Aromatic fused-ring derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to an aromatic fused-ring derivative, a preparation method therefor, and a pharmaceutical use of a pharmaceutical composition containing the derivative. Specifically, the present invention relates to a fused-ring derivative as represented by general formula (I), a preparation method therefor, and a pharmaceutically acceptable salt thereof, as well as a use thereof as a therapeutic agent, particularly as a WRN inhibitor. Definitions of each substituent in general formula (I) are the same as the definitions thereof in the description.

Description

Aromatic annulated derivatives, methods of preparation and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to the following patent applications: 1) a patent application entitled “Aromatic annulated derivatives, methods of preparation and uses thereof” filed on August 5, 2024, with the China National Intellectual Property Office, application number CN202411064260.5; 2) a patent application entitled “Aromatic annulated derivatives, methods of preparation and uses thereof” filed on August 21, 2024, with the China National Intellectual Property Office, application number CN202411147542.1; and 3) a patent application entitled “Aromatic annulated derivatives, methods of preparation and uses thereof” filed on September 27, 2024, with the China National Intellectual Property Office, application number CN202411356411.4, the contents of all of the above patent applications are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application relates to a kind of aromatic annulated derivatives, its preparation method and the pharmaceutical composition containing the derivative and its purposes as therapeutic agent, especially as WRN inhibitor. BACKGROUND

[0004] WRN of human is composed of 1432 amino acid residues, and contains five important components from N-terminal to C-terminal—exonuclease domain, ATPase domain, RecQ carbon terminal domain, helicase / ribonuclease D carbon terminal domain and nuclear localization signal. Among the five helicases of RecQ in human body, WRN is the only one with 3'→5' exonuclease activity, which is realized by the specific activation of its N-terminal exonuclease domain by Ku70 / 80 complex bound to DNA ends. The ATPase domain is the largest and most conserved component in the RecQ helicase family, which acts as an ATP-dependent DNA translocation module by binding and hydrolyzing ATP. The RecQ carbon terminal domain is the main site of DNA binding and catalyzes the unwinding of DNA double strands. Therefore, the ATPase domain and the RecQ carbon terminal domain together constitute the core of WRN helicase. WRN is a DNA helicase with multiple enzyme activities that can bind to DNA and other proteins. This makes the enzyme play an important role in maintaining the integrity and stability of the genome, including participating in DNA damage repair, replication and transcription, and maintaining telomere and heterochromatin stability.

[0005] Synthetic lethality refers to the phenomenon that two non-lethal genes are simultaneously inhibited (inhibited forms include gene defects such as gene mutation, gene silencing, and / or molecular perturbations such as gene expression knock-out, drug inhibition) to cause cell death. Using this mechanism, a specific mutation in cancer is found, and its "synthetic lethal partner" is found and inhibited, thereby specifically killing cancer cells with the mutation.

[0006] Studies have shown that WRN is a "synthetic lethal partner" of high microsatellite instability (MSI-H), a type of genomic damage. High microsatellite instability (MSI-H) is a hyper-variable state caused by frequent insertion and / or deletion mutations in nucleotide repeat regions due to defects in DNA mismatch repair (MMR), which is commonly seen in endometrial cancer (31%), colorectal cancer (25%), and gastric cancer (19%) and other cancers. In MSI-H cancer cells, thymine / adenine dinucleotide (TA) repeat sequences are highly unstable and undergo large-scale amplification, forming non-canonical right-handed double helix (non-B) DNA secondary structures (such as cruciform and G-quadruplex), which require WRN-specific unwinding to complete replication. In the absence of WRN, these DNA secondary structures are cut by the MUS81-EME1-SLX4 endonuclease complex, leading to extensive DNA end resection, depletion of replication protein A (RPA), chromosomal fragmentation, and cell death. In addition, in tumor models with MMR defects, the absence of WRN leads to the activation of multiple DNA damage signaling markers, inducing cell cycle arrest and apoptosis, thereby inhibiting the proliferation of tumor cells. Recent studies have shown that WRN small molecule inhibitors can specifically cause tumor regression in MSI-H tumor models, but have no effect in microsatellite stable (MSS) tumor models. Therefore, small molecule chemicals that can inhibit WRN helicase activity are expected to become a new method for effectively treating MSI-H cancer.

[0007] There is no drug on the market for WRN target inhibitors. Tumors still lack effective treatment drugs, which are a serious threat to human health, and there is still a huge unmet clinical need. SUMMARY

[0008] To solve the above technical problems, the present application provides a compound represented by general formula (I) or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof:

[0009] wherein:

[0010] is a 5-membered heteroaromatic ring;

[0011] X is selected from C and N;

[0012] Y is selected from O, S, N and NR a ;

[0013] R a is a hydrogen atom or a C 1-6 alkyl group or a C 3-6 cycloalkyl group, wherein said C 1-6 alkyl group or C 3-6 cycloalkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano or C 1-6 alkoxy;

[0014] Ring A is selected from C 6-10 aryl, 5- to 12-membered heterocyclyl, C 5-12 cycloalkyl and 5- to 6-membered heteroaryl;

[0015] L is selected from -C(=O)-, -C(=O)NR b -, -S(=O)2NR c - and -NR d C(=O)NR e -;

[0016] R b , R c , R d , R e are each independently selected from a hydrogen atom, a deuterium atom and a C 1-6 alkyl group;

[0017] W is selected from the following groups:

[0018] with the proviso that, when W is selected from L is -C(=O)-;

[0019] the bond indicates may exist as (Z)- or (E)-stereoisomers, wherein * indicates the point of attachment;

[0020] R f are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group and a 5- to 10-membered heterocyclyl group; wherein C 1-6 alkyl group, C 3-8Cycloalkyl or 5-10-membered heterocyclic groups optionally further selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0021] R g Each atom is independently selected from hydrogen atoms and deuterium atoms, preferably hydrogen atoms;

[0022] R 3a R 3b Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl;

[0023] R 4a Each is independently selected from C 1-6 Alkyl and C 1-6 Alkoxy, where C 1-6 Alkyl or C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0024] R 4b Each is independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 5-10 membered heterocyclic groups; wherein C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10-membered heterocyclic groups optionally further selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0025] R h R i Each is independently selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, and C. 1-6 Substituents of alkoxy groups;

[0026] R 1 Selected from hydrogen atoms, C 3-8 cycloalkyl, -OR A and S(O) r R A The C mentioned therein 3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -SF5, -OR 5 , -OC(=0)R 5 , -C(=0)R 5 , -C(=0)OR 5 , -N(R 6 )C(=0)R 7 , -N(R 6 )C(=0)OR 7 , -NR 6 R 7 , -C(=0)NR 6 R 7 , -S(=0) r NR 6 R 7 , and -S(=0) r R 5 ;

[0027] R A is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -SF5, -OR 5 , -OC(=0)R 5 , -C(=0)R 5 , -C(=0)OR 5 , -N(R 6 )C(=0)R 7 , -N(R 6 )C(=0)OR 7 , -NR 6 R 7 , -C(=0)NR 6 R 7 , -S(=0) r NR 6 R 7 , and -S(=0) r R 5 ;

[0028] R 2the same or different, are each independently selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a 5-10 membered heterocyclyl group, a C 6-10 aryl group, a 5-6 membered heteroaryl group, -SF5, -OR 5 , -OC(=O)R 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -S(=O) r NR 6 R 7 or -S(=O) r R 5 , wherein the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3- cycloalkyl group, the 5-10 membered heterocyclyl group, the C 6-10 aryl group, and the 5-6 membered heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR 8 , =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 , -N(R 9 )C(=O)R 10 , and -N(R 9 )C(=O)OR 10 ;

[0029] or, two R 2 together with the same carbon atom to which they are attached form a -C(=O);

[0030] or, two R 2with the atom to which it is attached forms a C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of deuterium atom, hydroxy, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 , -N(R 9 )C(=0)R 10 , and -N(R 9 )C(=0)OR 10 ;

[0031] R 5 each independently is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium atom, hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 , and -N(R 9 )C(=0)R 10 ;

[0032] R 6 and R 7 each independently is selected from the group consisting of hydrogen atom, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10-C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R 9 )C(=O)R 10 ;

[0033] or R 6 and R 7 , together with the atom to which they are attached, form a 4-8 membered heterocyclyl containing one or more N, O or S(=O) r , wherein said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 , and -N(R 9 )C(=O)R 10 ;

[0034] R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and carboxylate;

[0035] m is 1, 2, or 3;

[0036] n is 0, 1, 2, 3, or 4; and

[0037] each r is independently 0, 1, or 2.

