CN112898286A - Benzothiophene compound or pharmaceutically acceptable salt and isomer thereof, and preparation method, pharmaceutical composition and application thereof - Google Patents

Benzothiophene compound or pharmaceutically acceptable salt and isomer thereof, and preparation method, pharmaceutical composition and application thereof Download PDF

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CN112898286A
CN112898286A CN202110117453.2A CN202110117453A CN112898286A CN 112898286 A CN112898286 A CN 112898286A CN 202110117453 A CN202110117453 A CN 202110117453A CN 112898286 A CN112898286 A CN 112898286A
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蒋晟
肖易倍
郝海平
张阔军
张婉衡
卢之瑀
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Yaokang Zhongtuo Jiangsu Pharmaceutical Technology Co ltd
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China Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract

The invention discloses a benzothiophene compound with a structure shown in a general formula I or pharmaceutically acceptable salts and isomers thereof, a preparation method thereof, a pharmaceutical composition and application thereof. The invention overcomes the defects of lack of interferon gene stimulating protein micromolecule excitant, poor drug forming property of nucleotide interferon gene stimulating protein excitant and the like in the prior art, has good excitant activity to the interferon gene stimulating protein, and has good treatment effect to tumors and infectious diseases.

Description

Benzothiophene compound or pharmaceutically acceptable salt and isomer thereof, and preparation method, pharmaceutical composition and application thereof
Technical Field
The invention relates to the field of chemical medicine, in particular to a benzothiophene compound or pharmaceutically acceptable salt and isomer thereof, a preparation method, a pharmaceutical composition and application thereof.
Background
Innate immunity is the first line of defense against invading pathogens and tissue damage. Pattern Recognition Receptors (PRRs) recognize pathogen-associated molecular patterns from pathogens (PAMPs) or damage-associated molecular patterns from the body itself (DAMPs), initiate cascades, induce expression of genes such as Interferons (IFNs), chemokines and inflammatory factors. This innate immune response not only inhibits the proliferation and spread of pathogens at an early stage, but also induces an acquired immune response that ultimately clears the infection. In addition, this innate immune response monitors the development and invasion of tumors. Currently, various PRRs have been found, such as membrane-bound Toll-like receptors (TLRs), C-type lectin receptors (CLRs), non-binding intracellular nucleotide-binding oligomerization-domain receptors (nod) -like receptors (NLRs), retinoic acid-like receptors (RLRs), cytoplasmic DNA receptors, and the like.
Pathogen DNA and leakage of the body's nuclei or mitochondria into the cytoplasm, where much DNA is present, is an immunostimulatory moleculeReceptors such as melanoma-deficient factor 2 (antisense in melanoma 2, AIM2), interferon inducible protein 16 (IFI 16), RNA polymerase III and cyclic GMP-AMP synthase (cGAS), and the like. The STimulator of INterferon Genes (STING), located in the cytoplasmic endoplasmic reticulum, is the point of aggregation of these DNA receptors, controlling the innate immune response mediated by immunostimulatory molecules such as DNA. The hyperactivity suggests that cGAS recognizes double-stranded DNA within the cytoplasm, catalyzing GTP and ATP to produce 2 '3' -cGAMP. 2 '3' -cGAMP binds to interferon gene stimulator as a second messenger, inducing dimerization and translocation of interferon gene stimulator from the endoplasmic reticulum membrane to the perinuclear vesicle, recruiting TBK1 and then phosphorylating itself, thereby bringing IRF3 close to interferon gene stimulator. TBK1 then phosphorylates IRF3, which translocates to the nucleus to induce the expression of type I Interferons (IFNs) and other inflammatory factors. Type I interferons promote Dendritic Cell (DC) maturation, selectively stimulate cross presentation of antigens, and recruit CD8+T cells, thereby activating the acquired immune system to kill tumor cells or to fight pathogen infection. Therefore, interferon gene-stimulating proteins play an important role in innate and acquired immune responses in tumors and pathogen infections.
In view of the key role played by interferon gene-stimulating proteins in the immune response of the body, the application of interferon gene-stimulating protein agonists to immunotherapy of various diseases is of great interest. For example, intratumoral injection of 2 '3' -cGAMP results in tumor cell regression in mouse models and can inhibit the growth of distant tumor cells and induce long-term immunological memory. The interferon gene stimulating protein agonist is combined with an immune checkpoint inhibitor, so that the curative effect of the immune checkpoint inhibitor is improved. In addition, the immune response induced by the interferon gene stimulating protein agonist can effectively control the infection of influenza A virus, hepatitis B virus, herpes simplex virus, HIV and other viruses. Therefore, the development and development of interferon gene-stimulating protein agonists are of great significance for the immunotherapy of cancer and infectious diseases. However, most of the currently reported interferon gene-stimulated protein agonists are cyclic dinucleotide analogs, but the application of the interferon gene-stimulated protein agonists is greatly limited due to defects of in vivo metabolic instability, poor membrane permeability and the like, such as intratumoral administration, so that the investigation and development of the interferon gene-stimulated protein small-molecule agonists are of great significance.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to overcome the defect of single structure of the existing interferon gene stimulating protein small molecule agonist, and provides a benzothiophene compound, a preparation method, a pharmaceutical composition and application thereof. The benzothiophene compound has good agonistic activity on interferon gene stimulating protein and good treatment effect on tumors.
The technical scheme is as follows:
in a first aspect of the present invention, benzothiophenes having a structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, have the following structure:
Figure BDA0002921022140000021
wherein R is1And R2Independently selected from hydrogen, deuterium, halogen, unsubstituted or R1-1Substituted C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, -NR1-2R1-3、-(C＝O)NR1-4R1-5OR- (C ═ O) OR1-6；
R1-1Is halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or-NR1-1-1R1-1-2；
R1-1-1And R1-1-2Independently selected from hydrogen or C1-4An alkyl group;
R1-2～R1-6independently selected from hydrogen or C1-4An alkyl group;
R3and R4Independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, unsubstituted or R3-1Substituted C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C2-6Alkynyl, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -oxy, (C)3-10Cycloalkyl) - (C)1-6Alkoxy), heterocycloalkyl-oxy, heterocycloalkyl- (C)1-6Alkoxy group), C6-10Aryl group, (C)6-10Aryl) -oxy, (C)6-10Aryl group) - (C1-6Alkoxy), heteroaryl-oxy, heteroaryl- (C)1-6Alkoxy), -NR3-2R3-3、-(C＝O)R3-4、-(C＝O)NR3-5R3-6、-(C＝O)OR3-7、-S(＝O)2NR3-8R3-9Or R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R3-1is halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, or-NR3-1-1R3-1-2；
R3-1-1And R3-1-2Independently selected from hydrogen or C1-4An alkyl group;
R3-2～R3-9independently selected from hydrogen or C1-4An alkyl group;
R5is- (C ═ O) OR5-1、-(C＝O)SR5-2Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
R5-1And R5-2Independently selected from hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -, C3-10Cycloalkyl radical, C6-10Aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, or 4-10 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R5-3selected from halogen, hydroxy, amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, or C1-4A haloalkoxy group;
R5-4and R5-5Independently selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl or C3-10A cycloalkyl group;
R7is hydrogen, sulfonic group, phosphoryl group, unsubstituted or R7-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -C1-6Alkyl, heterocycloalkyl-C1-6Alkyl, unsubstituted or R7-2Substituted C6-10Aryl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R7-4Substituted heteroaryl-C1-6Alkyl or unsubstituted or R7-5Substituted heteroaryl; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R7-1is halogen, carboxyl, hydroxyl, -NR7-1-1R7-1-2Cyano or C1-4An alkyl group;
R7-1-1and R7-1-2Independently selected from hydrogen or C1-4An alkyl group;
R7-2～R7-5independently selected from deuterium, halogen, hydroxy, cyano, nitro, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, -NR7-2-3R7-2-4、-(C＝O)R7-2-5、-(C＝O)NR7-2-6R7-2-7、-(C＝O)OR7-2-8or-S (═ O)2NR7-2-9R7-2-10；
R7-2-1And R7-2-2Is halogen, hydroxy, cyano or-NR7-2-1-1R7-2-1-2；
R7-2-1-1And R7-2-1-2Independently selected from hydrogen or C1-4An alkyl group;
R7-2-3～R7-2-10independently selected from hydrogen or C1-4An alkyl group;
R8is hydrogen, cyano, R8-1O-、-NR8-2R8-3、R8-4S-, unsubstituted or R8-5Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -C1-6Alkyl, heterocycloalkyl-C1-6Alkyl, unsubstituted or R8-6Substituted C6-10Aryl, unsubstituted or R8-7Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-8Substituted heteroaryl, unsubstituted or R8-9Substituted heteroaryl-C1-6An alkyl group; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R8-1～R8-4independently selected from phosphoryl, unsubstituted or R8-1-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -C1-6Alkyl, heterocycloalkyl-C1-6Alkyl, unsubstituted or R8-1-2Substituted C6-10Aryl, unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl, unsubstituted or R8-1-5Substituted heteroaryl, or- (S ═ O)2OR8-1-6(ii) a Said heterocycloalkyl groupIs a 4-10 membered heterocycloalkyl group in which "the heteroatom is one or more selected from N, O and S, the number of the heteroatom is 1-3"; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R8-1-1is halogen, hydroxy, -cyano, -NR8-1-1-1R8-1-1-2Or C1-4An alkyl group;
R8-1-1-1and R8-1-1-2Independently selected from hydrogen or C1-4An alkyl group;
R8-1-2～R8-1-5independently selected from halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, -NR8-1-2-1R8-1-2-2、-(C＝O)R8-1-2-3、-(C＝O)NR8-1-2-4R8-1-2-5、-(C＝O)OR8-1-2-6、-S(＝O)2NR8-1-2-7R8-1-2-8or-S (═ O)2R8-1-2-9；
R8-1-6Is hydrogen, C1-6Alkyl radical, C1-6Haloalkyl or C3-10A cycloalkyl group;
R8-1-2-1～R8-1-2-9independently selected from hydrogen or C1-4An alkyl group;
R8-5is halogen, carboxyl, hydroxyl, -NR8-5-1R8-5-2Cyano or C1-4An alkyl group;
R8-5-1and R8-5-2Independently selected from hydrogen or C1-4An alkyl group;
R8-6～R8-9independently selected from deuterium, halogen, hydroxy, cyano, carboxy, nitro, unsubstituted or R8-6-1Substituted C1-4Alkyl, unsubstituted or R8-6-2Substituted C1-4Alkoxy, -NR8-6-3R8-6-4、-(C＝O)R8-6-5、-(C＝O)NR8-6-6R8-6-7、-(C＝O)OR8-6-8or-S (═ O)2NR8-6-9R8-6-10；
R8-6-1And R8-6-2Is halogen, hydroxy, cyano or-NR8-6-1-1R8-6-1-2；
R8-6-1-1And R8-6-1-2Independently selected from hydrogen or C1-4An alkyl group;
R8-6-3～R8-6-10independently selected from hydrogen or C1-4An alkyl group;
x is O, C ═ O, NR9、
Figure BDA0002921022140000041
Left end of X and
Figure BDA0002921022140000042
the right end of the L-shaped connecting rod is connected with the L;
R9～R11independently selected from hydrogen or C1-6An alkyl group;
R12is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2、-(S＝O)R12-3or-NR12- 4R12-5；
R12-1～R12-3Independently selected from C1-6An alkyl group;
R12-4and R12-5Independently selected from hydrogen, C1-6Alkyl or- (C ═ O) R12-4-1；
R12-4-1Is C1-6An alkyl group;
R13and R14Independently selected from hydrogen or C1-6An alkyl group;
x and R5Selected from any combination of:
when X is
Figure BDA0002921022140000043
When R is5Is- (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is C ═ O, R5Is- (C ═ O) NR5-4(S＝O)2R5-5Or is unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
when X is O, NR9、
Figure BDA0002921022140000044
When R is5Is- (C ═ O) OR5-1、-(C＝O)SR5-2Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
R6Selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, - (C ═ O) NR6-1R6-2、-(C＝O)OR6-3or-NR6-4R6-5；
R6-1～R6-5Independently selected from hydrogen or C1-4An alkyl group;
l is (C (R)15R16))n；
R15And R16Independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-6Cycloalkyl, -NR15-1R15-2Or R15And R16Ring synthesis of C with the carbon atom to which they are attached3-10A cycloalkyl group;
R15-1and R15-2Independently selected from hydrogen or C1-4An alkyl group;
n is an integer of 1, 2 or 3.
In one embodiment of the invention, certain groups are defined below, and undefined groups are as described in any of the preceding embodiments, hereinafter simply referred to as "in one embodiment of the invention" when R is1And R2Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;
in the inventionIn one embodiment, when R is3And R4Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, when R is3And R4Independently selected from C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group.
In one embodiment of the invention, when R is3And R4Independently selected from C1-6When halogenated alkoxy, said C1-6Haloalkoxy is C1-4A haloalkoxy group.
In one embodiment of the invention, when R is3And R4Independently selected from C2-6When alkenyl, said C2-6Alkenyl is C2-4An alkenyl group.
In one embodiment of the invention, when R is3And R4Independently selected from (C)3-10Cycloalkyl) -oxy, said (C)3-10Cycloalkyl) -oxy is (C)3-6Cycloalkyl) -oxy.
In one embodiment of the invention, when R is3And R4Independently selected from (C)3-10Cycloalkyl) - (C)1-6Alkoxy group), said (C)3-10Cycloalkyl) - (C)1-6Alkoxy) is (C)3-6Cycloalkyl) - (C)1-4Alkoxy groups).
In one embodiment of the invention, when R is3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)1-6Alkoxy) is 4-to 6-membered heterocycloalkyl- (C1-4Alkoxy groups).
In one embodiment of the invention, when R is3And R4Independently selected from (C)6-10Aryl) -oxy, said (C)6-10Aryl) -oxy is phenoxy.
In one embodiment of the invention, when R is3And R4Independently selected from (C)6-10Aryl group) - (C1-6Alkoxy radical) When is said to (C)6-10Aryl group) - (C1-6Alkoxy) is benzene- (C)1-4Alkoxy groups).
In one embodiment of the invention, when R is3And R4Independently selected from one or more of N, O and S as heteroatoms, and when the number of the heteroatoms is 1-3 and the 5-to 10-membered heteroaryl-oxy is 5-to 10-membered heteroaryl-oxy, the 5-to 10-membered heteroaryl-oxy is 5-to 6-membered heteroaryl-oxy.
In one embodiment of the invention, when R is3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of the heteroatoms, and 5-10-membered heteroaryl- (C)1-6Alkoxy), said 5-to 10-membered heteroaryl- (C)1-6Alkoxy) is 5-6 membered heteroaryl- (C)1-4Alkoxy groups).
In one embodiment of the invention, when R is3-2～R3-9Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl, or isopropyl.
In one embodiment of the invention, when R is3And R4And the carbon atoms connected with the heterocyclic groups form one or more heteroatoms selected from N, O and S, and when the number of the heteroatoms is 1-3, and the 4-20-membered heterocyclic alkoxy is the 4-12-membered heterocyclic alkoxy, the 4-20-membered heterocyclic alkyl is the 5-12-membered heterocyclic alkoxy.
In one embodiment of the invention, when R is5-1Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, when R is5-1Is (C)1-6Alkoxy group) - (C1-6Alkyl) -said (C)1-6Alkoxy group) - (C1-6Alkyl) -is (C)1-4Alkoxy group) - (C1-4Alkyl) -.
In one embodiment of the invention, when R is5-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group.
In one embodiment of the invention, when R is5Is unsubstituted or R5-3Substituted "hetero atoms selected from N, O and SAnd when the number of hetero atoms is 1 to 3, the number of hetero atoms is 5 to 10, R is5-3The number is one or more, when there are more than one R5-3When R is said5-3May be the same or different.
In one embodiment of the invention, when R is5Is unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the 5-10 membered heteroaryl is 5-6 membered heteroaryl.
In one embodiment of the invention, when R is5-4And R5-5Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, when R is7Is unsubstituted or R7-1Substituted C1-6When it is alkyl, said R7-1Is one or more, when there are more than one R7-1When R is said7-1May be the same or different.
In one embodiment of the invention, when R is7Is unsubstituted or R7-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, when R is7Is C2-6When alkenyl, said C2-6Alkenyl is C2-4An alkenyl group.
In one embodiment of the invention, when R is7Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group.
In one embodiment of the invention, when R is7Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6Alkyl is (C)3-6Cycloalkyl) -C1-4An alkyl group.
In one embodiment of the invention, when R is7Is unsubstituted or R7-2Substituted C6-10When aryl is said to R7-2Is one or more, when there are more than one R7-2When R is said7-2May be the same or different.
In one embodiment of the invention, when R is7Is unsubstituted or R7-2Substituted C6-10When aryl, said C6-10Aryl is phenyl.
In one embodiment of the invention, when R is7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When it is alkyl, said R7-3Is one or more, when there are more than one R7-3When R is said7-3May be the same or different.
In one embodiment of the invention, when R is7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6Alkyl is phenyl-C1-4An alkyl group.
In one embodiment of the invention, when R is7Is unsubstituted or R7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When it is alkyl, said R7-4Is one or more, when there are more than one R7-4When R is said7-4May be the same or different.
In one embodiment of the invention, when R is7Is unsubstituted or R7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6Alkyl is 5-to 6-membered heteroaryl-C1-4An alkyl group.
In one embodiment of the invention, when R is7-1When the halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, when R is7-1Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl or propyl.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from halogen, the halogen is fluorine, chlorine,Bromine or iodine.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from unsubstituted or R7-2-1Substituted C1-4When it is alkyl, said R7-2-1Is one or more, when there are more than one R7-2-1When R is said7-2-1May be the same or different.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from unsubstituted or R7-2-1Substituted C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl or isopropyl.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from unsubstituted or R7-2-2Substituted C1-4At alkoxy, said R7-2-2Is one or more, when there are more than one R7-2-2When R is said7-2-2May be the same or different.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from unsubstituted or R7-2-2Substituted C1-4At alkoxy, said C1-4Alkoxy is methoxy, ethoxy, propoxy or isopropoxy.
