Compounds having a nitrogen-containing azetidinyl phenyl piperidine-2,6-dione structure, pharmaceutical compositions thereof, and uses thereof

Abstract

The application relates to a compound containing a nitrogen-containing azetidinyl phenyl piperidine-2,6-dione structure, a pharmaceutical composition and application thereof. The compound containing the nitrogen-containing azetidinyl phenyl piperidine-2,6-dione structure has a structure shown in formula (I). The compound has improved proliferation inhibition activity on cancer cells and degradation effect on proteins such as GSPT1, and has practical value.

Description

[0001] This application claims priority to the earlier application filed on January 6, 2025 with the China National Intellectual Property Administration, patent application number 202510021377.3, entitled "Compounds with a nitrogen-containing heterocyclic butylphenylpiperidine-2,6-dione structure, pharmaceutical compositions thereof and applications".

[0002] The full text of the aforementioned prior application is incorporated herein by reference. Technical Field

[0003] This invention relates to the field of pharmaceutical technology, and in particular to a compound containing a nitrogen-containing heterocyclic butyl phenyl piperidine-2,6-dione structure, its pharmaceutical composition, and its application. Background Technology

[0004] Eukaryotic release factor 3a (eRF3a), encoded by the G1 to S phase transition 1 (GSPT1) gene, is upregulated in various human cancers and is a potential proto-oncogene. As a key member of the peptide release factor family, it participates in multiple biological processes, including terminating protein translation, regulating intracellular mRNA degradation, regulating cell cycle and apoptosis, and participating in cytoskeleton formation. Recent evidence suggests that GSPT1 is abnormally highly expressed in various malignant tumors and plays an important role in tumorigenesis and development. GSPT1 is a carcinogenic driver in several cancer types, including hematologic malignancies, breast cancer, liver cancer, gastric cancer, and prostate cancer. Furthermore, GSPT1 is significantly upregulated in cancer tissues and cell lines, its high expression is positively correlated with tumor size, and its overexpression can promote cancer cell proliferation and metastasis.

[0005] Several publications have reported GSPT1 degraders with different structures, including WO2023070120, WO2023201282, WO2023274246, and WO2023069708. The activity and selectivity of these compounds still require further improvement. Therefore, developing GSPT1 degraders with higher activity and selectivity to further improve the therapeutic effect of tumors and reduce the toxic side effects of drugs has significant research value and practical implications.

[0006] On the other hand, according to the WHO website, in 2022, an estimated 2.3 million women worldwide were diagnosed with breast cancer, and 670,000 died from it. Breast cancer can occur at any age after puberty in women of every country in the world, but the incidence rate increases in later life. Global estimates show that in countries with high Human Development Indices, one in 12 women will be diagnosed with breast cancer in their lifetime, and one in 71 women will die from it, making breast cancer the leading cause of cancer death among women.

[0007] In 2012, Jun Ren et al. published an article in Chin J Cancer Res (24(2):143-150, 2012) which stated that human epidermal growth factor receptor 2 (HER2) overexpression or HER2 gene amplification exists in about 25% to 30% of breast cancer cases. This is called HER2 positive breast cancer, which represents a unique disease type confirmed by gene expression profiling studies.

[0008] While the advancements in trastuzumab development have greatly improved the prognostic prospects for patients with HER2-positive breast cancer, most patients develop resistance to trastuzumab within one year of starting treatment, and approximately 15% of patients diagnosed with early-stage HER2-positive disease develop new resistance and relapse even after receiving trastuzumab treatment.

[0009] According to a 2012 article by Sandhu, Rupninder et al. published in *Breast Cancer Research and Treatment* (vol. 131,2 (2012): 385-99. doi:10.1007 / s10549-011-1409-2), some primary breast cancers and breast cancer cell lines exhibit hypermethylation defects (manifested as increased DNMT activity and DNMT3b overexpression), which lead to chemotherapy resistance. The article also listed the sensitivity data of common chemotherapy drugs to the hypermethylated breast cancer cell line (MDA-MB-453) without special treatment, such as the IC50 of doxorubicin hydrochloride (DOX). 50 IC50 value of 86 nM, 5-fluorouracil (5-FU) 50 The value was 817 μm, while Jun Ren et al. reported in Chin J Cancer Res (24(2):143-150,2012) that MDA-MB-453 was still resistant to trastuzumab even at an in vitro concentration of 10,000 ng / ml.

[0010] Therefore, current breast cancer treatments still face limitations due to primary and secondary drug resistance, and patients still have a widespread demand for new breast cancer drugs with higher efficacy and greater resistance. Summary of the Invention

[0011] The purpose of this invention is to provide a class of novel compounds with a nitrogen-containing heterocyclic butylphenylpiperidine-2,6-dione structure and their compositions, which, as cereblon regulators, exhibit enhanced proliferative inhibitory activity against cancer cells and degradation of proteins such as GSPT1, particularly showing significantly enhanced proliferative inhibitory activity against breast cancer cells.

[0012] The first aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0013] in,

[0014] R1 and R2 are each independently halogens; m and n are each independently 0, 1, 2, 3 or 4;

[0015] Z is either NH or O;

[0016] t is 1, 2, or 3;

[0017] T is O or NR n ;

[0018] L1 is CH2 or C(O);

[0019] L2 is CR L21 R L22 ;

[0020] Where R n R L21 R L22 Definitions selected from the following group:

[0021] (i)R n It is hydrogen or C 1-8 Alkyl; R L21 R L22 Each can be either hydrogen or halogen;

[0022] (ii)R L21 It is hydrogen; R L22 With R n Linkage forms 4- to 6-membered nitrogen-containing heterocyclic alkyl groups;

[0023] R3 is NR a R b , hydroxyl or hydroxy-substituted C 1-8 Alkyl; wherein R a R bEach independently is hydrogen, C 1-8 Alkyl or halogenated C 1-8 alkyl.

[0024] In some implementations, Z stands for oxygen.

[0025] In some implementations, R1 is fluorine.

[0026] In some implementations, n is 2.

[0027] In some implementations, R2 is chlorine.

[0028] In some implementations, m is 1.

[0029] In some implementations, t is 2 or 3.

[0030] In some implementations, T is 0; t is 2 or 3.

[0031] In some implementations, T is NR n ; t is 2 or 3; L1 is C(O); R n It is hydrogen or C 1-8 Alkyl; R L21 R L22 Each is independently hydrogen.

[0032] In some implementations, T is NR n t is 2 or 3; R L21 It is hydrogen or halogen; R L22 With R n They connect to form 4 to 6-membered nitrogen-containing heterocyclic alkyl groups.

[0033] In some embodiments, the 4- to 6-membered nitrogen-containing heterocyclic alkyl group is selected from nitrogen-containing heterocyclic butyl, tetrahydropyrrolyl, piperidinyl, piperazineyl, and morpholinyl.

[0034] In some embodiments, the compound represented by formula (I) has the structure shown in formula (IA) or formula (IB):

[0035] Where R0 is a halogen; q is 0, 1, 2 or 3; and s is 1, 2, 3 or 4.

[0036] In some implementations, R in formula (IA) a C 1-8 Alkyl or halogenated C 1-8 Alkyl; R b It is hydrogen.

[0037] In some implementations, R3 in equation (IB) is NR aR b , hydroxyl or hydroxy-substituted C 1-3 Alkyl; wherein R a R b Each independently is hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0038] In some implementations, R3 in formula (IB) is hydroxyl, hydroxymethyl, or methylamino.

[0039] In some implementations, R in formula (IA) a C 1-3 Alkyl or halogenated C 1-3 Alkyl; R b It is hydrogen.

[0040] In some implementations, R in formula (IA) a The following are compounds: methyl, ethyl, n-propyl, isopropyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethyl, trifluoron-propyl, or trifluoroisopropyl; R b It is hydrogen.

[0041] In some embodiments, the compound of formula (I) is selected from any of the following structures:

[0042] The compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, described in the first aspect of this invention has significant protein regulatory effects and enhanced cell proliferation inhibition effects, said proteins including GSPT1, N-MYC, and C-MYC, and is a protein regulator to restore protein homeostasis, including GSPT1 activity.

[0043] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0044] The third aspect of the present invention provides the use of the compounds described in the first aspect of the present invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, and the pharmaceutical compositions described in the second aspect of the present invention in the preparation of medicaments for treating breast cancer.

