyclic group containing N, O or S, 5-12 membered bridged ring group, 5-12 membered heterobridged ring group containing N, O or S, 6-12 membered fused ring group, 6-12 membered fused ring group containing N, O or S,; substituents are selected from H, NH2, OH, SH, C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; Z is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted by one selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; h is an integer of 0-10; i is an integer of 0-10; m is an integer of 0-6; n is an integer of 0-6; x is an integer of 1-6; and y is an integer of 0-10.

2. The compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to claim 1, characterized in that: In formula (II): L1 is selected from -[C(R4)(R5)] m -(A) q -or-[C(R4)(R5)] m -(A) p -C(O)-[C(R4)(R5)] n -(A) q -; A is selected from O or S; R1 is selected from R2 is selected from hydrogen, hydroxy, SH, alkyl, C1-C6 alkyl, C1-C6 alkoxy; R3 is selected from hydrogen, SH, alkyl, C1-C6 alkyl, C1-C6 alkoxy; m is an integer from 0 to 6; n is an integer from 0 to 6; p is 0, 1 or 2; q is 0, 1 or 2; t is 1 or 2。 3. The compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to claim 1, characterized in that: In formula (II): R1 is selected from R2 is selected from hydrogen, hydroxy, SH, alkyl, C 1-6 Alkyl, C 1-6 Alkoxy; p is 0, 1 or 2.

4. The compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to claim 1, characterized in that: In formula (III): R' is selected from H, C 1-6 alkyl, C 1-6 Alkoxy, nitro, nitrile, halogen; R" is selected from the following groups which are substituted or unsubstituted: 5-12 membered heterospiro ring containing N, O or S, -[C(R4)(R5)] m -N(R”')3 + ; The substituent is selected from H, OH, SH, NH2, C 1-4 Alkyl, C 1-4 haloalkyl, nitro, nitrile, halogen; m is 0, 1, 2, 3, 4, 5 or 6; R4 and R5 are independently selected from hydrogen, hydroxyl, SH, alkyl, C1-C4 alkyl; Or R' and R" together with the carbon atom to which they are attached form a substituted or unsubstituted group: It has a 5-12-membered spiro ring selected from N, O or S, a 5-12-membered heterobridged ring group containing N, O or S, or a 6-12-membered condensed ring containing N, O or S; the substituent is selected from H, OH, SH, NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, nitro, nitrile, halogen; x is 1, 2, 3, 4, 5 or 6; R"' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, alkenyl, alkynyl, nitrile; Preferably, R' is selected from H, C 1-6 alkyl, C 1-4 Alkoxy, nitro, nitrile, halogen; R" is selected from NH2, having a substituted or unsubstituted group selected from the following: -[C(R4)(R5)] m -N(R”')3 + ; The substituent is selected from H, OH, SH, NH2, C 1-4 Alkyl, C 1-4 haloalkyl, nitro, nitrile, halogen; m is 0, 1, 2, 3, 4, 5 or 6; R4 and R5 are independently selected from hydrogen, hydroxyl, SH, alkyl, C1-C4 alkyl; R"' is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, alkenyl, alkynyl, nitrile; preferably methyl, ethyl, propyl or isopropyl.

5. The compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to claim 1, characterized in that: In formula (IV), L2 is selected from -[C(R b )(R c )] x -、-[C(R b )(R c )] x -Z-、-[C(R b )(R c )] x -OC(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -SC(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -OC(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -OC(S)-[C(R d )(R e )] h -; R b is H or methyl; R c is H or methyl; Z is C 5-10 An aromatic ring or a 5-6 membered aromatic heterocyclic ring, preferably Z is a benzene ring, a naphthalene ring or a thiophene ring; R d is methyl or ethyl; R e is H or methyl or ethyl; x is 1, 2, 3, 4, 5 or 6; h is an integer from 0 to 10; preferably, L2 is selected from -CH2-, -CH(CH3)- or -C(CH3)2-; more preferably, L2 is selected from -CH2-; preferably, L2 is selected from -CH2-OC(O)-(CH2) h -、-CH2-SC(O)-(CH2) h -、-CH2-OC(O)-[C(R d )(R e )] h -、-CH2-OC(S)-[C(R d )(R e )] h -; R d is methyl; R e is H or methyl; h is an integer of 0 or 10; more preferably h is an integer of 0-6; h is 0, 1, 2, 3 or 4.

6. The compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to claim 1, characterized in that: In formula (IV), R a Selected from the following substituted or unsubstituted groups: C1-C 10 alkyl, -(CH2) h CHR x R y 、-(CH2) h NR m R n 、-(CH2) h N(R p )2 + -R j ; Substituents are selected from NH2, -OH, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 carboxyalkyl; h or y is an integer from 0 to 10; R x Selected from H, -COOH, C1-C4 alkyl; R y Selected from H, amino, C1-C4 alkyl; R m , R n independently selected from H, amino, -COOH, C1-C4 alkyl; or R m and R n Together with the N atom to which it is attached, it forms a 5- to 11-membered heterocyclic ring having 1 to 3 heteroatoms selected from N or O or S; R j Selected from H, C1-C6 alkyl; R p Selected from H, C1-C6 alkyl. Preferably, in formula (IV), R a Selected from the following substituted or unsubstituted groups: C1-C6 alkyl, -(CH2) h CHR x R y 、-(CH2) h NR m R n 、-(CH2) h N(R p )2 + -R j ; Substituents are selected from NH2, -OH, -COOH, y is 1, 2, 3, 4, 5 or 6; h is 0, 1, 2, 3 or 4; R x Selected from H, -COOH, methyl, ethyl, propyl, isopropyl; R y Selected from H, amino, methyl, ethyl, propyl, isopropyl; R m , R n are independently selected from H, amino, -COOH, methyl, ethyl, propyl, isopropyl; or R m and R n Together with the N atom to which it is attached, it forms a 5- to 11-membered heterocyclic ring having 1 to 3 heteroatoms selected from N or O or S; R j Selected from H, methyl, ethyl, propyl, isopropyl; R p Selected from H, methyl, ethyl, propyl, isopropyl.

7. A compound having the following structure, an isomer, or a pharmaceutically acceptable salt or acid or a deuterated derivative thereof:

8. A composition comprising the compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

9. Use of the compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to any one of claims 1 to 7 in the preparation of a neurokinin-1 receptor antagonist.

10. Use of the compound, isomer, or pharmaceutically acceptable salt or acid or deuterated product thereof according to any one of claims 1 to 7 in the preparation of a medicament for treating vomiting, nausea, asthma, anxiety, depression, cough or migraine.

Images