Five-membered aromatic ring derivative as well as preparation method and application thereof

Abstract

The invention relates to a five-membered aromatic ring derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. Specifically, the invention relates to a fused ring derivative as shown in a general formula (I), a preparation method and medicinal salts thereof, and application of the fused ring derivative and the medicinal salts thereof as therapeutic agents, especially as WRN inhibitors, and definitions of substituent groups in the general formula (I) are the same as those in the specification.

Description

Technical Field

[0001] This invention relates to a 5-membered aromatic ring derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a WRN inhibitor. Background Technology

[0002] Human helicase nuclease (WRN) consists of 1432 amino acid residues and comprises five important components from the N-terminus to the C-terminus: an exonuclease domain, an ATPase domain, a RecQ C-terminal domain, a helicase / ribonuclease D C-terminal domain, and a nuclear localization signal. Of the five RecQ helicases in the human body, WRN is the only one with 3'→5' exonuclease activity. This activity is achieved through the specific activation of its N-terminal exonuclease domain by the Ku70 / 80 complex, which binds to the DNA terminus. The ATPase domain is the largest and most conserved component of the RecQ helicase family, acting as an ATP-dependent DNA translocation module by binding and hydrolyzing ATP. The RecQ C-terminal domain is the primary site of DNA binding and catalyzes the unwinding of the DNA double helix. Therefore, the ATPase domain and the RecQ C-terminal domain together constitute the core of the WRN helicase. WRN is a DNA helicase with diverse enzymatic activities that can bind to both 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, as well as maintaining the stability of telomeres and heterochromatin.

[0003] Synthetic lethality refers to the phenomenon where cell death occurs when two non-lethal genes are simultaneously suppressed (suppression can take the form of gene mutations, gene silencing, or other gene defects and / or gene expression knockout, drug inhibition, or other molecular perturbations). This mechanism can be used to identify a specific mutation in cancer, find its "synthetic lethal partner," and suppress it, thereby specifically killing cancer cells with that mutation.

[0004] Studies have shown that wRNAs are the "synthetic lethal partner" for high microsatellite instability (MSI-H), a genomic injury. MSI-H is a highly variable state caused by frequent insertions and / or deletions in nucleotide repeat regions due to defects in DNA mismatch repair (MMR), commonly found in cancers such as endometrial cancer (31%), colorectal cancer (25%), and gastric cancer (19%). In MSI-H cancer cells, thymine / adenine dinucleotide (TA) repeat sequences are highly unstable and undergo massive amplification, forming non-classical right-handed double helix (non-B) DNA secondary structures (e.g., cruciform and G-quadruplex). These DNA secondary structures require specific unwinding by wRNAs to complete replication. In the absence of WRN, these DNA secondary structures are cleaved by the MUS81-EME1-SLX4 endonuclease complex, leading to extensive DNA end removal, depletion of replication protein A (RPA), chromosome fragmentation, and cell death. Furthermore, in tumor models with MMR deficiency, WRN loss activates multiple DNA damage signaling markers, inducing cell cycle arrest and apoptosis, thereby inhibiting tumor cell proliferation. Recent studies have shown that small molecule WRN inhibitors specifically induce tumor regression in MSI-H tumor models, but have no effect in microsatellite stable (MSS) tumor models. Therefore, small molecule chemotherapeutic drugs that inhibit WRN helicase activity hold promise as a novel approach for effectively treating MSI-H cancers.

[0005] No new inhibitors targeting WRN have been launched, nor is there any information on clinical compounds. As a cutting-edge research area, there is still enormous room for exploration in WRN-target research, and it is essential to continue developing new inhibitors. Summary of the Invention

[0006] To address the aforementioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically usable salts thereof:

[0007]

[0008] in:

[0009] It is a 5-membered heterocyclic aromatic ring;

[0010] X and Z are each independently selected from O, S, N, and CR. 2a or NRa ;

[0011] Y and V are each independently selected from C or N; the condition is that at least one of X, Z, Y, and V is a heteroatom.

