Substituted benzo seven-membered ring compound and application thereof

Abstract

The invention belongs to the field of medical chemistry, discloses a series of substituted benzo seven-membered ring compounds and application thereof, and particularly discloses a compound as shown in a formula (I), and stereoisomers and pharmaceutically acceptable salts thereof. # imgabs0 #

Description

Substituted benzo seven-membered ring compounds and their applications

[0001] Citation of Related Applications

[0002] This application claims priority and benefits of Chinese invention patent application No. 202310082505.6 filed with the State Intellectual Property Office of China on January 16, 2023, Chinese invention patent application No. 202310280328.2 filed with the State Intellectual Property Office of China on March 22, 2023, and Chinese invention patent application No. 202410042559.4 filed with the State Intellectual Property Office of China on January 10, 2024, and all the contents disclosed in said applications are incorporated herein by reference in their entirety.

[0003] The present application relates to the field of medicinal chemistry, and relates to a series of substituted benzo seven-membered ring compounds and their applications, and specifically to a compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0004] Breast cancer (BC) is one of the most common malignant tumors in women worldwide. Based on the status of tumor receptors, breast cancer can be further divided into estrogen receptor positive (ER-positive) + ), human epidermal growth factor receptor 2 positive (HER2 + ) and triple negative. Approximately 80% of newly diagnosed breast cancer patients are ER + Breast cancer. Estrogen receptors (ERα) and (ERβ) are members of the nuclear receptor family and are transcription factors that regulate gene expression and mediate the biological effects of estrogen. ERα and ERβ are widely expressed in different tissues, with ERα being considered the primary mediator of estrogen signaling in the female reproductive tract and breast.

[0005] Although inhibition of estrogen synthesis by aromatase inhibitors and inhibition of ER pathway signaling by selective estrogen receptor modulators (SERMs) have demonstrated considerable clinical benefit in the treatment of ER+ breast cancer, the development of intrinsic and acquired resistance to these drugs presents a hurdle for patients with advanced and metastatic breast cancer. While multiple resistance mechanisms to aromatase inhibitors and SERMs are evident, in the majority of resistant cases, tumor growth and disease progression remain dependent on ERα signaling, and ER proteins remain the primary driver of ER+ metastatic breast cancer.

[0006] Selective estrogen receptor downregulators (SERDs) are small molecules that target ERα for proteasome-dependent degradation. Currently, fulvestrant is the only SERD approved for use in postmenopausal women with advanced ER+ breast cancer treated with standard endocrine therapy. The clinical success of fulvestrant suggests that ER protein degradation is beneficial for patients with ER+ breast cancer, especially those whose disease continues to progress after standard endocrine therapy. The possible mechanism of action of traditional SERDs such as fulvestrant is by inducing ER protein misfolding, ultimately leading to proteasome-dependent degradation of ERα protein. SERD molecules are generally effective in inducing degradation of ER proteins in ER+ breast cancer cells, but they can only achieve partial degradation of ER proteins. Therefore, new therapeutic drugs that can achieve more complete degradation of ER may be more effective than traditional SERD molecules in the treatment of ER+ metastatic breast cancer.

[0007] The concept of protein degradation targeting chimeras (PROTACs) was first proposed in 2001. It is a technology that uses the ubiquitin-proteasome system to target specific proteins and induce their degradation in cells. PROTACs are heterogeneous bifunctional molecules composed of three parts: a ligand that binds to the target protein, a ligand that binds to the E3 ubiquitin ligase, and a linker that connects the two ligands. Its mechanism of action is to bind to the target protein, bringing the target protein and the E3 ligase close enough so that the E3 ligase can ubiquitinate and mark the target protein, and then degrade the marked protein through the proteasome.

[0008] PROTAC molecules based on ER ligands are expected to achieve more complete protein degradation than SERDs, and can maximally degrade ER proteins, thereby achieving + Better treatment outcomes for breast cancer.