[0045] The fourth aspect of the present invention provides the use of the compounds described in the first aspect of the present invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, and the pharmaceutical compositions described in the second aspect of the present invention in the preparation of medicaments for the treatment or prevention of diseases associated with mutations, expression imbalances, allosteric changes, and functional abnormalities of GSPT1, N-MYC, or C-MYC proteins.

[0046] In some implementations, the diseases include, but are not limited to, esophageal cancer, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, urothelial carcinoma, non-Hodgkin's lymphoma, central nervous system tumors, prostate cancer and thyroid cancer, acute myeloid leukemia, and myelodysplastic syndrome.

[0047] In some embodiments, the compounds described in the first aspect of the invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, and the pharmaceutical compositions described in the second aspect of the invention are used to prepare medicaments for treating diseases associated with or caused by GSPT1, particularly for treating GSPT1-related cancers such as glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, kidney cancer, urothelial carcinoma, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome.

[0048] In some embodiments, the compounds described in the first aspect of the invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, and the pharmaceutical compositions described in the second aspect of the invention are used to treat solid tumors, particularly for the treatment of breast cancer, including but not limited to HER2-positive or HER2-abnormally activated breast cancer and androgen receptor (AR)-positive breast cancer (LAR subtype breast cancer).

[0049] The fifth aspect of the present invention provides a method for treating breast cancer patients, particularly HER2-positive or HER2-abnormally activated breast cancer, and androgen receptor (AR)-positive breast cancer (LAR subtype breast cancer), comprising administering to the patient a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the second aspect of the present invention.

[0050] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0051] Through in-depth research, the inventors unexpectedly discovered compounds containing nitrogen-containing heterocyclic butylphenylpiperidine-2,6-dione structures. These compounds can regulate the levels of proteins such as GSPT1 and exhibit a significantly enhanced inhibitory effect on the proliferation of tumor cells, such as human breast ductal carcinoma cells, effectively alleviating or treating cancer and related diseases. Based on this, the inventors completed this invention.

[0052] Terminology Definition

[0053] To better understand the technical content of this invention, the terminology of this invention will be further explained below.

[0054] "alkyl" refers to straight-chain and branched saturated aliphatic hydrocarbon groups. "C 1-8 "Alkyl" refers to an alkyl group having 1 to 8 carbon atoms, preferably C14. 1-6 Alkyl, more preferably C 1-3 Alkyl; non-limiting examples of alkyl groups include: 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers.

[0055] "Cycloalkyl" and "cycloalkyl ring" are used interchangeably, both referring to a saturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon group that may be fused with an aryl or heteroaryl group. The cycloalkyl ring may optionally be substituted. In some embodiments, the cycloalkyl ring contains one or more carbonyl groups, such as oxo groups. "C" 3-8 "Cycloalkyl" refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. Preferably C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] The terms "heterocyclic alkyl" and "heterocyclic alkyl ring" are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, which may be fused with an aryl or heteroaryl group. The heterocyclic alkyl ring may optionally be substituted. In some embodiments, the heterocyclic alkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thio groups. "3- to 8-membered heterocyclic alkyl" refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, preferably a 4- to 8-membered heterocyclic alkyl. More preferably, it is a 3- to 6-membered heterocyclic alkyl having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Even more preferably, it is a 4- to 6-membered heterocyclic alkyl having 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples include azircycloyl, ethylene oxide, azircyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxopentyl, piperidinyl, piperazinyl, morpholinyl, dioxohexyl, thiomorpholinyl, thiomorpholin-1,1-dioxide, tetrahydropyranyl, azircyclobutane-2-one, oxacyclobutane-2-one, dihydrofuran-2(3H)-one, pyrrolidine-2-one, pyrrolidine-2,5-diketone, dihydrofuran-2,5-diketone, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazin-2-one, morpholin-3-one, etc.

[0057] "Heteroaryl" and "heteroaryl ring" are used interchangeably, both referring to a 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) of monocyclic, bicyclic, or polycyclic aromatic rings having a ring carbon atom and a ring heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may optionally be substituted. "5 to 10-membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl having 5 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. "5- to 6-membered heteroaryl" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. Non-limiting examples include thiophene, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrole, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridinyl, triazinyl, and tetraazinyl. "9 or 10-membered heteroaryl" refers to a bicyclic heteroaryl group having 9 or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. Non-limiting examples include indole, isoyindole, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzooxadiazolyl, benzothiazolyl, and benzoisothiazolyl. Azolyl, benzothiadiazolyl, indazinyl, purine, pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthidyl, 1,7-naphthidyl, 1,6-naphthidyl, 1,5-naphthidyl, pteridyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. "Heteroatom" refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings.

[0058] "Alkoxy" refers to -O-alkyl, where alkyl is defined as described above. Preferably C 1-8 Alkoxy, more preferably C 1-6 Alkoxy group, C is the most preferred. 1-3 Alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, etc.

[0059] "A bond" refers to two groups connected by a single covalent bond.

[0060] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0061] "Halogenated" means that one or more (such as 1, 2, 3, 4 or 5) hydrogen atoms in a group are replaced by halogens.

[0062] For example, "halogenated alkyl" refers to an alkyl group in which the hydrogen atom is replaced by one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the definition of alkyl is as described above. Preferably, it is a halogenated C. 1-8 Alkyl groups, preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl groups. Examples of haloalkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.

[0063] For example, "haloalkoxy" refers to an alkoxy group where the hydrogen atom is replaced by one or more (e.g., 1, 2, 3, 4, or 5) halogens, as defined above. Preferably, it is a halogenated C. 1-8 Alkoxy, more preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkyl groups. Halogenated alkoxy groups include (but are not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, etc.

[0064] For example, "halogenated cycloalkyl" refers to a cycloalkyl group in which the hydrogen atoms are replaced by one or more (e.g., 1, 2, 3, 4, or 5) halogens, as defined above. Preferably, the halogenated C atoms are used. 3-8 Cycloalkyl, more preferably halogenated C 3-6 Cycloalkyl groups. Halogenated cycloalkyl groups include (but are not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, etc.

[0065] "Deuterated alkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms are substituted for hydrogen atoms, as defined above. Preferably, it is a deuterated C-type alkyl group. 1-8 Alkyl groups, more preferably deuterated C4 groups 1-6 Alkyl groups, more preferably deuterated C4 groups 1-3 Alkyl groups. Examples of deuterated alkyl groups include (but are not limited to) monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, dideuterated ethyl, trideuterated methyl, trideuterated ethyl, etc.

[0066] "Amino" refers to NH2, "cyano" refers to CN, "nitro" refers to NO2, "benzyl" refers to -CH2-phenyl, "oxo" refers to =O, "carboxyl" refers to -C(O)OH, "acetyl" refers to -C(O)CH3, "hydroxymethyl" refers to -CH2OH, "hydroxyethyl" refers to -CH2CH2OH or -CHOHCH3, "hydroxy" refers to -OH, "mercapto" refers to SH, and the structure of "cyclopropyl" is: .

[0067] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5 hydrogen atoms independently substituted by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms independently substituted by a 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 (through 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).

[0068] Unless otherwise defined, the phrase "substituents selected independently of each other" in this invention means that when one or more hydrogen atoms on a group are replaced by substituents, the types of substituents may be the same or different, and the selected substituents are of independent types.

[0069] Unless otherwise defined, the phrase "...same or different, and each independently being..." in this invention means that when there are more than one identical substituent group in the general formula, the group can be the same or different, and each can be an independent type. For example, L is (CR 01 R 02 ) s When s is 2, that is, L is (CR) 01 R 02 )-(CR 01 R 02 ), where the two R 01 The two Rs can be the same or different. 02 They can be the same or different, and can be independent types. For example, L can be C(CH3)(CN)-C(CH2CH3)(OH), C(CH3)(CN)-C(CH3)(OH) or C(CN)(CH2CH3)-C(OH)(CH2CH3).

