Neurokinin-1 receptor antagonist compounds

Abstract

The invention discloses a neurokinin-1 receptor antagonist compound, a compound with a structure as shown in a formula (II), a formula (III) or a formula (IV), an isomer, or a pharmaceutically acceptable salt or acid or a deuterated substance thereof, the compound has proper solubility, can be quickly converted into an active metabolite rolapitant in plasma and liver, and can be used for preparing the neurokinin-1 receptor antagonist. The problems that rolapitant is poor in solubility and a conventional injection preparation is difficult to develop are solved, meanwhile, the hemolysis effect can be avoided, and the injection risk is reduced. Compared with an existing prodrug molecule (the compound shown in the formula (I)), the compound has the advantages that the speed of converting and releasing an active metabolite rolapitant in vivo is higher, the in-vivo exposure of the active metabolite rolapitant is higher, and better pharmacokinetic properties are shown. # imgabs0 #

Description

Technical Field

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

[0002] Neurokinin is a central neurotransmitter that participates in many physiological activities of the human body. Neurokinin contains a variety of substances, such as substance P, neurokinin A, neurokinin B, etc. There are three types of neurokinin receptors, namely neurokinin receptor 1 (NK1R), neurokinin receptor 2 (NK2R), and neurokinin receptor 3 (NK3R). Among them, NK1R is the most important and widely distributed. It exists in neurons, brainstem, vascular endothelium, gastrointestinal tract, urogenital system and other cells, and its content is highest in the vomiting center of the brain. Substance P is the most important neurotransmitter. It is widely distributed in the central nervous system and gastrointestinal tract of the human body and has the strongest binding ability with NK1R. After binding to NK1R, substance P acts on the calcium ion channel on the membrane through inositol triphosphate, causing membrane point depolarization and changes in protein kinase activity, participating in pain and stress signals, and stimulating physiological reactions 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) having 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 preparations for parenteral administration.

[0005]

[0006] 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 (formula (I)) of the invention 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 the side effects during administration. Prodrugs refer to compounds that are inactive or less active in vitro after chemical structure modification of drugs (parent drugs), and release active drugs in vivo through enzymatic or non-enzymatic conversion to exert their efficacy. The design of prodrugs of Rolapitant is mainly to improve its water solubility and facilitate the development of injections. Such prodrugs are fast in vivo in converting to release active metabolites Rolapitant, and the in vivo exposure of the converted active metabolites Rolapitant is high. They are considered to have ideal pharmacokinetic properties and are ideal prodrugs of Rolapitant.

[0007]

[0008] In view of this, more prodrug designs of rolapitant are provided, and it is found that the rate of conversion and release of the active metabolite rolapitant in vivo is faster, and the in vivo exposure of the converted active metabolite rolapitant is higher. The safer and more effective prodrug molecules have important clinical value. Summary of the invention

[0009] One of the purposes 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 a deuterated product thereof:

[0010]

[0011] in:

[0012] In formula (II),

[0013] 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-;

[0014] A is selected from O, S, N(R6);

[0015] 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 by one or more selected from alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, SH, halogen;

[0016] R1 is selected from

[0017]

[0018] 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;

[0019] 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;

[0020] 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 and

[0021]

[0022] 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

[0023] 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;

[0024] 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 selected from H, NH2, OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, halogen;

[0025] R7 is selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile;

[0026] 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;

[0027] In formula (III),

[0028] 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,

[0029] 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 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;

[0030] m is an integer from 0 to 6;

[0031] 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 1-6Alkyl, haloalkyl, alkenyl, alkynyl, nitro, nitrile, halogen; x is an integer of 1-6;

[0032] R"' is selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile;

[0033] In formula (IV),

[0034] 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 -;

[0035] 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 -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 ;

[0036] 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;

[0037] 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;

[0038] 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, -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: ),

[0039] 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;

[0040] R k Selected from hydrogen, C 1-6 Alkyl, haloalkyl, C 1-8 Cycloalkyl, C 1-8 Heterocyclyl, aryl, heteroaryl;

[0041] 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;

[0042] R p Selected from C 1-6 Alkyl, haloalkyl, alkenyl, alkynyl, nitrile;

[0043] A is selected from O, S, N (R k );

[0044] 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;

[0045] 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;

[0046] 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.

[0047] In some aspects, in formula (II) of the present invention:

[0048] In some embodiments, L1 is selected from -[C(R4)(R5)] m -(A) q -or

[0049] -[C(R4)(R5)] m -(A) p -C(O)-[C(R4)(R5)] n -(A) q -; A is selected from O or S;

[0050] R1 is selected from

[0051]

[0052] R2 is selected from hydrogen, hydroxy, SH, alkyl, C1-C6 alkyl, C1-C6 alkoxy;

[0053] R3 is selected from hydrogen, SH, alkyl, C1-C6 alkyl, C1-C6 alkoxy;

[0054] 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; t is 1 or 2.

[0055] In some more specific examples,

[0056] R1 is selected from

[0057]

[0058] R2 is selected from hydrogen, hydroxy, SH, alkyl, C 1-6 Alkyl, C 1-6 Alkoxy; p is 0, 1 or 2.

[0059] In some aspects, in formula (III) of the present invention:

[0060] R' is selected from H, C 1-6 alkyl, C 1-6 Alkoxy, nitro, nitrile, halogen;

[0061] 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;

[0062] 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;

[0063] R"' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, alkenyl, alkynyl, nitrile.

[0064] In some more specific examples,

[0065] R' is selected from H, C 1-6 alkyl, C 1-4 Alkoxy, nitro, nitrile, halogen;

[0066] 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;

[0067] R"' is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, alkenyl, alkynyl, nitrile; preferably methyl, ethyl, propyl or isopropyl.

[0068] In some aspects, in Formula (IV),

[0069] 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 bis H or methyl; R c is H or methyl; Z is C 5-10 An aromatic ring or an aromatic heterocyclic ring, and 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 of 0-10.

[0070] In some more specific examples, L2 is selected from -CH2-, -CH(CH3)- or -C(CH3)2-; further, L2 is selected from -CH2-.

[0071] 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.

[0072] 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;

[0073] h or y is an integer from 0 to 10;

[0074] R x Selected from H, -COOH, C1-C4 alkyl;

[0075] R ySelected from H, amino, C1-C4 alkyl;

[0076] 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;

[0077] R j Selected from H, C1-C6 alkyl;

[0078] R p Selected from H, C1-C6 alkyl.

[0079] 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,

[0080] y is 1, 2, 3, 4, 5 or 6; h is 0, 1, 2, 3 or 4;

[0081] R x Selected from H, -COOH, methyl, ethyl, propyl, isopropyl;

[0082] R y Selected from H, amino, methyl, ethyl, propyl, isopropyl;

[0083] 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;

[0084] R j Selected from H, methyl, ethyl, propyl, isopropyl;

[0085] R p Selected from H, methyl, ethyl, propyl, isopropyl.

[0086] 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 product thereof:

[0087]

[0088]

[0089]

[0090]

[0091]

[0092] The present invention also provides a composition having the compound of the present invention, wherein the composition comprises the compound of the present invention and a pharmaceutically acceptable carrier.