In one embodiment of the invention, when R is7-2-3～R7-2-10Independently selected from C1-4Alkyl radical, said C1-4Alkyl is methyl, ethyl, propyl or isopropyl.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-1Substituted C1-6When it is alkyl, said R8-1-1Is one or more, when there are more than one R8-1-1When R is said8-1-1May be the same or different.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, when R is8-1Is C2-6When alkenyl, said C2-6Alkenyl is C2-4An alkenyl group.
In one embodiment of the invention, when R is8-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group.
In one embodiment of the invention, when R is8-1Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6Alkyl is (C)3-6Cycloalkyl) -C1-4An alkyl group.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When it is alkyl, said R8-1-3Is one or more, when there are more than one R8-1-3When R is said8-1-3May be the same or different.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6Alkyl is phenyl-C1-4An alkyl group.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When it is alkyl, said R8-1-4Is one or more, when there are more than one R8-1-4When R is said8-1-4May be the same or different.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6Alkyl is 5-to 6-membered heteroaryl-C1-4An alkyl group.
In one embodiment of the invention, when R is8-1-1When the halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, when R is8-1-3When the halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, when R is8-1-4When the halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, when R is8-1-6Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, when R is9～R11Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, when R is12Is C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group.
In one embodiment of the invention, when R is12-1～R12-5Is independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, when X is
Figure BDA0002921022140000071
To, R5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8。
In one embodiment of the invention, when X is
Figure BDA0002921022140000072
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8。
In one embodiment of the invention, when X is
Figure BDA0002921022140000073
When R is5Independently selected from- (C ═ O) OR5-1。
In one embodiment of the invention, R15And R16Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, when R is15And R16Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
In one embodiment of the invention, n is an integer of 1 or 2.
In one embodiment of the invention, when R is3And R4Independently selected from C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.
In one embodiment of the invention, when R is3And R4Independently selected from C1-6When halogenated alkoxy, said C1-6Haloalkoxy is trifluoromethoxy.
In one embodiment of the invention, when R is3And R4Independently selected from C2-6When alkenyl, said C2-6Alkenyl is
Figure BDA0002921022140000081
Figure BDA0002921022140000082
In one embodiment of the invention, when R is3And R4Independently selected from (C)3-10Cycloalkyl) -oxy, said (C)3-10Cycloalkyl) -oxy is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
In one embodiment of the invention, when R is3And R4Independently selected from (C)3-10Cycloalkyl) - (C)1-6Alkoxy group), said (C)3-10Cycloalkyl) - (C)1-6Alkoxy) is cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropoxy, cyclopropylbutoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclobutylmethoxyPentyloxy, cyclohexylmethoxy, or cyclohexylethoxy.
In one embodiment of the invention, when R is3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)1-6Alkoxy) is piperidinemethyl, piperidinylethyl, piperidinopropyl, piperidinobutyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, morpholinobutyl, azetidinemethyl, azetidinoethyl, azetidinopropyl, azetidinobutyl, piperazinemethyl, piperazineethyl, piperazinopropyl, piperazinobutyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, or pyrrolidinylbutyl.
In one embodiment of the invention, when R is3And R4Independently selected from (C)6-10Aryl group) - (C1-6Alkoxy group), said (C)6-10Aryl group) - (C1-6Alkoxy) is benzyloxy, phenethyloxy, phenylpropyloxy, or phenylbutyloxy.
In one embodiment of the invention, when R is3And R4Independently selected from one or more of N, O and S as heteroatom, and when the number of heteroatoms is 1-3 and the number of heteroatoms is 5-10 membered heteroaryl-oxy, the 5-10 membered heteroaryl-oxy is pyridyloxy, pyrimidyloxy, pyrazinyloxy, pyridazinyloxy, pyrrolyloxy, imidazolyloxy or pyrazolyloxy.
In one embodiment of the invention, when R is3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of the heteroatoms, and 5-10-membered heteroaryl- (C)1-6Alkoxy), said 5-to 10-membered heteroaryl- (C)1-6Alkoxy) is pyridylmethoxy, pyrazolylethoxy, pyrimidylmethoxy, pyrazinylmethoxy, pyridazinylmethoxy, pyrrolylmethoxy, imidazolylmethoxy or pyrazolylmethoxy.
In one embodiment of the invention, when R is3And R4When taken together with the carbon atom to which they are attached to form a 4-20 membered heterocycloalkoxy group, said 4-20The heterocyclic alkyl is dioxolane, dioxahexane, 12-crown-4, 15-crown-5, or 18-crown-6.
In one embodiment of the invention, when R is5-1Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, when R is5-1Is (C)1-6Alkoxy group) - (C1-6Alkyl) -said (C)1-6Alkoxy group) - (C1-6Alkyl) -is methoxy-methyl-, ethoxy-methyl-, propoxy-methyl-, isopropoxy-methyl-, n-butoxy-methyl-, isobutoxy-methyl, sec-butoxy-methyl, or, tert-butoxy-methyl-.
In one embodiment of the invention, when R is5-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one embodiment of the invention, when R is5Is unsubstituted or R5-3When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is5-3The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is5Is unsubstituted or R5-3And when the substituted heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1-3, and the heteroaryl group has 5-10 members, the heteroaryl group having 5-10 members is pyrazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4-thiadiazolyl.
In one embodiment of the invention, when R is5-4And R5-5Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, when R is7Is unsubstituted or R7-1Substituted C1-6When it is alkyl, said R7-1The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is7Is unsubstituted or R7-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, when R is7Is C2-6When alkenyl, said C2-6Alkenyl is
Figure BDA0002921022140000091
Figure BDA0002921022140000092
In one embodiment of the invention, when R is7Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one embodiment of the invention, when R is7Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6The alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
In one embodiment of the invention, when R is7Is unsubstituted or R7-2Substituted C6-10When aryl is said to R7-2The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When it is alkyl, said R7-3The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6The alkyl group is benzyl.
In one embodiment of the invention, when R is7Is unsubstituted or R7-4Substituted "hetero atoms selected from N, O and SOne or more of (1) to (3)' 5 to 10-membered heteroaryl-C1-6When it is alkyl, said R7-4The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is7Is unsubstituted or R7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6The alkyl group is a picolyl, pyrimidylmethyl, pyrazinylmethyl, pyridazinylmethyl, pyrazolylmethyl, pyrrolylmethyl, thienylmethyl, furanmethyl, thiazolylmethyl, or imidazolylmethyl group.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from unsubstituted or R7-2-1Substituted C1-4When it is alkyl, said R7-2-1The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from unsubstituted or R7-2-2Substituted C1-4At alkoxy, said R7-2-2The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is7-2～R7-4Independently selected from-NR7-2-3R7-2-4When said is-NR7-2- 3R7-2-4is-NH2Or (b) or (c),
Figure BDA0002921022140000101
In one embodiment of the invention, when R is7-2～R7-4Independently selected from- (C ═ O) R7-2-5When said- (C ═ O) R7-2-5Is composed of
Figure BDA0002921022140000102
In one embodiment of the invention, when R is7-2～R7-4Independently selected from- (C ═ O) NR7-2-6R7-2-7When said- (C ═ O) NR7-2-6R7-2-7Is composed of
Figure BDA0002921022140000103
In one embodiment of the invention, when R is7-2～R7-4Independently selected from- (C ═ O) OR7-2-8When said- (C ═ O) OR7-2-8is-COOH, or,
Figure BDA0002921022140000104
In one embodiment of the invention, when R is7-2～R7-4Independently selected from-S (═ O)2NR7-2-9R7-2-10When the formula is-S (═ O)2NR7-2-9R7-2-10Is composed of
Figure BDA0002921022140000105
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-1Substituted C1-6When it is alkyl, said R8-1-1The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, when R is8-1Is C2-6When alkenyl, said C2-6Alkenyl is
Figure BDA0002921022140000106
Figure BDA0002921022140000107
In one embodiment of the invention, when R is8-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one embodiment of the invention, when R is8-1Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6The alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When it is alkyl, said R8-1-3The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6The alkyl is benzyl or phenethyl.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When it is alkyl, said R8-1-4The number of (a) is 1, 2 or 3.
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6The alkyl group is a picolyl, pyrimidylmethyl, pyrazinylmethyl, pyridazinylmethyl, pyrazolylmethyl, pyrrolylmethyl, thienylmethyl, furanmethyl, thiazolylmethyl, or imidazolylmethyl group.
In one embodiment of the invention, when R is8-1-6Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, when R is9～R11Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the present invention, the substrate is,when R is12Is C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
In one embodiment of the invention, when R is12-1～R12-5Is independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, when R is15And R16Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, when R is3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)1-6Alkoxy) is
Figure BDA0002921022140000111
In one embodiment of the invention, when R is3And R4Together with the carbon atom to which they are attached form "one or more heteroatoms selected from N, O and S, and when the number of heteroatoms is 1-3," 4-20 membered heterocycloalkyl group, said 4-20 membered heterocycloalkyl group is
Figure BDA0002921022140000112
In one embodiment of the invention, when R is5Is unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the substituent is unsubstituted or R5-3Substituted heteroaryl is
Figure BDA0002921022140000113
In the present inventionIn one embodiment, when R7Is R7-1Substituted C1-6When it is alkyl, said R7-1Substituted C1-6The alkyl is trifluoromethyl, difluoromethyl,
Figure BDA0002921022140000114
In one embodiment of the invention, when R is7Is unsubstituted or R7-2Substituted C6-10When aryl, said is unsubstituted or R7-2Substituted C6-10Aryl is
Figure BDA0002921022140000115
Figure BDA0002921022140000116
In one embodiment of the invention, when R is7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When alkyl, said is unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl is
Figure BDA0002921022140000117
Figure BDA0002921022140000121
In one embodiment of the invention, when R is7Is unsubstituted or R7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said is unsubstituted or R7-4Substituted heteroaryl-C1-6Alkyl is
Figure BDA0002921022140000122
In one embodiment of the invention, when R is8-4Is R8-1-1Substituted C1-6When it is alkyl, said R8-1-1Substituted C1-6Alkyl is
Figure BDA0002921022140000123
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When alkyl, said is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl is
Figure BDA0002921022140000124
In one embodiment of the invention, when R is8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said is unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl is
Figure BDA0002921022140000125
In one embodiment of the invention, R1Is hydrogen.
In one embodiment of the invention, R2Is hydrogen or halogen.
In one embodiment of the invention, R3Is halogen, C2-6Alkenyl radical, C1-6Alkoxy, or, -NR3-2R3-3。
In one embodiment of the invention, R4Is halogen, C1-6Alkoxy radical, C2-6Alkenyl, heterocycloalkyl- (C)1-6Alkoxy), or, -NR3-2R3-3。
In one embodiment of the invention, R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group.
In one embodiment of the invention, R3-2Is hydrogen or C1-4An alkyl group.
In one embodiment of the invention, R3-3Is hydrogen or C1-4An alkyl group.
In the inventionIn one embodiment, R5Is- (C ═ O) OR5-1Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8。
In one embodiment of the invention, R5-1Is hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -, or, C3-10A cycloalkyl group.
In one embodiment of the invention, R5-4Is hydrogen.
In one embodiment of the invention, R5-5Is C1-6An alkyl group.
In one embodiment of the invention, R7Is hydrogen, unsubstituted or R7-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl, unsubstituted or R7-2Substituted C6-10Aryl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl, or, unsubstituted or R7-4Substituted heteroaryl-C1-6An alkyl group.
In one embodiment of the invention, R7-1Is halogen, carboxyl, hydroxyl or cyano.
In one embodiment of the invention, R7-2Is halogen, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, or, -NR7-2-3R7-2-4。
In one embodiment of the invention, R7-3Is halogen, cyano, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, or- (C ═ O) NR7-2-6R7-2-7。
In one embodiment of the invention, R7-4Is halogen.
In one embodiment of the invention, R7-2-1Is halogen.
In one embodiment of the invention, R7-2-2Is halogen.
In one embodiment of the invention, R7-2-3Is hydrogen.
In one embodiment of the invention, R7-2-4Is hydrogen.
In one embodiment of the invention, R7-2-6Is hydrogen.
In one embodiment of the invention, R7-2-7Is hydrogen.
In one embodiment of the invention, R8Is hydrogen, cyano, R8-1O-, or, -NR8-2R8-3。
In one embodiment of the invention, R8-1Is hydrogen, unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl, or, - (S ═ O)2OR8-1-6。
In one embodiment of the invention, R8-1-1Is a hydroxyl group.
In one embodiment of the invention, R8-1-3Is halogen.
In one embodiment of the invention, R8-1-4Is halogen.
In one embodiment of the invention, R8-1-6Is hydrogen or C1-6An alkyl group.
In one embodiment of the invention, R8-2Is hydrogen or C1-6An alkyl group.
In one embodiment of the invention, R8-3Is hydrogen or C1-6An alkyl group.
In one embodiment of the present invention, X is C ═ O,
Figure BDA0002921022140000131
Wherein, the left end of X is connected with
Figure BDA0002921022140000132
And the right end is connected with L.
In one embodiment of the invention, R10Is hydrogen.
In one embodiment of the invention, R11Is hydrogen.
In one embodiment of the invention, R12Is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2Or, -NR12-4R12-5。
In one embodiment of the invention, R12-1Is C1-6An alkyl group.
In one embodiment of the invention, R12-2Is C1-6An alkyl group.
In one embodiment of the invention, R12-4Is hydrogen.
In one embodiment of the invention, R12-5Is hydrogen.
In one embodiment of the invention, R13Is hydrogen.
In one embodiment of the invention, R14Is hydrogen.
In one embodiment of the invention, when X is
Figure BDA0002921022140000133
To, R5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8。
In one embodiment of the invention, when X is
Figure BDA0002921022140000141
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8。
In one embodiment of the invention, when X is
Figure BDA0002921022140000142
When R is5Independently selected from- (C ═ O) OR5-1。
In one embodiment of the invention, R6Is hydrogen.
In one embodiment of the invention, R15Is hydrogen, halogen, or, C1-6An alkyl group.
In one embodiment of the invention, R16Is hydrogen, halogen, or, C1-6An alkyl group.
In one embodiment of the present invention, the substrate is,
R1is hydrogen;
R2is hydrogen, or halogen;
R3is halogen, C2-6Alkenyl radical, C1-6Alkoxy, or, -NR3-2R3-3；
R4Is halogen, C1-6Alkoxy radical, C2-6Alkenyl, heterocycloalkyl- (C)1-6Alkoxy), -NR3-2R3-3Or, R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;
R3-2is hydrogen or C1-4An alkyl group;
R3-3is hydrogen or C1-4An alkyl group;
R5is- (C ═ O) OR5-1Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
R5-1Is hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -, or, C3-10A cycloalkyl group;
R5-3is C1-4An alkyl group;
R5-4is hydrogen;
R5-5is C1-6An alkyl group;
R7is hydrogen, unsubstituted or R7-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl, unsubstituted or R7-2Substituted C6-10Aryl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl, or, unsubstituted or R7-4Substituted heteroaryl-C1-6An alkyl group;
R7-1is halogen, carboxyl, hydroxyl, or cyano;
R7-2is halogen, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, or, -NR7-2-3R7-2-4；
R7-3Is halogen, cyano, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, or- (C ═ O) NR7-2-6R7-2-7；
R7-4Is halogen;
R7-2-1is halogen;
R7-2-2is halogen;
R7-2-3is hydrogen;
R7-2-4is hydrogen;
R7-2-6is hydrogen;
R7-2-7is hydrogen;
R8is hydrogen, cyano, R8-1O-, or, -NR8-2R8-3；
R8-1Is hydrogen, unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl, or, - (S ═ O)2OR8-1-6；
R8-1-1Is a hydroxyl group;
R8-1-3is halogen;
R8-1-4is halogen;
R8-1-6is hydrogen or C1-6An alkyl group;
R8-1-2-3is C1-4An alkyl group;
R8-1-2-4is hydrogen;
R8-1-2-5is hydrogen;
R8-2is hydrogen or C1-6An alkyl group;
R8-3is hydrogen or C1-6An alkyl group;
x is C ═ O,
Figure BDA0002921022140000151
Wherein, the left end of X is connected with
Figure BDA0002921022140000152
The right end of the L-shaped connecting rod is connected with the L;
R10is hydrogen;
R11is hydrogen;
R12is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2Or, -NR12-4R12-5；
R12-1Is C1-6An alkyl group;
R12-2is C1-6An alkyl group;
R12-4is hydrogen;
R12-5is hydrogen;
R13is hydrogen;
R14is hydrogen;
x and R5Selected from any combination of:
when X is
Figure BDA0002921022140000155
When R is5Is- (C ═ O) NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
When X is C ═ O, R5Is- (C ═ O) NR5-4(S＝O)2R5-5Or, unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
when X is
Figure BDA0002921022140000153
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
When X is
Figure BDA0002921022140000154
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
When X is
Figure BDA0002921022140000161
When R is5Independently selected from- (C ═ O) OR5-1；
R6Is hydrogen;
R15is hydrogen, halogen, or, C1-6An alkyl group;
R16is hydrogen, halogen, or, C1-6An alkyl group.