[0038] In a preferred embodiment of the present application, a compound of Formula (I) or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, wherein L is -C(=O)NR b -, R b is as defined in Formula (I).

[0039] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein W is selected from... Where R g R f R 3a R 3b Or R 4b The definition is as stated in general formula (I).

[0040] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof is:

[0041] Where: R 3a R 3b Hydrogen atoms; X, Y, rings A and R b R g R f R 4b R 1 R 2 Or n is defined as in general formula (I).

[0042] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R b Selected from hydrogen atoms and methyl groups.

[0043] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R f Selected from C 3-8 Cycloalkyl, preferably cyclopropyl.

[0044] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 4b Selected from C 1-6 Alkyl group, preferably methyl group.

[0045] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 1 Selected from -OR A R A C is preferred 6-10 Aryl, more preferably phenyl.

[0046] In a preferred embodiment of the present application, a compound of general formula (I) or (II) or a stereoisomer, a tautomer, a deuterated form or a pharmaceutically acceptable salt thereof, wherein is selected from R a is selected from a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a trifluoroethyl group or a cyclopropyl group.

[0047] In a preferred embodiment of the present application, a compound of general formula (I) or (II) or a stereoisomer, a tautomer, a deuterated form or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a phenyl group, a C 5-6 cycloalkyl group, a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group.

[0048] In a preferred embodiment of the present application, a compound of general formula (I) or (II) or a stereoisomer, a tautomer, a deuterated form or a pharmaceutically acceptable salt thereof, wherein is selected from the following groups:

[0049] R a is selected from a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a trifluoroethyl group and a cyclopropyl group.

[0050] In a preferred embodiment of the present application, a compound of general formula (I) or (II) or a stereoisomer, a tautomer, a deuterated form or a pharmaceutically acceptable salt thereof, wherein R 2 are each independently selected from a hydroxyl group, a halogen, a cyano group, a C 1-6 alkyl group and a C 1-6 alkoxy group; wherein said C 1-6 alkyl group or C 1-6 alkoxy group is optionally further substituted by one or more halogens.

[0051] In a preferred embodiment of the present application, a compound of general formula (I) or (II) or a stereoisomer, a tautomer, a deuterated form or a pharmaceutically acceptable salt thereof, wherein R 2 are each independently selected from a hydroxyl group, a fluorine, a chlorine, a bromine, a cyano group, a methyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group and a trifluoromethoxy group.

[0052] In a preferred embodiment of the present application, a compound of general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is selected from:

[0053] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0054] Note: If there is a discrepancy between the structure drawn and the name given for the structure, the structure drawn is the correct one.

[0055] Further, the present application provides a pharmaceutical composition comprising a compound of general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0056] The present application provides use of a compound of general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a WRN inhibitor.

[0057] The present application also provides use of a compound of general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a WRN-mediated disease, wherein the WRN-mediated disease is preferably a microsatellite instability-high (MSI-H) cancer; wherein the WRN-mediated disease is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia and glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

[0058] The present application further provides use of a compound of general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a microsatellite instability-high (MSI-H) cancer.

[0059] The present application provides use of a compound of general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a WRN-mediated disease, wherein the WRN-mediated disease is preferably a microsatellite instability-high (MSI-H) cancer; wherein the WRN-mediated disease is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia and glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

[0060] Accordingly, the present application also provides a method for treating or preventing a WRN-mediated disease, comprising administering to a subject in need thereof a compound according to the general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. The WRN-mediated disease is preferably a microsatellite instability-high (MSI-H) cancer. Accordingly, the present application also provides a method for treating or preventing a microsatellite instability-high (MSI-H) cancer, comprising administering to a subject in need thereof a compound according to the general formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. The WRN-mediated disease can be selected from the group consisting of colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia and glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

[0061] Detailed description of the application

[0062] Unless otherwise indicated, the following terms used in the specification and claims have the following definitions:

[0063] "Alkyl" when used as a group or part of a group refers to a straight-chain or branched- chain alkyl radical having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Alkyl groups can be optionally substituted. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted. 20 straight-chain or branched-chain aliphatic hydrocarbon group. Preferably, the aliphatic hydrocarbon group is a C1-C6alkyl group. Aliphatic hydrocarbon groups can be optionally substituted. 10 Alkyl, more preferably C1-C6alkyl and C1-C4alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0064] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1- propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Preferably, C2-C4alkenyl. Alkenyl groups can be optionally substituted or unsubstituted.

[0065] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0066] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms, and the ring contains 0, 1, or more double bonds, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having a 3- to 7-membered monocyclic ring or a 5- to 18-membered bicyclic or tricyclic ring. In this document, cycloalkyl can be C 3-12 Cycloalkyl groups, for example, cycloalkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; in some embodiments, the cycloalkyl group may be C16-126. 5-12 cycloalkyl, C 3-6 cycloalkyl, C 3-7 cycloalkyl, C 3-8 cycloalkyl or C 5-6 Cycloalkyl group. In some embodiments, the cycloalkyl group is cyclopropyl.

[0067] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,

[0068] Monocyclic alkyl groups can be substituted or unsubstituted.

[0069] "Spirocycloalkyl" refers to a polycyclic group consisting of 5 to 18 quintiles, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, containing 0, 1, or more double bonds within the rings, but without any ring having fully conjugated π electrons. Preferably, it is a 6 to 14 quintile group, more preferably a 7 to 10 quintile group. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospiro, bispiro, or polyspirocycloalkyl groups, preferably monospiro and bispirocycloalkyl groups, and preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 quintile groups. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spirocycloalkyl groups can be substituted or unsubstituted.

[0070] "Condensed ring alkyl" refers to a fully carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings can contain 0, 1 or multiple double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 14 members, more preferably 6 to 10 members. It can be classified as bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl according to the number of rings, preferably bicyclic or tricyclic, more preferably 3 / 5, 5 / 5 or 5 / 6 bicyclic condensed ring alkyl. Non-limiting examples of "condensed ring alkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradeca-hydrophenanthryl, Condensed ring alkyl can be substituted or unsubstituted.

[0071] "Bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures sharing two non-adjacent carbon atoms with each other, 1, 2 or 3 rings can contain 0, 1 or multiple double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 14 members, more preferably 7 to 10 members. It can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged ring alkyl according to the number of rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged ring alkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, Bridged ring alkyl can be substituted or unsubstituted.

[0072] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to non-aromatic heterocyclic groups in which 1 or 2 or 3 ring-forming atoms are selected from nitrogen, oxygen and S(O) r (wherein r is selected from 0, 1 and 2) heteroatoms, containing 0, 1 or multiple double bonds within the ring, including monocyclic, polycyclic, condensed ring, bridged ring and spirocyclic. The heterocyclyl groups herein can contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. In some embodiments, the heterocyclyl group contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl group has a ring member count of 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In some embodiments, the heterocyclyl group is a 3-12 membered heterocyclyl group, a 3-10 membered heterocyclyl group, a 5-12 membered heterocyclyl group, a 5-10 membered heterocyclyl group, a 3-7 membered heterocyclyl group, a 4-8 membered heterocyclyl group, or a 5-6 membered heterocyclyl group.