[0093] The present invention also provides the use of the above compound in preparing medicines for treating vomiting, nausea, asthma, anxiety, depression, cough or migraine.

[0094] Unless otherwise specified, the terms used in the present invention have the following definitions:

[0095] "Spirocyclic": When there are two rings in a molecule and these two rings share one carbon atom, this system is called a spirocyclic.

[0096] 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.

[0097] "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.

[0098] "Alkyl" means a saturated aliphatic hydrocarbon group of 1-20 carbon atoms, including straight and branched groups (the numerical range mentioned in this application, such as "1-20", means that the group, in this case an alkyl group, 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 with 1-10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, etc. C1~C8 alkyl refers to a straight or branched alkyl group with 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 1-4 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.

[0099] "Haloalkyl" means halogen-substituted alkyl, preferably halogen-substituted lower alkyl 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.

[0100] "Alkoxy" means -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.

[0101] “C 1-6 The term "alkoxy" refers to a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, etc. Preferably, it is a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and particularly preferably, methoxy or ethoxy.

[0102] "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 do 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.

[0103] "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), the remaining ring atoms are C, one or two C atoms can be optionally replaced by a carbonyl group. The ring of the heterocyclic group can be optionally substituted by one, two or three substituents independently selected from lower alkyl (optionally substituted by one or two substituents, the substituents independently selected from carboxyl or ester group), 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.

[0104] 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, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, 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 their N-oxides. Attachment of the heterocyclic substituents may be via a carbon atom or via a heteroatom.

[0105] "Aryl" means a fully carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms with a completely conjugated π electron system. Non-limiting examples of aryl include phenyl, naphthyl and anthracenyl. Aryl 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, hydroxyl, 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 -NR 10 R 11 The group composed of R10 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 di-alkylamino, carboxyl or N-sulfonylamino.

[0106] "Heteroaryl" means a stable monocyclic ring of up to 3-10 atoms in the ring or a bicyclic carbocyclic 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, quinolyl, isoquinolyl, 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 following groups, including: 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 As defined above. 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 di-alkylamino, carboxyl or N-sulfonylamino.

[0107] "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 by 1, 2 or 3, 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 -NR10 R 11 The substituents of the group are heteroaryl substituted (bonded via a ring carbon atom), and optionally substituted by one or more, preferably by 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 substituted heteroalicyclic groups (bonded through a ring carbon atom), representative acyl groups include but are not limited to acetyl, trifluoroacetyl, benzoyl, and the like.

[0108] "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, 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 substituted (bonded via a ring carbon atom), and optionally substituted by one or more, preferably by 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 substituted heteroalicyclic groups (bonded through a ring carbon atom), representative acyl groups include but are not limited to methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl and the like.

[0109] A "carbonyl group" is an organic functional group composed of carbon and oxygen atoms connected by a double bond (C=O).

[0110] "Quaternary ammonium salt" is a compound formed by replacing all four hydrogen atoms in the ammonium ion with hydrocarbon groups.

[0111] The compound of the present invention has suitable solubility and can be rapidly converted into the active metabolite rolapitant in plasma and liver, thus solving the problem of poor solubility of rolapitant and difficulty in developing conventional injection preparations, while avoiding hemolysis and reducing injection risks. Compared with the existing prodrug molecules (compounds of formula (I)), the compound of the present invention is faster in converting and releasing the active metabolite rolapitant in vivo, and has a higher in vivo exposure of the active metabolite rolapitant, showing better pharmacokinetic properties. DETAILED DESCRIPTION

[0112] The following examples are provided for better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified.

[0113] Example 1

[0114]

[0115] Under N2 protection, compound 1 (3.0 g, 6.0 mmol) was weighed into a 100 mL three-necked flask and dissolved in dichloromethane (45 mL). Diisopropylethylamine (6.2 g, 48 mmol) was added, cooled to -30 °C, trimethylsilyl chloride (1.69 g, 15.6 mmol) was added, and stirred at room temperature for 2 h. After cooling to -25 °C, a dichloromethane solution of chloromethyl chloroformate (950 mg, 7.30 mmol) was added dropwise, and the temperature was controlled at -25 °C to -5 °C and stirred until the reaction was completed. The reaction solution was poured into ice water, separated, extracted with dichloromethane, water and 1N dilute hydrochloric acid were added, separated, and the organic phase was washed with water, saturated sodium bicarbonate aqueous solution and brine in turn, 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 with a yield of 83.3%. LC-MS [M+H] + :593.2.

[0116]

[0117] Compound 2 (1.439 g, 12.6 mmol) was dissolved in water (4 mL) and ion exchanged with 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 freeze-dried to obtain 3.0 g of compound 3 with a yield of 80.1%, which was directly used in the next step reaction.

[0118]

[0119] 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, and compound 3 (1.5 g, 5.04 mmol) was added and stirred at room temperature for 2 h. The reaction solution was separated by preparative separation (Solution A: 0.05% ammonia water, Solution B: acetonitrile) to obtain 3.6 mg of Example 1 compound, with a yield of 1.49%. LC-MS [M+H] + :670.1. 1H 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).

[0120] Example 2

[0121]

[0122] Under N2 protection, weigh tri(tetrabutylammonium) hydrogen pyrophosphate (567 mg, 1.36 mmol) in a 100 mL three-necked flask and dissolve it in acetonitrile (5 mL), add a solution of intermediate I (400 mg, 0.68 mmol) in acetonitrile (5 mL), and stir at room temperature for 3 hours. Directly perform HPLC preparation (preparation A solution: 0.1% HN3.H2O, B solution: acetonitrile) to obtain 150 mg of Example 2 compound, with a yield of 29.56%. LC-MS: 734.6 [M+H] + . 1 H 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).

[0123] Example 3

[0124]

[0125] In a 100 mL round-bottom flask, compound 1 (200 mg, 1.36 mmol) was weighed and dissolved in 10 mL of water. 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 directly used in the next step.

[0126]

[0127] Compound 3 (240 mg) was added to a solution of intermediate I (150 mg, 0.25 mmol) in anhydrous acetonitrile (3 mL). The resulting solution was stirred at room temperature for 1 hour, then the solvent was removed in vacuo, and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 um ACN-H2O, 0.1% NH4HCO3) to give 6 mg of Example 3, yield 3.25%. 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).

[0128] Example 4

[0129]

[0130] 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 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, with a yield of 72.6%. 1H 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).

[0131]

[0132] 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 for 16 hours under nitrogen protection at 25 ° C. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered, concentrated and the residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5um ACN-H2O, 0.1% NH4HCO3) to obtain 65 mg of compound 4 with a yield of 39.62%. LC-MS: 974.3 [M+H] + .

[0133]

[0134] 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 150 x 21.2 mm, 5 um ACN-H2O, 0.1% NH4HCO3) to give 2 mg of Example 4 in a yield of 11.22%. LC-MS: 861.6 [M+H] + . 1 H 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).

[0135] Example 5

[0136]

[0137] Compound 1 (5 g, 25.7 mmol) was dissolved in 40 mL of anhydrous acetonitrile, sodium hydride (1.54 g, 38.5 mmol) was added thereto at 0°C, the reaction solution was stirred for 30 minutes under nitrogen protection at room temperature, 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 mixture was concentrated to dryness, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain 4.74 g of compound 2, with a yield of 88.7%. 1 H NMR (400MHz, DMSO-d6) δ1.42 (s, 18H), 1.32 (d, J = 17.2Hz, 3H).