[0009]

[0010] The present application provides a compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof,

[0011] in,

[0012] represents a single bond or a double bond;

[0013] T1 is selected from C, CH or N;

[0014] T2, T3 and T4 are each independently selected from CH or N;

[0015] E1, E2 and E3 are each independently selected from O or CH2, wherein at most one of E1, E2 and E3 is selected from O;

[0016] R1 is selected from OH, C 1-6 Alkoxy or COOH;

[0017] R2 is selected from C 1-12 Alkyl, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 1-12 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by one or more R a replace;

[0018] Each R a Each independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, or -O-(3-12 membered heterocycloalkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-12 Cycloalkyl, -OC 3- 12 Cycloalkyl, 3-12 membered heterocycloalkyl and -O-(3-12 membered heterocycloalkyl) are optionally substituted with one or more R aa replace;

[0019] Each R aa Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0020] L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3- 12 Cycloalkyl or 3-12 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-12The cycloalkyl group and the 3-12 membered heterocycloalkyl group are each independently optionally substituted with one or more R b replace;

[0021] Each R b Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0022] Each R3 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0023] m is selected from 0, 1 or 2;

[0024] T1, T2, T3, T4, E1, E2, E3, R1, R aa 、R b and R3 is optionally substituted with one or more substituents.

[0025] The present application provides a compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof,

[0026] in,

[0027] represents a single bond or a double bond;

[0028] T1 is selected from C, CH or N;

[0029] T2, T3 and T4 are each independently selected from CH or N;

[0030] E1, E2 and E3 are each independently selected from O or CH2, wherein at most one of E1, E2 and E3 is selected from O;

[0031] R1 is selected from OH or COOH;

[0032] R2 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R a replace;

[0033] Each R a Each is independently selected from -F, -Cl, -Br, -I, -OH, -NH2, -COOH, -C(=O)H, =O, -NO2 or -S(O)2OH;

[0034] L is selected from C 1-5 Alkylene, the C 1-5 1, 2 or 3 CH2 on the alkylene group are each independently optionally selected from C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-6 Cycloalkyl and 4-8 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R b replace;

[0035] Each R b Each independently selected from -F, -Cl, -Br, -I, -OH, -NH2 or -CN;

[0036] Each R3 is independently selected from halogen;

[0037] m is selected from 0, 1 or 2.

[0038] In some embodiments of the present application, m is selected from 0, and R3 is absent.

[0039] In some aspects of this application, is a single bond, T1 is selected from CH or N, and other variables are as defined in this application.

[0040] In some aspects of this application, is a double bond, T1 is selected from C, and other variables are as defined in this application.

[0041] In some embodiments of the present application, at least one of T2, T3 and T4 is selected from CH, and the other variables are as defined in the present application.

[0042] In some embodiments of the present application, at least two of T2, T3 and T4 are selected from CH, and the other variables are as defined in the present application.

[0043] In some embodiments of the present application, T2 is selected from CH, T3 is selected from CH, T4 is selected from CH, and other variables are as defined herein.

[0044] In other embodiments of the present application, T2 is selected from N, T3 is selected from CH, T4 is selected from CH, and other variables are as defined in the present application.

[0045] In other embodiments of the present application, T2 is selected from CH, T3 is selected from N, T4 is selected from CH, and other variables are as defined in the present application.

[0046] In other embodiments of the present application, T2 is selected from CH, T3 is selected from CH, T4 is selected from N, and other variables are as defined in the present application.

[0047] In other embodiments of the present application, T2 is selected from N, T3 is selected from N, T4 is selected from CH, and other variables are as defined in the present application.

[0048] In other embodiments of the present application, T2 is selected from N, T3 is selected from CH, T4 is selected from N, and other variables are as defined in the present application.

[0049] In other embodiments of the present application, T2 is selected from CH, T3 is selected from N, T4 is selected from N, and other variables are as defined in the present application.

[0050] In some embodiments of the present application, E1 is selected from O, E2 and E3 are selected from CH2, and the other variables are as defined herein.

[0051] In some embodiments of the present application, E2 is selected from O, E1 and E3 are selected from CH2, and the other variables are as defined herein.

[0052] In other embodiments of the present application, E3 is selected from O, E1 and E2 are selected from CH2, and other variables are as defined herein.

[0053] In other embodiments of the present application, E1, E2 and E3 are selected from CH2, and other variables are as defined herein.

[0054] In other embodiments of the present application, R2 is selected from C 1-8 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-8 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more R a Substitution, other variables are as defined in this application.

[0055] In other embodiments of the present application, R2 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocycloalkyl, the C 1-6Alkyl, C 3- 8-membered cycloalkyl and 4-8-membered heterocycloalkyl are optionally substituted by one or more R a Substitution, other variables are as defined in this application.