[0073] Heterocyclyl can be substituted or unsubstituted.

[0074] Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, azetidinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidinyl,

[0075] "Spiroheterocyclyl" refers to a polycyclic radical of 5 to 18 members, two or more ring structures, and one atom in common between the single rings, containing 0, 1, or multiple double bonds within the ring, but no ring having a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r wherein r is selected from 0, 1, or 2, and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Spiroalkyls are classified as mono-, bi-, or polyspiroheterocyclyl, preferably mono- and bi-spiroheterocyclyl, based on the number of spiro atoms in common between the rings. More preferably 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, or 6 / 6 monospiroheterocyclyl. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0076] "Fused heterocyclyl" refers to a polycyclic radical of two or more ring structures sharing a pair of atoms in common between the single rings, one or more rings can contain 0, 1, or multiple double bonds, but no ring having a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r wherein r is selected from 0, 1, or 2, and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Fused heterocyclyls are classified as bi-, tri-, tetra-, or polycyclic, preferably bi- or tri-, more preferably 5 / 5 or 5 / 6 bicyclic fused heterocyclyl, based on the number of rings comprising the ring. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine,

[0077] "bridged heterocyclyl" means a polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two non-adjacent atoms with each other, one or more rings can contain 0, 1 or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r ranging from 6 to 14 members, more preferably from 7 to 10 members. Depending on the number of rings, it can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0078] "aryl" means a carbocyclic aromatic system containing one or two rings, wherein the rings can be connected together in a fused manner. The term "aryl" includes mono- or bicyclic aromatic groups such as the aromatic groups of phenyl, naphthyl, tetrahydronaphthyl. Preferably, aryl is C6-C 10 aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0079] "Heteroaryl" means an aromatic 5- to 6-membered monocyclic ring or 8- to 10-membered bicyclic ring, which can contain 1 to 4 (1, 2, 3, or 4) atoms selected from nitrogen, oxygen, and sulfur. Preferred heteroaryls are 6- to 10-membered heteroaryls or 5- to 6-membered heteroaryls, which can contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzoimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyrid-2(lH)-ononyl, pyrimidinyl, pyrazin-2(lH)-ononyl, pyrimidin-4(3H)-ononyl, pyrimidin-2(lH)-ononyl, pyridazin-3(2H)-ononyl, lH-indolyl, lH-benzo[d]imidazolyl, lH-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridinyl, furan[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thiophenyl, lH-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl,

[0080] Heteroaryl can be substituted or unsubstituted.

[0081] "Fused ring" means a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, at least one of which has an aromatic system of completely conjugated π electrons, while 1, 2, or 3 can contain 0, 1, or multiple double bonds, but at least one ring does not have an aromatic system of completely conjugated π electrons, in which the ring atoms are selected from 0, 1, or multiple atoms selected from nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. Fused rings preferably include bicyclic or tricyclic fused rings, wherein bicyclic fused rings are preferably those of aryl or heteroaryl with monocyclic heterocyclyl or monocyclic cycloalkyl. Preferred are 6- to 14-membered, more preferably 8- to 10-membered. Examples of "fused ring" include, but are not limited to:

[0082] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0083] "Alkylthio" refers to a (alkyl-S-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc.

[0084] "Nitro" refers to the -NO2 group.

[0085] "Hydroxy" refers to the -OH group.

[0086] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0087] "Amino" refers to -NH2.

[0088] "Hydroxyamino group" refers to -NHOH.

[0089] “Cyano” refers to -CN.

[0090] "Benzyl" refers to -CH2-phenyl.

[0091] "Carboxyl group" refers to -C(=O)OH.

[0092] "Carboxylic acid ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0093] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0094] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0095] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0096] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0097] In this document, for groups involving alkyl groups, such as alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxy and alkylthio, the corresponding groups of C1-C6 are preferred, or the corresponding groups of C1-C4, such as C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy and C1-C6 alkylthio.

[0098] "DMSO" refers to dimethyl sulfoxide.

[0099] "BOC" means tert-butyloxycarbonyl.

[0100] "Bn" means benzyl.

[0101] "THP" means 2-tetrahydropyranyl.

[0102] "TFA" means trifluoroacetic acid.

[0103] "Ts" means p-toluenesulfonyl.

[0104] "Bn" means benzyl.

[0105] "SEM" means (trimethylsilyl)ethoxymethyl.

[0106] "formyl" means

[0107] "leaving group", or leaving group, is an atom or functional group that departs from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that readily accept electrons and bear a negative charge well are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the more readily the leaving group departs from other molecules. This is because the smaller the pKa of its conjugate acid, the greater the tendency of the corresponding leaving group to exist as an anion (or a neutral leaving group) without bonding to other atoms. Common leaving groups include, but are not limited to, halogens, mesylate, -OTs, or -OH.

[0108] "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of one another replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by the person skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0109] In the present application, "one or more" means 1 or 2 or more, e.g. 1, 2, 3, 4, or 5 or more.

[0110] "substituted" or "substituted" as used herein, means that the group can be substituted with one or more substituents selected from the group consisting of deuterium atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylate, SF5, =0, -OR 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -CH2NHC(=O)OR 5 , -CH2NR 6 R 7 , -S(=O) r NR 6 R 7 or -S(O) r R 5 ;

[0111] R 5 each independently is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with 1, 2 or 3 substituents selected from deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 and -N(R 9 )C(=O)R 10 ;

[0112] R 6 and R 7each independently is selected from a hydrogen atom, a hydroxy group, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with 1, 2, or 3 substituents selected from a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 , and -N(R 9 )C(=0)R 10 ;

[0113] or, R 6 and R 7 together with the atom to which they are attached form a 4-8 membered heterocyclyl group containing 1, 2, or 3 N, O, or S(=0) r atoms, wherein said 4-8 membered heterocyclyl group is optionally further substituted with 1, 2, or 3 substituents selected from a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 , and -N(R 9 )C(=0)R 10 ;

[0114] R 8 , R 9 , and R 10 each independently is selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with 1, 2, or 3 substituents selected from a hydroxy group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group, and a carboxylate group;

[0115] each r is independently 0, 1, or 2.

[0116] In the present text, a wavy line in a group generally indicates the position at which the group is attached to the compound.

[0117] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, and atropisomeric forms and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present application.

[0118] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., diastereomeric, enantiomeric, and atropisomeric forms and geometric (conformational) isomers) and tautomeric forms of the structure; for example, structures having R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (conformational) mixtures of the present compounds are within the scope of the present application.

[0119] "Pharmaceutically acceptable salts" means salts of the above compounds which retain the biological activity of the parent compound and which are suitable for medical use. The pharmaceutically acceptable salts of the compounds of Formula (I) can be metal salts, amine salts with suitable acids.

[0120] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or physiologically acceptable salts or prodrugs thereof with other chemical components, such as physiologically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism. DETAILED DESCRIPTION

[0121] The following examples are intended to further describe the present application but are not intended to limit the scope of the application.

[0122] EXAMPLES

[0123] The examples below provide preparations of representative compounds of Formula (I) and related structural identification data. It must be understood that the examples described below are intended to illustrate the application and not to limit it. 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm using tetramethylsilane as internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. If coupling constants are given, they are in Hz.

[0124] Mass spectra were recorded on a LC / MS instrument, using either ESI or APCI ionization.