In one embodiment of the present invention, the substrate is,
R1is hydrogen;
R2is hydrogen, or halogen;
R3is C1-6An alkoxy group;
R4is C1-6Alkoxy, heterocycloalkyl- (C)1-6Alkoxy) or, R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;
R5is- (C ═ O) OR5-1Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
R5-1Is hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -, or, C3-10A cycloalkyl group;
R5-3is C1-4An alkyl group;
R5-4is hydrogen;
R5-5is C1-6An alkyl group;
R7is hydrogen, unsubstituted or R7-1Substituted C1-6Alkyl radical, C3-10Cycloalkyl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl, or, unsubstituted or R7-4Substituted heteroaryl-C1-6An alkyl group;
R7-1is halogen, hydroxy, or cyano;
R7-3is halogen, cyano, or, unsubstituted or R7-2-1Substituted C1-4Alkyl radical
R7-4Is halogen;
R7-2-1is halogen;
R8is hydrogen, cyano, R8-1O-, or, -NR8-2R8-3；
R8-1Is hydrogen, unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, or, unsubstituted or R8-1-4Substituted heteroaryl-C1-6An alkyl group;
R8-1-1is a hydroxyl group;
R8-1-3is halogen;
R8-1-4is halogen;
x is C ═ O,
Figure BDA0002921022140000162
Wherein, the left end of X is connected with
Figure BDA0002921022140000163
The right end of the L-shaped connecting rod is connected with the L;
R10is hydrogen;
R11is hydrogen;
R12is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2Or, -NR12-4R12-5；
R12-1Is C1-6An alkyl group;
R12-2is C1-6An alkyl group;
R12-4is hydrogen;
R12-5is hydrogen;
R13is hydrogen;
R14is hydrogen;
x and R5Selected from any combination of:
when X is
Figure BDA0002921022140000171
When R is5Is- (C ═ O) NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
When X is C ═ O, R5Is- (C ═ O) NR5-4(S＝O)2R5-5Or, unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
when X is
Figure BDA0002921022140000172
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
When X is
Figure BDA0002921022140000173
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8；
When X is
Figure BDA0002921022140000174
When R is5Independently selected from- (C ═ O) OR5-1；
R6Is hydrogen;
R15is hydrogen, halogen, or, C1-6An alkyl group;
R16is hydrogen, halogen, or, C1-6An alkyl group.
In one embodiment of the present invention, the compound of formula I may have any one of the following structures:
Figure BDA0002921022140000175
Figure BDA0002921022140000181
Figure BDA0002921022140000191
Figure BDA0002921022140000201
Figure BDA0002921022140000211
in a second aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:
(1) when X is
Figure BDA0002921022140000212
When R is5Is- (C ═ O) NR7R8Or, - (C ═ O) NR5-4(S＝O)2R5-5When the temperature of the water is higher than the set temperature,
Figure BDA0002921022140000213
wherein,
R17is hydrogen or C1-6An alkyl group;
R18is R7，R19Is R8(ii) a Or, R18Is R5-4，R19Is R5-5；
R1、R2、R3、R4、R5-4、R5-5、R6、R7、R8、R10And L is as defined in the first aspect of the invention;
step a: in a solvent, reacting the compound II-1 with the compound III-1 to generate IV;
step b: in a solvent, reacting the compound IV with the compound V to generate a compound I-1;
the second method comprises the following steps:
(2) when X is
Figure BDA0002921022140000221
R5Is- (C ═ O) OR5-1、-(C＝O)SR5-2Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8When the temperature of the water is higher than the set temperature,
Figure BDA0002921022140000222
wherein,
y is-NHR11or-NHR13；
R18Is R7，R19Is R8(ii) a Or, R18Is R5-4，R19Is R5-5；
R20is-COOH, or-NHR14；
XaIs composed of
Figure BDA0002921022140000223
R5aIs- (C ═ O) OR5-1、-(C＝O)SR5-2Or, unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
R1、R2、R3、R4、R6、R5-1、R5-2、R5-3、R5-4、R5-5、R7、R8、R11、R13、R14and L is as defined in the first aspect of the invention;
step c: in a solvent, the compound II-2 and the compound III-2 react to generate a compound I-2;
step d: reacting the compound I-2 with the compound V in a solvent to generate a compound I-3;
(3) when X is
Figure BDA0002921022140000224
R5Is- (C ═ O) OR5-1、-(C＝O)SR5-2Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or, - (C ═ O) NR7R8When the temperature of the water is higher than the set temperature,
Figure BDA0002921022140000231
wherein R is1、R2、R3、R4、R5、R6、R12And L is as defined in the first aspect of the invention;
step e: in a solvent, reacting a compound II-3 with a compound VI to generate a compound I-4;
(4) when X is C ═ O, R5Is- (C ═ O) NR5-4(S＝O)2R5-5When the temperature of the water is higher than the set temperature,
Figure BDA0002921022140000232
wherein R is1、R2、R3、R4、R6、R5-4、R5-5And L is as defined in the first aspect of the invention;
step f: in a solvent, the compound II-4 reacts with the compound VII to generate the compound I-5.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable adjuvant or carrier.
Further, in the above pharmaceutical composition, the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is used in a therapeutically effective amount.
Further, the pharmaceutical composition further comprises one or more second therapeutic agents, and the second therapeutic agents are drugs for preventing and/or treating tumors.
Further, the second therapeutic agent is a traditional cytotoxic chemotherapeutic agent, a DNA damaging agent, or other anti-tumor immune drug.
In a fourth aspect of the present invention, there is provided a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition according to the third aspect of the present invention for use in the manufacture of a medicament.
Furthermore, the medicine is a medicine for preventing and/or treating tumors or infectious diseases.
In a fifth aspect of the present invention, there is provided a use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition according to the third aspect of the present invention, in the preparation of a vaccine adjuvant.
Further, the vaccine adjuvant is used for treating tumors or infectious diseases.
In a sixth aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition according to the third aspect of the present invention for the preparation of an interferon gene stimulating protein agonist.
In a seventh aspect of the present invention, there is provided a pharmaceutical combination comprising: a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof and, an immune checkpoint inhibitor or a DNA damaging agent. The immune checkpoint inhibitor is LAG-3 inhibitor, TIM3 inhibitor, PD-1/PD-L1 inhibitor, IDO1 inhibitor, CTLA-4 inhibitor, TIGIT inhibitor or VISTA inhibitor, preferably PD-1/PD-L1 inhibitor, IDO1 inhibitor or CTLA-4 inhibitor. The DNA damaging agent is a PARP inhibitor. The compound of the first aspect of the invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and the immune checkpoint inhibitor may be administered simultaneously or separately; the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and the DNA damaging agent may be administered simultaneously or separately.
In an eighth aspect of the invention, there is provided a use of the pharmaceutical combination according to the sixth aspect of the invention in a medicament for treating a tumor.
In a ninth aspect, the present invention provides a use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, in the manufacture of a medicament for treating a tumor, wherein the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, is used in combination with an immune checkpoint inhibitor. The compound of the first aspect of the invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof and the immune checkpoint inhibitor may be administered simultaneously or separately.
In a tenth aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, in the manufacture of a medicament for treating a tumor, wherein the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, is used in combination with a DNA damaging agent. The compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and the DNA damaging agent may be administered simultaneously or separately.
In the present invention, the tumor includes, but is not limited to, non-small cell lung cancer, liver cancer, stomach cancer, leukemia, melanoma, colon cancer, glioma, kidney cancer, ovarian cancer, pancreatic cancer, breast cancer, head and neck cancer, prostate cancer, multiple myeloma or cervical cancer.
The term "immune checkpoint inhibitor" refers to a substance that inhibits the activity of co-inhibitory receptors, blocks negative regulatory signals, restores T cell activity, and thereby enhances the immune response.
The term "LAG-3 inhibitor" refers to a substance that inhibits LAG-3 activity, restores T cell activity, and thereby enhances the immune response.
The term "TIM 3 inhibitor" refers to a substance that inhibits TIM3 activity, restores T cell activity, and thereby enhances an immune response.
The term "PD-1/PD-L1 inhibitor" refers to a substance that blocks the binding of PD-1 to PD-L1, blocks negative regulatory signals, restores T cell activity, and thereby enhances the immune response.
The term "IDO 1 inhibitor" refers to a substance that inhibits IDO1 activity, restores T cell activity, and thereby enhances the immune response.
The term "CTLA-4 inhibitor" refers to a substance that blocks CTLA-4-mediated negative regulatory signals, restoring T cell activity, and thereby enhancing an immune response.
The term "VISTA inhibitor" refers to a substance that inhibits VISTA activity, restores T cell activity, and thereby enhances an immune response.
The term "TIGIT inhibitor" refers to a substance that inhibits TIGIT activity, restores T cell activity, and thereby enhances the immune response.
The term "DNA-damaging agent" refers to a substance that induces DNA damage.
The term "simultaneous administration" refers to administration at the same time point, e.g., administration of separate pharmaceutical compositions simultaneously comprising a benzothiophene compound having the structure shown in formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and an immune checkpoint inhibitor; alternatively, the "separate pharmaceutical composition comprising a benzothiophene compound having the structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof" and the "separate pharmaceutical composition comprising an immune checkpoint inhibitor" are administered at the same time point.
The term "separately administered" refers to administration at different time points, for example, administration of "a pharmaceutical composition comprising a benzothiophene compound having the structure shown in formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof" and "a separate pharmaceutical composition comprising an immune checkpoint inhibitor" at different time points; alternatively, for example, one of "a separate pharmaceutical composition comprising a benzothiophene compound having a structure represented by general formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate, or hydrate thereof" and "a separate pharmaceutical composition comprising an immune checkpoint inhibitor" is administered first, followed by administration of the other. The separate administrations may be close in time or at long intervals, but it is ensured that the benzothiophene compound having the structure shown in formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and the immune checkpoint inhibitor can act together to provide the desired therapeutic effect. For example, prior to administration of the immune checkpoint inhibitor (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or subsequent to administration of the immune checkpoint inhibitor (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) a benzothiophene compound having the structure shown in formula I, or a pharmaceutically acceptable salt, isomer, metabolite, or pharmaceutically acceptable salt thereof, A prodrug, solvate or hydrate.
The pharmaceutical excipients can be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of an acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bicarbonates), hydroiodic acid, phosphorous acid, and the like, as well as salts of organic acids including similar acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, salts of organic acids also including salts of amino acids such as arginine, and the like, and salts of organic acids such as glucuronic acid, certain specific compounds of the invention contain basic and acidic functional groups and thus can be converted to any base or acid addition salt. The free form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "isomers" refers to compounds having the same chemical formula but different arrangements of atoms.
The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of formula I or a salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by a method comprising contacting a compound of the invention with a mammal for a period of time sufficient to obtain a metabolite thereof.
Identification of metabolites is typically accomplished by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it at a detectable dose (e.g., greater than about 0.5mg/kg) to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from urine, blood or other biological samples. These products are easy to isolate because they are labelled (others by using a reagent capable of binding to a metabolite present in the metabolite)Antibody isolation of antigenic epitopes). Metabolite structure is determined in a conventional manner, e.g., by MS, LC/MS or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as in conventional drug metabolism studies well known to those skilled in the art. Metabolite products are useful in assays for the administration of therapeutic doses of the compounds of the invention, provided that they are not otherwise detectable in vivo. The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C3H) Iodine-125 (125I) Or C-14(14C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
The term "active ingredient", "therapeutic agent", or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
When the linking group as exemplified does not indicate its direction of attachment, its direction of attachment is in the same direction as the reading from left to right.
It will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in the radicals described herein
Figure BDA0002921022140000271
Means that the corresponding group is connected with other fragments and groups in the compound shown in the formula I through the site.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
Has the advantages that: the benzothiophene compound overcomes the defects of the lack of the existing interferon gene stimulating protein micromolecule agonist, the poor druggability of the nucleotide interferon gene stimulating protein agonist and the like. The pyrimido five-membered heterocyclic compound has good agonistic activity on interferon gene stimulating protein and has good treatment effect on tumors and infectious diseases.
Detailed Description
Example 1: synthesis of Compound S7
Figure BDA0002921022140000272
The method comprises the following steps: synthesis of Compound 2
Under the protection of nitrogen, compound 1(10g, 39.2mmol) was reacted with Na2S2O3·5H2O(48.6g，196.1mmol)，Pd(dppf)Cl2(2.9g，3.92mmol)，dppf(3.3g，5.88mmol)，Cs2CO3(38.3g, 117.6mmol) was dissolved in DMF (300mL) and ethylene glycol (16mL) and the reaction was allowed to warm to 140 ℃ overnight. After completion of the reaction, it was cooled to room temperature, and the reaction mixture was diluted with water (20mL), extracted with ethyl acetate (100mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 2(2.9g, 35%).1H NMR(500MHz，Chloroform-d)δ7.07(s，1H)，6.93(s，1H)，6.22(s，1H)，3.90(s，3H)，3.89(s，3H)，3.88(s，2H).
Step two: synthesis of Compound S7
Compound 2(100mg, 0.48mmol) and succinic anhydride (96mg, 0.96mmol) were dissolved in anhydrous THF (3ml)Triethylamine was added and the reaction was stirred at room temperature for 6 h. After the reaction was completed, the solvent was distilled off under reduced pressure. To the reaction residue was added water (3ml), extracted with ethyl acetate (10 ml. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S7(118mg, 80%).1H NMR(500MHz，(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.69(d，J＝2.1Hz，1H)，7.41-7.34(m，2H)，3.89(d，J＝17.6Hz，6H)，2.70-2.62(m，2H)，2.59-2.51(m，2H).
The following synthesis methods of compounds S8 to S15 in examples 2 to 9 were all referred to the synthesis method of example 1, and the corresponding raw materials were replaced.
Example 2: synthesis of Compound S8
Figure BDA0002921022140000281
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.69(d，J＝2.1Hz，1H)，7.37-7.30(m，2H)，3.91(s，3H)，3.87(s，3H)，3.45(s，2H).
Example 3: synthesis of Compound S9
Figure BDA0002921022140000282
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.79(d，J＝2.2Hz，1H)，7.53(d，J＝2.2Hz，1H)，7.24(s，1H)，3.94(s，3H)，3.44(s，2H).
Example 4: synthesis of Compound S10
Figure BDA0002921022140000283
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.81(d，J＝2.3Hz，1H)，7.50(d，J＝2.2Hz，1H)，7.28(s，1H)，6.84(t，J＝9.3Hz，1H)，5.70(dd，J＝9.3，1.8Hz，1H)，5.47(dd，J＝9.2，1.9Hz，1H)，3.87(s，3H)，3.45(s，2H).
Example 5: synthesis of Compound S11
Figure BDA0002921022140000284
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.69(d，J＝2.2Hz，1H)，7.39-7.35(m，2H)，4.14(q，J＝7.0Hz，2H)，3.89(d，J＝17.6Hz，5H)，3.54(s，2H)，1.26(t，J＝6.9Hz，3H).
Example 6: synthesis of Compound S12
Figure BDA0002921022140000285
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.69(d，J＝2.1Hz，1H)，7.37-7.30(m，2H)，3.91(s，3H)，3.87(s，3H)，2.84(s，2H)，1.39(s，3H)，1.37(s，3H).
Example 7: synthesis of Compound S13
Figure BDA0002921022140000286
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.71(d，J＝2.3Hz，1H)，7.37(d，J＝2.1Hz，1H)，7.24(s，1H)，4.27(t，J＝6.5Hz，2H)，3.90(s，3H)，3.68-3.57(m，4H)，3.39(s，2H)，2.73(t，J＝6.4Hz，2H)，2.58-2.44(m，4H).
Example 8: synthesis of Compound S14
Figure BDA0002921022140000291
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.70(s，1H)，7.26-7.20(m，2H)，6.00(s，2H)，3.45(s，2H).
Example 9: synthesis of Compound S15
Figure BDA0002921022140000292
1H NMR(500MHz，DMSO-d6)δ13.8(br，1H)，10.98(s，1H)，7.79(s，1H)，7.27(s，1H)，7.23(s，1H)，4.30-4.21(m，4H)，3.45(s，2H).
Example 10: synthesis of Compound S16
Figure BDA0002921022140000293
Compound S8(100mg, 0.34mmol) and hydrazine hydrochloride (24mg, 0.34mmol) were dissolved in anhydrous DMF (5mL), and HATU (193.2mg, 0.51mmol) and DIPEA (132mg, 1.02mmol) were added to the above solution and reacted at room temperature overnight. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate (10mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S16(86mg, 82%).1H NMR(500MHz，DMSO-d6)δ10.78(s，1H)，9.06(t，J＝3.7Hz，1H)，7.69(d，J＝2.1Hz，1H)，7.40-7.34(m，2H)，4.01(d，J＝3.7Hz，2H)，3.89(s，3H)，3.76(s，3H)，3.34(s，2H).
The following syntheses of compounds S17 to S35 in examples 11 to 29 can be performed by following the synthesis method in example 10, and only by replacing the corresponding starting materials.
Example 11: synthesis of Compound S17
Figure BDA0002921022140000294
1H NMR(500MHz，DMSO-d6)δ10.78(s，1H)，9.86(s，1H)，8.73(s，1H)，7.69(s，1H)，7.39-7.33(m，1H)，4.35(m，2H)，3.89(s，3H)，3.80(s，3H)，3.33(s，3H)，2.56(m，1H).
Example 12: synthesis of Compound S18
Figure BDA0002921022140000301
1H NMR(500MHz，DMSO-d6)δ12.88(s，1H)，10.78(s，1H)，7.71(d，J＝2.1Hz，1H)，7.40-7.33(m，2H)，3.89(d，J＝17.6Hz，6H)，3.43(s，2H)，3.12(s，3H).
Example 13: synthesis of Compound S19
Figure BDA0002921022140000302
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，8.86(s，1H)，7.69(d，J＝2.1Hz，1H)，7.41-7.34(m，2H)，3.89(d，J＝17.6Hz，6H)，3.41(s，2H).
Example 14: synthesis of Compound S20
Figure BDA0002921022140000303
1H NMR(500MHz，DMSO-d6)δ10.86(s，1H)，10.50(s，1H)，7.69(s，1H)，7.51(s，1H)，7.39(s，1H)，7.12(s，1H)，3.89(s，3H)，3.77(s，3H)，3.37(s，2H).
Example 15: synthesis of Compound S21
Figure BDA0002921022140000304
1H NMR(500MHz，DMSO-d6)δ10.83(s，1H)，7.69(d，J＝2.2Hz，1H)，7.39-7.33(m，2H)，3.91(s，3H)，3.87(s，3H)，3.63(s，3H)，3.36(s，2H)，3.18(s，3H).
Example 16: synthesis of Compound S22
Figure BDA0002921022140000305
1H NMR(500MHz，DMSO-d6)δ10.83(s，1H)，7.71(d，J＝2.2Hz，1H)，7.37-7.30(m，2H)，7.21(s，1H)，7.09(s，1H)，3.89(d，J＝17.6Hz，5H)，3.46(s，2H).