[0012] R a R 2a Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl or C 3-6 cycloalkyl, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 Substituents of alkoxy groups;

[0013] L is selected from -C(=O)- and -C(=O)NR. b -、-S(=O)2NR c –or -NR d C(=O)NR e -;

[0014] R b R c R d R e Each is independently selected from hydrogen atoms, deuterium atoms, or carbon atoms. 1-6 alkyl;

[0015] W is selected from the following groups:

[0016]

[0017] The condition is that when W is selected At that time, L is -C(=O)-;

[0018] key express It can exist as a (Z)- or (E)- stereoisomer, wherein Indicates the connection point;

[0019] R f Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups; wherein C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups optionally further selected from one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0020] R g Each atom is independently selected from hydrogen atoms or deuterium atoms, preferably hydrogen atoms;

[0021] R 3a R 3b Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl;

[0022] R 4a Each is independently selected from C 1-6 Alkyl or C 1-6 Alkoxy, where C 1-6 Alkyl or C 1-6 Alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0023] R 4b Each is independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups; wherein C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups optionally further selected from one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0024] 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 one or more halogens, hydroxyl groups, or C. 1-6 Substituents of alkoxy groups;

[0025] R 1 Selected from hydrogen atoms, C 3-8 cycloalkyl, -OR A Or S(O) r R A The C mentioned therein 3-8 The cycloalkyl group may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -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 The substituents are replaced;

[0026] R A Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heterocyclic groups, C 6-10 aryl or 5-6 heteroaryl groups optionally further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -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 The substituents are replaced;

[0027] R 2 Selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl, 5-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR5 -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 The C mentioned therein 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl, 5-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -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 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0028] Or, R 2 Together with Z and the atoms it is attached to, they form a C. 6-10 Aryl, 5-12 membered heterocyclic groups, C 5-12 cycloalkyl or 5-6-membered heteroaryl; wherein the C 6-10 Aryl, 5-12 membered heterocyclic groups, C 5-12 Cycloalkyl or 5-6-membered heteroaryl, optionally further divided by one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -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 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0029] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0030] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0031] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0032] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0033] m is 1, 2, or 3; and

[0034] r can be 0, 1, or 2 independently.

[0035] 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 L is -C(=O)NR. b -, R b The definition is as stated in general formula (I).

[0036] 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).

[0037] 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:

[0038]

[0039] in:

[0040] R 2 Selected from hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, -SF5, or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more groups selected from hydroxyl, halogen, cyano, or C. 1-6 Substituents of alkyl groups;

[0041] R 5 Each is independently selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be further selected from one or more deuterium atoms, hydroxyl groups, halogens, cyano groups, C16 groups, C2 ... 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0042] R 3a R 3b It is a hydrogen atom;

[0043] X, Y, Z, V, R b R g R f R 4b and R 1 The definition is as stated in general formula (I).

[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... Selected from

[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 2 Selected from hydroxyl, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl or -S(=O)2CF3.

[0046] A preferred embodiment of the present invention is a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein the compound of general formula (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof is:

[0047]

[0048] Wherein: ring A is selected from 5- to 12-membered heterocyclic groups;

[0049] R 2a Selected from hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl;

[0050] R 3a R 3b It is a hydrogen atom;

[0051] X, Y, Z, V, R b R g R f R 4b and R 1 The definition is as stated in general formula (I).

[0052] A preferred embodiment of the present invention is a compound of formula (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof:

[0053] in for

[0054] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R b Selected from hydrogen atoms or methyl groups.

[0055] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R f Selected from C 3-8 Cycloalkyl, preferably cyclopropyl.

[0056] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 4b Selected from C 1-6 Alkyl group, preferably methyl group.

[0057] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) 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.

[0058] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0059]

[0060]

[0061] Or its stereoisomers, tautomers, or medicinal salts.

[0062] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0063] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0064] The present invention provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a WRN inhibitor.