[0125] Thin layer chromatography silica gel plates were purchased from Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin layer chromatography (TLC) were 0.15 mm to 0.2 mm in thickness. The silica gel plates used in thin layer chromatography for purification were 0.4 mm to 0.5 mm in thickness.

[0126] Column chromatography generally used Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

[0127] In the following examples, all temperatures are in degrees Celsius, unless otherwise indicated. Unless otherwise indicated, all starting materials and reagents were obtained from commercial suppliers such as Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzhan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd., and used without further purification, unless otherwise indicated.

[0128] CD3OD: deuterated methanol.

[0129] CDCl3: deuterated chloroform.

[0130] DMSO-d6: deuterated dimethyl sulfoxide.

[0131] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a volume of about 1 L.

[0132] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0133] The compounds were purified by silica gel column chromatography and reverse phase column chromatography, and the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvents is different according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added for adjustment, such as acetic acid or triethylamine, etc.

[0134] Example 1

[0135] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzo[b]thiophene-2-carboxamide

[0136] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzo[b]thiophene-2-carboxamide (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzo[b]thiophene-2-carboxamide

[0137] First Step

[0138] methyl 3-phenoxybenzo[b]thiophene-2-carboxylate

[0139] 3-Phenoxybenzo[b]thiophene-2-carboxylic acid

[0140] Methyl 3-phenoxybenzo[b]thiophene-2-carboxylate 1c (34.0 mg, 119.6 pmol) was dissolved in methanol (2 mL), water (2 mL), sodium hydroxide (24 mg, 598 pmol) was added, and the reaction was stirred at 25 °C for 1 h. The reaction was diluted with ethyl acetate (10 mL) and quenched with 0.5 M aqueous hydrochloric acid (5 mL). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-Phenoxybenzo[b]thiophene-2-carboxylic acid Id (27.0 mg), 84% yield, which was used directly in the next step.

[0141] MS m / z (ESI): [M+H] + = 285.0

[0142] Second Step

[0143] 3-Phenoxybenzo[b]thiophene-2-carboxylic acid

[0144] 3-Phenoxybenzo[b]thiophene-2-carboxylic acid

[0145] Methyl 3-phenoxybenzo[b]thiophene-2-carboxylate 1c (34.0 mg, 119.6 pmol) was dissolved in methanol (2 mL), water (2 mL), sodium hydroxide (24 mg, 598 pmol) was added, and the reaction was stirred at 25 °C for 1 h. The reaction was diluted with ethyl acetate (10 mL) and quenched with 0.5 M aqueous hydrochloric acid (5 mL). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-Phenoxybenzo[b]thiophene-2-carboxylic acid Id (27.0 mg), 84% yield, which was used directly in the next step.

[0146] MS m / z (ESI): [M+H] + = 271.0

[0147] Third Step

[0148] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzo[b]thiophene-2-carboxamide

[0149] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzo[b]thiophene-2-carboxamide

[0150] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzo[b]thiophene-2-carboxamide 18 , 19*250mm, 10μm; mobile phase A: 0.1% FA / H20, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzo[b]thiophene-2-carboxamide 1 (18 mg) in 42% yield.

[0151] MS m / z (ESI): [M+H] + = 428.3

[0152] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.48 - 7.44 (m, 1H), 7.42 - 7.35 (m, 3H), 7.16 - 7.10 (m, 1H), 7.06 - 7.02 (m, 2H), 6.81 - 6.75 (m, 1H), 6.67 - 6.60 (m, 1H), 4.05 - 3.97 (m, 1H), 2.93 (s, 3H), 1.13 - 1.01 (m, 1H), 0.53 - 0.42 (m, 1H), 0.39 - 0.23 (m, 2H), 0.19 - 0.10 (m, 1H) ppm.

[0153] Examples 2-5 were synthesized according to the synthetic procedure of Example 1, with the specific structures and characterization shown in the table below: Examples 2-5 were synthesized according to the synthetic procedure of Example 1, with the specific structures and characterization shown in the table below:

[0154] The compound of Example 4 can also be prepared by the following method:

[0155] First Step

[0156] methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate-1-oxide

[0157] methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate-1-oxide

[0158] Methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate-1-oxide 4b (100 mg) was obtained by the reaction of methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate 4a (500 mg, 2.04 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) at 0 °C, slowly dropwise adding 30% mass fraction hydrogen peroxide solution (231.2 mg, 2.04 mmol), and continuing the reaction at room temperature for 16 hours. The reaction liquid was poured into ice water (50 mL), extracted with dichloromethane (25 mL x 2), and the combined organic phase was washed with saturated sodium bicarbonate solution (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (eluent: A system) to obtain methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate-1-oxide 4b (100 mg) in a yield of 18.8%.

[0159] MS m / z (ESI): [M+H] + = 261.0

[0160] Second Step

[0161] methyl 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylate-1-oxide

[0162] methyl 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylate-1-oxide

[0163] Phenol 1b (54.15 mg, 575.44 μmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (60% mass fraction, 22.05 mg, 575.44 μmol) was added at 0 °C, and the reaction was carried out for half an hour under nitrogen protection. The reaction solution was slowly added dropwise to a tetrahydrofuran (5 mL) solution of 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylic acid methyl ester-1-oxide 4b (100 mg, 383.63 μmol) at 0 °C, and the reaction was continued for half an hour at 0 °C. The reaction solution was quenched by adding ice water (50 mL), extracted with dichloromethane (25 mL x 2), and the combined organic phase was washed with saturated ammonium chloride solution (20 mL) and saturated saline solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (eluent: A system) to obtain 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid methyl ester-1-oxide 4c (70 mg) with a yield of 57.3%.

[0164] MS m / z (ESI): [M+H] + = 319.1

[0165] Third step

[0166] 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid methyl ester-1-oxide

[0167] 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid methyl ester-1-oxide

[0168] 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid methyl ester-1-oxide 4c (70 mg, 219.91 μmol) was dissolved in acetonitrile (5 mL), and sodium iodide (164.81 mg, 1.10 mmol) and trimethylsilyl chloride (119.45 mg, 1.10 mmol) were added. The reaction was carried out at room temperature for 16 hours under nitrogen protection. The reaction solution was added with water (50 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic phase was washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid methyl ester 4d (60 mg), which was directly used in the next step.

[0169] MS m / z (ESI): [M+H] + = 303.1

[0170] Fourth step

[0171] 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid

[0172] 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid

[0173] Methyl 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylate 4d (60 mg, 198.47 μmol) and lithium hydroxide monohydrate (83.28 mg, 1.98 mmol) were added into a mixed solvent of water (1 mL) and tetrahydrofuran (4 mL), and the reaction was carried out at room temperature for 3 hours. The pH was adjusted to 6 by adding 0.5 M hydrochloric acid solution, and dichloromethane (25 mL x 2) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid 4e (52 mg), which was directly used in the next step.

[0174] MS m / z (ESI): [M+H] + = 289.1

[0175] Fifth step

[0176] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxamide

[0177] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxamide

[0178] Methyl 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylate 4d (60 mg, 198.47 μmol) and lithium hydroxide monohydrate (83.28 mg, 1.98 mmol) were added into a mixed solvent of water (1 mL) and tetrahydrofuran (4 mL), and the reaction was carried out at room temperature for 3 hours. The pH was adjusted to 6 by adding 0.5 M hydrochloric acid solution, and dichloromethane (25 mL x 2) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-fluoro-3-phenoxybenzo[b]thiophene-2-carboxylic acid 4e (52 mg), which was directly used in the next step.