Example 17: synthesis of Compound S23
Figure BDA0002921022140000306
1H NMR(500MHz，DMSO-d6)δ10.83(s，1H)，7.70(d，J＝2.1Hz，1H)，7.34(s，1H)，7.28(d，J＝2.2Hz，1H)，6.73(s，1H)，4.10(s，2H)，3.89(d，J＝17.6Hz，6H)，3.42(s，2H).
Example 18: synthesis of Compound S24
Figure BDA0002921022140000311
1H NMR(500MHz，DMSO-d6)δ10.83(s，1H)，7.70(d，J＝2.3Hz，1H)，7.37-7.33(m，2H)，7.09(s，1H)，6.33(s，2H)，5.89(tt，J＝13.8，5.5Hz，1H)，5.21(dt，J＝13.9，1.0Hz，2H)，3.93-3.85(m，6H)，3.40(s，2H).
Example 19: synthesis of Compound S25
Figure BDA0002921022140000312
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，8.34(s，1H)，7.70(d，J＝2.1Hz，1H)，7.37(s，1H)，7.29(d，J＝2.0Hz，1H)，7.09(s，1H)，3.89(d，J＝17.6Hz，5H)，3.60(t，J＝5.5Hz，2H)，3.43(s，2H)，2.80(t，J＝5.5Hz，2H).
Example 20: synthesis of Compound S26
Figure BDA0002921022140000313
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，7.70(d，J＝2.1Hz，1H)，7.40-7.30(m，2H)，7.09(s，1H)，4.80(d，J＝6.8Hz，1H)，4.13(t，J＝7.0Hz，1H)，3.99-3.90(m，1H)，3.88(d，J＝15.9Hz，6H)，3.77-3.67(m，2H)，3.51-3.41(m，2H)，3.37-3.29(m，2H).
Example 21: synthesis of Compound S27
Figure BDA0002921022140000314
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，8.16(s，1H)，7.72-7.64(m，3H)，7.44-7.36(m，4H)，7.18(tt，J＝7.2，1.5Hz，1H)，3.89(d，J＝16.7Hz，6H)，3.55(s，2H).
Example 22: synthesis of Compound S28
Figure BDA0002921022140000315
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，8.16(s，1H)，7.72(d，J＝2.1Hz，1H)，7.60-7.54(m，2H)，7.44-7.39(m，2H)，7.17-7.10(m，2H)，3.89(d，J＝17.6Hz，6H)，3.55(s，2H)，2.33(s，3H).
Example 23: synthesis of Compound S29
Figure BDA0002921022140000321
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，8.27(s，1H)，7.72(d，J＝2.1Hz，1H)，7.68-7.61(m，2H)，7.44-7.39(m，2H)，7.19-7.11(m，2H)，3.89(d，J＝17.6Hz，6H)，3.56(s，2H).
Example 24: synthesis of Compound S30
Figure BDA0002921022140000322
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，7.72(d，J＝2.1Hz，1H)，7.45-7.40(m，2H)，7.39-7.29(m，3H)，7.33-7.23(m，3H)，6.04(s，1H)，4.63(t，J＝1.0Hz，2H)，3.89(d，J＝17.6Hz，6H)，3.42(s，2H).
Example 25: synthesis of Compound S31
Figure BDA0002921022140000323
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，8.73(t，J＝1.7Hz，1H)，8.47-8.40(m，1H)，7.70(dt，J＝9.9，2.1Hz，2H)，7.40-7.35(m，2H)，7.25(dd，J＝7.9，3.5Hz，1H)，7.06(s，1H)，4.67(s，2H)，3.89(d，J＝17.6Hz，6H)，3.46(s，2H).
Example 26: synthesis of Compound S32
Figure BDA0002921022140000324
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，8.19(s，1H)，7.72(d，J＝2.1Hz，1H)，7.40-7.27(m，7H)，4.66(t，J＝1.0Hz，2H)，3.89(d，J＝17.6Hz，6H)，3.35(s，2H).
Example 27: synthesis of Compound S33
Figure BDA0002921022140000325
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，9.33(s，1H)，7.74(d，J＝2.1Hz，1H)，7.35(s，1H)，7.21(d，J＝2.2Hz，1H)，4.08-4.01(m，1H)，3.89(d，J＝17.6Hz，6H)，3.81-3.72(m，4H)，3.33(s，2H).
Example 28: synthesis of Compound S34
Figure BDA0002921022140000331
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，9.52(s，1H)，7.70(d，J＝2.1Hz，1H)，7.39-7.32(m，2H)，3.88(d，J＝15.4Hz，6H)，3.36(s，2H).
Example 29: synthesis of Compound S35
Figure BDA0002921022140000332
1H NMR(500MHz，DMSO-d6)δ10.88(s，1H)，7.69(d，J＝2.1Hz，1H)，7.40-7.37(m，1H)，7.34(s，1H)，7.32(d，J＝7.7Hz，1H)，7.20(d，J＝7.7Hz，1H)，3.91(s，3H)，3.87(s，3H)，3.25(s，2H).
Example 30: synthesis of Compound S36
Figure BDA0002921022140000333
The method comprises the following steps: synthesis of Compound 5
Compound 3(10g, 47.4mmol) was dissolved in anhydrous DMF under nitrogen, anhydrous potassium carbonate (13g, 94.8mmol) was added, compound 4(6.9g, 57.8mmol) was added dropwise to the suspension at 0 deg.C and stirred at 0 deg.C for 30 min. Then, the temperature was raised to 80 ℃ for overnight reaction. After completion of the reaction, it was cooled to room temperature, DMF was evaporated under reduced pressure, water was added, DCM extraction (100mL × 3) was performed, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 5(9.1g, 72%).
Step two: formation of Compound 6
Compound 5 was dissolved in THF, 2M NaOH aqueous solution was added at 0 deg.C, the mixture was transferred to room temperature, and the reaction was stirred for 2 hours. And after the reaction is completed, adding 2M dilute hydrochloric acid to adjust the pH value to 2-3, separating out a white precipitate, carrying out suction filtration, washing a filter cake with THF, collecting the filter cake, drying to obtain a compound 6, and directly putting the compound 6 into the next reaction.
Step three: formation of Compound 8
Compound 6(5g, 21mmol) was dissolved in anhydrous DMF (20mL) and HATU (12g, 31.5mmol), DIPEA (8.1g, 63mmol) and compound 7(2.8g, 21mmol) were added sequentially. The reaction was carried out at room temperature overnight. After the reaction was complete, the DMF was evaporated under reduced pressure. To the reaction residue was added water (10mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 8(6.3g, 85%).1H NMR(500MHz，Chloroform-d)δ8.28-8.18(m，2H)，7.51(d，J＝2.1Hz，1H)，7.46(s，1H)，4.09(d，J＝5.7Hz，2H)，3.89(d，J＝14.6Hz，6H)，1.42(s，9H).
Step four: synthesis of Compound S36
Compound 8(600mg, 1.7mmol) was dissolved in DCM (5mL), placed at 0 deg.C and CF was added3COOH (1 mL). The reaction was transferred to room temperature and stirred for 2 h. After the reaction is completed, the solvent and excess CF are distilled off under reduced pressure3COOH. The resulting product was then dissolved in anhydrous DMF (5mL) and hydroxylamine hydrochloride (120mg, 1.7mmol), HATU (970mg, 2.6mmol) and DIPEA (1.1g, 8.5mmol) were added sequentially. The reaction was stirred at room temperature for 6h, after completion of the reaction, DMF was evaporated off under reduced pressure. To the reaction residue was added water (20mL), extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S36(421mg, 80%).1H NMR(500MHz，DMSO-d6)δ9.50(d，J＝4.8Hz，1H)，8.25(t，J＝5.8Hz，1H)，8.12(d，J＝4.8Hz，1H)，7.73(d，J＝2.2Hz，1H)，7.57(d，J＝2.1Hz，1H)，7.42(s，1H)，3.96-3.86(m，8H).
The following syntheses of the compounds S37 to S70 in examples 31 to 64 can all be performed by the same method as that used in example 30, except that the corresponding starting materials are replaced.
Example 31: synthesis of Compound S37
Figure BDA0002921022140000341
1H NMR(500MHz，DMSO-d6)δ9.83(d，J＝4.8Hz，1H)，8.28(d，J＝2.1Hz，1H)，8.07(t，J＝4.4Hz，1H)，8.01(d，J＝4.9Hz，1H)，7.53(d，J＝2.0Hz，1H)，7.44(s，1H)，3.90(d，J＝12.8Hz，6H)，3.37(td，J＝6.2，4.4Hz，2H)，2.74(t，J＝6.2Hz，2H).
Example 32: synthesis of Compound S38
Figure BDA0002921022140000342
1H NMR(500MHz，DMSO-d6)δ8.28(d，J＝2.1Hz，1H)，8.18-8.10(m，2H)，7.65(t，J＝5.3Hz，1H)，7.54(d，J＝2.1Hz，1H)，7.44(s，1H)，3.89(d，J＝14.6Hz，6H)，3.59(d，J＝5.3Hz，2H)，1.20(s，6H).
Example 33: synthesis of Compound S39
Figure BDA0002921022140000343
1H NMR(500MHz，DMSO-d6)δ8.15(t，J＝5.8Hz，1H)，7.74(d，J＝2.2Hz，1H)，7.44(d，J＝2.1Hz，1H)，7.32(s，1H)，4.01(d，J＝5.7Hz，2H)，3.89(d，J＝14.6Hz，6H)，3.58(s，3H)，3.15(s，3H).
Example 34: synthesis of Compound S40
Figure BDA0002921022140000351
1H NMR(500MHz，DMSO-d6)δ8.24(d，J＝2.0Hz，1H)，8.18(t，J＝5.8Hz，1H)，7.46-7.39(m，2H)，7.16(s，1H)，4.06-3.95(m，2H)，3.97-3.80(m，7H)，1.24(d，J＝6.6Hz，6H).
Example 35: synthesis of Compound S41
Figure BDA0002921022140000352
1H NMR(500MHz，DMSO-d6)δ8.22(d，J＝2.2Hz，1H)，8.16(t，J＝5.8Hz，1H)，7.41(d，J＝3.6Hz，2H)，7.35(d，J＝2.2Hz，1H)，4.57(t，J＝7.3Hz，1H)，4.04(d，J＝5.9Hz，2H)，3.93-3.83(m，8H)，3.42(t，J＝6.8Hz，2H).
Example 36: synthesis of Compound S42
Figure BDA0002921022140000353
1H NMR(500MHz，DMSO-d6)δ8.25-8.15(m，1H)，7.48-7.41(m，1H)，7.38(s，1H)，7.20(s，1H)，7.09(s，1H)，6.09(s，1H)，4.09(d，J＝5.7Hz，2H)，3.89(d，J＝13.7Hz，6H).
Example 37: synthesis of Compound S43
Figure BDA0002921022140000354
1H NMR(500MHz，DMSO-d6)δ8.24(d，J＝2.0Hz，1H)，8.18(t，J＝5.8Hz，1H)，7.49(d，J＝2.1Hz，1H)，7.43(s，1H)，7.10(s，1H)，4.09-3.94(m，2H)，3.89(d，J＝14.8Hz，6H)，2.39(p，J＝5.8Hz，1H)，1.41(ddd，J＝10.4，9.7，5.7Hz，2H)，1.04(ddd，J＝10.7，9.7，5.6Hz，2H).
Example 38: synthesis of Compound S44
Figure BDA0002921022140000355
1H NMR(500MHz，DMSO-d6)δ8.27(d，J＝2.1Hz，1H)，8.15(t，J＝5.8Hz，1H)，7.61-7.54(m，2H)，7.47(s，1H)，7.41(ddt，J＝7.5，2.6，1.1Hz，2H)，7.34-7.22(m，3H)，4.64(t，J＝1.0Hz，2H)，4.08(d，J＝5.9Hz，2H)，3.89(d，J＝14.3Hz，6H).
Example 39: synthesis of Compound S45
Figure BDA0002921022140000356
1H NMR(500MHz，DMSO-d6)δ8.27(d，J＝2.2Hz，1H)，8.10(t，J＝5.8Hz，1H)，7.55(d，J＝2.1Hz，1H)，7.46(s，1H)，7.17(dtt，J＝8.0，4.9，1.0Hz，1H)，7.11(s，1H)，6.97(td，J＝8.1，5.0Hz，1H)，4.69(d，J＝1.1Hz，2H)，4.10(d，J＝5.9Hz，2H)，3.88(d，J＝15.6Hz，6H).
Example 40: synthesis of Compound S46
Figure BDA0002921022140000361
1H NMR(500MHz，DMSO-d6)δ8.27(d，J＝2.1Hz，1H)，8.14(t，J＝5.8Hz，1H)，7.69-7.63(m，2H)，7.57-7.48(m，4H)，7.45(s，1H)，4.65(t，J＝1.0Hz，2H)，4.10(d，J＝5.7Hz，2H)，3.89(d，J＝15.0Hz，6H).
Example 41: synthesis of Compound S47
Figure BDA0002921022140000362
1H NMR(500MHz，DMSO-d6)δ8.27(d，J＝2.3Hz，1H)，8.14(t，J＝5.8Hz，1H)，7.56(d，J＝2.1Hz，1H)，7.43(s，1H)，7.32(dt，J＝8.4，1.0Hz，2H)，7.15(s，1H)，6.85-6.78(m，2H)，4.63(t，J＝1.0Hz，2H)，4.05(d，J＝5.9Hz，2H)，3.89(d，J＝15.2Hz，6H)，3.78(s，3H).
Example 42: synthesis of Compound S48
Figure BDA0002921022140000363
1H NMR(500MHz，DMSO-d6)δ8.27(d，J＝2.3Hz，1H)，8.10(t，J＝5.8Hz，1H)，7.66(s，1H)，7.62-7.54(m，3H)，7.48-7.40(m，3H)，4.65(t，J＝1.0Hz，2H)，4.12(d，J＝5.9Hz，2H)，3.88(d，J＝13.6Hz，6H).
Example 43: synthesis of Compound S49
Figure BDA0002921022140000364
1H NMR(500MHz，DMSO-d6)δ8.26(d，J＝2.2Hz，1H)，8.10(t，J＝5.8Hz，1H)，7.55(d，J＝2.2Hz，1H)，7.46(s，1H)，7.40-7.33(m，3H)，7.15-7.09(m，2H)，4.63(t，J＝1.0Hz，2H)，4.04(d，J＝5.9Hz，2H)，3.88(d，J＝11.4Hz，6H).
Example 44: synthesis of Compound S50
Figure BDA0002921022140000365
1H NMR(500MHz，DMSO-d6)δ8.27(d，J＝2.3Hz，1H)，8.10(t，J＝5.8Hz，1H)，7.85-7.79(m，2H)，7.59(s，1H)，7.53(d，J＝2.2Hz，1H)，7.47-7.38(m，3H)，6.99(s，2H)，4.65(t，J＝1.0Hz，2H)，4.12(d，J＝5.9Hz，2H)，3.89(d，J＝12.6Hz，6H).
Example 45: synthesis of Compound S51
Figure BDA0002921022140000371
1H NMR(500MHz，DMSO-d6)δ8.26(d，J＝2.3Hz，1H)，8.14(t，J＝5.8Hz，1H)，7.59-7.53(m，2H)，7.47(s，1H)，7.32(dt，J＝8.4，1.1Hz，2H)，7.11(dp，J＝8.2，0.9Hz，2H)，4.65(t，J＝1.0Hz，2H)，4.09(d，J＝5.9Hz，2H)，3.89(d，J＝15.2Hz，6H)，2.33(d，J＝0.8Hz，3H).
Example 46: synthesis of Compound S52
Figure BDA0002921022140000372
1H NMR(500MHz，DMSO-d6)δ8.38(s，1H)，8.30(d，J＝5.0Hz，1H)，8.23(t，J＝5.8Hz，1H)，7.51(ddt，J＝8.3，4.9，1.0Hz，2H)，7.25(s，1H)，7.20-7.12(m，2H)，4.67(t，J＝1.0Hz，2H)，3.94(d，J＝5.9Hz，2H)，3.89(d，J＝10.6Hz，6H).
Example 47: synthesis of Compound S53
Figure BDA0002921022140000373
1H NMR(500MHz，DMSO-d6)δ8.40(dd，J＝8.0，1.5Hz，1H)，8.35(s，1H)，8.29(d，J＝1.5Hz，1H)，8.18-8.10(m，2H)，7.57(d，J＝2.1Hz，1H)，7.49-7.40(m，2H)，4.80(s，2H)，3.94(d，J＝5.7Hz，2H)，3.89(d，J＝15.2Hz，6H).
Example 48: synthesis of Compound S54
Figure BDA0002921022140000374
1H NMR(500MHz，DMSO-d6)δ8.30(d，J＝2.3Hz，1H)，8.15(t，J＝5.8Hz，1H)，7.98(d，J＝2.3Hz，1H)，7.37(s，1H)，7.12(s，1H)，6.91(t，J＝9.2Hz，1H)，5.71(dd，J＝9.3，1.8Hz，1H)，5.49(dd，J＝9.3，2.0Hz，1H)，3.99(d，J＝5.9Hz，2H)，3.90(s，3H)，3.87(p，J＝6.5Hz，1H)，1.24(d，J＝6.6Hz，6H).
Example 49: synthesis of Compound S55
Figure BDA0002921022140000375
1H NMR(500MHz，DMSO-d6)δ8.15(t，J＝5.8Hz，1H)，8.00(s，1H)，7.73(d，J＝2.2Hz，1H)，7.44(d，J＝2.3Hz，1H)，6.43(s，1H)，4.06-3.92(m，2H)，3.92-3.80(m，4H)，1.23(d，J＝6.6Hz，6H).
Example 50: synthesis of Compound S56
Figure BDA0002921022140000381
1H NMR(500MHz，DMSO-d6)δ8.31(d，J＝2.1Hz，1H)，8.12(t，J＝5.8Hz，1H)，8.06-8.00(m，2H)，7.14(s，1H)，3.99(d，J＝5.9Hz，2H)，3.86(p，J＝6.5Hz，1H)，1.24(d，J＝6.6Hz，6H).