[0065] The present invention also provides the use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating WRN-mediated diseases, wherein the WRN-mediated diseases are preferably highly microsatellite unstable (MSI-H) cancers; wherein the WRN-mediated diseases are selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia, or glioma, preferably colorectal cancer, gastric cancer, or endometrial cancer.

[0066] The present invention further provides the use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating highly microsatellite unstable (MSI-H) cancer.

[0067] This invention provides the use of a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, melanoma of the skin, squamous cell carcinoma of the lung, prostate cancer, lung adenocarcinoma, transitional cell carcinoma of the bladder, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably in the preparation of medicaments for treating colorectal cancer, gastric cancer or endometrial cancer.

[0068] Detailed description of the invention

[0069] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0070] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-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, etc. The alkyl group may be substituted or unsubstituted.

[0071] "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, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. C2-C4 alkenyl groups are preferred. Alkenyl groups may be optionally substituted or unsubstituted.

[0072] "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. 10The 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.

[0073] "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 ring, bridged ring and spirocyclic, preferably having a 3 to 7 member monocyclic or a 5 to 18 member bicyclic or tricyclic.

[0074] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,

[0075] Monocyclic alkyl groups can be substituted or unsubstituted.

[0076] "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.

[0077] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably a 6- to 14-membered aromatic system, more preferably a 6- to 10-membered system. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrene, etc. The fused cycloalkyl group can be substituted or unsubstituted.

[0078] "Bridged cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms, and one or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" 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 cycloalkyl groups can be substituted or unsubstituted.

[0079] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, containing 0, 1 or more double bonds in the ring, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having 3 to 8-membered monocyclic or 5 to 18-membered bicyclic or tricyclic, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0080] The heterocyclic group can be substituted or unsubstituted.

[0081] Examples of "monocyclic heterocyclic groups" include, but are not limited to, morpholino, oxetane, azabolane, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine,

[0082] "Spirocyclone" refers to a polycyclic aromatic group with 5 to 18 members, two or more ring structures, in which the monocyclic rings share an atom with each other, and contains 0, 1 or more double bonds within the rings, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r(where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl groups according to the number of shared spiroatoms between rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 3 / 6 membered, 4 / 4 membered, 4 / 5 membered, 4 / 6 membered, 5 / 5 membered, 5 / 6 membered or 6 / 6 membered monospirocycloalkyl. Non-limiting examples of "spirocycloalkyl" 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,

[0083] "Densely fused cyclic groups" refer to polycyclic groups containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain 0, 1, or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting embodiments of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0084] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain 0, 1 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0085] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0086] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyridine- 2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl

[0087] The heteroaryl group can be substituted or unsubstituted.

[0088] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O). r (where r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 6 to 14 quinary, more preferably 8 to 10 quinary. Examples of "fused rings" include, but are not limited to:

[0089]

[0090] "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.

[0091] "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.

[0092] "Nitro" refers to the -NO2 group.

[0093] "Hydroxy" refers to the -OH group.

[0094] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0095] "Amino" refers to -NH2.

[0096] "Hydroxyamino group" refers to -NHOH.

[0097] “Cyano” refers to -CN.

[0098] "Benzyl" refers to -CH2-phenyl.

[0099] "Carboxyl group" refers to -C(=O)OH.

[0100] "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.

[0101] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0102] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0103] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0104] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0105] "DMSO" refers to dimethyl sulfoxide.

[0106] “BOC” refers to tert-butoxycarbonyl.

[0107] “Bn” refers to benzyl.

[0108] "THP" refers to 2-tetrahydropyranyl.

[0109] "TFA" refers to trifluoroacetic acid.

[0110] “Ts” refers to p-toluenesulfonyl group.

[0111] “Bn” refers to benzyl.

[0112] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0113] "Formyl group" refers to

[0114] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0115] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0116] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylic acid ester, SF5, =O, -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 The substituents are replaced;

[0117] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0118] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0119] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0120] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0121] r can be 0, 1, or 2 independently.

[0122] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0123] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0124] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0125] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Detailed Implementation

[0126] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0127] Example

[0128] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0129] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0130] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0131] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0132] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0133] CD3OD: Deuterated methanol.