[0179] MS m / z(ESI):[M+H] + =446.1

[0180] 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=8.2Hz,1H),8.04(dd,J=9.3,2.3Hz,1H),7.47(dd,J=8.9 ,5.1Hz,1H),7.37(t,J=7.8Hz,2H),7.29(td,J=9.0,2.4Hz,1H),7.13(t,J=7.4Hz,1H),7.05 (d,J=8.1Hz,2H),6.78(dd,J=15.3,5.3Hz,1H),6.63(d,J=15.3Hz,1H),4.04-3.96(m,1H),2 .93(s,3H),1.11-1.03(m,1H),0.52-0.43(m,1H),0.34-0.24(m,2H),0.16-0.09(m,1H)ppm.

[0181] Example 6

[0182] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxy-1H-indole-2-carboxamide

[0183] (S,E)-N-(1-Cyclopropyl-3-(Methanesulfonyl)allyl)-3-phenoxy-1H-indole-2-carboxamide

[0184] first step

[0185] ethyl 3-diazo-3H-indole-2-carboxylate

[0186] Ethyl 3-azo-3H-indole-2-carboxylate

[0187] Acetic acid (3.97 g, 66.06 mmol, 3.78 mL) was added dropwise to a suspension of ethyl 1H-indole-2-carboxylate 6a (1 g, 5.29 mmol) and sodium nitrite (4.01 g, 58.14 mmol) in dichloromethane (30 mL). The reaction mixture was reacted at 25 °C for 16 hours under a nitrogen atmosphere. The reaction solution was quenched in water (40 mL), extracted with dichloromethane (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium bicarbonate (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 3-azo-3H-indole-2-carboxylate 6b (1.2 g), with a yield of 73.9%.

[0188] (ESI): [M+H] + = 216.2

[0189] Second Step

[0190] ethyl 3-phenoxy-1H-indole-2-carboxylate

[0191] 3-phenoxy-1H-indole-2-carboxylate

[0192] Ethyl 3-phenoxy-1H-indole-2-carboxylate 6c (150 mg, 533.23 pmol) and sodium hydroxide (63.98 mg, 1.60 mmol) were added to a mixture solution of water (2 mL) and tetrahydrofuran (2 mL), and reacted at 25 °C for 12 hours. The reaction solution was adjusted to pH 6 with hydrochloric acid (0.5 M), extracted with ethyl acetate (15 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3-phenoxy-1H-indole-2-carboxylic acid 6d (135 mg) with a yield of >99%.

[0193] MS m / z (ESI): [M+H] + = 282.1

[0194] Third Step

[0195] 3-phenoxy-1H-indole-2-carboxylic acid

[0196] 3-phenoxy-1H-indole-2-carboxylic acid

[0197] Ethyl 3-phenoxy-1H-indole-2-carboxylate 6c (150 mg, 533.23 pmol) and sodium hydroxide (63.98 mg, 1.60 mmol) were added to a mixture solution of water (2 mL) and tetrahydrofuran (2 mL), and reacted at 25 °C for 12 hours. The reaction solution was adjusted to pH 6 with hydrochloric acid (0.5 M), extracted with ethyl acetate (15 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3-phenoxy-1H-indole-2-carboxylic acid 6d (135 mg) with a yield of >99%.

[0198] MS m / z (ESI): [M+H] + = 253.9

[0199] Fourth Step

[0200] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxy-1H-indole-2-carboxamide

[0201] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxy-1H-indole-2-carboxamide

[0202] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxy-1H-indole-2-carboxamide 18 , 19*250mm, 10μm; mobile phase A: 0.1% FA / H20, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxy-1H-indole-2-carboxamide 6 (124.7 mg) in 66.9% yield.

[0203] MS m / z (ESI): [M+H] + = 411.3.

[0204] 1 H NMR (400 MHz, MeOH-d4) δ 7.47 (d, J = 8.4 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.30 - 7.23 (m, 1H), 7.22 - 7.17 (m, 1H), 7.15 - 7.10 (m, 1H), 7.09 - 7.05 (m, 2H), 7.03 - 6.98 (m, 1H), 6.91 (dd, J = 15.2, 4.8 Hz, 1H), 6.50 (dd, J = 15.2, 1.7 Hz, 1H), 4.16 - 4.06 (m, 1H), 2.88 (s, 3H), 1.11 - 1.01 (m, 1H), 0.67 - 0.59 (m, 1H), 0.49 - 0.35 (m, 2H), 0.33 - 0.26 (m, 1H) ppm.

[0205] Following the synthesis method of Example 6, Examples 7-15 were synthesized, and their specific structures and characterizations are shown in the table below:

[0206] Example 16

[0207] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-3-phenoxy-1H-indole-2-carboxamide

[0208] (S,E)-N-(1-Cyclopropyl-3-(Methanesulfonyl)allyl)-1-Methyl-3-phenoxy-1H-indole-2-carboxamide

[0209] first step

[0210] ethyl 1-methyl-3-phenoxy-1H-indole-2-carboxylate

[0211] ethyl 1-methyl-3-phenoxy-1H-indole-2-carboxylate

[0212] Ethyl 3-phenoxy-1H-indole-2-carboxylate 6c (300 mg, 1.07 mmol) and iodomethane (227.06 mg, 1.60 mmol) were dissolved in N,N-dimethylformamide (8 mL), and sodium hydride (51.19 mg, 1.28 mmol, 60% purity) was added in portions. The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was quenched in saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (15 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (eluent: system A) to give ethyl 1-methyl-3-phenoxy-1H-indole-2-carboxylate 16a (260 mg), yield 82.6%.

[0213] MS m / z(ESI):[M+H] + =296.2

[0214] Step 2

[0215] 1-methyl-3-phenoxy-1H-indole-2-carboxylic acid

[0216] 1-Methyl-3-phenoxy-1H-indole-2-carboxylic acid

[0217] To a mixture of 1-methyl-3-phenoxy-1H-indole-2-carboxylic acid ethyl ester 16a (240 mg, 812.65 μmol) and sodium hydroxide (162.52 mg, 4.06 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added at 25 °C for 12 h. The reaction was adjusted to pH 6 with dilute hydrochloric acid (0.5 M), extracted with ethyl acetate (15 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-methyl-3-phenoxy-1H-indole-2-carboxylic acid 16b (220 mg), yield 91.2 %.

[0218] MS m / z (ESI): [M+H] + = 268.2

[0219] Third step

[0220] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-3-phenoxy-1H-indole-2-carboxamide

[0221] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-3-phenoxy-1H-indole-2-carboxamide

[0222] To a mixture of 1-methyl-3-phenoxy-1H-indole-2-carboxylic acid 16b (100 mg, 374.14 μmol) and (S,E)-1-cyclopropyl-3-(methylsulfonyl)propyl-2-en-1-amine p-toluenesulfonate 1e (155.99 mg, 448.97 μmol) in pyridine (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107.58 mg, 561.21 μmol) at 35 °C for 2 h. The reaction was concentrated under vacuum, the residue was diluted with acetonitrile and N,N-dimethylformamide, and the reaction was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (Waters 3767 / QDA column: SunFire Sunfire C 18 18*250 mm, 10 μm; mobile phase A: 0.1 % FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-3-phenoxy-1H-indole-2-carboxamide 16 (56.1 mg), yield 53.2 %.

[0223] MS m / z (ESI): [M+H] + = 425.3

[0224] 1 H NMR (400 MHz, MeOH-d4) δ 7.54 (d, J = 8.6 Hz, 1H), 7.37 - 7.30 (m, 3H), 7.25 (d, J = 8.1 Hz, 1H), 7.07 (dt, J = 15.3, 7.7 Hz, 2H), 7.03 - 7.00 (m, 2H), 6.88 (dd, J = 15.2, 4.7 Hz, 1H), 6.53 (dd, J = 15.2, 1.7 Hz, 1H), 4.10 - 4.06 (m, 1H), 4.03 (s, 3H), 2.83 (s, 3H), 1.07 - 0.98 (m, 1H), 0.64 - 0.58 (m, 1H), 0.44 - 0.35 (m, 2H), 0.29 - 0.22 (m, 1H) ppm.