[0070] Unless otherwise defined, any group herein may be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 or fewer groups, independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C)1-6 Alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 Alkyl (preferably halogenated C) 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 3-8 cycloalkyl (preferably C) 3-6 cycloalkyl), halogenated C 1-8 Alkoxy (preferably halogenated C) 1-6 Alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 Alkyl-substituted amino groups, halogenated C 1-8 Alkyl-substituted amino, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, nitro, C 6-10 Aryl (preferably phenyl), C 3-8 Cycloalkyloxy (preferably C) 3-6 cycloalkyloxy), C 2-8 alkenyl (preferably C) 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-8 alkynyl group (preferably C) 2-6 Alkyne group, more preferably C 2-4 alkynyl group), -CONR a0 R b0 -C(O)OC 1-10 Alkyl (preferably -C(O)OC) 1-6 Alkyl groups, more preferably -C(O)OC 1-3 Alkyl groups, -CHO, -OC(O)C 1-10 Alkyl groups (preferably -OC(O)C) 1-6 Alkyl groups, more preferably -OC(O)C 1-3 alkyl), -SO2C 1-10 Alkyl groups (preferably -SO2C) 1-6 Alkyl groups, more preferably -SO2C 1-3 alkyl), -SO2C 6-10 Aryl (preferably -SO2C6 aryl, such as -SO2-phenyl), -COC 6-10 aryl (preferably -COC6 aryl, such as -CO-phenyl), 4 to 6 membered saturated or unsaturated mono-heterocyclic rings, 4 to 6 membered saturated or unsaturated mono-cyclic rings, 5 to 6 membered monocyclic heteroaryl rings, 8 to 10 membered bicyclic heteroaryl rings, spirocyclic rings, spiroheterocyclic rings, bridged rings or bridged heterocyclic rings, wherein R a0 R b0 Each is independently hydrogen or C 1-3 alkyl.

[0071] In this invention, when two or more "preferred" options appear in a solution, any two "preferred" options can be independent of each other.

[0072] In this invention, when the number of substituents is greater than 1, any two substituents can be the same or different. For example, they can be substituted with two identical or different halogens, or with one halogen and one hydroxyl group.

[0073] The various substituents described above can themselves be replaced by the groups described in this article.

[0074] When the 4- to 6-membered saturated monoheterocycles described herein are substituted, the substituents can be located at their possible chemical positions. Representative substitution cases of exemplary monoheterocycles are shown below: , , , , , ; , , , , , , , , , , ; , , , , , , , , , , , , , , , , , , , , , Where "Sub" represents the various substituents described in this article; "" indicates the connection position with other atoms.

[0075] Pharmaceutical Composition

[0076] Typically, the compounds of this invention, or their pharmaceutically acceptable salts or stereoisomers, can be formulated with one or more pharmaceutical carriers into suitable dosage forms for administration. These dosage forms are suitable for oral, rectal, topical, intraoral, and other non-gastrointestinal administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, suitable dosage forms for oral administration include capsules, tablets, granules, and syrups. The compounds of this invention contained in these formulations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc. The above dosage forms can be prepared from the active compound and one or more carriers or excipients using conventional pharmaceutical methods. The carriers must be compatible with the active compound or other excipients. The active compound can form a solution or suspension with the carrier.

[0077] "Pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, or semi-solid substance or liquid filling machine, diluent, encapsulation material, or excipient or any type of excipient that is compatible with patients, preferably mammalian, more preferably human, and suitable for delivering an active agent to a target site without terminating the agent's activity.

[0078] "The compound of the present invention" refers to the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which has the effect of regulating the level of proteins such as GSPT1 and inhibiting the proliferation of tumor cells, as well as intermediate compounds for preparing the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0079] The compositions of the present invention are formulated, quantified, and administered in accordance with medical practice guidelines. The "therapeutic effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the route of administration.

[0080] "Therapeutic effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0081] "Patient" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including animals such as cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.

[0082] "Treatment" refers to reducing, slowing the progression of, attenuating, preventing, or maintaining an existing disease or condition (such as cancer). Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of a disease or condition.

[0083] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Pharmaceutically acceptable acid addition salts are salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. These salts can be prepared using methods known in the art.

[0084] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium, and magnesium salts. They also include, but are not limited to, salts of organic bases such as ammonium, triethylamine, lysine, and arginine salts. These salts can be prepared using methods known in this field.

[0085] When the compound represented by formula (I) contains one or more chiral centers, it can exist in different optically active forms. When the compound of formula (I) contains one chiral center, the compound comprises a pair of enantiomers. The two enantiomers of the compound, as well as mixtures of the pair of enantiomers, such as racemic mixtures, are also within the scope of protection of this invention. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound of formula (I) contains more than one chiral center, the compound comprises enantiomers and diastereomers. All enantiomers and diastereomers of the compound, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers, are also within the scope of protection of this invention. Enantiomers and diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.

[0086] Preparation method

[0087] This invention provides a method for preparing compounds of formula (I), which can be synthesized using standard synthetic techniques known to those skilled in the art or by combining methods known in the art with the methods described herein. The solvents, temperatures, and other reaction conditions given in this invention can be varied according to the art. The reactions can be used sequentially to provide the compounds of this invention, or they can be used to synthesize fragments subsequently added by the methods described herein and / or methods known in the art.

[0088] The compounds described in this invention can be synthesized using appropriate, selectable starting materials, similar to those described in the examples below or relevant publications used by those skilled in the art. The starting materials used to synthesize the compounds described in this invention can be synthesized or are available from commercial sources. The compounds described in this invention and other related compounds with different substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing the compounds disclosed in this invention can be derived from reactions known in the art, and these reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various parts of the molecules provided in this invention.

[0089] The main advantages of this invention include:

[0090] The compounds containing a nitrogen-containing heterocyclic butyl phenyl piperidine-2,6-dione structure of this application, which are protein degraders such as GSPT1, have a significant inhibitory effect on the proliferation of tumor cells, such as human breast ductal carcinoma cells, and exhibit an inhibitory activity of IC50 against the proliferation of MDA-MB-453 cells. 50 Values ​​less than 500 nM, and in some implementations, ICs with values ​​less than 300 nM. 50 Values, in some implementations, have ICs with a value less than 100 nM. 50 Values, in some implementations, have ICs with a value less than 50 nM. 50 Values, in some implementations, have ICs with a value less than 30 nM. 50 Therefore, it can be used to prepare protein degraders such as GSPT1 for the treatment or prevention of diseases related to or caused by GSPT1; it can also be used to prepare drugs for the treatment of breast cancer, such as for the treatment of HER2-positive or HER2-abnormally activated breast cancer and androgen receptor (AR)-positive breast cancer (LAR subtype breast cancer).

[0091] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Unless otherwise defined, the terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the present invention.

[0092] The known starting materials can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCRGmbH & Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc., and Darui Chemicals.

[0093] Unless otherwise specified, the reactions in the examples are carried out under a nitrogen or argon atmosphere.

[0094] DCM: Dichloromethane, DMF: Dimethylformamide, THF: Tetrahydrofuran, Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, Pin2B2: Pinacol diborate, SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride, ACN: Acetonitrile, n-BuLi: n-Butyllithium, KOAc: Potassium acetate, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, EDCl: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride, EtOAc: ethyl acetate, PE: petroleum ether, Xantphos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, Pd2(dba)3: tris(dibenzylideneacetone)dipalladium, FA: formic acid, DBU: 1,8-diazabicycloundec-7-ene, 9-BBN: 9-boronbicyclo(3,3,1)-nonane, IBX: 2-iodobenzoic acid, TBSCl: tert-butyldimethylchlorosilane, DMAP: 4-dimethylaminopyridine.

[0095] Unless otherwise specified, the percentage content involved in this invention refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0096] The final product of this invention can be obtained through preparation and purification. The purification and separation conditions are obtained by those skilled in the art based on the characteristics of the compound and conventional knowledge in the field.

[0097] As used in this article, room temperature refers to approximately 20-30°C.

[0098] Preparation of intermediate compound V1

[0099] Step 1: V1-1 (9.0 g, 38.79 mmol) and methyl acrylate (3.34 g, 38.79 mmol) were dissolved in tetrahydrofuran (90 mL) and stirred in an ice-water bath at 0 °C. Sodium methoxide (209.55 mg, 3.88 mmol) was added, and the reaction was stirred for another hour after the addition was complete. The reaction mixture was poured into a separatory funnel, and water (150 mL) was added. The mixture was extracted with ethyl acetate (40 mL × 2), and the organic phases were combined and washed with brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by Combi Flash silica gel column chromatography (80 g, 0–6% EtOAc / PE) to obtain a yellow oily liquid, V1-2 (9.0 g, 72.94% yield).