Example 51: synthesis of Compound S57
Figure BDA0002921022140000382
1H NMR(500MHz，DMSO-d6)δ8.25(d，J＝2.1Hz，1H)，8.15(t，J＝5.8Hz，1H)，7.33(s，1H)，7.20(d，J＝2.2Hz，1H)，7.13(s，1H)，6.18(q，J＝4.6Hz，1H)，3.99(d，J＝5.9Hz，2H)，3.86(s，3H)，3.86(p，J＝6.5Hz，1H)，2.97(d，J＝4.6Hz，3H)，1.24(d，J＝6.4Hz，6H).
Example 52: synthesis of Compound S58
Figure BDA0002921022140000383
1H NMR(500MHz，DMSO-d6)δ8.15(t，J＝5.8Hz，1H)，7.97(s，1H)，7.78(d，J＝2.2Hz，1H)，7.29(d，J＝2.1Hz，1H)，7.12(s，1H)，6.87(t，J＝13.5Hz，1H)，5.69(dd，J＝13.5，1.9Hz，1H)，5.47(dd，J＝13.5，1.9Hz，1H)，3.98(d，J＝5.7Hz，2H)，3.90(s，3H)，3.87(p，J＝6.5Hz，1H)，1.24(d，J＝6.4Hz，6H).
Example 53: synthesis of Compound S59
Figure BDA0002921022140000384
1H NMR(500MHz，DMSO-d6)δ8.29-8.19(m，2H)，7.56-7.49(m，3H)，7.44-7.36(m，3H)，7.33(s，1H)，7.18(tt，J＝7.3，1.5Hz，1H)，4.14(d，J＝5.7Hz，2H)，3.89(d，J＝12.1Hz，6H).
Example 54: synthesis of Compound S60
Figure BDA0002921022140000391
1H NMR(500MHz，DMSO-d6)δ8.23(t，J＝5.8Hz，1H)，7.78(d，J＝2.1Hz，1H)，7.60-7.53(m，3H)，7.50(s，1H)，7.20-7.14(m，2H)，5.67(s，1H)，4.15(d，J＝5.9Hz，2H)，3.89(d，J＝14.3Hz，6H)，2.33(d，J＝0.9Hz，3H).
Example 55: synthesis of Compound S61
Figure BDA0002921022140000392
1H NMR(500MHz，DMSO-d6)δ8.29(d，J＝2.0Hz，1H)，8.23(t，J＝5.8Hz，1H)，8.15(s，1H)，7.57(d，J＝2.1Hz，1H)，7.49-7.42(m，3H)，7.21-7.13(m，2H)，4.12(d，J＝5.9Hz，2H)，3.89(d，J＝13.6Hz，6H).
Example 56: synthesis of Compound S62
Figure BDA0002921022140000393
1H NMR(500MHz，DMSO-d6)δ8.31-8.24(m，2H)，8.03(s，1H)，7.74-7.68(m，2H)，7.54-7.47(m，3H)，7.38(s，1H)，4.16(d，J＝5.9Hz，2H)，3.88(d，J＝15.6Hz，6H).
Example 57: synthesis of Compound S63
Figure BDA0002921022140000394
1H NMR(500MHz，DMSO-d6)δ8.29-8.20(m，2H)，8.11(s，1H)，7.54(d，J＝2.1Hz，1H)，7.43-7.37(m，3H)，6.99-6.93(m，2H)，4.15(d，J＝5.9Hz，2H)，3.89(d，J＝15.2Hz，6H)，3.81(s，3H).
Example 58: synthesis of Compound S64
Figure BDA0002921022140000395
1H NMR(500MHz，DMSO-d6)δ8.27-8.19(m，2H)，7.72(s，1H)，7.52(d，J＝2.1Hz，1H)，7.38(s，1H)，7.25-7.18(m，2H)，6.79-6.73(m，2H)，5.01(s，2H)，4.15(d，J＝5.9Hz，2H)，3.89(d，J＝13.5Hz，6H).
Example 59: synthesis of Compound S65
Figure BDA0002921022140000401
1H NMR(500MHz，DMSO-d6)δ8.31-8.22(m，1H)，8.12(s，1H)，7.46-7.39(m，4H)，7.23-7.16(m，3H)，4.19(d，J＝5.7Hz，2H)，3.88(d，J＝13.6Hz，6H).
Example 60: synthesis of Compound S66
Figure BDA0002921022140000402
1H NMR(500MHz，DMSO-d6)δ9.16(s，1H)，8.27-8.20(m，2H)，7.46(d，J＝2.1Hz，1H)，7.41(s，1H)，3.96(d，J＝5.7Hz，2H)，3.89(d，J＝12.6Hz，6H).
Example 61: synthesis of Compound S67
Figure BDA0002921022140000403
1H NMR(500MHz，DMSO-d6)δ8.69(s，1H)，8.27-8.18(m，2H)，7.45-7.38(m，2H)，4.00-3.94(m，5H)，3.89(d，J＝9.5Hz，6H).
Example 62: synthesis of Compound S68
Figure BDA0002921022140000404
1H NMR(500MHz，DMSO-d6)δ9.59(s，1H)，8.28(d，J＝2.3Hz，1H)，8.20(t，J＝5.8Hz，1H)，7.43-7.35(m，2H)，3.99(d，J＝5.7Hz，2H)，3.89(d，J＝13.7Hz，6H)，3.11(s，3H).
Example 63: synthesis of Compound S69
Figure BDA0002921022140000405
1H NMR(500MHz，DMSO-d6)δ8.31-8.22(m，2H)，8.13(s，1H)，7.48-7.40(m，2H)，3.99(d，J＝5.7Hz，2H)，3.90(d，J＝12.8Hz，6H).
Example 64: synthesis of Compound S70
Figure BDA0002921022140000406
1H NMR(500MHz，DMSO-d6)δ8.43(d，J＝5.0Hz，1H)，8.26(t，J＝5.8Hz，1H)，8.06(s，1H)，7.21(s，1H)，3.99(d，J＝5.9Hz，2H)，3.93(s，3H)，3.88(s，3H).
Example 65: synthesis of Compounds S71 and S72
Figure BDA0002921022140000411
The method comprises the following steps: synthesis of Compound 10
Compound 6(10g, 42mmol) was dissolved in anhydrous DMF (80mL) and compound 9(4.9g, 50.4mmol), EDCI (13.7g, 71.4mmol) and TEA (29mL, 210mmol) were added sequentially. The reaction was carried out overnight at room temperature, and after completion of the reaction, the solvent was distilled off under reduced pressure. To the reaction residue was added water (20mL), extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 10(10g, 87%).
Step two: synthesis of Compound 11
Compound 10(10g, 35.1mmol) was dissolved in anhydrous THF (80mL) under nitrogen, placed at 0 deg.C, and methylmagnesium bromide in tetrahydrofuran (1M, 36mL, 35.1mmol) was slowly added dropwise to the solution, after which time the solution was transferred to room temperature and the reaction was stirred for 4 h. After the reaction is completed, the mixture is placed at 0 ℃, and dilute hydrochloric acid is slowly added dropwise until no bubbles are generated. The solvent was distilled off under reduced pressure, extracted with ethyl acetate (50mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 11(7.3g, 88%).
Step three: synthesis of Compound 12
Compound 11(7g, 30mmol) was dissolved in anhydrous THF (100mL) under nitrogen, HMPA (3.2mL, 18mmol) was added, the mixture was cooled at-78 deg.C, and LDA in THF (1M, 36mL, 36mmol) was slowly added dropwise to the above solution, and the reaction was maintained at this temperature for 30 min. Then, ethyl bromoacetate was slowly added dropwise to the above solution, and after completion of the addition, the solution was transferred to room temperature for overnight reaction. After the reaction is completed, placing the mixture at 0 ℃, and slowly dropwise adding a saturated ammonium chloride solution until no bubbles are generated. The solvent was removed by evaporation under reduced pressure, extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 12(6.8g, 70%).
Step four: synthesis of Compound S71
A mixed solution (1: 1, 60mL) of hydroxylamine hydrochloride (13g, 186mmol) in ethanol/water was stirred at room temperature, and after completely dissolving, the raw material 12(6g, 18.6mmol) was added to the above solution, and the mixture was heated to reflux and reacted overnight. After completion of the reaction, ethanol and water were distilled off under reduced pressure, and the resulting product was purified by column chromatography to give compound S71(6.3g, 45%).1H NMR (500MHz，DMSO-d6)δ11.52(s，1H)，7.58(s，1H)，7.49(s，1H)，7.37(s，1H)，4.08(q，J＝7.1Hz，2H)，3.85(s，3H)，3.83(s，3H)，3.00(t，J＝7.9，Hz，2H)，2.60(t，J＝7.9Hz，2H)，1.19(t，J＝7.1Hz，3H).
Step five: synthesis of Compound S72
Compound S71(100mg, 0.3mmol) was dissolved in THF (2mL), placed at 0 deg.C, aqueous sodium hydroxide (1M, 0.6mL, 0.6mmol) was slowly added dropwise, transferred to room temperature, and reacted for 2 h. After completion of the reaction, it was transferred to 0 ℃ and diluted hydrochloric acid (1M) was added to adjust the pH to neutral, and lyophilized to give compound S72(93mg, 95%).1H NMR(500MHz，DMSO-d6)δ11.52(s，1H)，7.58(s，1H)，7.49(s，1H)，7.37(s，1H)，3.85(s，3H)，3.83(s，3H)，3.00(t，J＝7.9，Hz，2H)，2.60(t，J＝7.9Hz，2H).
Example 66: synthesis of Compound S73
Figure BDA0002921022140000421
Raw material S72(100 m)g, 0.32mmol) was dissolved in THF (5mL), and chloromethyl acetate (139mg, 1.28mmol) KI (212mg, 1.28mmol) and cesium carbonate (209mg, 0.64mmol) were added to the above reaction solution to react at room temperature for 5 hours. After the reaction was completed, suction filtration was performed, the filtrate was concentrated, water (2mL) was added, ethyl acetate extraction (5mL × 3) was performed, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S73.1H NMR(500MHz，DMSO-d6)δ11.52(s，1H)，7.44-7.35(m，1H)，7.49(s，1H)，7.37(s，1H)，5.96(s，2H)，3.89(s，3H)，3.83(s，3H)，3.12(t，J＝8.4Hz，2H)，2.60(t，J＝8.5Hz，2H)，2.10(s，3H).
Example 67: synthesis of Compound S5
Figure BDA0002921022140000422
The method comprises the following steps: synthesis of Compound 13
Compound 12(200mg, 0.62mmol) was dissolved in methanol (2mL), placed at 0 deg.C, aqueous NaOH (1M, 1.2mL, 1.2mmol) was added, and the reaction stirred at room temperature for 2 h. And after the reaction is completed, placing at 0 ℃, adding dilute hydrochloric acid to adjust the pH value to 2-3, precipitating, performing suction filtration, washing a filter cake with methanol, collecting the filter cake, drying to obtain a compound 13(164mg, 90%), and directly putting into the next reaction.
Step two: synthesis of Compound S5
Compound 13(100mg, 0.34mmol) was dissolved in anhydrous DMF (5mL) and HATU (194mg, 0.51mmol), DIPEA (219mg, 1.7mmol) and methanesulfonamide (36mg, 0.37mmol) were added sequentially. The reaction was stirred at room temperature overnight. After completion of the reaction, DMF was removed by evaporation under reduced pressure, water (1mL) was added, extraction was performed with ethyl acetate (5 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S5(71mg, 56%).1H NMR(500MHz，DMSO-d6)δ8.08(d，J＝2.3Hz，1H)，7.52(d，J＝2.1Hz，1H)，7.45(s，1H)，4.36(s，1H)，3.89(d，J＝11.9Hz，6H)，3.54(t，J＝8.4Hz，2H)，3.14(s，3H)，2.62(t，J＝8.5Hz，2H).
Example 68: synthesis of Compound S6
Synthesis the synthesis method of reference example 67 was carried out by replacing the corresponding raw materials.
Figure BDA0002921022140000431
1H NMR(500MHz，DMSO-d6)δ8.08(d，J＝2.0Hz，2H)，7.48(d，J＝2.2Hz，1H)，7.43(s，1H)，3.89(d，J＝11.0Hz，6H)，3.55(t，J＝8.4Hz，2H)，3.22-3.03(m，2H)，2.62(t，J＝8.4Hz，2H)，1.35(t，J＝6.9Hz，3H).
Example 69: synthesis of Compound S1
Figure BDA0002921022140000432
Compound 13(200mg, 0.68mmol) and N-methylmorpholine (0.22mL, 2.04mmol) were dissolved in anhydrous THF (5mL), placed at-78 deg.C, chloromethyl isobutyl ester (97. mu.L, 0.75mmol) was added dropwise to the above solution, and the reaction was stirred at this temperature for 15 min. Then, formyl hydrazine (41mg, 0.68mmol) was added to the above solution, slowly warmed to room temperature, and stirred at room temperature for 1 h. After the reaction is completed, adding water to quench the reaction, evaporating the solvent under reduced pressure, extracting with ethyl acetate (5 mL. times.3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a residue, and directly putting the residue into the next reaction.
The reaction residue obtained in the previous step was dissolved in DCM, TEA (0.29mL, 2.04mmol) was added, p-toluenesulfonyl chloride (195mg, 1.02mmol) was added to the above solution, and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, water was added to quench the reaction, DCM extraction (5mL × 3) was performed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S1(97mg, 45%).1H NMR(500MHz，DMSO-d6)δ8.08(d，J＝2.2Hz，2H)，7.44-7.36(m，2H)，3.90(d，J＝12.1Hz，6H)，3.54(t，J＝7.8Hz，2H)，3.19(t，J＝7.8Hz，2H).
Example 70: synthesis of Compound S2
Figure BDA0002921022140000433
Compound 13(200mg, 0.68mmol) and N-methylmorpholine (0.22mL, 2.04mmol) were dissolved in anhydrous THF (5mL), placed at-78 deg.C, chloromethyl isobutyl ester (97. mu.L, 0.75mmol) was added dropwise to the above solution, and the reaction was stirred at this temperature for 15 min. Then, compound 14(51mg, 0.68mmol) was added to the above solution, slowly warmed to room temperature, and the reaction was stirred at room temperature for 1 h. After the reaction is completed, adding water to quench the reaction, evaporating the solvent under reduced pressure, extracting with ethyl acetate (5 mL. times.3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a residue, and directly putting the residue into the next reaction.
The reaction residue was dissolved in pyridine, and the mixture was refluxed overnight. After the reaction is completed, cooling to room temperature, and adding water to quench the reaction. The solvent was distilled off under reduced pressure, extracted with ethyl acetate (5 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S2(90mg, 40%).1H NMR(500MHz，DMSO-d6)δ8.09(d，J＝2.3Hz，1H)，7.52-7.46(m，2H)，3.89(d，J＝14.1Hz，6H)，3.62-3.54(m，3H)，3.44-3.37(m，2H)，2.39(s，2H).
Example 71: synthesis of Compound S3
Figure BDA0002921022140000441
The method comprises the following steps: synthesis of Compound 14
Compound 11(2g, 8.5mmol) was dissolved in anhydrous THF (10mL) under nitrogen, HMPA (0.9mL, 5.0mmol) was added, the mixture was cooled at-78 deg.C, and LDA in THF (1M, 9.5mL, 9.4mmol) was slowly added dropwise to the above solution, and the reaction was maintained at this temperature for 30 min. Then, bromoacetonitrile was slowly added dropwise to the above solution, and after completion of the addition, the mixture was transferred to room temperature for overnight reaction. After the reaction is completed, placing the mixture at 0 ℃, and slowly dropwise adding a saturated ammonium chloride solution until no bubbles are generated. The solvent was removed by evaporation under reduced pressure, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 14(1.1g, 50%).
Step two: synthesis of Compound 15
Compound 14(1g, 3.83mmol) was dissolved in ethanol (10mL), and potassium carbonate (1.6g, 11.5mmol) and hydroxylamine hydrochloride (798mg, 11.5mmol) were added to the solution, followed by refluxing under heating overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added, extraction was performed with ethyl acetate (10mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 15(943mg, 80%).
Step three: synthesis of Compound S3
Compound 15(200mg, 0.65mmol) was added to triethyl orthoformate (5mL), a catalytic amount of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 10min, then warmed to 60 ℃ and stirred for reaction for 30 min. After completion of the reaction, it was cooled to room temperature, concentrated under reduced pressure, added with water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S3(103mg, 50%).1H NMR(500MHz，DMSO-d6)δ9.33(s，1H)，8.10(d，J＝2.1Hz，1H)，7.51(s，1H)，7.45(d，J＝2.2Hz，1H)，3.90(d，J＝12.1Hz，6H)，3.41(t，J＝7.8Hz，2H)，2.96(t，J＝7.8Hz，2H).
Example 72: synthesis of Compound S4
Figure BDA0002921022140000451
Compound 13(200mg, 0.68mmol) and N-methylmorpholine (0.22mL, 2.04mmol) were dissolved in anhydrous THF (5mL), placed at-78 deg.C, chloromethyl isobutyl ester (97. mu.L, 0.75mmol) was added dropwise to the above solution, and the reaction was stirred at this temperature for 15 min. Then, formyl hydrazine (41mg, 0.68mmol) was added to the above solution, slowly warmed to room temperature, and stirred at room temperature for 1 h. After the reaction is completed, adding water to quench the reaction, evaporating the solvent under reduced pressure, extracting with ethyl acetate (5 mL. times.3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a residue, and directly putting the residue into the next reaction.
The reaction residue was dissolved in toluene (5mL), and Lawson's reagent (412mg, 1.02mmol) was added thereto, followed by refluxing under heating for overnight reaction. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give compound S4(73mg, 32%).1H NMR(500MHz，DMSO-d6)δ8.90(s，1H)，8.10(d，J＝2.3Hz，1H)，7.57-7.51(m，2H)，3.90(d，J＝11.5Hz，6H)，3.45(dd，J＝8.2，7.5Hz，2H)，3.30-3.23(m，2H).