[0225] Examples 17-18 were synthesized following the synthetic procedure of Example 16, the specific structures and characterization are shown in the table below:

[0226] Example 19

[0227] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxythieno[2,3-c]pyridine-2-carboxamide

[0228] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxythieno[2,3-c]pyridine-2-carboxamide

[0229] First step

[0230] ethyl 3-hydroxythieno[2,3-c]pyridine-2-carboxylate

[0231] ethyl 3-hydroxythieno[2,3-c]pyridine-2-carboxylate

[0232] Ethyl 3-hydroxythieno[2,3-c]pyridine-2-carboxylate Ethyl 3-chlorothieno[2,3-c]pyridine-2-carboxylate 19a (1.8 g, 9.70 mmol) and ethyl mercaptoacetate 19b (3.24 g, 26.96 mmol) were dissolved in N,N-dimethylformamide (30 mL), cooled to 0 °C, sodium hydride (1.01 g, 25.20 mmol, 60% purity) was added portionwise under nitrogen atmosphere, the temperature was allowed to recover to room temperature and the reaction was allowed to proceed for 12 h. The reaction was quenched with water (60 mL), the pH was adjusted to 6-7 by adding acetic acid (4 mL), and the reaction was extracted with ethyl acetate (30 mL x 2). The aqueous phase was collected and concentrated under reduced pressure. The residue was dissolved in a mixture of N,N-dimethylformamide / methanol / dichloromethane (8:1:8; 150 mL), insoluble materials were filtered, and the filtrate was concentrated under reduced pressure to give ethyl 3-hydroxythieno[2,3-c]pyridine-2-carboxylate 19c (2.05 g) in 94.7% yield.

[0233] MS m / z (ESI): [M+H] + = 224.0

[0234] Second Step

[0235] Ethyl 3-phenoxythieno[2,3-c]pyridine-2-carboxylate

[0236] Ethyl 3-phenoxythieno[2,3-c]pyridine-2-carboxylate Ethyl 3-chlorothieno[2,3-c]pyridine-2-carboxylate 19a (1.8 g, 9.70 mmol) and ethyl mercaptoacetate 19b (3.24 g, 26.96 mmol) were dissolved in N,N-dimethylformamide (30 mL), cooled to 0 °C, sodium hydride (1.01 g, 25.20 mmol, 60% purity) was added portionwise under nitrogen atmosphere, the temperature was allowed to recover to room temperature and the reaction was allowed to proceed for 12 h. The reaction was quenched with water (60 mL), the pH was adjusted to 6-7 by adding acetic acid (4 mL), and the reaction was extracted with ethyl acetate (30 mL x 2). The aqueous phase was collected and concentrated under reduced pressure. The residue was dissolved in a mixture of N,N-dimethylformamide / methanol / dichloromethane (8:1:8; 150 mL), insoluble materials were filtered, and the filtrate was concentrated under reduced pressure to give ethyl 3-hydroxythieno[2,3-c]pyridine-2-carboxylate 19c (2.05 g) in 94.7% yield.

[0237] MS m / z (ESI): [M+H] + = 300.2

[0238] Third Step

[0239] 3-phenoxythieno[2,3-c]pyridine-2-carboxylic acid

[0240] 3-phenoxythieno[2,3-c]pyridine-2-carboxylic acid

[0241] Ethyl 3-phenoxythieno[2,3-c]pyridine-2-carboxylate 19e (200 mg, 668.13 μmol) and sodium hydroxide (133.62 mg, 3.34 mmol) were added into tetrahydrofuran (2 mL) and water (2 mL) and reacted at room temperature for 2 hours. The reaction solution was added dropwise into 0.5 M dilute hydrochloric acid under stirring, adjusted to pH 6, extracted with ethyl acetate (15 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-phenoxythieno[2,3-c]pyridine-2-carboxylic acid 19f (180 mg) in a yield of 99.3%.

[0242] MS m / z (ESI): [M+H] + = 272.0

[0243] Fourth step

[0244] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxythieno[2,3-c]pyridine-2-carboxamide

[0245] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxythieno[2,3-c]pyridine-2-carboxamide

[0246] 3-Phenoxythieno[2,3-c]pyridine-2-carboxylic acid 19f (100 mg, 368.61 μmol) and (S,E)-1-cyclopropyl-3-(methylsulfonyl)propyl-2-en-1-amine p-toluenesulfonate 1e (153.69 mg, 442.33 μmol) were dissolved in pyridine (2 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (105.99 mg, 552.91 μmol) was added, and the reaction was carried out at 35 °C for 2 hours. The reaction was concentrated under vacuum, the residue was diluted with acetonitrile and N,N-dimethylformamide, filtered, and the reaction was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (Waters 3767 / QDA column: SunFire Sunfire C 18 18*250mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min) to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxythieno[2,3-c]pyridine-2-carboxamide 19 (113.43 mg) in a yield of 71.8%.

[0247] MS m / z (ESI): [M+H] + = 429.3

[0248] 1 H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.47 (d, J = 5.5 Hz, 1H), 7.42 - 7.33 (m, 3H), 7.15 (t, J = 7.4 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.79 (dd, J = 15.3, 5.2 Hz, 1H), 6.68 (dd, J = 15.3, 1.2 Hz, 1H), 4.07 - 3.97 (m, 1H), 2.94 (s, 3H), 1.16 - 1.03 (m, 1H), 0.56 - 0.43 (m, 1H), 0.40 - 0.25 (m, 2H), 0.20 - 0.11 (m, 1H) ppm.

[0249] Examples 20-21, 23-34 were synthesized following the synthetic procedure of Example 19, the specific structures and characterization are shown in the following table:

[0250] Example 22

[0251] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzofuran-2-carboxamide

[0252] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzofuran-2-carboxamide

[0253] First step

[0254] ethyl 2-(2-ethoxy-2-oxoethoxy)benzoate

[0255] 2-(2-ethoxy-2-oxoethoxy)benzoate

[0256] Ethyl 2-hydroxybenzoate 22a (5 g, 30.09 mmol) was dissolved in acetone (10 mL), ethyl bromoacetate 22b (5.02 g, 30.09 mmol), potassium carbonate (12.48 g, 90.27 mmol) were added, and the reaction was carried out at 60 °C for 3 hours. It was returned to room temperature, filtered, the filtrate was collected and concentrated under reduced pressure to obtain ethyl 2-(2-ethoxy-2-oxoethoxy)benzoate 22c (7.1 g) with a yield of 93.5%.

[0257] MS m / z (ESI): [M+H] += 253.2

[0258] Second step

[0259] ethyl 3-hydroxybenzofuran-2-carboxylate

[0260] 3-hydroxybenzofuran-2-carboxylate

[0261] Potassium tert-butoxide (2.67 g, 23.78 mmol) was dissolved in tetrahydrofuran (20 mL), and a solution of ethyl 2-(2-ethoxy-2-oxoethoxy)benzoate 22c (3 g, 11.89 mmol) in tetrahydrofuran (20 mL) was added slowly at 30 °C for half an hour. The reaction was quenched by adding saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (100 mL x 2), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: A system) to give ethyl 3-hydroxybenzofuran-2-carboxylate 22d (1.7 g), 69.3%.