[0138]

[0139] Compound 2 (3.6g, 17.3mmol) was dissolved in 60mL anhydrous tetrahydrofuran, cooled to minus 78 degrees Celsius under nitrogen protection, and lithium diisopropylamide (17.3mL, 34.6mmol, 2.0M / L) was slowly added dropwise, and the reaction solution was stirred for 30 minutes at this temperature. Then a tetrahydrofuran (35mL) solution of compound 3 (4.62g, 17.3mmol) was added. The reactant was stirred and heated to room temperature overnight. The reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate (200mL). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered and concentrated to the filtrate. Purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1+1% triethylamine), 1.9g compound 4 was obtained, and the yield was 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).

[0140]

[0141] 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 reactants were 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 obtain 900 mg of compound 5 in a yield of 51.16%. 1HNMR (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).

[0142]

[0143] Tetrazolyl (204 mg, 2.92 mmol) was added to a mixed solution of compound 5 (300 mg, 0.73 mmol) and compound 6 (122 mg, 0.73 mmol) in dimethylformamide (2 mL), and the mixture was reacted at room temperature for 2 hours. Hydrogen peroxide solution (165 mg, 30%) was then added dropwise at 0°C, and the reaction was quenched with water (50 mL) after stirring for 16 hours, and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine in turn, dried over sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=100 / 0-92 / 8) to obtain 150 mg of compound 7 with a yield of 41.70%. 1 HNMR (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).

[0144]

[0145] 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 for 4 hours under hydrogenation at room temperature. The solid was filtered out, and the filtrate was concentrated under vacuum to obtain 70 mg of compound 8 with 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).

[0146]

[0147] 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 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 brine in turn, dried over sodium sulfate, filtered, concentrated and the residue was purified by preparative HPLC (A solution: 0.1% NH4HCO3, B solution: acetonitrile) to give 70 mg of compound 9 with a yield of 33.36%. LC-MS: 981.2 [M+Na] + .

[0148]

[0149] Compound 9 (25 mg, 0.026 mmol) was dissolved in anhydrous dichloromethane (2 mL), phosphoric acid (0.1 mL) was added thereto at -10°C, the resulting solution was stirred at -10°C for 1 hour, then the solvent was removed in vacuo, and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 um ACN-H2O, 0.1% NH4HCO3) to give 1 mg of Example 5 compound, with a yield of 4.85%. LC-MS: 790.6 [M+H] + .

[0150] Example 6

[0151]

[0152] Under ice bath, 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 solution (30 mL), and the reaction mixture was stirred at 25 ° C for 1 hour under nitrogen protection. 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 h. Saturated aqueous ammonium chloride solution (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, concentrated, and the residue was separated and purified by silica gel column (dichloromethane / methanol = 97 / 3) to obtain 13.8 g of crude compound 3 with a yield of 35.98%, which was directly used in the next step. LC-MS: 882.6.[2M+Na] + .

[0153]

[0154] At room temperature, p-toluenesulfonic acid (0.19 g, 1.1 mmol) was added to a solution of compound 3 (2.4 g, 5.6 mmol) in methanol (10 mL), and the reaction mixture was stirred at 25 ° C for 16 h under nitrogen protection. Saturated sodium bicarbonate aqueous solution was added to the reaction system to adjust the pH to 8-9, and the resulting solution was concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 96:4) to obtain 0.8 g of compound 4, with a yield of 37.50%. LC-MS: 346.9 [M+H] + .

[0155]

[0156] At room temperature, PDC (13.17 g, 35 mmol) was added to a DMF (20 mL) solution of compound 4 (1.2 g, 3.5 mmol), and the reaction mixture was stirred at 25 ° C for 16 h under nitrogen protection. Water (300 mL) was added to the reaction system for dilution, and 1 M sodium hydroxide aqueous solution was added to adjust the pH value of the solution to 8.0. The obtained solution was cooled to 0 ° C, and then 6.1 wt% Na2SO3 aqueous solution (30 mL) was slowly added. The mixture was stirred at 0 ° C for 30 min, and ether (30 mL) was added to wash the aqueous phase. 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 separated and purified by silica gel column (dichloromethane / methanol = 90 / 10-85 / 15) to obtain 0.35 g of compound 5 with a yield of 22.86%. LC-MS: 361.1[M+H] + .

[0157]

[0158] 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), and the solution was stirred for 16 hours at 30 ° C under nitrogen protection. 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 in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by 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] + .

[0159]

[0160] 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 150 x 21.2 mm, 5 um ACN-H2O (0.1% TFA) to give 2 mg of Example 6 compound-, yield 7.8%. LC-MS: 804.6 [M+H] + .

[0161] Example 7

[0162]

[0163] Under N2 protection, compound 1 (20 mg, 0.031 mmol) was weighed into a 25 mL three-necked flask and dissolved in dimethylformamide (1 mL), (2-bromoethyl)trimethylammonium bromide (38 mg, 0.155 mmol) and 4A molecular sieves (20 mg) in dimethylformamide (1 mL) were added, and finally diisopropylethylamine (80 mg, 0.62 mmol) in dimethylformamide (1 mL) was added, and stirred at 55°C for 3 hours. After filtration, HPLC purification (A solution: 0.1% NH4HCO3, B solution: acetonitrile) was directly performed to obtain 5 mg of Example 7 compound-, with 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).

[0164] Example 8

[0165]

[0166] 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 for 16 hours under nitrogen protection at 25 ° C. 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 in turn, dried with sodium sulfate, filtered, and concentrated to obtain 260 mg of compound 3, which was directly used in the next step without purification. LC-MS: 299.2 [M+H] + .

[0167]

[0168] 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 thereto. The solution was stirred for 16 hours under nitrogen protection at room temperature. The residue was concentrated and purified by preparative HPLC (A solution: 0.1% NH4HCO3, B solution: acetonitrile) to obtain 75 mg of compound 4 with a yield of 15.62%. LC-MS: 855.4 [M+H] + .

[0169]

[0170] 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 solution 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 compound with a yield of 21.20%. LC-MS: 755.0 [M+H] + . 1H 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).

[0171] Example 9

[0172]

[0173] The compound of Example 8 (50 mg, 0.066 mmol) was dissolved in 3 mL of methanol, sodium cyanoborohydride (8.31 mg, 0.132 mmol) and paraformaldehyde (9.92 mg, 0.331 mmol) were added thereto at zero degrees, the reaction solution was stirred at room temperature for 16 hours, then filtered, concentrated and the residue was purified by preparative HPLC (A solution: 0.1% TFA, B solution: acetonitrile), and freeze-dried to obtain 8 mg of the compound of Example 9, with 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).

[0174] Example 10

[0175]

[0176] 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 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 brine in turn, 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] + .

[0177]

[0178] Compound 3 (500 mg) was dissolved in 10 mL of ethyl acetate, Pd / C (500 mg) was added thereto, and stirred at room temperature for 6 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated to dryness to obtain 400 mg of compound 4, which was used directly in the next step without purification. LC-MS: 271.1 [M+H] + .