Synthesis of Compounds S74 to S90 in examples 73 to 89 to follow, the synthesis method in example 65 was followed by replacing the corresponding starting materials.
Example 73: synthesis of Compound S74
Figure BDA0002921022140000452
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，11.52(s，1H)，7.58(s，1H)，7.51(d，J＝4.9Hz，1H)，3.94(s，3H)，3.87(s，3H)，3.11(t，J＝8.5Hz，2H)，2.56(t，J＝8.5Hz，2H).
Example 74: synthesis of Compound S75
Figure BDA0002921022140000453
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，11.52(s，1H)，7.65(s，1H)，7.35(d，J＝2.1Hz，1H)，7.28(s，1H)，3.92(s，3H)，3.09(t，J＝8.5Hz，2H)，2.57(t，J＝8.5Hz，2H).
Example 75: synthesis of Compound S76
Figure BDA0002921022140000454
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，11.52(s，1H)，8.28(s，2H)，7.30-7.24(m，1H)，6.02(s，2H)，3.07(t，J＝8.4Hz，2H)，2.56(t，J＝8.4Hz，2H).
Example 76: synthesis of Compound S77
Figure BDA0002921022140000461
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，11.52(s，1H)，7.93(d，J＝2.1Hz，1H)，7.40(d，J＝2.1Hz，1H)，7.27(s，1H)，6.86(t，J＝9.2Hz，1H)，5.68(dd，J＝9.3，2.0Hz，1H)，5.46(dd，J＝9.3，1.8Hz，1H)，3.87(s，3H)，3.17(t，J＝8-5Hz，2H)，2.57(t，J＝8.4Hz，2H).
Example 77: synthesis of Compound S78
Figure BDA0002921022140000462
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，11.52(s，1H)，7.92(d，J＝2.1Hz，1H)，7.40(d，J＝2.1Hz，1H)，7.27(s，1H)，6.86(t，J＝9.2Hz，1H)，5.68(dd，J＝9.3，2.0Hz，1H)，5.46(dd，J＝9.3，1.8Hz，1H)，3.87(s，3H)，3.17(t，J＝8.5Hz，2H)，2.57(t，J＝8.4Hz，2H).
Example 78: synthesis of Compound S79
Figure BDA0002921022140000463
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，8.26(s，1H)，7.34(d，J＝2.2Hz，1H)，7.18(s，1H)，7.09(d，J＝2.2Hz，1H)，6.11(q，J＝4.5Hz，1H)，3.86(s，3H)，3.16(t，J＝8.5Hz，2H)，2.97(d，J＝4.6Hz，3H)，2.57(t，J＝8.4Hz，2H).
Example 79: synthesis of Compound S80
Figure BDA0002921022140000464
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，11.26(s，1H)，7.78(s，1H)，7.44-7.37(m，2H)，3.89(d，J＝7.5Hz，6H)，3.15(s，2H)，1.31(s，6H).
Example 80: synthesis of Compound S81
Figure BDA0002921022140000465
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，10.65(s，1H)，7.46-7.40(m，2H)，7.37(d，J＝2.2Hz，1H)，3.89(d，J＝9.7Hz，6H)，3.37-3.29(m，1H).
Example 81: synthesis of Compound S82
Figure BDA0002921022140000471
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，7.58(s，1H)，7.49(s，1H)，7.37(s，1H)，3.85(s，3H)，3.83(s，3H)，3.66(s，3H)，3.00(t，J＝7.9，Hz，2H)，2.60(t，J＝7.9Hz，2H).
Example 82: synthesis of Compound S83
Figure BDA0002921022140000472
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，7.46-7.38(m，2H)，7.32(d，J＝2.2Hz，1H)，3.89(d，J＝9.9Hz，6H)，3.21(t，J＝8.4Hz，2H)，2.59(t，J＝8.4Hz，2H)，2.13(s，2H).
Example 83: synthesis of Compound S84
Figure BDA0002921022140000473
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，7.46(d，J＝2.1Hz，1H)，7.38(s，1H)，7.28(d，J＝2.0Hz，1H)，3.89(d，J＝5.3Hz，6H)，3.04(t，J＝8.5Hz，2H)，2.57(t，J＝8.4Hz，2H).
Example 84: synthesis of Compound S85
Figure BDA0002921022140000474
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，7.52(d，J＝5.0Hz，1H)，7.18(s，1H)，3.94(s，3H)，3.87(s，3H)，3.06(t，J＝8.4Hz，2H)，2.60(t，J＝8.5Hz，2H).
Example 85: synthesis of Compound S86
Figure BDA0002921022140000475
1H NMR(500MHz，DMSO-d6)δ7.48(d，J＝2.0Hz，1H)，7.44-7.38(m，2H)，4.10(q，J＝7.0Hz，2H)，3.89(d，J＝9.0Hz，6H)，3.04(t，J＝8.5Hz，2H)，2.61(t，J＝8.5Hz，2H)，1.26(t，J＝7.0Hz，3H).
Example 86: synthesis of Compound S87
Figure BDA0002921022140000481
1H NMR(500MHz，DMSO-d6)δ7.49(d，J＝2.1Hz，1H)，7.46-7.40(m，2H)，3.89(d，J＝8.2Hz，6H)，3.65(p，J＝5.5Hz，1H)，3.01(t，J＝8.4Hz，2H)，2.59(t，J＝8.4Hz，2H)，1.60(dd，J＝5.5，2.3Hz，4H).
Example 87: synthesis of Compound S88
Figure BDA0002921022140000482
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，7.89(d，J＝2.3Hz，1H)，7.52(d，J＝2.1Hz，1H)，7.29(s，1H)，3.92(s，3H)，3.05(t，J＝8.5Hz，2H)，2.55(t，J＝8.4Hz，2H).
Example 88: synthesis of Compound S89
Figure BDA0002921022140000483
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，7.38(d，J＝2.1Hz，1H)，7.33-7.27(m，2H)，6.01(s，2H)，3.04(t，J＝8.4Hz，2H)，2.59(t，J＝8.4Hz，2H).
Example 89: synthesis of Compound S90
Figure BDA0002921022140000484
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，7.42-7.37(m，2H)，7.34(d，J＝2.2Hz，1H)，5.26(s，2H)，3.89(d，J＝5.3Hz，6H)，3.06(t，J＝8.5Hz，2H)，2.53(t，J＝8.4Hz，2H).
Example 90: synthesis of Compound S91
Figure BDA0002921022140000485
Compound S84(100mg, 0.31mmol) was dissolved in anhydrous DMF (5mL), HATU (179mg, 0.47mmol), methanesulfonamide (32mg, 0.33mol) and DIPEA (120mg, 0.93mmol) were added in that order, and the reaction was stirred at room temperature for 5 h. After the reaction is completed, adding water to quench the reaction, evaporating DMF under reduced pressure, extracting with ethyl acetate (5 mL. times.3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give Compound S91(55mg, 45%).1H NMR(500MHz，DMSO-d6)δ7.58(s，1H)，7.49(s，1H)，7.37(s，1H)，7.10(s，1H)，3.89(s，3H)，3.74(s，3H)，3.14(s，3H)，2.95(t，J＝8.5Hz，2H)，2.57(t，J＝8.4Hz，2H).
The syntheses of S92 to S94 in examples 91 to 93 were all as follows, referring to the synthesis method in example 90, and the corresponding raw materials were replaced.
Example 91: synthesis of Compound S92
Figure BDA0002921022140000491
1H NMR(500MHz，DMSO-d6)δ11.52(s，1H)，8.10(s，1H)，7.58(s，1H)，7.49(s，1H)，7.37(s，1H)，3.85(s，3H)，3.83(s，3H)，3.00(t，J＝7.9，Hz，2H)，2.99(s，3H)，2.60(t，J＝7.9Hz，2H).
Example 92: synthesis of Compound S93
Figure BDA0002921022140000492
1H NMR(500MHz，DMSO-d6)δ11.52(s，1H)，7.96(s，1H)，7.79(s，1H)，7.39-7.32(m，2H)，3.89(d，J＝8.2Hz，6H)，3.63(s，3H)，3.06(t，J＝8.5Hz，2H)，2.48(t，J＝8.5Hz，2H).
Example 93: synthesis of Compound S94
Figure BDA0002921022140000493
1H NMR(500MHz，DMSO-d6)δ8.01(s，1H)，7.65(s，1H)，7.49(dd，J＝17.4，2.0Hz，1H)，7.42(s，1H)，3.89(d，J＝9.0Hz，6H)，3.63(s，3H)，2.99(t，J＝8.5Hz，2H)，2.43(t，J＝8.5Hz，2H).
Example 94: synthesis of Compounds S95 and S96
Figure BDA0002921022140000494
The method comprises the following steps: synthesis of Compound S95
Compound 2(200mg, 0.96mmol) was dissolved in anhydrous THF (2mL), placed at 0 deg.C, a solution of triphosgene (142mg, 0.48mmol) in anhydrous THF (2mL) was slowly added dropwise to the solution, followed by addition of triethylamine (0.2mL, 1.5mmol), heated at reflux, and reacted overnight. After the reaction is completed, cooling to room temperature, carrying out suction filtration, washing a filter cake with anhydrous THF, concentrating the filtrate, and drying. The residue obtained by drying was redissolved in 2mL of anhydrous THF, and the solution was left at 0 ℃ to slowly add dropwise a solution of Compound 13 in anhydrous THF (2mL), and after completion of the addition, the reaction was refluxed for 4 hours. After completion of the reaction, it was cooled to room temperature, the solvent was evaporated under reduced pressure, water (2mL) was added, ethyl acetate was extracted (5mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound S95(169mg, 52%).1H NMR(500MHz，DMSO-d6)δ9.69(s，1H)，7.69(d，J＝2.1Hz，1H)，7.43-7.35(m，2H)，6.71(t，J＝5.8Hz，1H)，4.16(q，J＝7.0Hz，2H)，3.98-3.89(m，6H)，3.87(s，2H)，1.24(t，J＝6.9Hz，3H).
Step two: synthesis of Compound S96
Compound S95(100mg, 0.30mmol) was dissolved in methanol (2mL), and aqueous NaOH (1M, 0.6mL, 0.6mmol) was added dropwise to the solution, and the reaction was stirred at room temperature for 2 h. After the reaction is completed, adjusting the pH value to 2-3 with dilute hydrochloric acid, precipitating, filtering, washing a filter cake with methanol, collecting the filter cake, and drying to obtain a compound S96(84mg, 90%).1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，9.60(s，1H)，7.69(d，J＝2.1Hz，1H)，7.32-7.24(m，2H)，7.15(t，J＝5.8Hz，1H)，4.00(d，J＝5.7Hz，2H)，3.89(d，J＝17.9Hz，6H).
Example 95: synthesis of Compound S97
The synthesis was performed according to the method described in example 90, except that the corresponding raw materials were replaced.
Figure BDA0002921022140000501
1H NMR(500MHz，DMSO-d6)δ12.88(br，1H)，9.60(s，1H)，7.70(d，J＝2.1Hz，1H)，7.41-7.36(m，2H)，7.08(t，J＝4.3Hz，1H)，3.89(d，J＝17.9Hz，6H)，3.47(td，J＝6.2，4.4Hz，2H)，2.62(t，J＝6.2Hz，2H).
Example 96: test of binding force of compound to human interferon gene stimulus protein
The specific procedure of the competitive binding assay for the interferon gene-stimulated protein was according to the kit of the CISBIO company. The basic principle is as follows: specific Anti 6His-Tb3+The antibody is used as a donor and is combined with the 6 His-marked h interferon gene stimulating protein, the d 2-marked interferon gene stimulating protein ligand is used as a receptor (CISBIO, catalogue No.64BDSTGPEG), the compound is dissolved in DMSO and is provided with 10 concentration points, the compound and the ligand and the receptor are incubated together, and the IC of the compound to be detected and the ligand in the system which competitively combines with the interferon gene stimulating protein is detected50。
The specific experimental operating procedures are as follows
Setting a negative control hole, a standard substance hole and a compound hole in an experiment, and adding 5 mu L of a negative control substance, standard substance cGAMP with different concentrations and samples to be detected with different concentrations into the negative control hole, the standard substance hole and the compound hole respectively;
② adding 5 uL 1X detection buffer into the negative control hole, adding 5 uL 1X 6His marked h interferon gene stimulating protein into the standard substance and compound hole;
③ to all the wells, 10. mu.L of 1X interferon gene-stimulating protein ligand-d 2 and 1X Anti 6His-Tb were added3+Mixing the working solution;
sealing the plate with a membrane, and incubating at room temperature for 4 hours;
the film was peeled off and absorbance values were read at 616nm and 665nm, respectively, using an HTRF compatible reader.
Sixthly, calculating the ratio of the emission signals of the receptor and the donor: ratio is Signal 665nm/Signal 616nm X104
Using Ratio value to calculate IC50Value, and IC for compound by standard cGAMP50The values are scaled.
The results of the experiment are shown in table 1 below, C: IC (integrated circuit)50＞100nM；B：IC50＝100nM-10nM；A：IC50＜10nM；
TABLE 1 binding of test compounds to human interferon gene-stimulated protein
Figure BDA0002921022140000511
Figure BDA0002921022140000521
Example 97: measurement of IFN beta Release amount
The experimental operation steps are as follows: THP-1 cells were plated (1X 10)5Wells), the next day, after changing the cell culture fluid, co-incubating the test compound with different concentrations and THP-1 cells for 24h, then collecting the culture medium supernatant, and performing ELISA to detect the IFN-beta content according to the following steps.
Sample adding of a standard product: standard wells and sample wells were set, and 50. mu.L of each standard was added at different concentrations (0, 25, 50, 100, 200, 400 pg/ml).
Sample adding: blank holes (the blank reference holes are not added with the sample and the enzyme labeling reagent, and the rest steps are operated in the same way) and sample holes to be detected are respectively arranged. 40 mu L of sample diluent is added into sample holes to be detected on the enzyme-labeled coated plate, and then 10 mu L of sample to be detected is added (the final dilution of the sample is 5 times). Adding sample to the bottom of the plate hole of the enzyme label, keeping the sample from touching the hole wall as much as possible, and gently shaking and mixing the sample and the hole wall.
Adding enzyme: add enzyme labeling reagent 100. mu.L to each well except for blank wells.
Fourthly, incubation: the plates were sealed with a sealing plate and incubated at 37 ℃ for 60 minutes.
Preparing a liquid: diluting the 20 times of concentrated washing solution with 20 times of distilled water for later use.
Sixthly, washing: carefully uncovering the sealing plate film, discarding liquid, spin-drying, filling washing liquid into each hole, standing for 30 seconds, then discarding, repeating the steps for 5 times, and patting dry.
And color development: adding 50 μ l of color-developing agent A and 50 μ l of color-developing agent B into each well, shaking gently, mixing, and developing at 37 deg.C in dark for 15 min.
And stopping the step of: the reaction was stopped by adding 50. mu.L of stop solution to each well (blue color turned to yellow color).
Ninthly, determination: the absorbance (OD value) of each well was measured sequentially at a wavelength of 450nm with the blank well being zeroed. The measurement should be performed within 15 minutes after the addition of the stop solution.
And (c) calculating: obtaining a standard curve through a standard substance, calculating the IFN-beta content in each sample, and calculating EC according to the IFN-beta content induced by the compound to be detected under different concentrations50The value is obtained.