[0262] MS m / z (ESI): [M+H] + = 207.2

[0263] Third step

[0264] ethyl 3-phenoxybenzofuran-2-carboxylate

[0265] 3-phenoxybenzofuran-2-carboxylate

[0266] Ethyl 3-hydroxybenzofuran-2-carboxylate 22d (100 mg, 484.98 μmol) was dissolved in N,N-dimethylformamide (3 mL), and diphenyl iodyl chloride 19d (184.23 mg, 581.98 μmol), potassium carbonate (201.08 mg, 1.45 mmol) were added. The reaction was carried out at 80 °C for 16 hours. After cooling to room temperature, the reaction solution was purified by reverse preparation (Isolera-Biotage column: Agela C18 20 g; mobile phase A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give ethyl 3-phenoxybenzofuran-2-carboxylate 22e (67 mg), with a yield of 48.9%. 18 20 g; mobile phase A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give ethyl 3-phenoxybenzofuran-2-carboxylate 22e (67 mg), with a yield of 48.9%.

[0267] MS m / z (ESI): [M+H] + = 283.0

[0268] Fourth step

[0269] 3-phenoxybenzofuran-2-carboxylic acid

[0270] 3-phenoxybenzofuran-2-carboxylic acid

[0271] Ethyl 3-phenoxybenzofuran-2-carboxylate 22e (100 mg, 354.25 μmol) was dissolved in methanol (0.5 mL), water (0.5 mL), tetrahydrofuran (0.5 mL), cooled to 0 °C, and lithium hydroxide (16.97 mg, 708.49 μmol) was added. The reaction was stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC (Isolera-Biotage column: Agela C18 19*250mm, 10 μm; mobile phase A: 0.1% FA / H20, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give 3-phenoxybenzofuran-2-carboxylic acid 22f (14 mg) in 15.5% yield. 18 12g; mobile phase A: 0.1% FA / H20, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzofuran-2- carboxamide 22 (5.02 mg) in 22.2% yield.

[0272] MS m / z (ESI): [M+H] + = 255.3

[0273] Fifth Step

[0274] (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzofuran-2-carboxamide

[0275] (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxybenzofuran-2-carboxamide

[0276] Ethyl 3-phenoxybenzofuran-2-carboxylate 22e (100 mg, 354.25 μmol) was dissolved in methanol (0.5 mL), water (0.5 mL), tetrahydrofuran (0.5 mL), cooled to 0 °C, and lithium hydroxide (16.97 mg, 708.49 μmol) was added. The reaction was stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC (Isolera-Biotage column: Agela C18 19*250mm, 10 μm; mobile phase A: 0.1% FA / H20, mobile phase B: acetonitrile; flow rate: 20 mL / min) to give 3-phenoxybenzofuran-2-carboxylic acid 22f (14 mg) in 15.5% yield. 18 mobile phase B: acetonitrile; flow rate: 20 mL / min) to give (S,E)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-3-phenoxybenzofuran-2-carboxamide 22 (5.02 mg) in 22.2% yield.

[0277] MS m / z (ESI): [M+H] + = 412.3

[0278] 1 H NMR (400 MHz, MeOH-d4) δ 7.63 (d, J = 8.5 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.41 - 7.35 (m, 2H), 7.23 - 7.09 (m, 5H), 6.97 (dd, J = 15.2, 5.1 Hz, 1H), 6.74 (dd, J = 15.2, 1.6 Hz, 1H), 4.14 - 4.06 (m, 1H), 2.96 (s, 3H), 1.25 - 1.13 (m, 1H), 0.74 - 0.66 (m, 1H), 0.63 - 0.56 (m, 1H), 0.49 - 0.41 (m, 2H) ppm.

[0279] Examples 35-41 were synthesized according to the synthetic procedure of Example 22, and the specific structures and characterization are shown in the following table:

[0280] Biological Evaluation

[0281] Example 1, Inhibition of SW48 Cell Proliferation by Compounds of the Invention

[0282] The following method was used to determine the effect of compounds of the invention on SW48 cell proliferation. SW48 cells (MSI-H cells) were purchased from the ATCC cell bank in the United States and were cultured in Leibovitz's L-15 (Gibco, Cat. No. 11415064) medium containing 10% fetal bovine serum, 100 U of penicillin and 100 μg / mL of streptomycin. Cell viability was determined by Luminescent Cell Viability Assay kit (Promega, Cat. No. G7573).

[0283] The experimental method is operated according to the steps of the kit instruction, and the brief description is as follows: the test compound is first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with the above-mentioned culture medium to prepare a test sample, and the final concentration of the compound ranges from 10000 nM to 1.52 nM. Cells in the logarithmic growth phase are inoculated into a 96-well cell culture plate at a density of 500 cells per well, incubated in a 37°C air incubator overnight, and then incubated for 120 hours after the addition of the test compound. After the end of the culture, 40 uL of CellTiter-Glo detection solution is added to each well, shaken for 5 minutes, and then incubated for 10 minutes. Then, the luminescence value of each well of the sample is read on a microplate reader using the Luminescence mode. The percentage inhibition of the compound at each concentration point is calculated by comparing the values with the control group (0.1% DMSO), and then the compound concentration logarithm-inhibition rate is analyzed by non-linear regression analysis in GraphPad Prism 9 software to obtain the IC 50 value of the compound for inhibiting cell proliferation.

[0284] The IC 50 value of the compound of the present application is represented by AA, A, respectively, as follows:

[0285] AA: IC 50 ≤ 10 nM

[0286] A: 10 nM < IC 50 ≤ 100 nM

[0287] Conclusion: The compound of the present application has a good inhibitory effect on the proliferation of SW48 cells.

[0288] Test Example 2, Determination of the Inhibition of the Proliferation of RL95-2 Cells by the Compound of the Present Invention

[0289] The following method is used to determine the effect of the compound of the present application on the proliferation of RL95-2 cells. RL95-2 cells (MSI-H cells) are purchased from the Cell Resource Center of Shanghai Life Sciences Research Institute, Chinese Academy of Sciences, and cultured in DMEM / F12 medium (Gibco, catalog number A4192001) containing 10% fetal bovine serum, 100 U of penicillin and 100 μg / mL of streptomycin. Cell viability is determined by Luminescent Cell Viability Assay kit (Promega, catalog number G7573).

[0290] The experimental method is operated according to the steps of the kit instruction, and the brief description is as follows: the test compound is first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with the above-mentioned culture medium to prepare a test sample, and the final concentration of the compound is in the range of 10000 nM-1.52 nM. Cells in the logarithmic growth phase are inoculated into a 96-well cell culture plate at a density of 500 cells per well, incubated in a 37°C, 5% CO2 incubator overnight, then continue to incubate for 120 hours after adding the test compound. After the end of the culture, 50 uL of CellTiter-Glo detection solution is added to each well, shaken for 5 minutes, then placed for 10 minutes, then the luminescence value of each well of the sample is read on the enzyme label instrument using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point is calculated by comparing the value with the control group (0.1% DMSO), and then the compound concentration-log-inhibition rate is analyzed by non-linear regression in the GraphPad Prism 9 software, and the IC 50 value of the compound for inhibiting cell proliferation is obtained.

[0291] The IC 50 value of the compound of the present application is represented by A,

[0292] “A” represents 10 nM < IC 50 ≤ 100 nM

[0293] Conclusion: The compound of the present application has a good inhibitory effect on the proliferation of RL95-2 cells.

[0294] Test Example 3, Determination of the Inhibition of the Proliferation of HCT116 Cells by the Compound of the Present Invention

[0295] The following method is used to determine the effect of the compound of the present application on the proliferation of HCT116 cells. HCT116 cells are purchased from the Cell Resource Center of Shanghai Life Sciences Research Institute of the Chinese Academy of Sciences and cultured in McCoy's 5a medium containing 10% fetal bovine serum, 100 U of penicillin and 100 ug / mL of streptomycin. Cell viability is determined by Luminescent Cell Viability Assay kit (Promega, item number G7573).