[0179]

[0180] 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 protection 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 in turn, dried with sodium sulfate, filtered, concentrated, and separated and purified by silica gel separation (petroleum ether / ethyl acetate = 1 / 1) to obtain 150 mg of compound 5 with a yield of 35.86%. LC-MS: 827.3 [M + H] + .

[0181]

[0182] Compound 5 (50 mg, 0.0603 mmol) was dissolved in 3 mL of dichloromethane, 1 mL of trifluoroacetic acid was added under nitrogen protection at zero degrees, the reaction solution was stirred at room temperature for 1 h, then concentrated and the residue was purified by preparative HPLC (A solution: 0.1% TFA, B solution: acetonitrile), and lyophilized to obtain 10 mg of Example 10 compound, with a yield of 22.72%. LC-MS: 727.2 [M+H] + . 1H 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).

[0183] Embodiment 11

[0184]

[0185] 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), stirred at room temperature for half an hour, and then intermediate I (200 mg, 0.34 mmol) dissolved in 10 mL of dimethylformamide was added dropwise to the reaction system, reacted overnight, and water (50 mL) was added to quench the reaction, extracted twice with ethyl acetate (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 200 mg of compound 2, with a yield of 75.6%. LC-MS [M+H] + :784.3.

[0186]

[0187] Compound 2 (200 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added under ice bath, the mixture was warmed to room temperature, stirred for 1 hour, concentrated, and the crude product was separated by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to obtain 47.4 mg of Example 11 compound, with a yield of 26.6%. LC-MS [M+H] + :684.3. 1H 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).

[0188] Example 12

[0189]

[0190] Under N2 protection, weigh Intermediate I (150 mg, 0.25 mmol) and Compound 1 (115 mg, 0.5 mmol) in a 25 mL three-necked flask and dissolve in dimethylformamide (3 mL), add sodium iodide (76 mg, 0.5 mmol) and potassium bicarbonate (76 mg, 0.75 mmol), and stir at room temperature for 5 hours. Add water (10 mL), extract with ethyl acetate (5 mL) three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / methanol=3 / 1) to obtain 160 mg of Compound 2, with a yield of 70.96%. LC / MS: 806.2 [M+Na] + .

[0191]

[0192] Compound 2 (160 mg, 0.2 mmol) was weighed and dissolved in dichloromethane (3 mL) in a 25 mL three-necked flask, and trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours. After concentration under reduced pressure, the mixture was purified by C18 column chromatography (Solution A: 0.1% TFA, Solution B: acetonitrile) to obtain 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).

[0193] Embodiment 13

[0194]

[0195] In a 25mL three-necked flask, weigh the compound of Example 12 (20mg, 0.03mmol) and dissolve it in methanol (5mL). Add paraformaldehyde (3.5mg, 0.12mmol) and stir at room temperature for 1 hour. Add sodium cyanoborohydride (3.7mg, 0.06mmol) and continue stirring at room temperature for 2 hours. Filter with suction, concentrate the filtrate under reduced pressure and purify it by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to obtain 2.5mg of the compound of Example 13, with a yield of 12.24%. 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).

[0196] Embodiment 14

[0197]

[0198] 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 in 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, and then a solution of intermediate I (200 mg, 0.361 mmol) in N, N-dimethylformamide (5 mL) was added, and 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 with sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (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] +.

[0199]

[0200] Compound 2 (200 mg, 0.258 mmol) was weighed and dissolved in anhydrous dichloromethane (6 mL) in a 50 mL single-mouth bottle. Trifluoroacetic acid (2 mL) was added under ice bath. The reaction solution 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 um ACN-H2O, 0.1% TFA) to obtain 23.10 mg of Example 14 compound with 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).

[0201] Embodiment 15

[0202]

[0203] 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 for 16 hours under nitrogen protection at 25 ° C. 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 in turn, 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] + .

[0204]

[0205] Compound 2 (150 mg, 0.227 mmol) was dissolved in (5 mL) anhydrous toluene, iodomethane (644 mg, 4.53 mmol) was added thereto, and the solution was stirred for 16 hours at 50°C under nitrogen protection. The solvent was then removed in vacuo, and the residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 um ACN-H2O, 0.1% FA) to give 8.46 mg of Example 15 compound, with a yield of 5.51%. 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).

[0206] Example 16

[0207]

[0208] 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), stirred at room temperature for half an hour, and then intermediate I (200 mg, 0.336 mmol) dissolved in 10 mL of dimethylformamide was dripped into the reaction system, reacted overnight, 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 in turn, dried with sodium sulfate, filtered, and the residue was purified with 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.

[0209]

[0210] Compound 2 (210 mg, 0.271 mmol) was dissolved in dichloromethane (6 mL), and 1.5 mL of trifluoroacetic acid was added dropwise under ice-bath cooling. After the addition, the reaction solution was warmed to room temperature, stirred for 1 hour, concentrated, and the residue was purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain 150 mg of compound 3, with a yield of 82%. LC-MS [M+H] + :674.4.

[0211]

[0212] Compound 3 (50 mg, 0.074 mmol) and ethyl acetate (5 mL) were added to a 100 mL three-necked flask, and palladium carbon (50 mg) and paraformaldehyde (88.9 mg, 2.96 mmol) were added under stirring at room temperature. The gas was replaced with hydrogen three times and stirred at room temperature for 24 h. Filtered and concentrated to obtain 50 mg of compound 4. LC-MS [M+H] + :702.2.

[0213]

[0214] Compound 4 (50 mg, 0.0711 mmol, 1 eq) was weighed and dissolved in anhydrous toluene (5 mL) in a 100 mL single-mouth bottle, and iodomethane (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 obtain 5.16 mg of Example 16 compound, with a yield of 10.1%. LC-MS [M+H] + :716.0. 1 HNMR(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).

[0215] Embodiment 17

[0216]

[0217] 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 thereto. Stir at room temperature for 18 hours under nitrogen protection, then quench the reaction with water (3 mL), and extract 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 um ACN-H2O, 0.1% FA), and lyophilized to obtain 3.3 mg of Example 17 compound, with 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).

[0218] Embodiment 18

[0219]

[0220] According to the method of Example 17, intermediate I and stachydrine hydrochloride were reacted to obtain the compound of Example 18. LC-MS [M+H] + :700.4.

[0221] Embodiment 19

[0222]

[0223] According to the method of Example 17, intermediate I and ergothioneine were reacted to obtain the compound of Example 19. LC-MS [M+H] + :786.3. 1H 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).

[0224] Embodiment 20

[0225]

[0226] 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 for 18 hours under nitrogen protection at room temperature, then the reaction was quenched with water (30 mL), and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water and brine in turn, dried with sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 150 mg of compound 2, with a yield of 66.02%. LC-MS: 674.2 [M + H] + .

[0227]

[0228] Compound 2 (150 mg, 0.223 mmol) was dissolved in anhydrous toluene (5 mL), iodomethane (630.21 mg, 4.44 mmol) was added thereto, and the reaction solution was stirred at 50°C for 16 hours under nitrogen protection. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Gemini-C18 150x 21.2 mm, 5um ACN-H2O, 0.1% FA) to obtain 30 mg of Example 20 compound with a yield of 19.56%. LC-MS: 688.3 [M+H] + . 1H 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).