[0100] Step 2: V1-2 (9.0 g, 28.29 mmol) was dissolved in acetic acid (90 mL) and stirred at room temperature. Then, concentrated sulfuric acid (16.65 g, 169.75 mmol, 9.05 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was placed in a 90 °C oil bath and heated with stirring for 2 hours. After the reaction solution cooled to room temperature, it was slowly added to 350 mL of ice water, precipitating a large amount of white solid product. The product was filtered and dried under reduced pressure using a water pump. The obtained solid was transferred to a 250 mL single-necked flask and lyophilized to obtain white solid V1-3 (8.12 g, 94.38% yield). LC-MS m / z (ESI): 304.0 [M+1] + .

[0101] Step 3: V1-3 (3.04 g, 10.00 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (3.00 g, 17.99 mmol) were dissolved in tetrahydrofuran (30.0 mL). The mixture was stirred in an ice-water bath at 0 °C, and then DBU (3.04 g, 19.99 mmol, 2.98 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by adding saturated sodium carbonate aqueous solution (50 mL), poured into a separatory funnel, extracted with ethyl acetate (40 mL × 2), and the organic phases were combined and washed with brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by CombiFlash silica gel column chromatography (40 g, 0–25% EtOAc / PE) to give a yellow oily liquid V1-4 (3.52 g, 81.06% yield). LC-MS m / z (ESI): 406.0 [M+1–28] + .

[0102] Step 4: V1-4 (1.30 g, 3.00 mmol) and 3-hydroxyazacyclobutane hydrochloride (657.31 mg, 6.00 mmol) were dissolved in toluene (15.0 mL), and Xantphos (260.37 mg, 449.99 μmol) and cesium carbonate (2.93 g, 9.00 mmol) were added. Under nitrogen protection, Pd2(dba)3 (137.35 mg, 150.00 μmol) was added. After the addition was complete, the reaction was placed in an oil bath at 110 °C and heated and stirred for 12 hours. After the reaction solution cooled to room temperature, it was evaporated to dryness under reduced pressure. The crude product was purified by CombiFlash silica gel column chromatography (12 g, 0~45% EtOAc / PE) to obtain a yellow oily liquid V1-5 (650 mg, 32.00% yield). LC-MS m / z (ESI): 399.1 [M+1-28] + .

[0103] Step 5: V1-5 (650 mg, 960.08 μmol) was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (1.09 g, 9.60 mmol) was added. The mixture was stirred at 20 °C for 12 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dried under reduced pressure using an oil pump. The crude product was purified by Combi Flash silica gel column chromatography (12 g, 0–7% methanol / dichloromethane) to give a yellow solid V1-6 (265 mg, 84.59% yield). LC-MS m / z (ESI): 326.9 [M+1] + .

[0104] Step 6: V1-6 (265 mg, 812.15 μmol) was dissolved in acetonitrile (1.0 mL), and ammonia (1.63 g, 16.24 mmol, 35% purity) was added. The mixture was stirred at 20 °C for 12 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dried under reduced pressure using an oil pump. The crude product was purified by Combi Flash silica gel column chromatography (12 g, 0–8% methanol / dichloromethane) to give a yellow solid V1 (66 mg, 27.43% yield). LC-MS m / z (ESI): 297.1 [M+1] + .

[0105] Preparation of intermediate compound V2

[0106] Step 1: Add V1-4 (13.1 g, 30.16 mmol), 3-N-tert-butoxycarbonylaminocyclobutane (7.79 g, 45.24 mmol), Pd2(dba)3 (2.76 g, 3.02 mmol), Xantphos (1.75 g, 3.02 mmol), cesium carbonate (78.61 g, 241.28 mmol), and 1,4-dioxane (200 mL) to a reaction flask, purging with argon gas. React at 90 °C for 16 hours. Recycle the solvent to obtain a yellow oil, which is purified by column chromatography (petroleum ether / ethyl acetate, 0 to 30%) to give a yellow oily liquid V2-1 (10.5 g, 19.97 mmol, 66.2% yield). LC-MS m / z (ESI): 526.3 [M+1] + .

[0107] Step 2: Add V2-1 (10.5 g, 19.97 mmol), dichloromethane (60 mL), and trifluoroacetic acid (61.49 g, 539.32 mmol) to the reaction flask and react at 20 °C for 1 hour. Recycle the solvent to obtain a yellow oily liquid V2-2 (8.7 g, 19.80 mmol, 99.1% yield). LC-MS m / z (ESI): 326.2 [M+1] + .

[0108] Step 3: Add V2-2 (8.7 g, 19.80 mmol), acetonitrile (60 mL), and ammonia (2.08 g, 59.41 mmol) to the reaction flask and react at 20°C for 1 hour. Recycle the solvent to obtain a yellow oil, which was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 10%-40%). After freeze-drying, a white solid V2 (3.51 g, 11.89 mmol, 60.0% yield) was obtained. LC-MS m / z (ESI): 296.1 [M+1] + .

[0109] Example 1: Preparation of Compound 1

[0110] Step 1: Compound 1a (10.65 g, 41.02 mmol) and methylamine hydrochloride (3.32 g, 49.22 mmol) were dissolved in DMF (50.62 mL), and HATU (18.55 g, 49.22 mmol) and N,N-diisopropylethylamine (15.89 g, 123.05 mmol, 21.41 mL) were added sequentially. The mixture was stirred at 20 °C for 4 hours. The reaction mixture was poured into a separatory funnel, and water (300 mL) was added. The mixture was extracted with ethyl acetate (60 mL × 2), and the organic phases were combined and washed with brine (80 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by Combi Flash silica gel column chromatography (120 g, 0–65% EtOAc / PE) to give a yellow oily liquid 1b (10.41 g, 93.07% yield). LC-MS m / z (ESI): 273.1 [M+1] + .

[0111] Step 2: Compound 1b (10.41 g, 38.18 mmol) was added to a 500 mL three-necked reaction flask and dissolved in tetrahydrofuran (60 mL). The mixture was stirred in an ice-water bath at 0 °C under nitrogen protection. Borane tetrahydrofuran (381.76 mL, 381.76 mmol, 1 M) was slowly added dropwise. After the addition was complete, the reaction mixture was placed in a 70 °C oil bath and heated and stirred for 12 hours. After the reaction cooled to room temperature, it was stirred in a water bath and methanol was slowly added dropwise to quench the reaction. The mixture was then evaporated to dryness under reduced pressure until no more bubbles were produced. A small amount of methanol was added to the resulting liquid to dissolve it, and the mixture was stirred. HCl / Dioxane (5.0 eq 4 M) was added, and the mixture was stirred for ten minutes. LC-MS analysis showed that the intermediate had been completely converted to the target product. The solution was evaporated to dryness under reduced pressure, dissolved in ethyl acetate (100 mL), and poured into a separatory funnel. The pH of the solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution (200 mL). Extraction was performed with ethyl acetate (80 mL × 2). The organic phases were combined and washed with brine (100 mL). The solution was dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness under reduced pressure, and the crude product was then dried under reduced pressure using an oil pump to give a yellow oily liquid, 1c (9.81 g, 79.46% yield). LC-MS m / z (ESI): 259.1 [M+1] + .

[0112] Step 3: Compound 1c (9.81 g, 30.34 mmol) and di-tert-butyl dicarbonate (7.95 g, 36.40 mmol) were dissolved in tetrahydrofuran (60.0 mL). The mixture was stirred at 20 °C, and triethylamine (9.21 g, 91.01 mmol, 12.69 mL) was slowly added. After the addition was complete, the reaction mixture was stirred for another 12 hours. The reaction solution was evaporated to dryness under reduced pressure. The crude product was purified by Combi Flash silica gel column chromatography (120 g, 0–16% EtOAc / PE) to give a yellow oily liquid 1d (5.63 g, 51.72% yield). LC-MS m / z (ESI): 259.1 [M+1–100] + .

[0113] Step 4: Compound 1d (5.63 g, 15.69 mmol) and ammonium chloride (2.52 g, 47.07 mmol) were dissolved in ethanol (100 mL) and water (20 mL). Iron powder (4.38 g, 78.45 mmol) was added. After the addition was complete, nitrogen gas was introduced, and the mixture was heated and stirred in an oil bath at 80 °C for 4 hours. The cooled reaction solution was filtered through a diatomaceous earth layer, and the filter cake was washed with ethanol (80 mL × 3). The filtrates were combined and evaporated to dryness under reduced pressure. The crude product was purified by separation using a Combi Flash silica gel column (40 g, 0~28% EtOAc / PE) to give a yellow oily liquid 1e (4.71 g, 91.29% yield). LC-MS m / z (ESI): 229.1 [M+1-100] + .