[0134] CDCl3: Deuterated chloroform.

[0135] DMSO-d6: Deuterated dimethyl sulfoxide.

[0136] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0137] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0138] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0139] Example 1

[0140] (S,E)-5-bromo-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxythiophene-2-carboxamide

[0141]

[0142] first step

[0143] methyl 5-bromo-3-fluorothiophene-2-carboxylate

[0144] methyl 5-bromo-3-fluorothiophene-2-carboxylate

[0145] 1 g (6.24 mmol) of methyl 3-fluorothiophene-2-carboxylate 1a was dissolved in 20 mL of tetrahydrofuran. A 1 M, 12 mL solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride in tetrahydrofuran was added at -40 °C, and the reaction was maintained at -40 °C for 1 hour, then allowed to return to room temperature for 12 hours. The reaction mixture was quenched with 5 mL of 0.5 M dilute hydrochloric acid, extracted with 100 mL of water and 2 x 50 mL of ethyl acetate. The combined organic phases were washed with 3 x 20 mL of water and 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: system A) to give 1.4 g (1.4 g) of methyl 5-bromo-3-fluorothiophene-2-carboxylate 1b, with a yield of 93.8%.

[0146] MSm / z(ESI):[M+H] + =240.1

[0147] Step 2

[0148] methyl 5-bromo-3-phenoxythiophene-2-carboxylate

[0149] methyl 5-bromo-3-phenoxythiophene-2-carboxylate

[0150] Methyl 5-bromo-3-fluorothiophene-2-carboxylate 1b (500 mg, 2.09 mmol), phenol (295.25 mg, 3.14 mmol), and cesium carbonate (2.04 g, 6.27 mmol) were sequentially added to N,N-dimethylformamide (5 mL). The reaction mixture was reacted at 70 °C for 3 hours, then allowed to return to room temperature. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (25 mL × 2), and the combined organic phases were washed with water (15 mL × 2) and saturated brine (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: system A) to give methyl 5-bromo-3-phenoxythiophene-2-carboxylate 1c (400 mg), yield 61.1%.

[0151] MSm / z(ESI):[M+H] + =314.1

[0152] Step 3

[0153] 5-bromo-3-phenoxythiophene-2-carboxylic acid

[0154] 5-Bromo-3-phenoxythiophen-2-carboxylic acid was prepared by adding methyl 5-bromo-3-phenoxythiophen-2-carboxylic acid 1c (400 mg, 1.28 mmol) and lithium hydroxide monohydrate (535.94 mg, 12.77 mmol) to a mixed solvent of tetrahydrofuran and water (5 mL, V:V = 4:1). After reacting at room temperature for 1 hour, water (50 mL) was added, and the pH of the reaction solution was adjusted to 6 with 0.1 M dilute hydrochloric acid. The mixture was extracted with dichloromethane (25 mL × 3), and the combined organic phases were washed with saturated brine (20 mL). The organic phases were dried over anhydrous sodium sulfate to give 5-bromo-3-phenoxythiophen-2-carboxylic acid 1d (320 mg), with a yield of 83.8%.

[0155] MSm / z(ESI):[M+H] + =300.1

[0156] Step 4

[0157] (S,E)-5-bromo-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-phenoxythiophene-2-carboxamide

[0158] 5-Bromo-3-phenoxythiophene-2-carboxylic acid 1d (200 mg, 668.58 μmol) and (S,E)-1-cyclopropyl-3-(methanesulfonyl)propyl-2-en-1-amine p-toluenesulfonate 1e (255.4 mg, 735.44 μmol) were dissolved in DMF (5 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (381.32 mg, 1.00 mmol) and N,N-diisopropyl Ethylamine (259.22 mg, 2.01 mmol) was reacted at room temperature for 1 hour, quenched with saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (25 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: system A) to give (S,E)-5-bromo-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-3-phenoxythiophene-2-carboxamide 1 (50 mg), yield 15.6%.