[0229] Embodiment 21

[0230]

[0231] Intermediate I (150 mg, 0.25 mmol), compound 1 (59 mg, 0.50 mmol), 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 the reaction was completed, the reaction solution 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 obtain 80 mg of compound 2, with a yield of 46.9%. LC-MS [M+H] +: 674.3.

[0232]

[0233] Compound 2 (80 mg, 0.118 mmol, 1 eq) was dissolved in toluene (2 mL), 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 completed, the reaction solution was concentrated to dryness, and the residue was separated and purified by preparative HPLC to obtain 11 mg of Example 21 compound, with a yield of 13.4%. LC-MS [M+H] + :688.3. 1H 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).

[0234] Embodiment 22

[0235]

[0236] 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).

[0237] Embodiment 23

[0238]

[0239] Under nitrogen protection, 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). After the addition was complete, stirring was continued for 3 hours. A 1N aqueous hydrochloric acid solution (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 separated and purified by 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.

[0240]

[0241] At room temperature, compound 3 (6.92 g, 31.4 mmol) was added to a solution of compound 2 (2.2 g, 15.7 mmol) in dichloromethane (550 mL), and the mixture was stirred at 25°C for 16 hours under nitrogen protection. After the reaction was completed, the solvent was removed by vacuum concentration, and the residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 2.0 g of compound 4 with a yield of 45.86%. LC-MS [M+H] + :250.1.

[0242]

[0243] Under ice bath, compound 4 (400 mg, 1.60 mmol) and N,N-diisopropylethylamine (207 mg, 1.60 mmol) were dissolved in dichloromethane (10 mL), the reaction system was protected by nitrogen, triphosgene (476 mg, 1.60 mmol) was slowly added, the reaction mixture was stirred at 0 ° C for 0.5 hours, then heated 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 organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude compound 5 was directly used in the next step. LC-MS [M+H] + :312.0.

[0244]

[0245] Under ice bath, compound 6 (200 mg, 0.39 mmol) and anhydrous potassium carbonate (440 mg, 3.18 mmol) were dissolved in anhydrous acetonitrile (10 mL), the reaction system was protected by nitrogen, and a solution of compound 5 (372 mg, 1.19 mmol) in ethyl acetate (5 mL) was slowly added, and the reaction mixture was stirred at 50°C for 16 h. Ice water (10 mL) was added thereto, 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, concentrated, and the residue was separated and purified by silica gel column (dichloromethane / methanol=100 / 2) to obtain 50 mg of compound 7, with a yield of 12.9%. LC-MS [M+H] + :776.1.

[0246]

[0247] 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 compound 9 was directly used in the next step. LC-MS [M+H] + :842.2.

[0248]

[0249] Under ice bath, compound 9 (30 mg, 0.03 mmol) was dissolved in anhydrous dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was slowly added, the reaction system was protected by nitrogen, 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 (A solution: 0.1% TFA, B solution: acetonitrile) to obtain 30 mg of Example 23 compound, with a yield of 14.65%. LC-MS [M+H] + :742.1. 1 H 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).

[0250] Embodiment 24

[0251]

[0252] Under nitrogen protection, weigh Intermediate I (50.0 mg, 0.08 mmol) in a 50 mL three-necked flask and dissolve it in N, N-dimethylformamide (1 mL), add 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), and stir 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 compound, with 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).

[0253] Embodiment 25

[0254]

[0255] 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. 1H NMR(400MHz,DMSO-d6)δ12.09(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).

[0256] Embodiment 26

[0257]

[0258] Compound 1 (100 mg, 0.37 mmol), compound 2 (40 mg, 0.37 mmol), cupric 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 3 times with ethyl acetate (50 mL). The organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 60 mg of compound 3 with a yield of 43.24%. LC-MS: 373.1 [M+H] + .

[0259]

[0260] 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 with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC (Gemini-C18 150x21.2 mm, 5um ACN-H2O, 0.1% TFA) to give 10 mg of Example 26 compound in a yield of 10.62%. LC-MS: 928.9 [M+H] +.

[0261] Embodiment 27

[0262]

[0263] Compound 1 (500 mg, 1.0 mmol) was placed in a 25 mL three-necked flask, 10 mL of anhydrous dichloromethane was added, N2 was replaced three times, diisopropylethylamine (1032 mg, 8 mmol) was added, cooled to -30 ° C, trimethylsilyl chloride (283 mg, 2.6 mmol) was added, and stirred at room temperature for 2 h. Then cooled to -30 ° C, a solution of compound 2 (175 mg, 1.23 mmol) in anhydrous dichloromethane (2 mL) was added dropwise. The reaction temperature was controlled at -20 ° C to -5 ° C until the reaction was completed. 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, concentrated, and the residue was separated and purified by silica gel column (dichloromethane / methanol = 20 / 1) to obtain 300 mg of compound 3 with a yield of 62%. LC-MS: 620.6 [M + H] + .

[0264]

[0265] 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, N2 was replaced three times, and stirred at 80°C for 2 days. The reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column (dichloromethane / methanol=20 / 1) to obtain 120 mg of compound 4 with a yield of 52%. LC-MS: 712.5 [M+H] + .

[0266]

[0267] 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, N2 was replaced three times, stirred at 100 ° C for 3 hours, and then stirred at room temperature overnight. The reaction solution was concentrated to dryness, water (10 mL) was added to the residue for dilution, 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] + .

[0268]

[0269] 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 N2 was replaced 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 completed, the reaction was carried out 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] + .

[0270]

[0271] At 0°C, compound 8 (10 mg, 0.0126 mmol) was dissolved in a mixture of 2 mL of dichloromethane and 0.5 mL of trifluoroacetic acid and stirred for 0.5 h. The reaction solution was concentrated to dryness, and the crude product was separated and purified using a C18 column (ACN-H2O (0.1% TFA) gradient: 30-60) to obtain 2.32 mg of Example 27 compound with a yield of 27%. LC-MS: 693.6 [M+H] + . 1 HNMR (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).

[0272] Embodiment 28

[0273]

[0274] Compound 1 (200 mg, 0.4 mmol) was placed in a 25 mL three-necked flask, 5 mL of anhydrous dichloromethane was added, N2 was replaced three times, diisopropylethylamine (413 mg, 3.2 mmol) was added, cooled to -30 ° C, trimethylsilyl chloride (113 mg, 1.04 mmol) was added, and stirred at room temperature for 2 h. Then cooled to -30 ° C, a solution of compound 2 (70 mg, 0.492 mmol) in anhydrous dichloromethane (2 mL) was added dropwise. The reaction temperature was controlled at -20 ° C to -5 ° C until the reaction was completed. 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, concentrated, and the residue was separated and purified by 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] + .

[0275]

[0276] 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, N2 was replaced three times, and stirred at 100 ° C for 6 hours. 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] + .

[0277]

[0278] 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 N2 was replaced 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 completed, the reaction was carried out 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] + .