After the interferon gene stimulating protein is activated, the expression of IFN beta is induced, thereby playing the anti-tumor or anti-infection effect. The amount of IFN β produced is an important indicator of the degree of activation of the protein stimulated by the interferon gene. In the experiment, the condition of the generation amount of IFN beta after the co-incubation of the compounds to be detected with different concentrations and THP-1 cells is detected by adopting an ELISA method, and the result is shown in the following table 2. C: EC (EC)50＞10μM；B：EC50＝10μM-1μM；A：EC50＜1μM。
TABLE 2 conditions of IFN beta production after incubation of THP-1 cells with test compounds of different concentrations
Compound numbering IC50(μM) Compound numbering IC50(μM)
S1 B S37 A
S2 B S38 A
S3 B S39 A
S5 B S45 B
S6 A S53 A
S7 A S68 A
S8 A S69 A
S12 A S70 A
S13 B S71 A
S14 A S72 A
S16 B S73 A
S18 A S74 A
S19 A S76 A
S20 A S80 A
S21 A S81 A
S22 B S82 B
S26 B S83 A
S30 A S84 A
S31 B S85 A
S32 B S86 A
S33 A S89 A
S35 A S92 B
S36 A cGAMP A

Claims (13)

1. Benzothiophene compounds with a structure shown in a general formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, wherein the structure is as follows:
Figure FDA0002921022130000011
wherein R is1And R2Independently selected from hydrogen, deuterium, halogen, unsubstituted or R1-1Substituted C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, -NR1-2R1-3、-(C＝O)NR1-4R1-5OR- (C ═ O) OR1-6；
R1-1Is halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or-NR1-1-1R1-1-2
R1-1-1And R1-1-2Independently selected from hydrogen or C1-4An alkyl group;
R1-2～R1-6independently selected from hydrogen or C1-4An alkyl group;
R3and R4Independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, unsubstituted or R3-1Substituted C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C2-6Alkynyl, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -oxy, (C)3-10Cycloalkyl) - (C)1-6Alkoxy), heterocycloalkyl-oxy, heterocycloalkyl- (C)1-6Alkoxy group), C6-10Aryl group, (C)6-10Aryl) -oxy, (C)6-10Aryl group) - (C1-6Alkoxy), heteroaryl-oxy, heteroaryl- (C)1-6Alkoxy), -NR3-2R3-3、-(C＝O)R3-4、-(C＝O)NR3-5R3-6、-(C＝O)OR3-7、-S(＝O)2NR3-8R3-9Or R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R3-1is halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, or-NR3-1-1R3-1-2；
R3-1-1And R3-1-2Independently selected from hydrogen or C1-4An alkyl group;
R3-2～R3-9independently selected from hydrogen or C1-4An alkyl group;
R5is- (C ═ O) OR5-1、-(C＝O)SR5-2Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
R5-1And R5-2Independently selected from hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -, C3-10Cycloalkyl radical, C6-10Aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, or 4-10 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R5-3selected from halogen, hydroxy, amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, or C1-4A haloalkoxy group;
R5-4and R5-5Is independently selected fromHydrogen, C1-6Alkyl radical, C1-6Haloalkyl or C3-10A cycloalkyl group;
R7is hydrogen, sulfonic group, phosphoryl group, unsubstituted or R7-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -C1-6Alkyl, heterocycloalkyl-C1-6Alkyl, unsubstituted or R7-2Substituted C6-10Aryl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R7-4Substituted heteroaryl-C1-6Alkyl or unsubstituted or R7-5Substituted heteroaryl; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R7-1is halogen, carboxyl, hydroxyl, -NR7-1-1R7-1-2Cyano or C1-4An alkyl group;
R7-1-1and R7-1-2Independently selected from hydrogen or C1-4An alkyl group;
R7-2～R7-5independently selected from deuterium, halogen, hydroxy, cyano, nitro, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, -NR7-2-3R7-2-4、-(C＝O)R7-2-5、-(C＝O)NR7-2-6R7-2-7、-(C＝O)OR7-2-8or-S (═ O)2NR7-2-9R7-2-10；
R7-2-1And R7-2-2Is halogen, hydroxy, cyano or-NR7-2-1-1R7-2-1-2
R7-2-1-1And R7-2-1-2Independently selected from hydrogen or C1-4An alkyl group;
R7-2-3R7-2-10independently selected from hydrogen or C1-4An alkyl group;
R8is hydrogen, cyano、R8-1O-、-NR8-2R8-3、R84S-, unsubstituted or R8-5Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -C1-6Alkyl, heterocycloalkyl-C1-6Alkyl, unsubstituted or R8-6Substituted C6-10Aryl, unsubstituted or R8-7Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-8Substituted heteroaryl, unsubstituted or R8-9Substituted heteroaryl-C1-6An alkyl group; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R8-1～R8-4independently selected from phosphoryl, unsubstituted or R8-1-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl group, (C)3-10Cycloalkyl) -C1-6Alkyl, heterocycloalkyl-C1-6Alkyl, unsubstituted or R8-1-2Substituted C6-10Aryl, unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl, unsubstituted or R8-1-5Substituted heteroaryl, or- (S ═ O)2OR8-1-6(ii) a The heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;
R8-1-1is halogen, hydroxy, -cyano, -NR8-1-1-1R8-1-1-2Or C1-4An alkyl group;
R8-1-1-1and R8-1-1-2Independently selected from hydrogen or C1-4An alkyl group;
R8-1-2R8-1-5independently selected from halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, -NR8-1-2-1R8-1-2-2、-(C＝O)R8-1-2-3、-(C＝O)NR8-1-2-4R8-1-2-5、-(C＝O)OR8-1-2-6、-S(＝O)2NR8-1-2-7R8-1-2-8or-S (═ O)2R8-1-2-9；
R8-1-6Is hydrogen, C1-6Alkyl radical, C1-6Haloalkyl or C3-10A cycloalkyl group;
R8-1-2-1R8-1-2-9independently selected from hydrogen or C1-4An alkyl group;
R8-5is halogen, carboxyl, hydroxyl, -NR8-5-1R8-5-2Cyano or C1-4An alkyl group;
R8-5-1and R8-5-2Independently selected from hydrogen or C1-4An alkyl group;
R8-6～R8-9independently selected from deuterium, halogen, hydroxy, cyano, carboxy, nitro, unsubstituted or R8-6-1Substituted C1-4Alkyl, unsubstituted or R8-6-2Substituted C1-4Alkoxy, -NR8-6-3R8-6-4、-(C＝O)R8-6-5、-(C＝O)NR8-6-6R8-6-7、-(C＝O)OR8-6-8or-S (═ O)2NR8-6-9R8-6-10
R8-6-1And R8-6-2Is halogen, hydroxy, cyano or-NR8-6-1-1R8-6-1-2；
R8-6-1-1And R8-6-1-2Independently selected from hydrogen or C1-4An alkyl group;
R8-6-3R8-6-10independently selected from hydrogen or C1-4An alkyl group;
x is O, C ═ O, NR9、
Figure FDA0002921022130000021
Left end of X and
Figure FDA0002921022130000031
the right end of the L-shaped connecting rod is connected with the L;
R9～R11independently selected from hydrogen or C1-6An alkyl group;
R12is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2、-(S＝O)R12-3or-NR124R12-5；
R12-1～R12-3Independently selected from C1-6An alkyl group;
R12-4and R12-5Independently selected from hydrogen, C1-6Alkyl or- (C ═ O) R12-4-1；
R12-4-1Is C1-6An alkyl group;
R13and R14Independently selected from hydrogen or C1-6An alkyl group;
x and R5Selected from any combination of:
when X is
Figure FDA0002921022130000032
When R is5Is- (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is C ═ O, R5Is- (C ═ O) NR5-4(S＝O)2R5-5Or is unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
when X is O, NR9、
Figure FDA0002921022130000033
To, R5Is- (C ═ O) OR5-1、-(C＝O)SR5-2Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
R6Selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, - (C ═ O) NR6- 1R6-2、-(C＝O)OR6-3or-NR6-4R6-5；
R6-1～R6-5Independently selected from hydrogen or C1-4An alkyl group;
l is (C (R)15R16))n；
R15And R16Independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-6Cycloalkyl, -NR15-1R15-2Or R15And R16Ring synthesis of C with the carbon atom to which they are attached3-10A cycloalkyl group;
R15-1and R15-2Independently selected from hydrogen or C1-4An alkyl group;
n is an integer of 1, 2 or 3.
2. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I: when R is1And R2Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;
and/or when R3And R4Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;
and/or when R3And R4Independently selected from C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group;
and/or when R3And R4Independently selected from C1-6When halogenated alkoxy, said C1-6Haloalkoxy is C1-4A haloalkoxy group;
and/or when R3And R4Independently selected from C2-6When alkenyl, said C2-6Alkenyl is C2-4An alkenyl group;
and/or when R3And R4Independently selected from (C)3-10Cycloalkyl) -oxy, said (C)3-10Cycloalkyl) -oxy is (C)3-6Cycloalkyl) -oxy;
and/or when R3And R4Independently selected from (C)3-10Cycloalkyl) - (C)1-6Alkoxy group), said (C)3-10Cycloalkyl) - (C)1-6Alkoxy) is (C)3-6Cycloalkyl) - (C)1-4Alkoxy groups);
and/or when R3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)1-6Alkoxy) is 4-to 6-membered heterocycloalkyl- (C1-4Alkoxy groups);
and/or when R3And R4Independently selected from (C)6-10Aryl) -oxy, said (C)6-10Aryl) -oxy is phenoxy;
and/or when R3And R4Independently selected from (C)6-10Aryl group) - (C1-6Alkoxy group), said (C)6-10Aryl group) - (C1-6Alkoxy) is benzene- (C)1-4Alkoxy groups);
and/or when R3And R4Independently selected from one or more of N, O and S as heteroatoms, and when the number of the heteroatoms is 1-3 and the 5-10 membered heteroaryl-oxy is 5-10 membered heteroaryl-oxy, the 5-10 membered heteroaryl-oxy is 5-6 membered heteroaryl-oxy;
and/or when R3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of the heteroatoms, and 5-10-membered heteroaryl- (C)1-6Alkoxy), said 5-to 10-membered heteroaryl- (C)1-6Alkoxy) is 5-6 membered heteroaryl- (C)1-4Alkoxy groups);
and/or when R3-2And R3-3Independently selected from C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl or isopropyl;
and/or when R3And R4Form one or more of "heteroatom is selected from N, O and S together with the carbon atom to which they are attached, and when the number of heteroatoms is 1-3," 4-20 membered heterocycloalkoxy group, the 4-20 membered heterocycloalkyl group is 5-12 membered heterocycloalkoxy group;
and/or when R5-1Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R5-1Is (C)1-6Alkoxy group) - (C1-6Alkyl) -said (C)1-6Alkoxy group) - (C1-6Alkyl) -is (C)1-4Alkoxy group) - (C1-4Alkyl) -;
and/or when R5-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group;
and/or when R5Is unsubstituted or R5-3When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is5-3The number is one or more, when there are more than one R5-3When R is said5-3May be the same or different;
and/or when R5Is unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the 5-10 membered heteroaryl is 5-6 membered heteroaryl;
and/or when R5-4And R5-5Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R7Is unsubstituted or R7-1Substituted C1-6When it is alkyl, said R7-1Is one or more, when there are more than one R7-1When R is said7-1May be the same or different;
and/or when R7Is unsubstituted or R7-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R7Is C2-6When alkenyl, said C2-6Alkenyl is C2-4An alkenyl group;
and/or when R7Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group;
and/or when R7Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6Alkyl is (C)3-6Cycloalkyl) -C1-4An alkyl group;
and/or when R7Is unsubstituted or R7-2Substituted C6-10When aryl is said to R7-2Is one or more, when there are more than one R7-2When R is said7-2May be the same or different;
and/or when R7Is unsubstituted or R7-2Substituted C6-10When aryl, said C6-10Aryl is phenyl;
and/or when R7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When it is alkyl, said R7-3Is one or more, when there are more than one R7-3When R is said7-3May be the same or different;
and/or when R7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6Alkyl is phenyl-C1-4An alkyl group;
and/or when R7Is unsubstituted or R7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When it is alkyl, said R7-4Is one or more, when there are more than one R7-4When R is said7-4May be the same or different;
and/or when R7Is unsubstituted or R7-4The substituted heteroatom is selected from N, O and SOr more than one kind of 5-10 membered heteroaryl-C with 1-3 hetero atoms1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6Alkyl is 5-to 6-membered heteroaryl-C1-4An alkyl group;
and/or when R7-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R7-1Is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl or propyl;
and/or when R7-2～R7-4Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;
and/or when R7-2～R7-4Independently selected from unsubstituted or R7-2-1Substituted C1-4When it is alkyl, said R7-2-1Is one or more, when there are more than one R7-2-1When R is said7-2-1May be the same or different;
and/or when R7-2～R7-4Independently selected from unsubstituted or R7-2-1Substituted C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl or isopropyl;
and/or when R7-2～R7-4Independently selected from unsubstituted or R7-2-2Substituted C1-4At alkoxy, said R7-2-2Is one or more, when there are more than one R7-2-2When R is said7-2-2May be the same or different;
and/or when R7-2～R7-4Independently selected from unsubstituted or R7-2-2Substituted C1-4At alkoxy, said C1-4Alkoxy is methoxy, ethoxy, propoxy or isopropoxy;
and/or when R7-2-3R7-2-10Independently selected from C1-4Alkyl radical, said C1-4Alkyl is methyl, ethyl, propyl or isopropyl;
and/or when R8-1Independently selected from unsubstituted or R8-1-1Substituted C1-6When it is alkyl, said R8-1-1Is one or more, when there are more than one R8-1-1When R is said8-1-1May be the same or different;
and/or when R8-1Is unsubstituted or R8-1-1Substituted C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R8-1Is C2-6When alkenyl, said C2-6Alkenyl is C24An alkenyl group;
and/or when R8-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl being C3-6A cycloalkyl group;
and/or when R8-1Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6Alkyl is (C)3-6Cycloalkyl) -C1-4An alkyl group;
and/or when R8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When it is alkyl, said R8-1-3Is one or more, when there are more than one R8-1-3When R is said8-1-3May be the same or different;
and/or when R8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6Alkyl is phenyl-C1-4An alkyl group;
and/or when R8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When it is alkyl, said R8-1-4Is one or more, when there are more than one R8-1-4When R is said8-1-4May be the same or different;
and/or when R8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6Alkyl is 5-to 6-membered heteroaryl-C1-4An alkyl group;
and/or when R8-1-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R8-1-3When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R8-1-4When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R8-1-6Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R8-1-3When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R8-1-4When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R9～R11Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R12Is C1-6At alkoxy, said C1-6Alkoxy is C1-4An alkoxy group;
and/or when R12-1～R12-5Is independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or, when X is
Figure FDA0002921022130000061
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
Or, when X is
Figure FDA0002921022130000062
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
Or, when X is
Figure FDA0002921022130000063
When R is5Independently selected from- (C ═ O) OR5-1；
And/or when R15And R16Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;
and/or when R15And R16Independently selected from C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or n is an integer of 1 or 2.
3. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I: when R is3And R4Independently selected from C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy;
and/or when R3And R4Independently selected from C1-6When halogenated alkoxy, said C1-6Haloalkoxy is trifluoromethoxy;
and/or when R3And R4Independently selected from C2-6When alkenyl, said C2-6Alkenyl is
Figure FDA0002921022130000064
Figure FDA0002921022130000065
And/or when R3And R4Independently selected from (C)3-10Cycloalkyl) -oxy, said (C)3-10Cycloalkyl) -oxy is cyclopropoxy, cyclobutoxy, cyclopentyloxy or cyclohexyloxy;
and/or when R3And R4Independently selected from (C)3-10Cycloalkyl) - (C)1-6Alkoxy group), said (C)3-10Cycloalkyl) - (C)1-6Alkoxy) is cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropoxy, cyclopropylbutoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy or cyclohexylethoxy;
and/or when R3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)1-6Alkoxy) is piperidinemethyl, piperidinylethyl, piperidinopropyl, piperidinobutyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, morpholinobutyl, azetidinemethyl, azetidinoethyl, azetidinopropyl, azetidinobutyl, piperazinemethyl, piperazineethyl, piperazinopropyl, piperazinobutyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, or pyrrolidinylbutyl;
and/or when R3And R4Independently selected from (C)6-10Aryl group) - (C1-6Alkoxy group), said (C)6-10Aryl group) - (C1-6Alkoxy) is benzyloxy, phenethyloxy, phenylpropyloxy or phenylbutyloxy;
and/or when R3And R4Independently selected from one or more of N, O and S as heteroatoms, and 1-3 heteroatoms, when the number of the heteroatoms is' 5-10 membered heteroaryl-oxy, the 5-10 membered heteroaryl-oxy is pyridyloxy, pyrimidyloxy, pyrazinyloxy, pyridazinyloxy, pyrrolyloxy, imidazolyloxy or pyrazolyloxy;
and/or when R3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of the heteroatoms, and 5-10-membered heteroaryl- (C)1-6Alkoxy), said 5-to 10-membered heteroaryl- (C)1-6Alkoxy) is pyridylmethoxy, pyrazolylethoxy, pyrimidylmethoxy, pyrazinylmethoxy, pyridazinylmethoxy, pyrrolylmethoxy, imidazolylmethoxy or pyrazolylmethoxy;
and/or when R3And R4When the compounds and the carbon atoms connected with the compounds form 4-20-membered heterocyclic alkoxy, the 4-20-membered heterocyclic alkyl is dioxolane, dioxahexane alkyl, 12-crown-4, 15-crown-5 or 18-crown-6;
and/or when R5-1Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R5-1Is (C)1-6Alkoxy group) - (C1-6Alkyl) -said (C)1-6Alkoxy group) - (C1-6Alkyl) -is methoxy-methyl-, ethoxy-methyl-, propoxy-methyl-, isopropoxy-methyl-, n-butoxy-methyl-, isobutoxy-methyl, sec-butoxy-methyl or tert-butoxy-methyl-;
and/or when R5-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or when R5Is unsubstituted or R5-3When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is5-3The number of (a) is 1, 2 or 3;
and/or when R5Is unsubstituted or R5-3When the substituted heteroatom is selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroaryl group has 5-10 members, the heteroaryl group having 5-10 members is pyrazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4-thiadiazolyl;
and/or when R5-4And R5-5Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R7Is unsubstituted or R7-1Substituted C1-6When it is alkyl, said R7-1The number of (a) is 1, 2 or 3;
and/or when R7Is unsubstituted or R7-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R7Is C2-6When alkenyl, said C2-6Alkenyl is
Figure FDA0002921022130000071
Figure FDA0002921022130000072
And/or when R7Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or when R7Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6The alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl;