[0114] Step 5: Compound 1e (165 mg, 501.77 μmol) was dissolved in dichloromethane (2.0 mL) and stirred at 20 °C, purging with nitrogen. Pyridine (119.07 mg, 1.51 mmol, 121.27 μL) was added, followed by dropwise addition of a solution of phenyl chloroformate (117.84 mg, 752.66 μmol) dissolved in dichloromethane (0.5 mL). The reaction mixture was stirred for another 2 hours. The reaction solution was evaporated to dryness under reduced pressure. The crude product was then dried by an oil pump to give a yellow solid 1f (460 mg, 48% purity, 98.02% yield). LC-MS m / z (ESI): 349.1 [M+1-100] + .

[0115] Step 6: Compound 1f (460 mg, 491.83 μmol) was dissolved in DMF (1.0 mL) and stirred at 0 °C. Nitrogen gas was purged, and sodium hydride (14.58 mg, 364.53 μmol, 60% purity) was added. Then, compound V1 (54 mg, 182.27 μmol) was dissolved in dichloromethane (0.5 mL), and the reaction was stirred for another hour. Formic acid was added dropwise to the reaction solution until pH 5-6. The solution was evaporated to dryness under reduced pressure and then dried using an oil pump. The crude product was purified by Combi Flash silica gel column chromatography (4 g, EtOAc / Pet.ether = 0-55%) to give 1 g (62 mg, 52.24% yield) of a yellow solid. LC-MS m / z (ESI): 551.1 [M+1-100] + .

[0116] Step 7: 1 g (62 mg, 66.66 μmol) of compound was dissolved in dichloromethane (1.0 mL), stirred at 20 °C, and trifluoroacetic acid (304.01 mg, 2.67 mmol) was added. After the addition was complete, the reaction mixture was stirred for another 1.5 hours. The reaction solution was evaporated to dryness under reduced pressure, and then further dried under reduced pressure using an oil pump. The crude product was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 12%-75%). After freeze-drying, a white solid 1 (2.79 mg, 6.08% yield) was obtained. LC-MS m / z (ESI): 550.7 [M+1] + . 1H NMR (400 MHz, DMSOd6) δ10.85 (s, 1H), 10.04 (s, 1H), 8.17 (s, 1H),7.57 (s, 1H), 7.30 (d, J = 3.0 Hz,2H), 6.25 – 6.16 (m, 2H), 5.26 (tt, J = 6.7, 4.0 Hz, 1H), 4.24 – 4.17 (m,2H), 4.02 (dd, J = 12.6, 5.4 Hz, 1H), 3.81 (dd, J = 9.1, 4.2 Hz, 2H), 3.62 –3.57 (m, 4H), 2.99 (t, J = 5.1 Hz, 2H), 2.88 (t, J = 7.0 Hz, 2H), 2.76 (ddd,J = 17.9, 13.2, 5.5 Hz, 1H), 2.48 – 2.40 (m, 4H), 2.12 – 1.99 (m, 1H), 1.92(d, J = 13.3 Hz, 1H).

[0117] Example 2: Preparation of Compound 2

[0118] Step 1: Compound 2a (1.1 g, 5.5 mmol), zinc powder (1.79 g, 27.5 mmol), and ammonium chloride (1.49 g, 27.5 mmol) were dissolved in methanol (20 mL) and water (4 mL), and reacted at room temperature for 4 hours. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give yellow solid 2b (650 mg, 69.1% yield). LC-MS m / z (ESI): 172.1 [M+1-100] + .

[0119] Step 2: Compound 2b (650 mg, 3.8 mmol) and pyridine (451 mg, 5.7 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of phenyl chloroformate (595 mg, 3.8 mmol). The reaction was carried out at 0 °C for 1 hour. After the reaction was complete, the solution was directly concentrated to give a yellow oil, 2c (860 mg, 77.9% yield). LC-MS m / z (ESI): 292.1 [M+1] + .

[0120] Step 3: Compound 2c (860 mg, 3.0 mmol) and imidazole (204 mg, 3.0 mmol) were dissolved in DMF (10 mL), followed by the addition of tert-butyldimethylchlorosilane (452 ​​mg, 3.0 mmol). The reaction was carried out at 25 °C for 1 hour. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oil. The yellow oil was then separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give a yellow solid 2d (935 mg, 76.8% yield). LC-MS m / z (ESI): 406.1 [M+1] + .

[0121] Step 4: Compound 2d (935 mg, 2.3 mmol) and compound V1 (680 mg, 2.3 mmol) were dissolved in DMF (10 mL), and sodium hydride (184 mg, 4.6 mmol) was added at 0 °C. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 × 3 mL). The mixture was filtered through anhydrous sodium sulfate and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give a yellow solid 2e (325 mg, 22.9% yield). LC-MS m / z (ESI): 608.1 [M+1] + .

[0122] Step 5: Compound 2e (325 mg, 0.54 mmol) was dissolved in EtOH (5 mL), followed by the addition of hydrogen chloride-ethanol solution (2 mL). The reaction was carried out at 25 °C for 0.5 hours. After the reaction was complete, the solution was directly concentrated by rotary evaporation to obtain a yellow oily substance 2f (315 mg, crude product). LC-MS m / z (ESI): 494.1 [M+1] + .

[0123] Step 6: Compound 2f (315 mg, 0.62 mmol) and Dys-Martin oxidant (263 mg, 0.62 mmol) were dissolved in dichloromethane (10 mL) and reacted at 25 °C for 1 hour. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oil. The yellow oil was then separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to directly give 2 g of yellow solid (147 mg, 47.0% yield). LC-MS m / z (ESI): 492.1 [M+1] + .

[0124] Step 7: 2 g (147 mg, 0.30 mmol) of compound and aziridine-3-ol (22 mg, 0.62 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of sodium borohydride acetate (57 mg, 1.5 mmol). The reaction was carried out at 25 °C for 1 hour. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oily substance. The yellow oily substance was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 20%-40%). After freeze-drying, a pale yellow solid 2 (3.2 mg, 2.0% yield) was obtained. LC-MS m / z (ESI): 549.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.12 – 10.05 (m, 1H), 7.58 (s, 1H), 7.29 (s, 2H), 6.21 (d, J = 10.9 Hz, 2H), 5.31 – 5.23 (m, 1H), 4.20 (s, 2H), 4.08 – 3.95 (m,2H), 3.83 – 3.78 (m, 2H), 3.06 – 2.89 (m, 2H), 2.85 – 2.78 (m, 1H), 2.77 –2.72 (m, 4H), 2.65 (s, 1H), 2.31 (s, 1H), 2.13 – 2.00 (m, 2H), 1.99 – 1.84 (m, 2H).

[0125] Example 3: Preparation of Compound 3

[0126] Step 1: Compound 3a (2.0 g, 28.2 mmol) and triethylamine (2.85 g, 28.2 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of di-tert-butyl dicarbonate (6.15 g, 28.2 mmol). The reaction was heated to 25 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with 100 mL of ethyl acetate and water, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give yellow liquid 3b (3.6 g, 75% yield). LC-MS m / z (ESI): 172.1 [M+1]+ .

[0127] Step 2: Compound 3b (3.6 g, 21.1 mmol) and 9-BBN (2.57 g, 21.1 mmol) were dissolved in tetrahydrofuran (50 mL), and the reaction was heated to 65 °C for 12 hours. Then, compound 3c (6.0 g, 21.1 mmol), Pd(dppf)Cl2 (684 mg, 1.06 mmol), potassium carbonate (5.8 g, 42.2 mmol), and water (10 mL) were added, and the reaction was heated to 100 °C for 12 hours. After cooling to room temperature, the reaction solution was diluted with 100 mL of ethyl acetate and water, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give a brown liquid 3d (750 mg, 10.9% yield). LC-MS m / z (ESI): 329.1 [M+1] + .

[0128] Step 3: Compound 3d (750 mg, 2.3 mmol), zinc powder (748 mg, 11.5 mmol), and ammonium chloride (621 mg, 11.5 mmol) were dissolved in ethanol (10 mL) and water (2 mL), and reacted at room temperature for 4 hours. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oil. The yellow oil was then separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give a brown solid 3e (512 mg, 74.7% yield). LC-MS m / z (ESI): 299.1 [M+1] + .

[0129] Step 4: Compound 3e (512 mg, 1.72 mmol) and pyridine (271 mg, 3.44 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of phenyl chloroformate (268 mg, 1.72 mmol). The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the solution was directly concentrated to give a yellow oil, 3f (516 mg, 71.8% yield). LC-MS m / z (ESI): 419.1 [M+1] + .