[0159] MSm / z(ESI):[M+H] + =457.0

[0160] 1H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.3Hz,1H),7.46(t,J=7.7Hz,2H),7.25(d,J=7.3Hz,1H),7.21(d,J=8.2Hz,2H),6.93(s,1H),6.84(dd,J=15.3,5 .3Hz,1H),6.73(d,J=15.4Hz,1H),4.02-3.96(m,1H),2.98(s,3H),1.21- 1.13(m,1H),0.55-0.49(m,1H),0.44-0.33(m,2H),0.28-0.23(m,1H)ppm.

[0161] Example 2

[0162] (S,E)-2-(tert-butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide(S,E)-2-(tert-butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0163]

[0164]

[0165] first step

[0166] ethyl 2-(tert-butyl)-4-hydroxythiazole-5-carboxylate

[0167] 2-(tert-butyl)-4-hydroxythiazol-5-carboxylic acid ethyl ester

[0168] 2,2-Dimethylthiopropionamide 2a (5 g, 42.66 mmol) was dissolved in ethanol (3 mL), and diethyl 2-bromo-malonate 2b (10.20 g, 42.66 mmol) and pyridine (13.50 g, 170.63 mmol) were added. The mixture was reacted at 80 °C for 2 hours. After returning to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent: system A) to give ethyl 2-(tert-butyl)-4-hydroxythiazol-5-carboxylate 2c (10 g), with a yield of 97.1%.

[0169] MSm / z(ESI):[M+H] + =230.2

[0170] Step 2

[0171] ethyl 2-(tert-butyl)-4-phenoxythiazole-5-carboxylate

[0172] 2-(tert-butyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester

[0173] Ethyl 2-(tert-butyl)-4-hydroxythiazolium-5-carboxylate 2c (1 g, 4.36 mmol) was dissolved in N,N-dimethylformamide (5 mL), and diphenyliodoacryl chloride 2d (1.66 g, 5.23 mmol) and potassium carbonate (1.21 g, 8.72 mmol) were added. The reaction was carried out at 80 °C for 2 hours. After returning to room temperature, the reaction was quenched with water (5 mL), and ethyl acetate (40 mL) was added. The mixture was separated by separation, washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and separated by silica gel column chromatography (eluent: system A) to give ethyl 2-(tert-butyl)-4-phenoxythiazolium-5-carboxylate 2e (175 mg), with a yield of 13.1%.

[0174] MSm / z(ESI):[M+H] + =306.2

[0175] Step 3

[0176] 2-(tert-butyl)-4-phenoxythiazole-5-carboxylic acid

[0177] 2-(tert-butyl)-4-phenoxythiazol-5-carboxylic acid

[0178] Ethyl 2-(tert-butyl)-4-phenoxythiazol-5-carboxylic acid 2e (250 mg, 818.62 μmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and a tetrahydrofuran solution of sodium hydroxide (163.72 mg, 4.09 mmol) (2 mL) was added. The reaction was carried out at room temperature for 2 hours. Water (5 mL) was added to the reaction solution, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 2-(tert-butyl)-4-phenoxythiazol-5-carboxylic acid 2f (220 mg), with a yield of 77.5%.

[0179] MSm / z(ESI):[M+H] + =278.3

[0180] Step 4 (S,E)-2-(tert-butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0181] (S,E)-2-(tert-butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0182] 2-(tert-butyl)-4-phenoxythiazolyl-5-carboxylic acid 2f (70 mg, 252.40 μmol) and (S,E)-1-cyclopropyl-3-(methanesulfonyl)propyl-2-en-1-amine p-toluenesulfonate 1e (105.3 mg, 302.88 μmol) were dissolved in pyridine (1 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.58 mg, 378.60 μmol) was added. The reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (Waters). 2767 / QDA column: UniSil C4, 21.2*250mm, 10μm; mobile phase A: 0.05% TFA / H2O, B: acetonitrile; flow rate: 20mL / min), yielding (S,E)-2-(tert-butyl)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-4-phenoxythiazol-5-carboxamide 2 (36.7mg), yield 33.5%.