[0296] The experimental method is operated according to the steps of the kit instruction, and the brief description is as follows: the test compound is first dissolved in DMSO to prepare a 10mM stock solution, then diluted with the above-mentioned culture medium to prepare a test sample, and the final concentration of the compound is in the range of 10000nM-1.52nM. Cells in the logarithmic growth phase are inoculated into a 96-well cell culture plate at a density of 300 cells per well, incubated in a 37℃, 5% CO2 incubator overnight, then continue to incubate for 120 hours after adding the test compound. After the end of the culture, 50uL of CellTiter-Glo detection solution is added to each well, shaken for 5 minutes, then placed for 10 minutes, then the luminescence value of each well of the sample is read on the enzyme-labeled instrument using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point is calculated by comparing the value with the control group (0.1% DMSO), and then the compound concentration-log-inhibition rate is analyzed by non-linear regression in the GraphPad Prism 9 software to obtain the IC 50 value of the compound for inhibiting cell proliferation.

[0297] AA: IC 50 ≤10nM

[0298] A: 10nM < IC 50 ≤100nM

[0299] Conclusion: The compound of the present application has good inhibitory effect on HCT116 cell proliferation.

Claims

1. A compound of Formula (I) or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof: ###0001### (I) ​ wherein: is a 5-membered heteroaromatic ring; X is selected from C and N; Y is selected from O, S, N and NR a ; R a is a hydrogen atom or C 1-6 alkyl or C 3-6 cycloalkyl, wherein said C 1-6 alkyl or C 3-6 cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano or C 1-6 alkoxy; Ring A is selected from C 6-10 aryl, 5-12 membered heterocyclyl, C 5-12 cycloalkyl and 5-6 membered heteroaryl; L is selected from -C(=O)-, -C(=O)NR b -, -S(=O)2NR c - and -NR d C(=O)NR e -; R b , R c , R d , R e are each independently selected from the group consisting of a hydrogen atom, a deuterium atom and a C 1-6 alkyl group; W is selected from the group consisting of: provided that when W is selected from when L is -C(=0)-; key denotes may exist as (Z)- or (E)-stereoisomers, wherein * denotes the point of attachment; R f each independently is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and 5-10 membered heterocyclyl; wherein C 1-6 alkyl, C 3-8 cycloalkyl or 5-10 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R g each independently is selected from a hydrogen atom and a deuterium atom, preferably a hydrogen atom; R 3a , R 3b are each independently selected from the group consisting of a hydrogen atom and a C 1-6 alkyl group; R 4a each independently is selected from C 1-6 alkyl and C 1-6 alkoxy, wherein C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R 4b are each independently selected from C 1-6 alkyl, C 3-8 cycloalkyl and 5-10 membered heterocyclyl; wherein C 1-6 alkyl, C 3-8 cycloalkyl or 5-10 membered heterocyclyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R h , R i are each independently selected from the group consisting of C 1-6 alkyl, wherein said C 1-6 alkyl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C 1-6 alkoxy; R 1 is selected from the group consisting of hydrogen atom, C 3-8 ycloalkyl, -OR A and S(O) r R A wherein said C 3-8 ycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -SF5, -OR 5 , -OC(=O)R 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -S(=O) r NR 6 R 7 and -S(=O) r R 5 ; R A selected from C 1-6 alkyl, C 3-8 ycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-8 ycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl is optionally further substituted by one or more substituents selected from a deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -SF5, -OR 5 , -OC(=0)R 5 , -C(=0)R 5 , -C(=0)OR 5 , -N(R 6 )C(=0)R 7 , -N(R 6 )C(=0)OR 7 , -NR 6 R 7 , -C(=0)NR 6 R 7 , -S(=0) r NR 6 R 7 and -S(=0) r R 5 ; R 2 the same or different, each independently selected from a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a 5-10 membered heterocyclyl group, a C 6-10 aryl group, a 5-6 membered heteroaryl group, -SF5, -OR 5 , -OC(=O)R 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -S(=O) r NR 6 R 7 or -S(=O) r R 5 , wherein said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3- 8cycloalkyl group, 5-10 membered heterocyclyl group, C 6-10 aryl group, 5-6 membered heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR 8 , =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 , -N(R 9 )C(=O)R 10 and -N(R 9 )C(=O)OR 10 ; or two R 2 with the same carbon atom to which they are attached forms a -C(=0); or two R 2 with the atom to which it is attached form a C 3-7 cycloalkyl or 3-7 membered heterocyclyl, optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, hydroxy, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 , -N(R 9 )C(=0)R 10 , and -N(R 9 )C(=0)OR 10 ; R 5 each independently is selected from the group consisting of an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 8 , -C(=0)0R 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 , and -N(R 9 )C(=0)R 10 ; R 6 and R 7 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 and -N(R 9 )C(=0)R 10 ; or R 6 and R 7 together with the atom to which they are attached form a 4-8 membered heterocyclyl group containing one or more N, O or S(=O) r wherein said 4-8 membered heterocyclyl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 and -N(R 9 )C(=O)R 10 ; R 8 , R 9 and R 10 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of a hydroxyl group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group and a carboxylate group; m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; and r is each independently 0, 1 or 2.

2. The compound according to claim 1, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein L is -C(=0)NR b -; R b is defined as in claim 1.

3. The compound according to claim 1 or 2, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein W is selected from wherein R g , R f , R 3a , R 3b or R 4b are as defined in claim 1.

4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, which is a compound according to Formula (II), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof: ###00003### (II) wherein: R 3a , R 3b is a hydrogen atom; X, Y, ring A, R b , R g , R f , R 4b , R 1 , R 2 or n are as defined in claim 1.

5. The compound according to any one of claims 1-4, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R b is selected from a hydrogen atom and a methyl group.

6. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R f is selected from C 3-8 cycloalkyl, preferably cyclopropyl.

7. The compound according to any one of claims 1-6, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 4b is selected from C 1-6 alkyl, preferably methyl.

8. The compound according to any one of claims 1-7, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from -OR A , R A is preferably C 6-10 aryl, more preferably phenyl.

9. The compound of any one of claims 1-8, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein is selected from R a is selected from a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a trifluoroethyl group, or a cyclopropyl group.

10. The compound according to any one of claims 1-9, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, C 5-6 cycloalkyl, 5-6 membered heterocyclyl, or 5-6 membered heteroaryl.

11. The compound of any one of claims 1-10 or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: R a is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a trifluoroethyl group and a cyclopropyl group.

12. The compound according to any one of claims 1-11, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 2 each is independently selected from hydroxy, halogen, cyano, C 1-6 alkyl and C 1-6 alkoxy; wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with one or more halogen.

13. The compound according to claim 12, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein R 2 each is independently selected from the group consisting of hydroxyl, fluorine, chlorine, bromine, cyano, methyl, methoxy, difluoromethyl, trifluoromethyl, and trifluoromethoxy.

14. The compound of any one of claims 1-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein the compound is:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1 to 14, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the manufacture of a WRN inhibitor.

17. Use of a compound according to any one of claims 1 to 14, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the treatment of a WRN-mediated disease; preferably, wherein the WRN-mediated disease is a microsatellite instability-high cancer; further preferably, the microsatellite instability-high cancer is selected from the group consisting of colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia and glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

18. Use of a compound according to any one of claims 1 to 14, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the treatment of a microsatellite instability-high cancer; preferably, wherein the microsatellite instability-high cancer is selected from the group consisting of colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia and glioma, further preferably colorectal cancer, gastric cancer or endometrial cancer.

Images