[0130] Step 5: Compound 3f (516 mg, 1.23 mmol) and compound V1 (364 mg, 1.23 mmol) were dissolved in DMF (10 mL), and sodium hydride (98.4 mg, 2.46 mmol) was added at 0 °C. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 × 3 mL). The mixture was filtered through anhydrous sodium sulfate and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give 3 g of yellow solid (312 mg, 40.8% yield). LC-MS m / z (ESI): 521.1 [M+1-100] + .

[0131] Step 6: Dissolve 3 g (312 mg, 0.50 mmol) of the compound in dichloromethane (5 mL), then add trifluoroacetic acid (1 mL) and react at 25 °C for 0.5 h. After the reaction is complete, directly evaporate to dryness and concentrate to give a yellow oil (165 mg, 63.3% yield) for 3 h. LC-MS m / z (ESI): 521.1 [M+1] + .

[0132] Step 7: Compound 3h (165 mg, 0.32 mmol), glycolic acid (25 mg, 0.32 mmol), and HATU (121.6 mg, 0.32 mmol) were dissolved in DMF (5 mL), followed by the addition of triethylamine (32.5 mg, 0.32 mmol). The reaction was carried out at room temperature for 4 hours. After the reaction, the mixture was filtered through diatomaceous earth, extracted with ethyl acetate (30 × 2 mL), washed with water (50 × 3 mL), and concentrated to obtain a yellow oil. The yellow oil was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 24%-44%), and after freeze-drying, a pale yellow solid 3 (5.8 mg, 3.1% yield) was obtained. LC-MS m / z (ESI): 579.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.04 (s,1H), 7.56 (s, 1H), 7.29 (d, J = 12.6 Hz, 2H), 6.21 (d, J = 10.9 Hz, 2H), 5.26(s, 1H), 4.92 (s, 1H), 4.39 (dd, J = 19.6, 14.0 Hz, 1H), 4.21 (d, J = 8.2 Hz, 2H), 4.04 (s, 1H), 4.01 (d, J = 7.9 Hz, 2H), 3.81 (d, J = 8.6 Hz, 2H), 3.18(d, J = 7.2 Hz, 1H), 2.82 (d, J = 5.8 Hz, 3H), 2.81 – 2.64 (m, 2H), 2.56 (d,J = 6.1 Hz, 2H), 2.06 (d, J = 13.4 Hz, 2H), 1.76 – 1.67 (m, 2H).

[0133] Example 4: Preparation of Compound 4

[0134] Step 1: Compound 2a (300 mg, 1.5 mmol) and IBX (840 mg, 3.0 mmol) were dissolved in acetonitrile (10 mL), and the reaction was carried out at 75 °C for 3 hours. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 25:1 to 10:1) to directly give a yellow solid 4a (261 mg, 87.0% yield). LC-MS m / z (ESI): 200.1 [M+1] + .

[0135] Step 2: Compound 4a (261 mg, 1.31 mmol), (zazocyclobut-3-yl)(methyl)carbamate tert-butyl hydrochloride (244 mg, 1.31 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL), followed by the addition of sodium borohydride acetate (50 mg, 1.31 mmol). The reaction was carried out at 25 °C for 1 hour. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to directly give a yellow solid 4b (203 mg, 41.9% yield). LC-MS m / z (ESI): 370.1 [M+1] + .

[0136] Step 3: Compound 4b (203 mg, 0.55 mmol), zinc powder (179 mg, 2.75 mmol), and ammonium chloride (146 mg, 2.75 mmol) were dissolved in ethanol (10 mL) and water (2 mL), and reacted at room temperature for 4 hours. After the reaction, the mixture was filtered through diatomaceous earth and concentrated to obtain a yellow oil. The yellow oil was then separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give a brown solid 4c (126 mg, 67.7% yield). LC-MS m / z (ESI): 340.1 [M+1] + .

[0137] Step 4: Compound 4c (126 mg, 0.37 mmol) and pyridine (58.5 mg, 0.74 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of phenyl chloroformate (58 mg, 0.37 mmol). The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the solution was directly concentrated to give a yellow oil, 4d (138 mg, 81.2% yield). LC-MS m / z (ESI): 460.1 [M+1] + .

[0138] Step 5: Compound 4d (138 mg, 0.30 mmol) and compound V1 (89 mg, 0.30 mmol) were dissolved in DMF (10 mL), and sodium hydride (23 mg, 0.6 mmol) was added at 0 °C. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give a yellow solid 4e (62 mg, 31.2% yield). LC-MS m / z (ESI): 562.1 [M+1-100] + .

[0139] Step 6: Compound 4e (62 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (1 mL). The reaction was carried out at 25 °C for 0.5 hours. After the reaction was complete, the mixture was directly concentrated by rotary evaporation to obtain a yellow oil. The yellow oil was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 24%-44%). After freeze-drying, a pale yellow solid 4 (4.5 mg, 8.6% yield) was obtained. LC-MS m / z (ESI): 562.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.01 (s, 1H), 8.22(s, 1H), 7.54 (s, 1H), 7.24 (s, 1H), 6.21 (d, J = 11.1 Hz, 2H), 5.25 (s, 1H),4.20 (s, 2H), 4.07 – 3.98 (m, 1H), 3.82 (s, 2H), 3.44 (s, 2H), 3.21 – 3.15(m, 2H), 2.78 – 2.73 (m, 1H), 2.67 (s, 3H), 2.56 (s, 2H), 2.50 (s, 2H), 2.37– 2.30 (m, 2H), 2.17 (s, 3H).

[0140] Example 5: Preparation of Compound 5

[0141] Step 1: Compound 4a (900 mg, 4.51 mmol), azacyclobutane-3-ol (329.60 mg, 4.51 mmol), dichloromethane (20 mL), and sodium triacetoxyborohydride (955.68 mg, 4.51 mmol) were added to a reaction flask, and the reaction was carried out at 20 °C for 16 hours. The mixture was extracted with saturated sodium carbonate aqueous solution (20 mL) and dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was purified by column chromatography (dichloromethane / methanol, 0 to 20%) to give a yellow oily liquid 5a (490 mg, 1.91 mmol, 42.3% yield). LC-MS m / z (ESI): 257.1 [M+1] + .

[0142] Step 2: Compound 5a (490 mg, 1.91 mmol), TBSCl (287.72 mg, 1.91 mmol), DMAP (193.17 mg, 1.58 mmol), and dichloromethane (10 mL) were added to the reaction flask, and the reaction was carried out at 20 °C for 16 hours. The solvent was evaporated to silica gel, and the mixture was purified by column chromatography (PE / EA, 0 to 30%) to give a yellow solid 5b (296 mg, 797.96 μmol, 41.8% yield). LC-MS m / z (ESI): 371.2 [M+1] + .

[0143] Step 3: Compound 5b (296 mg, 797.96 μmol), iron powder (222.83 mg, 3.99 mmol), ammonium chloride (213.42 mg, 3.99 mmol), water (20 mL), and ethanol (20 mL) were added to the reaction flask. Argon gas was purged, and the mixture was heated in an oil bath to 70 °C for 2 hours. The ethanol was evaporated to dryness, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol, 0 to 10%) to give a yellow oily liquid 5c (210 mg, 615.90 μmol, 77.2% yield). LC-MS m / z (ESI): 341.1 [M+1] + .

[0144] Step 4: Compound 5c (210 mg, 591.57 μmol), dichloromethane (10 mL), N,N-diisopropylethylamine (152.91 mg, 1.18 mmol, 206.08 μL), and triphosgene (52.66 mg, 177.47 μmol) were added to the reaction flask, and the reaction was carried out at 0°C for 1 hour. Subsequently, compound V2 (139.74 mg, 473.25 μmol) was added, and the reaction was carried out at 0°C for 2 hours. After the reaction was completed, the product was directly concentrated by rotary evaporation to obtain a yellow oil. The yellow oil was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 20%-45%), and after freeze-drying, a yellow solid 5d (40 mg, 60.40 μmol, 10.2% yield) was obtained. LC-MS m / z (ESI): 662.3 [M+1] + .