[0183] MSm / z(ESI):[M+H] + =411.3

[0184] 1 H NMR(400MHz,CH3OH-d4)δ7.91(d,J=7.1Hz,1H),7.44-7.38(m,2H),7.26-7.18(m,1H),7.18-7.13(m,2H),6.93(dd,J=15.2,5.0Hz,1H),6.67(dd, J=15.2,1.6Hz,1H),4.09-3.97(m,1H),2.94(s,3H),1.37(s,9H),1.19-1 .10(m,1H),0.70-0.62(m,1H),0.58-0.51(m,1H),0.45-0.35(m,2H)ppm.

[0185] Referring to the synthesis method of Example 2, Examples 3-6 can be synthesized, and their specific structures and characterizations are shown in the table below:

[0186]

[0187]

[0188] Biological evaluation

[0189] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on the proliferation of SW48 cells.

[0190] The following methods were used to determine the effect of the compounds of this invention on the proliferation of SW48 cells. SW48 cells (MSI-H cells) were purchased from the ATCC cell bank in the United States and cultured in Leibovitz's L-15 (Gibco, catalog number 11415064) medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The Luminescent Cell Viability Assay kit (Promega, catalog number G7573) was used for the determination.

[0191] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with the above-mentioned culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 500 cells per well into 96-well cell culture plates and cultured overnight at 37°C in an air incubator. The test compound was then added, and the cells were cultured for another 120 hours. After the culture, 40 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 value.

[0192] IC of the compound of the present invention 50 The values ​​are represented by A, B, and C, respectively:

[0193] AA:IC 50 ≤10nM

[0194] A:IC 50 ≤100nM

[0195] compound <![CDATA[IC 50 (nM)]]> 1 A 2 A 3 A 4 A 5 AA 6 A

[0196] Conclusion: The compound of this invention has a good inhibitory effect on the proliferation of SW48 cells.

[0197] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the proliferation of RL95-2 cells.

[0198] The following methods were used to determine the effect of the compounds of this invention on the proliferation of RL95-2 cells. RL95-2 cells (MSI-H cells) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in DMEM / F12 medium (Gibco, catalog number A4192001) containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The Luminescent Cell Viability Assay kit (Promega, catalog number G7573) was used for the determination.

[0199] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with the above-mentioned culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 500 cells per well into 96-well cell culture plates and cultured overnight at 37°C in a 5% CO2 incubator. The test compound was then added, and the cells were cultured for another 120 hours. After the culture, 50 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 value.

[0200] Conclusion: The compound of this invention has an IC50 inhibitory effect on the proliferation of RL95-2 cells. 50 <100nM, exhibiting good inhibitory effect.

[0201] Test Example 3: Determination of the inhibitory effect of the compound of the present invention on the proliferation of HCT116 cells.

[0202] The following methods were used to determine the effect of the compounds of this invention on the proliferation of HCT116 cells. HCT116 cells were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in McCoy's 5a medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The assay was performed using the Luminescent CellViability Assay kit (Promega, catalog number G7573).

[0203] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with the above-mentioned culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 300 cells per well into 96-well cell culture plates and cultured overnight at 37°C in a 5% CO2 incubator. The test compound was then added, and the cells were cultured for another 120 hours. After the culture, 50 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 value.