[0279]

[0280] At 0°C, compound 7 (12 mg, 0.0154 mmol) was dissolved in a mixture of 2 mL of dichloromethane and 0.5 mL of trifluoroacetic acid and stirred for 0.5 h. The reaction solution was concentrated to dryness, and the residue was separated and purified by C18 column (ACN-H2O (0.1% TFA), gradient: 30-70) to obtain 5.3 mg of Example 28 compound with a yield of 50%. 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).

[0281] Embodiment 29

[0282]

[0283] According to the method of the third and fourth steps of Example 28, N-tert-butyloxycarbonyl-L-cysteine ​​was used to replace 2-tert-butyloxycarbonylaminoethanethiol to synthesize the compound of Example 29. LC-MS [M+H] + :723.8. 1 H NMR (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).

[0284] Embodiment 30

[0285]

[0286] 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, N2 was replaced three times, stirred at 100 ° C for 3 h, and 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] + .

[0287]

[0288] 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 N2 was replaced three times. Cool 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 completed, the reaction was carried out at -40 ° C for 1 h. 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] + .

[0289]

[0290] 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 h. The reaction solution was concentrated to dryness, and the residue was separated and purified using a C18 column (ACN-H2O (0.1% TFA) gradient: 25-60) to obtain 10 mg of Example 30 compound with a yield of 55%. LC-MS [M+H] + :665.7. 1H 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).

[0291] Embodiment 31

[0292]

[0293] 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 in turn, 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] + .

[0294]

[0295] Triphenylphosphine (471 mg, 1.8 mmol) was added to a solution of N-chlorosuccinimide (240 mg, 1.8 mmol) in anhydrous tetrahydrofuran (5 mL). 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, and 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] + .

[0296]

[0297] Compound 3 (100 mg, 0.31 mmol) was dissolved in anhydrous dimethylformamide (3 mL), potassium thioacetate (47 mg, 0.42 mmol) was added thereto under nitrogen protection, and 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), and 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 by 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] + .

[0298]

[0299] 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) at -40 ° C. The solution was stirred for 30 minutes under nitrogen protection at -40 ° C. The reaction was then quenched with water (50 mL) and extracted 3 times with ethyl acetate (50 mL). The combined organic phases were washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 50 mg of compound 5 with a yield of 68.24%. LC-MS: 931.3 [M + Na] + .

[0300]

[0301] Compound 5 (50 mg, 0.055 mmol) was weighed and dissolved in 5 mL of anhydrous dichloromethane in a 50 mL single-mouth bottle, and 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 separation and purification (Gemini-C18 150 x 21.2 mm, 5 um ACN-H2O, 0.1% TFA) to obtain 1.5 mg of Example 31 compound, with a yield of 3.85%. LC-MS: 708.6 [M+H] + . 1H 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).

[0302] Embodiment 32

[0303]

[0304] Compound 1 (2 g, 8.04 mmol) and compound 2 (1.22 g, 16.08 mmol) were weighed in 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] + .

[0305]

[0306] In a 50 mL three-necked flask, intermediate II (200 mg, 0.269 mmol) was weighed 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 in turn, 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] + .

[0307]

[0308] Compound 4 (200 mg, 0.269 mmol) was weighed and dissolved in dichloromethane (4 mL) in a 50 mL three-necked flask. 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. The residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 um ACN-H2O, 0.1% TFA) to obtain 29.12 mg of Example 32 compound with a yield of 16.54%. LC-MS: 734.6 [M+H] + . 1 H 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).

[0309] Embodiment 33

[0310]

[0311] 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 in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC (Gemini-C18 150x 21.2 mm, 5um ACN-H2O, 0.1% FA) to obtain 25.73 mg of Example 33 compound with a yield of 34.48%. LC-MS: 694.6 [M+H] + . 1H 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).

[0312] Embodiment 34

[0313]

[0314] Under nitrogen protection, weigh Intermediate II (50.0 mg, 0.07 mmol) in a 50 mL three-necked flask and dissolve it in anhydrous tetrahydrofuran (1 mL), add Compound 1 (10.1 mg, 0.07 mmol) and triethylamine (13.6 mg, 0.13 mmol), and stir at -40°C for 0.5 hours. Pour the reaction solution into ice water (10 mL), extract the resulting solution three times with dichloromethane (10 mL), combine the organic phases, wash with water (10 mL), dry with anhydrous sodium sulfate, filter, concentrate, and obtain 4.00 mg of Example 34 compound by preparative separation (Solution A: 0.05% ammonia water, Solution B: acetonitrile), with 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).

[0315] Embodiment 35

[0316]

[0317] Diisopropylethylamine (1.59 g, 12.3 mmol) was added to a solution of compound 1 (1 g, 4.1 mmol) in 1,2-dibromoethane (10 mL). 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 in turn, dried over sodium sulfate, filtered, concentrated, and 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] + .

[0318]

[0319] 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, and 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] + .

[0320]

[0321] In a 50mL three-necked flask, intermediate II (200mg, 0.268mmol) was weighed and dissolved in anhydrous dichloromethane (5mL). Triethylamine (81.3mg, 0.804mmol) and compound 4 (164mg, 0.536mmol) were added at -40°C under nitrogen protection. The reaction solution was stirred at this temperature for 30 minutes, then quenched with water (50mL), and extracted three times with ethyl acetate (50mL). The combined organic phases were washed with water and saturated brine in turn, dried with sodium sulfate, filtered, and concentrated to obtain 200mg of compound 5 with a yield of 83.31%. LC-MS: 893.6[M+H] + .

[0322]

[0323] Compound 5 (200 mg, 0.224 mmol) was weighed and dissolved in anhydrous dichloromethane (5 mL) in a 50 mL single-mouth bottle, and trifluoroacetic acid (1 mL) was added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours, and the reaction solution was concentrated to dryness. The residue was purified by preparative HPLC (Gemini-C18 150x 21.2 mm, 5um ACN-H2O, 0.1% TFA) to obtain 15 mg of Example 35 compound, with a yield of 8.58%. LC-MS: 781.5 [M+H] + . 1 H 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).

[0324] Embodiment 36

[0325]

[0326] Under N2 protection, intermediate II (130.0 mg, 0.17 mmol) was weighed and dissolved in anhydrous dichloromethane (3 mL) in a 50 mL three-necked flask, triethylamine (35.2 mg, 0.34 mmol) and compound 1 (16.0 mg, 0.17 mmol) were added, and after stirring 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), and the combined organic phases were washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, concentrated, and prepared by separation (A solution: 0.1% formic acid, B solution: acetonitrile) to obtain 30.00 mg of Example 36 compound, with a yield of 25.0%. LC-MS [M+H] +: 680.6. 1H 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).

[0327] Embodiment 37

[0328]

[0329] 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 completed, the reaction was carried out at -40 ° C for 1 h. 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] + .

[0330]

[0331] At 0°C, compound 2 (10 mg, 0.037 mmol) was dissolved in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) and stirred for 0.5 hours. The reaction solution was concentrated to dryness, and the residue was purified by reverse phase preparation (ACN-H2O, 0.1% TFA) to obtain 10 mg of Example 37 compound with a yield of 38%. LC-MS: 709.6 [M+H] + . 1H 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).