[0056] In other embodiments of the present application, R2 is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 1-4 Alkyl, C 3- 6-membered cycloalkyl and 4-7-membered heterocycloalkyl are optionally substituted by one or more R a Substitution, other variables are as defined in this application.

[0057] In other embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0058] In other embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 or 2 N atoms.

[0059] In some other embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 O atom.

[0060] In other embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 N atom and 1 O atom.

[0061] In other embodiments of the present application, the R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl are optionally replaced by one or more R a Substitution, other variables are as defined in this application.

[0062] In some embodiments of the present application, the R2 is selected from isopropyl, isobutyl, cyclobutyl, cyclohexyl, cyclopentyl or tetrahydropyranyl, and the isopropyl, isobutyl, cyclobutyl, cyclohexyl, cyclopentyl or tetrahydropyranyl is optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in this application.

[0063] In other embodiments of the present application, the R2 is selected from described or optionally one or more R a Substitution, other variables are as defined in this application.

[0064] In other embodiments of the present application, each of the R a Each independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-10 Cycloalkyl, -OC 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, or -O-(3-10 membered heterocycloalkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-10 Cycloalkyl, -OC 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or -O-(3-10 membered heterocycloalkyl) optionally substituted by one or more R aa Substitution, other variables are as defined in this application.

[0065] In other embodiments of the present application, each of the R a Each independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, or -O-(4-8 membered heterocycloalkyl), the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl or -O-(4-8 membered heterocycloalkyl) optionally substituted by one or more R aa Substitution, other variables are as defined in this application.

[0066] In other embodiments of the present application, each of the R aEach independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, or -O-(4-7 membered heterocycloalkyl), the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl or -O-(4-7 membered heterocycloalkyl) optionally substituted by one or more R aa Substitution, other variables are as defined in this application.

[0067] In other embodiments of the present application, each of the R a Each is independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, alkyl, -O-tetrahydrofuranyl, -O-piperidinyl, or -O-tetrahydropyranyl, the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl or -O-tetrahydropyranyl optionally substituted by one or more R aa Substitution, other variables are as defined in this application.

[0068] In other embodiments of the present application, each of the R aEach independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, azetidinyl, or oxetanyl, wherein the methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, azetidinyl or oxetanyl is optionally replaced by one or more R aa Substitution, other variables are as defined in this application.

[0069] In other embodiments of the present application, each of the R a Each independently selected from deuterium, -F, -Cl, -OH, -NH2, -CN, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, or -O-cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl or -O-cyclopropyl is optionally replaced by one or more R aa Substitution, other variables are as defined in this application.

[0070] In other embodiments of the present application, each of the R a are each independently selected from deuterium, -F, -Cl, -OH, methyl, isopropyl, methoxy, cyclopropyl, or -O-cyclopropyl, wherein the methyl, isopropyl, methoxy, cyclopropyl, or -O-cyclopropyl is optionally substituted by one or more R aa Substitution, other variables are as defined in this application.

[0071] In other embodiments of the present application, each of the R aa Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino, and other variables are as defined herein.

[0072] In other embodiments of the present application, each of the R aa Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino, and other variables are as defined herein.

[0073] In other embodiments of the present application, each of the R aa Each is independently selected from deuterium, =O, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino, and other variables are as defined herein.

[0074] In other embodiments of the present application, each of the R aa Each is independently selected from deuterium, -F, -Cl, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy, and other variables are as defined herein.

[0075] In other embodiments of the present application, each of the R aa are each independently selected from deuterium, -F, -Cl, or -OH, and other variables are as defined herein.

[0076] In other embodiments of the present application, each of the R a Each independently selected from deuterium, -F, -Cl, -OH, -NH2, methyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, or -O-cyclopropyl, and other variables are as defined herein.

[0077] In other embodiments of the present application, each of the R a Each is independently selected from deuterium, -F, -Cl, -OH, or methyl, and other variables are as defined in this application.

[0078] In some embodiments of the present application, the R2 is selected from Other variables are as defined in this application.

[0079] In other embodiments of the present application, the L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl group replacement, the C 1-5Alkylene, C 3-10 Cycloalkyl and 3-10 membered heterocycloalkyl are each independently optionally substituted with one or more R b Substitution, other variables are as defined in this application.