[0145] Step 5: Compound 5d (40 mg, 60.40 μmol), tetrahydrofuran (0.5 mL), and tetrabutylammonium fluoride (78.96 mg, 302.01 μmol) were added to the reaction flask, and the reaction was carried out at 20°C for 12 hours. After the reaction, the product was directly concentrated by rotary evaporation to obtain a yellow oil. The yellow oil was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 20%-40%). After freeze-drying, a white solid 5 (4.58 mg, 8.15 μmol, 13.5% yield) was obtained. LC-MS m / z (ESI): 548.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ10.84 (s, 1H), 8.78 (s, 1H), 8.18 (s, 1H), 7.59 (s, 1H), 7.15 (s, 2H), 7.02(d, J = 7.3 Hz, 1H), 6.15 (d, J = 11.2 Hz, 2H), 4.52 (q, J = 6.7 Hz, 1H), 4.27 – 3.93 (m, 5H), 3.69 – 3.54 (m, 7H), 2.77 (q, J = 6.6 Hz, 3H), 2.15 –1.87 (m, 3H).

[0146] Example 6: Preparation of Compound 6

[0147] Step 1: Compound 4a (2 g, 10.02 mmol), (S)-3-pyrrolidone (872.99 mg, 10.02 mmol), dichloromethane (30 mL), and sodium triacetoxyborohydride (4.25 g, 20.04 mmol) were added to a reaction flask, and the reaction was carried out at 20 °C for 16 hours. Saturated sodium carbonate aqueous solution (40 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was purified by column chromatography (dichloromethane / methanol, 0 to 20%) to give a yellow oily liquid 6a (510 mg, 1.88 mmol, 18.8% yield). LC-MS m / z (ESI): 271.1 [M+1] + .

[0148] Step 2: Compound 6a (510 mg, 1.88 mmol), dichloromethane (10 mL), DMAP (345.23 mg, 2.83 mmol), and TBSCl (425.92 mg, 2.83 mmol) were added to a reaction flask, and the reaction was carried out at 20 °C for 16 hours. The solvent was evaporated to silica gel, and the mixture was purified by column chromatography (dichloromethane / methanol, 0 to 10%) to give a yellow oily liquid 6b (450 mg, 1.17 mmol, 62.1% yield). LC-MS m / z (ESI): 385.2 [M+1] + .

[0149] Step 3: Compound 6b (450 mg, 1.17 mmol), water (10 mL), ethanol (10 mL), ammonium chloride (312.63 mg, 5.84 mmol), and iron powder (326.39 mg, 5.84 mmol) were added to the reaction flask. Argon gas was purged, and the mixture was reacted in an oil bath at 70 °C for 2 hours. The ethanol was evaporated to dryness, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol, 0 to 10%) to give a yellow oily liquid 6c (380 mg, 1.07 mmol, 91.6% yield). LC-MS m / z (ESI): 355.2 [M+1] + .

[0150] Step 4: Compound 6c (380 mg, 1.07 mmol) and dichloromethane (10 mL) were added to a reaction flask and stirred at 0 °C. N,N-diisopropylethylamine (691.74 mg, 5.35 mmol, 932.27 μL) and triphosgene (317.66 mg, 1.07 mmol) were then added, and the reaction was carried out at 0 °C for 1 hour. Subsequently, 3-[4-(3-aminoazacyclobutane-1-yl)-2,6-difluorophenyl]piperidine-2,6-dione (158.04 mg, 535.23 μmol) was added, and the reaction was carried out at 0 °C for 2 hours. Resilience drying yielded a yellow oily substance, which was directly sent for preparative separation (acid method, Gilson, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 10%-40%). After freeze-drying, a yellow solid was obtained (91 mg, 134.56 μmol, 12.6% yield) over 6 days. LC-MS m / z (ESI): 676.3 [M+1] + .

[0151] Step 5: Add a tetrahydrofuran (0.7 mL) solution of compound 6d (91 mg, 134.56 μmol) and TBAF (175.91 mg, 672.81 μmol) to the reaction flask and react at 20°C for 2 hours. The solvent was evaporated to obtain a yellow oil, which was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 10%-40%). After freeze-drying, a white solid 6 (24.8 mg, 43.31 μmol, 32.2% yield) was obtained. LC-MS m / z (ESI): 562.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.82 (s,1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.19 (t, J = 6.8 Hz, 2H), 7.04 (d, J = 7.4Hz, 1H), 6.15 (d, J = 11.2 Hz, 2H), 4.53 (q, J = 6.7 Hz, 1H), 4.23 (dq, J =6.8, 3.2 Hz, 1H), 4.06 (dt, J = 35.5, 6.4 Hz, 3H), 3.64 (t, J = 6.9 Hz, 2H),2.96 – 2.59 (m, 10H), 2.00 (tdd, J = 26.4, 13.0, 5.3 Hz, 3H), 1.70 – 1.56 (m,1H).

[0152] Example 7: Preparation of Compound 7

[0153] Step 1: Compound 7a (42 mg, 0.11 mmol) and pyridine (13 mg, 0.165 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of phenyl chloroformate (17 mg, 0.11 mmol). The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the solution was directly concentrated to give a yellow oil 7b (54 mg, 99% yield). LC-MS m / z (ESI): 417.1 [M+1-100] + .

[0154] Step 2: Compound 7b (54 mg, 0.11 mmol) and compound V1 (32.6 mg, 0.11 mmol) were dissolved in DMF (10 mL), and sodium hydride (8.4 mg, 0.22 mmol) was added at 0 °C. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The yellow oil was separated by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to directly give a yellow solid 7c (26 mg, 32.9% yield). LC-MS m / z (ESI): 619.2 [M+1-100] + .

[0155] Step 3: Compound 7c (26 mg, 0.036 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (1 mL). The reaction was carried out at 25 °C for 0.5 hours. After the reaction was complete, the mixture was directly concentrated by rotary evaporation to obtain a yellow oil. The yellow oil was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 24%-44%). After freeze-drying, a pale yellow solid 7 (5.3 mg, 23.8% yield) was obtained. LC-MS m / z (ESI): 619.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.03 (s, 1H), 7.56 (s, 1H), 7.28 (s, 2H), 6.20 (d, J = 11.0 Hz, 2H), 5.26 (s, 1H), 4.22 – 4.18 (m, 2H),4.04 (s, 1H), 3.82 (s, 2H), 3.54 (t, J = 6.8 Hz, 2H), 3.42 (t, J = 5.6 Hz, 2H), 3.29 – 3.27 (m, 1H), 3.19 (d, J = 10.0 Hz, 2H), 2.86 (d, J = 7.1 Hz, 2H), 2.68 (d, J = 20.7 Hz, 4H), 1.98 (d, J = 45.6 Hz, 2H).

[0156] Example 8: Preparation of Compound 8

[0157] Step 1: Compound 8a (50 mg, 0.16 mmol) and pyridine (13 mg, 0.16 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of phenyl chloroformate (25 mg, 0.16 mmol). The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the solution was directly concentrated to give a yellow oil, 8b (63 mg, 91.3% yield). LC-MS m / z (ESI): 431.1 [M+1] + .

[0158] Step 2: Compound 8b (63 mg, 0.15 mmol) and compound V1 (43 mg, 0.15 mmol) were dissolved in DMF (5 mL), followed by the addition of sodium hydride (12 mg, 0.30 mmol). The reaction was carried out at 25 °C for 0.5 hours. After the reaction, the mixture was directly concentrated by rotary evaporation to obtain a yellow oil. The yellow oil was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 24%-44%). After freeze-drying, a pale yellow solid 8 (8.5 mg, 9.2% yield) was obtained. LC-MS m / z (ESI): 633.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s,1H), 10.03 (s, 1H), 8.45 (s, 1H), 7.56 (s, 1H), 7.28 (s, 2H), 6.20 (d, J =11.0 Hz, 2H), 5.26 (s, 1H), 4.23 – 4.18 (m, 2H), 4.02 (s, 1H), 3.80 (s, 2H), 3.53 (d, J = 6.6 Hz, 2H), 3.40 (d, J = 3.9 Hz, 2H), 3.25 – 3.19 (m, 1H), 2.85(d, J = 6.7 Hz, 2H), 2.77 – 2.65 (m, 3H), 2.10 – 1.82 (m, 3H), 1.08 (d, J = 6.8Hz, 3H).

[0159] Example 9: Preparation of Compound 9

[0160] Step 1: Compound 9a (50 mg, 0.16 mmol) and pyridine (13 mg, 0.16 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of phenyl chloroformate (25 mg, 0.16 mmol). The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the solution was directly concentrated to give a yellow oil 9b (56 mg, 81.2% yield). LC-MS m / z (ESI): 431.1 [M+1] + .