[0332] Embodiment 38

[0333]

[0334] Under N2 protection, intermediate II (400.0 mg, 0.53 mmol) was weighed and dissolved in anhydrous dichloromethane (10 mL) in a 50 mL three-necked flask, triethylamine (108.4 mg, 1.06 mmol) and compound 1 (41.8 mg, 0.53 mmol) were added, and after stirring at -40°C for 10 minutes, the reaction solution was poured into ice water (20 mL), and the resulting solution was extracted three times with dichloromethane (20 mL), and the combined organic phases were washed once with water (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 320 mg of compound 2, with a yield of 56.7%, which was directly used in the next step without purification. LC-MS: 666.6 [M+H] + .

[0335]

[0336] Compound 2 (100 mg, 0.150 mmol) was weighed and dissolved in anhydrous dichloromethane (5 mL) in a 50 mL three-necked flask. Chlorosulfonic acid (20.97 mg, 0.180 mmol) was added under zero-degree N2 protection. 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 150 x 21.2 mm, 5 um ACN-H2O, 0.1% ammonia water) to obtain 70.12 mg of Example 38 compound with a yield of 62.60%. LC-MS: 744.5 [MH] - . 1H 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).

[0337] Embodiment 39

[0338]

[0339] 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=9.3H z,1H),4.01(d,J=8.9Hz,2H),3.75(t,J=6.1Hz,2H),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).

[0340] Embodiment 40

[0341]

[0342] According to the method of Example 38, 2-mercaptopropanol was used instead of 2-mercaptoethanol to synthesize the compound of Example 40 through two steps. 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).

[0343] Embodiment 41

[0344]

[0345] According to the method of Example 38, 2-mercaptoethanol was replaced with mercapto-PEG4-ol to obtain the compound of Example 41 through two-step reaction. LC-MS: 876.7 [MH] - . 1 H 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).

[0346] Embodiment 42

[0347]

[0348] In a 50mL three-necked flask, intermediate II (100mg, 0.150mmol) was weighed and dissolved in anhydrous dichloromethane (5mL). Compound 1 (26.45mg, 0.180mmol) and triethylamine (40.65mg, 0.450mmol) were added at -40°C under nitrogen protection. The reaction solution was stirred at this temperature for 30min, then concentrated to dryness, and the residue was purified by preparative HPLC (Gemini-C18 150x21.2mm, 5um ACN-H2O, 0.1% ammonia water) to obtain 25mg of Example 42 compound with a yield of 25.48%. LC-MS: 728.6[MH] - . 1H 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).

[0349] Embodiment 43

[0350]

[0351] 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 N2 was replaced three times. The temperature was lowered to -40 ° C, and a dichloromethane (2 mL) solution of compound 1 (28.2 mg, 0.2688 mmol) was added dropwise. After the addition was completed, 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, concentrated, and the residue was purified by reverse phase preparation (ACN-H2O (0.1% TFA) gradient: 30-60) to obtain 20 mg of Example 43 compound 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,6 H),2.35-2.12(m,2H),2.09-1.82(m,2H),1.75-1.65(m,2H),1.45-1.39(m,4H).

[0352] Embodiment 44

[0353]

[0354] The compound of Example 43 (20 mg, 0.02886 mmol, 1 eq) was placed in a 25 mL three-necked flask, and 2 mL of anhydrous dichloromethane was added, and N2 was replaced 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 a crude product, and the crude product was purified by reverse phase preparation (ACN-H2O (0.1% TFA) gradient: 30-60) to obtain the compound of Example 44, with a yield of 21%. LC-MS: 707.6 [M+H] + . 1 H 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).

[0355] Embodiment 45

[0356]

[0357] Under N2 protection, the compound of Example 43 (20.0 mg, 0.03 mmol) was weighed and dissolved in anhydrous dichloromethane (4 mL) in a 50 mL three-necked flask, tert-butyl bromoacetate (16.8 mg, 0.09 mmol) was added, and after stirring at room temperature for 16 hours, the reaction solution was poured into ice water (10 mL), and the resulting solution was extracted three times with dichloromethane (10 mL), and 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%, and the next step of reaction was carried out directly without purification. LC-MS [M+H] + :807.6.

[0358]

[0359] Under N2 protection, compound 2 (20.0 mg, 0.01 mmol) was weighed into a 25 mL single-mouth bottle and dissolved in a mixed solution 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 obtain 4.0 mg of Example 45 compound, with a yield of 41.5%. LC-MS [M+H] +: 751.9. 1 H 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).

[0360] Embodiment 46

[0361]

[0362] In a 50mL three-necked flask, weigh Intermediate II (30mg, 0.042mmol) and dissolve it in water (2mL). Add triethylamine (8.14mg, 0.08mmol) and compound 1 (30mg, 0.042mmol) at -40℃ under nitrogen protection. Stir the reaction solution at this temperature for 30 minutes, then quench the reaction with water (5mL), and extract the resulting solution three times with ethyl acetate (10mL). The combined organic phases were washed with water and saturated brine in turn, dried with sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC (Solution A: 0.1% TFA, Solution B: acetonitrile) to obtain 8.66mg of Example 46 compound with a yield of 25.12%. LC-MS: 857.3[M+H] + . 1H 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,1H),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).

[0363] Embodiment 47

[0364]

[0365] According to the method of Example 46, thiol-triethylene glycol-carboxylic acid was used to replace 3,6,9,12,15-pentaoxahexane-1-thiol and react with intermediate II to synthesize the compound of 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).

[0366] Embodiment 48

[0367]

[0368] Intermediate II (100 mg, 0.107 mmol, 1 eq) was weighed and dissolved in 5 mL of anhydrous dichloromethane in a 50 mL three-necked flask. Triethylamine (21.67 mg, 0.214 mmol, 2 eq) and compound 1 (98.54 mg, 0.161 mmol, 1.5 eq) were added under N2 protection at -40 degrees Celsius. 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 layer was 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 um ACN-H2O (0.1% TFA), gradient: 50-70) to obtain 25 mg of Example 48 compound with a yield of 17.63%. LC-MS [M+H] + :1046.8. 1 H 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).

[0369] Embodiment 49

[0370]

[0371] Under N2 protection, weigh Intermediate II (200.0 mg, 0.27 mmol) in a 50 mL three-necked flask and dissolve it in anhydrous dichloromethane (10 mL), add triethylamine (81.3 mg, 0.80 mmol) and compound 1 (113.6 mg, 0.32 mmol), stir at -40 ° C for 10 minutes, pour the reaction solution into ice water (20 mL), extract the resulting solution three times with dichloromethane (20 mL), combine the organic phases, wash once with water, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 200 mg of compound 2, with a yield of 71.2%, and directly proceed to the next step without purification. LC-MS [M+H] + :941.5.

[0372]

[0373] Under N2 protection, compound 2 (200.0 mg, 0.2 mmol) was weighed into a 25 mL single-mouth bottle and dissolved in a mixed solution 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 compound, with a yield of 16.0%. LC-MS [M+H] + :841.6. 1 H NMR(400MHz,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. 11(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).

[0374] Embodiment 50

[0375]

[0376] 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 turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to obtain 700 mg of compound 3 in a yield of 52.51%. LC-MS: 606.9 [M+H] + .