and/or when R7Is unsubstituted or R7-2Substituted C6-10When aryl is said to R7-2The number of (a) is 1, 2 or 3;
and/or when R7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When it is alkyl, said R7-3The number of (a) is 1, 2 or 3;
and/or when R7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6Alkyl is benzyl;
and/or when R7Is unsubstituted or R7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When it is alkyl, said R7-4The number of (a) is 1, 2 or 3;
and/or when R7Is unsubstituted or R7-4Substituted "hetero atoms selected from one or more of N, O and S, the number of hetero atoms being 1-3"5-to 10-membered heteroaryl-C1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6The alkyl is pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl, pyridazinmethyl, pyrazolylmethyl, pyrrolylmethyl, thienylmethyl, furylmethyl, thiazolylmethyl or imidazolylmethyl;
and/or when R7-2～R7-4Independently selected from unsubstituted or R7-2-1Substituted C1-4When it is alkyl, said R7-2-1The number of (a) is 1, 2 or 3;
and/or when R7-2～R7-4Independently selected from unsubstituted or R7-2-2Substituted C1-4At alkoxy, said R7-2-2The number of (a) is 1, 2 or 3;
and/or when R7-2～R7-4Independently selected from-NR7-2-3R7-2-4When said is-NR7-2-3R7-2-4is-NH2Or
Figure FDA0002921022130000081
And/or when R7-2～R7-4Independently selected from- (C ═ O) R7-2-5When said- (C ═ O) R7-2-5Is composed of
Figure FDA0002921022130000082
And/or when R7-2～R7-4Independently selected from- (C ═ O) NR7-2-6R7-2-7When said- (C ═ O) NR7-2-6R7-2-7Is composed of
Figure FDA0002921022130000083
And/or when R7-2R7-4Independently selected from- (C ═ O) OR7-2-8When said- (C ═ O) OR7-2-8is-COOH or
Figure FDA0002921022130000084
And &Or, when R is7-2～R7-4Independently selected from-S (═ O)2NR7-2-9R7-2-10When the formula is-S (═ O)2NR7-2-9R7-2-10Is composed of
Figure FDA0002921022130000085
And/or when R8-1Is unsubstituted or R8-1-1Substituted C1-6When it is alkyl, said R8-1-1The number of (a) is 1, 2 or 3;
and/or when R8-1Is unsubstituted or R8-1-1Substituted C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R8-1Is C2-6When alkenyl, said C2-6Alkenyl is
Figure FDA0002921022130000086
Figure FDA0002921022130000091
And/or when R8-1Is C3-10When there is a cycloalkyl group, said C3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or when R8-1Is (C)3-10Cycloalkyl) -C1-6When alkyl is present, said (C)3-10Cycloalkyl) -C1-6The alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl;
and/or when R8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When it is alkyl, said R8-1-3The number of (a) is 1, 2 or 3;
and/or when R8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When alkyl, said C6-10aryl-C1-6Alkyl is benzyl or phenethyl;
and/or when R8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When it is alkyl, said R8-1-4The number of (a) is 1, 2 or 3;
and/or when R8-1Is unsubstituted or R8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said 5-to 10-membered heteroaryl-C1-6The alkyl is pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl, pyridazinmethyl, pyrazolylmethyl, pyrrolylmethyl, thienylmethyl, furylmethyl, thiazolylmethyl or imidazolylmethyl;
and/or when R8-1-6Is C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R9～R11Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R12Is C1-6At alkoxy, said C1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
and/or when R12-1～R12-5Is independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R15And R16Independently selected from C1-6When alkyl, said C1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
4. Benzothiophenes of claim 1, having the structure of formula IA compound, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, wherein when R is3And R4Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)1-6Alkoxy) is
Figure FDA0002921022130000092
And/or when R3And R4Together with the carbon atom to which they are attached form "one or more heteroatoms selected from N, O and S, and when the number of heteroatoms is 1-3," 4-20 membered heterocycloalkyl group, said 4-20 membered heterocycloalkyl group is
Figure FDA0002921022130000093
Figure FDA0002921022130000094
And/or when R5Is unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the substituent is unsubstituted or R5-3Substituted heteroaryl is
Figure FDA0002921022130000101
Figure FDA0002921022130000102
And/or when R7Is R7-1Substituted C1-6When it is alkyl, said R7-1Substituted C1-6The alkyl is trifluoromethyl, difluoromethyl,
Figure FDA0002921022130000103
And/or when R7Is unsubstituted or R7-2Substituted C6-10When aryl, said is unsubstituted or R7-2Substituted C6-10Aryl is
Figure FDA0002921022130000104
And/or when R7Is unsubstituted or R7-3Substituted C6-10aryl-C1-6When alkyl, said is unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl is
Figure FDA0002921022130000105
Figure FDA0002921022130000106
And/or when R7Is unsubstituted or R7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C1-6When alkyl, said is unsubstituted or R7-4Substituted heteroaryl-C1-6Alkyl is
Figure FDA0002921022130000107
And/or when R8-1Is R8-1-1Substituted C1-6When it is alkyl, said R8-1-1Substituted C1-6Alkyl is
Figure FDA0002921022130000108
And/or when R8-1Is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6When alkyl, said is unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl is
Figure FDA0002921022130000109
And/or when R8-1Is unsubstituted or R8-1-4Substituted "hetero atomsOne or more selected from N, O and S, and 1-3 hetero atoms of 5-10 membered heteroaryl-C1-6When alkyl, said is unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl is
Figure FDA00029210221300001010
5. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I:
R1is hydrogen;
and/or, R2Is hydrogen, or halogen;
and/or, R3Is halogen, C2-6Alkenyl radical, C1-6Alkoxy, or-NR3-2R3-3；
And/or, R4Is halogen, C1-6Alkoxy radical, C2-6Alkenyl, heterocycloalkyl- (C)1-6Alkoxy), -NR3-2R3-3Or R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;
and/or, R3-2Is hydrogen or C1-4An alkyl group;
and/or, R3-3Is hydrogen or C1-4An alkyl group;
and/or, R5Is- (C ═ O) OR5-1Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
And/or, R5-1Is hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -, or C3-10A cycloalkyl group;
and/or, R5-4Is hydrogen;
and/or, R5-5Is C1-6An alkyl group;
and/or, R7Is hydrogen, unsubstituted or R7-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl, unsubstituted or R7-2Substituted C6-10Aryl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl, or unsubstituted or R7-4Substituted heteroaryl-C1-6An alkyl group;
and/or, R7-1Is halogen, carboxyl, hydroxyl or cyano;
and/or, R7-2Is halogen, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, or-NR7-2-3R7-2-4；
And/or, R7-3Is halogen, cyano, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, or- (C ═ O) NR7-2-6R7-2-7；
And/or, R7-4Is halogen;
and/or, R7-2-1Is halogen;
and/or, R7-2-2Is halogen;
and/or, R7-2-3Is hydrogen;
and/or, R7-2-4Is hydrogen;
and/or, R7-2-6Is hydrogen;
and/or, R7-2-7Is hydrogen;
and/or, R8Is hydrogen, cyano, R8-1O-, or, -NR8-2R8-3；
And/or, R8-1Is hydrogen, unsubstituted or R8-1-1Substituted C1-6Alkyl, unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl, or- (S ═ O)2OR8-1-6；
And/or, R8-1-1Is a hydroxyl group;
and/or, R8-1-3Is halogen;
and/or, R8-1-4Is halogen;
and/or, R8-1-6Is hydrogen or C1-6An alkyl group;
and/or, R8-2Is hydrogen or C1-6An alkyl group;
and/or, R8-3Is hydrogen or C1-6An alkyl group;
and/or X is C ═ O,
Figure FDA0002921022130000111
Wherein, the left end of X is connected with
Figure FDA0002921022130000112
The right end of the L-shaped connecting rod is connected with the L;
and/or, R10Is hydrogen;
and/or, R11Is hydrogen;
and/or, R12Is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2or-NR12-4R12-5；
And/or, R12-1Is C1-6An alkyl group;
and/or, R12-2Is C1-6An alkyl group;
and/or, R12-4Is hydrogen;
and/or, R12-5Is hydrogen;
and/or, R13Is hydrogen;
and/or, R14Is hydrogen;
and/or, when X is
Figure FDA0002921022130000121
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
Or, when X is
Figure FDA0002921022130000122
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
Or, when X is
Figure FDA0002921022130000123
To, R5Independently selected from- (C ═ O) OR5-1；
And/or, R6Is hydrogen;
and/or, R15Is hydrogen, halogen, or, C1-6An alkyl group;
and/or, R16Is hydrogen, halogen, or, C1-6An alkyl group.
6. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I:
R1is hydrogen;
R2is hydrogen, or halogen;
R3is halogen, C2-6Alkenyl radical, C1-6Alkoxy, or-NR3-2R3-3；
R4Is halogen, C1-6Alkoxy radical, C2-6Alkenyl, heterocycloalkyl- (C)1-6Alkoxy), -NR3-2R3-3Or R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;
R3-2is hydrogen or C1-4An alkyl group;
R3-3is hydrogen or C1-4An alkyl group;
R5is- (C ═ O) OR5-1Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
R5-1Is hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -or C3-10A cycloalkyl group;
R5-3is C1-4An alkyl group;
R5-4is hydrogen;
R5-5is C1-6An alkyl group;
R7is hydrogen, unsubstituted or R7-1Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C3-10Cycloalkyl, unsubstituted or R7-2Substituted C6-10Aryl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl or unsubstituted or R7-4Substituted heteroaryl-C1-6An alkyl group;
R7-1is halogen, carboxyl, hydroxyl or cyano;
R7-2is halogen, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy or-NR7-2- 3R7-2-4；
R7-3Is halogen, cyano, unsubstituted or R7-2-1Substituted C1-4Alkyl, unsubstituted or R7-2-2Substituted C1-4Alkoxy, or- (C ═ O) NR7-2-6R7-2-7
R7-4Is halogen;
R7-2-1is halogen;
R7-2-2is halogen;
R7-2-3is hydrogen;
R7-2-4is hydrogen;
R7-2-6is hydrogen;
R7-2-7is hydrogen;
R8is hydrogen, cyano, R8-1O-, or, -NR8-2R8-3；
R8-1Is hydrogen, unsubstituted or R8-1-1Substituted C1-6Alkyl radical, aminoSubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, unsubstituted or R8-1-4Substituted heteroaryl-C1-6Alkyl or- (S ═ O)2OR8-1-6；
R8-1-1Is a hydroxyl group;
R8-1-6is hydrogen or C1-6An alkyl group;
R8-1-2-3is C1-4Alkyl radical
R8-1-2-4Is hydrogen;
R8-1-2-5is hydrogen;
R8-1-3is halogen;
R8-1-4is halogen;
R8-2is hydrogen or C1-6An alkyl group;
R8-3is hydrogen or C1-6An alkyl group;
x is C ═ O,
Figure FDA0002921022130000131
Wherein, the left end of X is connected with
Figure FDA0002921022130000132
The right end of the L-shaped connecting rod is connected with the L;
R10is hydrogen;
R11is hydrogen;
R12is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2or-NR12-4R12-5；
R12-1Is C1-6An alkyl group;
R12-2is C1-6An alkyl group;
R12-4is hydrogen;
R12-5is hydrogen;
R13is hydrogen;
R14is hydrogen;
x and R5Selected from any combination of:
when X is
Figure FDA0002921022130000141
When R is5Is- (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is C ═ O, R5Is- (C ═ O) NR5-4(S＝O)2R5-5Or is unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
when X is
Figure FDA0002921022130000142
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is
Figure FDA0002921022130000143
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is
Figure FDA0002921022130000144
When R is5Independently selected from- (C ═ O) OR5-1；
R6Is hydrogen;
R15is hydrogen, halogen or C1-6An alkyl group;
R16is hydrogen, halogen or C1-6An alkyl group.
7. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I:
R1is hydrogen;
R2is hydrogen or halogen;
R3is C1-6An alkoxy group;
R4is C1-6Alkoxy, heterocycloalkyl- (C)1-6Alkoxy) or R3And R4Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;
R5is- (C ═ O) OR5-1Unsubstituted or R5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
R5-1Is hydrogen, C1-6Alkyl, (C)1-6Alkoxy group) - (C1-6Alkyl) -or C3-10A cycloalkyl group;
R5-3is C1-4An alkyl group;
R5-4is hydrogen;
R5-5is C1-6An alkyl group;
R7is hydrogen, unsubstituted or R7-1Substituted C1-6Alkyl radical, C3-10Cycloalkyl, unsubstituted or R7-3Substituted C6-10aryl-C1-6Alkyl or unsubstituted or R7-4Substituted heteroaryl-C1-6An alkyl group;
R7-1is halogen, hydroxy or cyano;
R7-3is halogen, cyano or unsubstituted or R7-2-1Substituted C1-4Alkyl radical
R7-4Is halogen;
R7-2-1is halogen;
R8is hydrogen, cyano, R8-1O-, or, -NR8-2R8-3；
R8-1Is hydrogen, unsubstituted or R8-1-1Substituted C1-6Alkyl, unsubstituted or R8-1-3Substituted C6-10aryl-C1-6Alkyl, or, unsubstituted or R8-1-4Substituted heteroaryl-C1-6An alkyl group;
R8-1-1is a hydroxyl group;
R8-1-3is halogen;
R8-1-4is halogen;
x is C ═ O,
Figure FDA0002921022130000151
Wherein, the left end of X is connected with
Figure FDA0002921022130000152
The right end of the L-shaped connecting rod is connected with the L;
R10is hydrogen;
R11is hydrogen;
R12is hydroxy, cyano, C1-6Alkoxy, -O (C ═ O) R12-1、-(S＝O)2R12-2or-NR12-4R12-5；
R12-1Is C1-6An alkyl group;
R12-2is C1-6An alkyl group;
R12-4is hydrogen;
R12-5is hydrogen;
R13is hydrogen;
R14is hydrogen;
x and R5Selected from any combination of:
when X is
Figure FDA0002921022130000153
When R is5Is- (C ═ O) NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is C ═ O, R5Is- (C ═ O) NR5-4(S＝O)2R5-5Or is unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
when X is
Figure FDA0002921022130000154
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is
Figure FDA0002921022130000155
When R is5Is- (C ═ O) OR5-1、-(C＝O)NR5-4(S＝O)2R5-5Or- (C ═ O) NR7R8；
When X is
Figure FDA0002921022130000156
When R is5Independently selected from- (C ═ O) OR5-1；
R6Is hydrogen;
R15is hydrogen, halogen or C1-6An alkyl group;
R16is hydrogen, halogen or C1-6An alkyl group.
8. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I: the compound shown in the formula I is any one of the following compounds:
Figure FDA0002921022130000161
Figure FDA0002921022130000171
Figure FDA0002921022130000181
Figure FDA0002921022130000191
Figure FDA0002921022130000201
9. the method for preparing benzothiophenes having the structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, as claimed in claim 1, wherein: the method comprises the following steps:
the method one comprises the following steps:
Figure FDA0002921022130000202
wherein,
R17is hydrogen or C1-6An alkyl group;
R18is R7，R19Is R8(ii) a Or, R18Is R5-4，R19Is R5-5；
R1、R2、R3、R4、R5-4、R5-5、R6、R7、R8、R10And L is as defined in claim 1;
step a: in a solvent, reacting the compound II-1 with the compound III-1 to generate IV;
step b: in a solvent, reacting the compound IV with the compound V to generate a compound I-1;
the second method comprises the following steps:
Figure FDA0002921022130000211
wherein,
y is-NHR11or-NHR13；
R18Is R7，R19Is R8(ii) a Or, R18Is R5-4，R19Is R5-5；
R20is-COOH, or-NHR14；
XaIs composed of
Figure FDA0002921022130000212
R5aIs- (C ═ O) OR5-1、-(C＝O)SR5-2Or, unsubstituted or R5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;
R1、R2、R3、R4、R6、R5-1、R5-2、R5-3、R5-4、R5-5、R7、R8、R11、R13、R14and L is as defined in claim 1;
step c: in a solvent, the compound II-2 and the compound III-2 react to generate a compound I-2;
step d: reacting the compound I-2 with the compound V in a solvent to generate a compound I-3;
the third method comprises the following steps:
Figure FDA0002921022130000213
wherein R is1、R2、R3、R4、R6、R5、R12And L is as defined in claim 1;
step e: in a solvent, reacting a compound II-3 with a compound VI to generate a compound I-4;
the method IV comprises the following steps:
Figure FDA0002921022130000214
wherein R is1、R2、R3、R4、R5-4、R5-5、R6And L is as defined in claim 1;
step f: in a solvent, the compound II-4 reacts with the compound VII to generate the compound I-5.
10. A pharmaceutical composition, which comprises a therapeutically effective amount of one or more benzothiophenes having a structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, as claimed in any one of claims 1 to 8, and a pharmaceutically acceptable adjuvant or carrier.
11. Use of the benzothiophene compound having a structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, as defined in any one of claims 1 to 8, or a pharmaceutical composition thereof as defined in claim 10, in the preparation of a medicament for the prevention and/or treatment of tumors or infectious diseases.
12. Use of the benzothiophene compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or the pharmaceutical composition of claim 10, for the preparation of a vaccine adjuvant for the prevention and/or treatment of tumors or infectious diseases.
13. Use of the benzothiophene compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having the structure represented by formula I, or the pharmaceutical composition of claim 10, for the preparation of an interferon gene stimulating protein agonist.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022002077A1 (en) * 2020-06-30 2022-01-06 上海海和药物研究开发股份有限公司 Aryl aromatic heterocyclic derivative and preparation method therefor and use thereof
US11939343B2 (en) 2019-08-02 2024-03-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070675A2 (en) * 2000-03-24 2001-09-27 Methylgene, Inc. Inhibitors of histone deacetylase
US20040006011A1 (en) * 1996-07-12 2004-01-08 Gour Barbara J. Peptidomimetic modulators of cell adhesion
WO2005039548A2 (en) * 2003-10-15 2005-05-06 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
CN101837127A (en) * 2003-05-05 2010-09-22 前体生物药物股份公司 The application of glutaminyl and glutamate cyclase effector
WO2020059660A1 (en) * 2018-09-20 2020-03-26 日清食品ホールディングス株式会社 Compound having enac activation potency
CN111393404A (en) * 2019-01-02 2020-07-10 中国科学院上海药物研究所 Benzothiophene compounds, and pharmaceutical composition and application thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006011A1 (en) * 1996-07-12 2004-01-08 Gour Barbara J. Peptidomimetic modulators of cell adhesion
WO2001070675A2 (en) * 2000-03-24 2001-09-27 Methylgene, Inc. Inhibitors of histone deacetylase
CN101837127A (en) * 2003-05-05 2010-09-22 前体生物药物股份公司 The application of glutaminyl and glutamate cyclase effector
WO2005039548A2 (en) * 2003-10-15 2005-05-06 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
WO2020059660A1 (en) * 2018-09-20 2020-03-26 日清食品ホールディングス株式会社 Compound having enac activation potency
CN111393404A (en) * 2019-01-02 2020-07-10 中国科学院上海药物研究所 Benzothiophene compounds, and pharmaceutical composition and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AGNIESZKA TAFELSKA-KACZMAREK 等: "Highly Asymmetric Reduction of New Benzofuryl and Benzothiophenyl α-Amino Ketones", 《INTERNATIONAL ELECTRONIC CONFERENCE ON SYNTHETIC ORGANIC CHEMISTRY》 *
DMITRY A. ANDROSOV 等: "A convenient approach towards 2- and 3-aminobenzo[b]thiophenes", 《TETRAHEDRON》 *
NOBUYUKI MATSUNAGA 等: "C17,20-Lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11939343B2 (en) 2019-08-02 2024-03-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
WO2022002077A1 (en) * 2020-06-30 2022-01-06 上海海和药物研究开发股份有限公司 Aryl aromatic heterocyclic derivative and preparation method therefor and use thereof

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