[0080] In other embodiments of the present application, the L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-8 Cycloalkyl or 4-8 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-8 Cycloalkyl and 4-8 membered heterocycloalkyl are each independently optionally substituted with one or more R b Substitution, other variables are as defined in this application.

[0081] In other embodiments of the present application, the L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-6 The cycloalkyl group and the 4-7 membered heterocycloalkyl group are each independently optionally substituted with one or more R b Substitution, other variables are as defined in this application.

[0082] In other embodiments of the present application, the L is selected from C 1-4 Alkylene, the C 1-4 1, 2, 3 or 4 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl group replacement, the C 1-4 Alkylene, C 3-6 The cycloalkyl group and the 4-7 membered heterocycloalkyl group are each independently optionally substituted with one or more R b Substitution, other variables are as defined in this application.

[0083] In other embodiments of the present application, the L is selected from C 1-3 Alkylene, the C 1-3 1, 2 or 3 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl group replacement, the C 1-3 Alkylene, C 3-6 The cycloalkyl group and the 4-7 membered heterocycloalkyl group are each independently optionally substituted with one or more R b Substitution, other variables are as defined in this application.

[0084] In other embodiments of the present application, the L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, tetrahydrothiophenyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, and the C 1-5 Alkylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, tetrahydrothiophenyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by one or more R b Substitution, other variables are as defined in this application.

[0085] In other embodiments of the present application, the L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, piperidinyl, or piperazinyl, wherein the C 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with one or more R b Substitution, other variables are as defined in this application.

[0086] In other embodiments of the present application, the L is selected from C 1-5 Alkylene, the C 1-5 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, piperidinyl, or piperazinyl, wherein the C 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R b Substitution, other variables are as defined in this application.

[0087] In other embodiments of the present application, the L is selected from C 1-3 Alkylene, the C 1-3 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, piperidinyl, or piperazinyl, wherein the C 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2 or 3 R b Substitution, other variables are as defined in this application.

[0088] In some embodiments of the present application, the L is selected from C 1-5 Alkylene, the C1-5 1 or 2 CH2 on the alkylene group are each independently optionally replaced by a group selected from piperidinyl or piperazinyl, wherein 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R b Substitution, other variables are as defined in this application.

[0089] In some embodiments of the present application, the L is selected from C 1-3 Alkylene, the C 1-3 1 or 2 CH2 on the alkylene group are each independently optionally replaced by a group selected from piperidinyl or piperazinyl, wherein 1-3 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R b Substitution, other variables are as defined in this application.

[0090] In other embodiments of the present application, each of the R b Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino, and other variables are as defined herein.

[0091] In some embodiments of the present application, each R b Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino, and other variables are as defined herein.

[0092] In other embodiments of the present application, each of the R b Each is independently selected from deuterium, =O, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino, and other variables are as defined herein.

[0093] In other embodiments of the present application, each of the R b Each is independently selected from deuterium, -F, -Cl, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy, and other variables are as defined herein.

[0094] In other embodiments of the present application, each of the R b Each is independently selected from deuterium, -F, -Cl, -OH, -NH2, or -CN, and other variables are as defined in this application.

[0095] In other embodiments of the present application, L is selected from the structure shown in formula (L-1):

[0096] in,

[0097] Ring B and Ring C are independently selected from C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl;

[0098] n is selected from 1 and 2, and other variables are as defined in this application.

[0099] In other embodiments of the present application, the ring B and the ring C are independently selected from C 3-10 cycloalkyl and 3-10 membered heterocycloalkyl.

[0100] In other embodiments of the present application, the ring B and the ring C are independently selected from C 3-8 cycloalkyl and 4-8 membered heterocycloalkyl.

[0101] In other embodiments of the present application, the ring B and the ring C are independently selected from C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl.

[0102] In some other embodiments of the present application, the ring B and ring C are each independently selected from a 4-7 membered heterocycloalkyl group, wherein the heterocycloalkyl group contains 1 or 2 N atoms.

[0103] In other embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0104] In other embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 or 2 N atoms.

[0105] In other embodiments of the present application, the ring B and ring C are independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0106] In other embodiments of the present application, the ring B and the ring C are independently selected from piperidinyl, piperazinyl or morpholinyl.

[0107] In some embodiments of the present application, L is selected from the structure shown in formula (L-1):

[0108] in,

[0109] Ring B and Ring C are independently selected from C 3-6 Cycloalkyl and 4-8 membered heterocycloalkyl;

[0110] n is selected from 1 and 2, and other variables are as defined in this application.