[0377]

[0378] 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 obtain 300 mg of compound 5 with a yield of 80.04%. LC-MS: 759.2 [M+H] + .

[0379]

[0380] 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 under nitrogen protection at 0°C. 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 150 x 21.2 mm, 5 um ACN-H2O, 0.1% FA) to obtain 5 mg of Example 50 compound with 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,1 H), 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). Test Example 1: Plasma stability test

[0381] 1.1 Test plasma

[0382] Human plasma (Vendor: AoNeng Biotech).

[0383] 1.2 Preparation of compound solution

[0384] Weigh a certain amount of the example compound, add DMSO to prepare a 10 mM stock solution; take a certain volume of the 10 mM stock solution, dilute it with DMSO to a 1600 μM stock solution; then take a certain volume of the 1600 μM stock solution and dilute it with 45% methanol to a 16 μM working solution.

[0385] 1.3 Experimental procedures

[0386] 1) Pre-incubate plasma in a 37°C water bath for 5 min.

[0387] 2) Take 4 μL of the 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.

[0388] 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, centrifugation at 3700 rpm, and 4 °C for 20 min, and the supernatant was collected for LC-MS analysis.

[0389] 2. Results

[0390] The conversion of the embodiments of the present invention in human plasma is as follows, and the data are shown in Table 1:

[0391] Table 1

[0392]

[0393] Note: The parent drug in the table refers to Rolapitant.

[0394] Conclusion: The compound of formula (I) is not substantially converted into the active metabolite rolapitant in plasma. Nearly half or more of Examples 17, 25, 38, 39, and 42 are converted into the active metabolite rolapitant in plasma.

[0395] Test Example 2: Liver S9 Stability Test

[0396] 1.1 Liver S9

[0397] Human mixed liver S9 (Vendor: Xenotech) was thawed in a 37°C water bath before use.

[0398] 1.2 Preparation of compound solution

[0399] 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 a working solution with a concentration of 200 μM.

[0400] 1.3 Sample incubation

[0401] Take 1.5 μL of the working solution of the 200 μM example compound and add it to 238.5 μL of liver S9 working solution, pre-incubate in a 37°C water bath for 5 min; then add 60 μL of NADPH working solution to start the reaction, mix by inverting; at 0 min, take the above mixture and add it to the quenching solution and mix; at 5, 15, 30, and 60 min, take the above mixture and add it to the quenching solution and DMSO and mix. Vortex vigorously for 1 min, centrifuge at 3700 rpm, 4°C for 15 min. Collect the supernatant and analyze it by LC-MS.

[0402] 2. Results

[0403] The transformation of the compounds of the present invention in human liver S9 is as follows, and the data are shown in Table 2:

[0404] Table 2

[0405]

[0406]

[0407] Note: The parent drug in the table refers to Rolapitant.

[0408] 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 high degree and at a fast conversion rate, among which 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).

[0409] Test Example 3: Thermodynamic Solubility

[0410] 1.1 Reagent preparation

[0411] 100mM phosphate buffer solution: Dissolve 7.94g K2HPO4.3H2O and 2.07g KH2PO4 in 500mL ultrapure water, adjust the pH of the solution to 7.4 with 1N NaOH, and filter for later use.

[0412] 1.2 Test Method

[0413] Accurately weigh an appropriate amount of the example compound and add it to a 100 mM phosphate buffer solution in small amounts several times to prepare a solution with a final concentration of 20 mg / mL. After shaking at room temperature for 16 hours, let it stand for 30 minutes, take the supernatant, filter it, and dilute it with DMSO. Add the diluted example sample solution to the quenching solution, mix well, and analyze by LC / MS. The data are shown in Table 3.

[0414] 2. Results

[0415] Table 3

[0416] Example Solubility (pH = 7.4) 33 13.8mg / mL 38 17.7 mg / mL 39 6.54mg / mL 42 13.2mg / mL 47 10.9 mg / mL

[0417] Test Example 4: In vitro human hemolysis test

[0418] 1.1 Test samples

[0419] Examples 38, 39, and 42.

[0420] 1.2 Whole blood test

[0421] Fresh whole human blood.

[0422] 1.3 Preparation of cell resuspension

[0423] Collect whole blood, store in a 250ml conical flask, 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, 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 is no longer 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.

[0424] 1.4 Preparation of working solution

[0425] Examples 38, 39 and 42 were prepared with DMSO to concentrations of 200, 80 and 20 μM, respectively, for later use.

[0426] 1.5 Experimental procedures

[0427] 1) Add the working solution of the example compound to the red blood cell suspension and mix gently.

[0428] 2) Incubate the mixture in a CO2 incubator at 37±0.5°C for 45 minutes and observe the aggregation every 15 minutes.

[0429] 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 (%).

[0430] 2. Results

[0431] The compounds of Examples 38, 39 and 42 showed no hemolytic effect at a concentration as high as 200 μM.

[0432] Test Example 5: Pharmacokinetics test in rats

[0433] With rats as test subjects, the drug concentrations in whole blood 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 to study the pharmacokinetic behavior of the compounds in rats and evaluate their pharmacokinetic characteristics.

[0434] 1.1 Drug preparation

[0435] 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 with 20 mmol / L sodium dihydrogen phosphate for later use.

[0436] 1.2 Administration

[0437] Intravenous push injection, the 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.

[0438] 1.3 Operation

[0439] Blood was collected by jugular sinus puncture before administration and 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h and 48h after administration, 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.

[0440] 1.3 The results of pharmacokinetic parameters are shown in Table 4.

[0441] Table 4

[0442]

[0443] 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

[0444] Conclusion: Examples 38, 39, and 42 were rapidly converted into active metabolites, 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 to 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).

[0445] Test Example 6: Pharmacokinetic test of the compound in cynomolgus monkeys

[0446] Using cynomolgus monkeys as test subjects, the drug concentrations in whole blood at different times after intravenous injection of the compound of formula (I) and the compound of Example 42 were determined by LC / MS / MS to study the pharmacokinetic behavior of the compound in cynomolgus monkeys and evaluate its pharmacokinetic characteristics.

[0447] 1.1 Drug preparation

[0448] 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.

[0449] 1.2 Administration

[0450] Intravenous infusion, infusion time 30min, dosage 2mg / kg, dosage concentration 0.4mg / mL, dosage volume 5mL / kg.

[0451] 1.3 Operation

[0452] Blood was collected from the forelimb vein before administration and at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 10h, 24h, 36h, 48h and 72h after the start of administration, 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.

[0453] 1.3 Pharmacokinetic parameters The results are shown in Table 5

[0454] Table 5

[0455]

[0456]

[0457] 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

[0458] Conclusion: After intravenous infusion, the compound of formula (I) and Example 42 were rapidly converted into the active metabolite rolapitant in cynomolgus monkeys. The identification of plasma metabolites showed that rolapitant was the main metabolite of Example 42, and about 98% of Example 42 was converted into the active metabolite rolapitant. 1 / 2 The data showed that Example 42 was converted to 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 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 alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, nitrile, hydroxyl, SH, 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 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 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 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 1-6 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, -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 of 0-6; n is an integer of 0-6; 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 -O-C(O)-[C(R d )(R e )] h -、-[C(R b )(R c )] x -S-C(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.

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