[0161] Step 2: Compound 9b (56 mg, 0.13 mmol) and compound V1 (38.5 mg, 0.13 mmol) were dissolved in DMF (5 mL), followed by the addition of sodium hydride (11 mg, 0.26 mmol). The reaction was carried out at 25 °C for 0.5 hours. After the reaction, the mixture was directly concentrated by rotary evaporation to obtain a yellow oil. The yellow oil was directly sent for preparative separation (acid method, GILSON, Waters-SunFire C18; ACN / Water + 0.04% FA; gradient, 24%-44%). After freeze-drying, a pale yellow solid 9 (4.5 mg, 5.5% yield) was obtained. LC-MS m / z (ESI): 633.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ10.85 (s, 1H), 10.03 (s, 1H), 8.45 (s, 1H), 7.56 (s, 1H), 7.28 (s, 1H), 6.20(d, J = 11.0 Hz, 2H), 5.26 (s, 1H), 4.23 – 4.18 (m, 2H), 4.02 (s, 1H), 3.80(s, 2H), 3.53 (d, J = 6.6 Hz, 2H), 3.40 (d, J = 3.9 Hz, 2H), 3.25 – 3.19 (m,1H), 2.85 (d, J = 6.7 Hz, 2H), 2.77 – 2.65 (m, 3H), 2.10 – 1.82 (m, 3H), 1.08 (d, J = 6.8 Hz, 3H).

[0162] Example 10: Preparation of Compound 10

[0163] Following the preparation method of Example 6, the starting material (S)-3-pyrrolanol was replaced with (R)-3-pyrrolanol to obtain title product 10 (15 mg, 14% yield).

[0164] 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.84 (s, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.19 (t, J = 6.9 Hz, 2H), 7.06 (s, 1H), 6.15 (d, J = 11.7 Hz, 2H), 4.52 (q, J = 7.6, 6.9 Hz, 1H), 4.22 (s, 1H), 4.10 (t, J = 7.7 Hz, 2H), 4.06 – 3.97 (m, 1H), 3.63 (t, J = 6.8 Hz, 2H), 2.89 - 2.70 (m, 9H), 2.60 (s,1H), 2.09 – 1.88 (m, 3H), 1.61 (s, 1H).

[0165] LC-MS m / z (ESI): 562.2 [M+1] + .

[0166] Example 11: Preparation of Compound 11

[0167] Following the preparation method of Example 6, the starting material (S)-3-pyrrolidone was replaced with 3-hydroxymethylazine to obtain title product 11 (34 mg, 8% yield).

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.18 (s, 1H), 8.26 (s, 1H), 7.62 (s, 1H), 7.46 – 7.44 (m, 1H), 7.22 – 7.18 (m, 2H), 6.15 (d, J = 12.0 Hz,2H), 4.52 (m, 1H), 4.112 – 3.98 (m, 3H), 3.65-3.40 (m, 7H), 3.17 – 3.13 (m,2H), 2.78 – 2.50 (m, 6H), 2.11 – 1.89 (m, 2H).

[0169] LC-MS m / z (ESI): 562.2 [M+1] + .

[0170] Example 12: Preparation of Compound 12

[0171] Following the preparation method of Example 1, intermediate V1 was replaced with V2 to obtain title product 12 (18 mg, 16% yield).

[0172] 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.47 (s, 1H), 7.50 (s, 1H), 7.37 (s, 1H), 7.23 (s, 1H), 6.45 (s, 1H), 6.32 (d, J = 12.0 Hz, 2H), 4.33 (s,1H), 3.99 – 3.95 (m, 1H), 3.66 – 3.55 (m, 4H), 3.43 – 3.20 (m, 5H), 3.09-3.07(m, 2H), 2.92 – 2.90 (m, 2H), 2.80 – 2.71 (m, 1H), 2.57 – 2.45 (m, 4H), 2.09–1.88 (m, 2H).

[0173] LC-MS m / z (ESI): 549.8 [M+1] + .

[0174] Biological Experiment Examples

[0175] Assay on inhibition of MDA-MB-453 cell activity

[0176] I. Reagents required for the experiment

[0177] II. Boards and instruments required for the experiment

[0178] III. Experimental Methods

[0179] 1. MDA-MB-453 cells in the logarithmic growth phase were seeded into 384 cell culture plates except for the negative control wells. The culture medium was 45 μL of IMDM medium containing 10% FBS, and the cell density was 2000 / well. The negative control wells contained 45 μL of IMDM medium containing 10% FBS without cells.

[0180] 2. Prepare 10 times the required compound using 100% DMSO to test the final concentration;

[0181] 3. Add 5 μL of the prepared compound to the compound test well, and add 5 μL of 2.5% DMSO solution to the negative control well and the positive control well;

[0182] 4. The compound test plate was placed in a 37°C, 5% CO2 cell culture incubator and cultured for 3 days;

[0183] 5. Remove the compound test plate from the incubator and let it stand at room temperature for 0.5 h to allow it to return to room temperature.

[0184] 6. Remove the CTG reagent from the refrigerator beforehand to thaw and allow it to return to room temperature;

[0185] 7. Add 40 μL of CTG reagent to each well of the compound test plate;

[0186] 8. Place the compound test plate at room temperature and incubate in the dark for 0.5 h;

[0187] 9. Use Tecan to read the Luminescence value.

[0188] IV. Data Calculation

[0189] 1. PC wells are positive control wells, i.e., the wells with the maximum value measured on day 3, and NC wells are negative control wells, i.e., the wells with the minimum value measured on day 3.

[0190] 2. Calculation of compound inhibition rate

[0191] The inhibitory activity of the compounds disclosed in this application against the proliferation of MDA-MB-453 cells is shown in Table 1:

[0192] Table 1

[0193] Test results show that the compounds disclosed herein have significant inhibitory activity against the proliferation of cancer cells MDA-MB-453.

[0194] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0195] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0196] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: ； in, R1 and R2 are each independently halogens; m and n are each independently 0, 1, 2, 3 or 4; Z is either NH or O; t is 1, 2, or 3; T is O or NR n ; L1 is CH2 or C(O); L2 is CR L21 R L22 ; Where R n R L21 R L22 Definitions selected from the following group: (i)R n It is hydrogen or C 1-8 Alkyl; R L21 R L22 Each can be either hydrogen or halogen; (ii)R L21 It is hydrogen; R L22 With R n Linkage forms 4- to 6-membered nitrogen-containing heterocyclic alkyl groups; R3 is NR a R b , hydroxyl or hydroxy-substituted C 1-8 Alkyl; wherein R a R b Each independently is hydrogen, C 1-8 Alkyl or halogenated C 1-8 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, R1 is fluorine.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, n is 2.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, R2 is chlorine.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, m is 1.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, t is 2 or 3.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, T is 0; t is 2 or 3.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, T is NR n ; t is 2 or 3; L1 is C(O); R n It is hydrogen or C 1-8 Alkyl; R L21 R L22 Each is independently hydrogen.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, T is NR n t is 2 or 3; R L21 It is hydrogen or halogen; R L22 With R n They connect to form 4 to 6-membered nitrogen-containing heterocyclic alkyl groups.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, Z is O.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, The compound represented by formula (I) has the structure shown in formula (IA) or formula (IB): ； Where R0 is a halogen; q is 0, 1, 2 or 3; and s is 1, 2, 3 or 4.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, In formula (IA), R a C 1-8 Alkyl or halogenated C 1-8 Alkyl; R b It is hydrogen.

13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, In equation (IB), R3 represents NR. a R b , hydroxyl or hydroxy-substituted C 1-3 Alkyl; wherein R a R b Each independently is hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, Compounds of formula (I) are selected from any of the following structures: 。 15. A pharmaceutical composition, characterized in that, It includes the compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

16. Use of a compound as described in any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition as described in claim 15, in the preparation of a medicament for treating or preventing diseases associated with mutations, expression imbalances, allosteric changes, or functional abnormalities of GSPT1, N-MYC, or C-MYC proteins; Preferably, the disease is selected from esophageal cancer, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, urothelial carcinoma, non-Hodgkin's lymphoma, central nervous system tumors, prostate cancer and thyroid cancer, acute myeloid leukemia, and myelodysplastic syndrome.

17. Use of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of claim 15 in the preparation of a GSPT1 degrader or a medicament for a disease related to or caused by GSPT1; Preferably, the disease is a cancer related to GSPT1, selected from glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, kidney cancer, urothelial carcinoma, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome.

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