[0111] In some embodiments of the present application, L is selected from the structure shown in formula (L-1):

[0112] wherein Ring B and Ring C are each independently selected from cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, and other variables are as defined herein.

[0113] In some embodiments of the present application, the L is selected from Other variables are as defined in this application.

[0114] In other embodiments of the present application, each R3 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1- 4 alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino, and other variables are as defined herein.

[0115] In other embodiments of the present application, each R3 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C1-3 Alkyl, C 1- 3 alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino, and other variables are as defined herein.

[0116] In other embodiments of the present application, each R3 is independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino, and other variables are as defined in the present application.

[0117] In other embodiments of the present application, each R3 is independently selected from deuterium, -F, -Cl, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in the present application.

[0118] In other embodiments of the present application, each R3 is independently selected from deuterium, -F or -Cl, and other variables are as defined in the present application.

[0119] In some embodiments of the present application, the compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are selected from the structure represented by formula (I-1) or (I-2), its stereoisomers and pharmaceutically acceptable salts thereof:

[0120] Wherein, E1, E2, R2, R3 and m are as defined in formula (I) of the present application.

[0121] In other embodiments of the present application, the compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are selected from the compound represented by formula (I-1a) or (I-2a), its stereoisomers and pharmaceutically acceptable salts thereof:

[0122] wherein E1, E2, R2, R3 and m are as defined in this application.

[0123] In other embodiments of the present application, the compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts thereof are selected from the compound represented by formula (I-2aa) or formula (I-2ab), its stereoisomers, and pharmaceutically acceptable salts thereof:

[0124] wherein E1, E2, R2, R3 and m are as defined in this application.

[0125] In other embodiments of the present application, the compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are selected from the compound represented by formula (II) or (III), its stereoisomers and pharmaceutically acceptable salts thereof:

[0126] Among them, E1, E2, R2, R3, R a , and m are as defined in this application;

[0127] Ring A is selected from C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl;

[0128] p is selected from 0, 1, 2, or 3.

[0129] In other embodiments of the present application, the compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are selected from the compound represented by formula (II-1) or (III-1), its stereoisomers and pharmaceutically acceptable salts thereof:

[0130] Among them, E1, E2, R2, R3, R a , and m are as defined in this application;

[0131] Ring A is selected from C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl;

[0132] p is selected from 0, 1, 2, or 3.

[0133] In some embodiments of the present application, the ring A is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, and other variables are as defined in the present application.

[0134] In some embodiments of the present application, the ring A is selected from C 3-8 cycloalkyl or 4-8 membered heterocycloalkyl, and other variables are as defined in the present application.

[0135] In some embodiments of the present application, the ring A is selected from C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, and other variables are as defined in the present application.

[0136] In some embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0137] In some embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 or 2 N atoms.

[0138] In some embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 O atom.

[0139] In some embodiments of the present application, the 3-12 membered, 3-10 membered, 4-8 membered, or 4-7 membered heterocycloalkyl group contains 1 N atom and 1 O atom.

[0140] In some embodiments of the present application, the ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl, and other variables are as defined herein.

[0141] In some embodiments of the present application, the ring A is selected from cyclobutyl, cyclohexyl, cyclopentyl or tetrahydropyranyl, and other variables are as defined herein.

[0142] In some embodiments of the present application, the ring A is selected from Other variables are as defined in this application.

[0143] In some embodiments of the present application, the structural unit Selected from Other variables are as defined in this application.

[0144] In some embodiments of the present application, the C 1-6 Alkyl is selected from C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0145] In some embodiments of the present application, the C 1-5 Alkylene is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0146] In some embodiments of the present application, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0147] In some embodiments, the term "one or more" as used herein may refer to an integer from one to ten. For example, "one or more" may refer to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or, "one or more" may refer to 1, 2, 3, 4, 5, or 6; or, "one or more" may refer to 1, 2, 3, or 4; or, "one or more" may refer to 1, 2, or 3.

[0148] In some embodiments, the 3-12-membered group of the present disclosure is selected from 3-10-membered, 3-8-membered, 3-6-membered, 4-7-membered, 4-6-membered, 5-8-membered, 5-7-membered, or 5-6-membered.