[0204] Conclusion: The compound of this invention has an IC50 inhibitory effect on the proliferation of HCT116 cells. 50 <100nM, exhibiting good inhibitory effect.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: It is a 5-membered heterocyclic aromatic ring; X and Z are each independently selected from O, S, N, and CR. 2a or NR a ; Y and V are each independently selected from C or N; the condition is that at least one of X, Z, Y, and V is a heteroatom. R a R 2a Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl or C 3-6 cycloalkyl, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 Substituents of alkoxy groups; L is selected from -C(=O)- and -C(=O)NR. b -、-S(=O)2NR c –or -NR d C(=O)NR e -; R b R c R d R e Each is independently selected from hydrogen atoms, deuterium atoms, or carbon atoms. 1-6 alkyl; W is selected from the following groups: The condition is that when W is selected At that time, L is -C(=O)-; key express It can exist as a (Z)- or (E)- stereoisomer, where -* indicates a connection point; R f Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups; wherein C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups optionally further selected from one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; R g Each atom is independently selected from hydrogen atoms or deuterium atoms, preferably hydrogen atoms; R 3a R 3b Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl; R 4a Each is independently selected from C 1-6 Alkyl or C 1-6 Alkoxy, where C 1-6 Alkyl or C 1-6 Alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; R 4b Each is independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups; wherein C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-10 membered heterocyclic groups optionally further selected from one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; 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 one or more halogens, hydroxyl groups, or C. 1-6 Substituents of alkoxy groups; R 1 Selected from hydrogen atoms, C 3-8 cycloalkyl, -OR A Or S(O) r R A The C mentioned therein 3-8 The cycloalkyl group may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -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 The substituents are replaced; R A Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heterocyclic groups, C 6-10 aryl or 5-6 heteroaryl groups optionally further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -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 The substituents are replaced; R 2 Selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl, 5-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -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 The C mentioned therein 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-8 cycloalkyl, 5-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -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 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; Or, R 2 Together with Z and the atoms it is attached to, they form a C. 6-10 Aryl, 5-12 membered heterocyclic groups, C 5-12 cycloalkyl or 5-6-membered heteroaryl; wherein the C 6-10 Aryl, 5-12 membered heterocyclic groups, C 5-12 Cycloalkyl or 5-6-membered heteroaryl, optionally further divided by one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -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 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced; Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group; m is 1, 2, or 3; and r can be 0, 1, or 2 independently.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein L is -C(=O)NR. b -, R b The definition is as described in claim 1.

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein W is selected from... Where R g R f R 3a R 3b or R 4b The definition is as described in claim 1.

4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof of general formula (II): in: R 2 Selected from hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, -SF5, or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more groups selected from hydroxyl, halogen, cyano, or C. 1-6 Substituents of alkyl groups; R 5 Each is independently selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be further selected from one or more deuterium atoms, hydroxyl groups, halogens, cyano groups, C16 groups, C2 ... 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; R 3a R 3b It is a hydrogen atom; X, Y, Z, V, R b R g R f R 4b and R 1 The definition is as described in claim 1.

5. The compound according to any one of claims 1-4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein... Selected from 6. The compound according to claim 4 or 5, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R 2 Selected from hydroxyl, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl or -S(=O)2CF3.

7. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof of general formula (III): in: Ring A is selected from 5- to 12-membered heterocyclic groups; R 2a Selected from hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; R 3a R 3b It is a hydrogen atom; X, Y, Z, V, R b R g R f R 4b and R 1 The definition is as described in claim 1.

8. The compound according to claim 7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein... for 9. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein R b Selected from hydrogen atoms or methyl groups.

10. The compound according to any one of claims 1-9, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R f Selected from C 3-8 Cycloalkyl, preferably cyclopropyl.

11. The compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 4b Selected from C 1-6 Alkyl group, preferably methyl group.

12. The compound according to any one of claims 1-11, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from -OR A R A C is preferred 6-10 Aryl, more preferably phenyl.

13. The compound according to any one of claims 1-12, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is:

14. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1-13 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

15. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-13, or the pharmaceutical composition according to claim 14, in the preparation of a WRN inhibitor.

16. The use of the compound or its stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating WRN-mediated diseases; preferably, wherein the WRN-mediated disease is a highly microsatellite unstable cancer; more preferably, the highly microsatellite unstable cancer is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, melanoma of the skin, squamous cell carcinoma of the lung, prostate cancer, lung adenocarcinoma, transitional cell carcinoma of the bladder, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, and even more preferably colorectal cancer, gastric cancer or endometrial cancer.

17. The use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-13, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating highly microsatellite unstable cancers; preferably, wherein the highly microsatellite unstable cancers are selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, more preferably colorectal cancer, gastric cancer or endometrial cancer.

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