[0149] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 or 2 heteroatoms selected from N or O.

[0150] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom.

[0151] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 O atom.

[0152] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom and 1 O atom.

[0153] In some embodiments, the cycloalkyl or heterocycloalkyl of the present disclosure is selected from a monocyclic, spirocyclic, fused ring or bridged ring. In some embodiments, the cycloalkyl or heterocycloalkyl is selected from a monocyclic, spirocyclic or fused ring. In some embodiments, the cycloalkyl or heterocycloalkyl is a monocyclic ring.

[0154] Some solutions of this application are derived from any combination of the above variables.

[0155] The present application also provides the following compounds, their stereoisomers and pharmaceutically acceptable salts:

[0156] In some embodiments of the present application, the compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:

[0157] In some embodiments of the present application, the compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:

[0158] The present application also provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound described herein, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0159] In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0160] The present application also provides the use of the compound of the present application, its stereoisomers and pharmaceutically acceptable salts thereof in the preparation of drugs for treating or preventing diseases related to estrogen receptor protein degradation targeting chimeras.

[0161] The present application also provides a method for treating or preventing diseases associated with estrogen receptor protein degradation targeting chimeras, comprising administering a therapeutically or preventively effective amount of the compound described herein, its stereoisomers, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment or prevention.

[0162] The present application also provides the use of the compounds described herein, their stereoisomers, their pharmaceutically acceptable salts, or their pharmaceutical compositions in treating or preventing diseases associated with estrogen receptor protein degradation-targeted chimeras.

[0163] The present application also provides the compounds described herein, their stereoisomers, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for treating or preventing diseases associated with estrogen receptor protein degradation targeting chimeras.

[0164] In some embodiments of the present application, the estrogen receptor protein degradation targeting chimera-related disease is selected from breast cancer.

[0165] The present application also provides use of the compound of the present application, its stereoisomers and pharmaceutically acceptable salts thereof in the preparation of drugs for treating or preventing diseases.

[0166] The present application also provides a method for treating or preventing a disease, comprising administering a therapeutically or preventively effective amount of the compound described herein, its stereoisomers, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment or prevention.

[0167] The present application also provides the use of the compounds described herein, their stereoisomers, their pharmaceutically acceptable salts, or their pharmaceutical compositions in treating or preventing diseases.

[0168] The present application also provides the compounds described herein, their stereoisomers, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for use in treating or preventing diseases.

[0169] In some embodiments of the present application, the disease is selected from diseases associated with estrogen receptors.

[0170] In some embodiments of the present application, the disease is selected from diseases associated with estrogen receptor α protein.

[0171] In some embodiments of the present application, the disease is selected from breast cancer.

[0172] In some embodiments of the present application, the disease is selected from estrogen receptor-positive breast cancer.

[0173] The present invention also provides the following biological testing method

[0174] Test method 1: In vitro testing of ERα protein levels in human breast cancer cells MCF-7

[0175] Purpose of the experiment:

[0176] The compounds were tested for their ability to degrade ERα protein under experimental conditions.

[0177] Experimental Materials:

[0178] Phenol red-free MEM medium was purchased from Wisent, fetal bovine serum was purchased from Biosera, and the Human Total ERα / NR3A1 ELISA kit was purchased from R&D. The BCA protein concentration assay kit was purchased from Yisheng, and the MCF-7 cell line was purchased from Purnosel. The Nivo5 multi-label analyzer was purchased from PerkinElmer.

[0179] Experimental methods:

[0180] Day 1:

[0181] 1. Resuspend MCF-7 cells in culture medium (phenol red-free MEM + 5% Charcoal Dextran Stripped FBS + 1% PS) and seed 20,000 cells per well in 80 μl of a 96-well clear cell culture plate. Incubate the plate in a CO2 incubator overnight.

[0182] the next day:

[0183] 1. Dosing cells: Use a dispenser to perform serial dilutions of the test compound in duplicate. Add 78 μL of culture medium to the middle plate. Transfer 2 μL of the serially diluted compound to each well of the middle plate according to the corresponding position. Mix thoroughly and transfer 20 μL per well to the cell plate. The final DMSO concentration is 0.5%. Incubate at 37°C for 24 hours.

[0184] 2. Coat the ELISA strips, dilute Human Total ERα Capture Antibody with 1X PBS to a final concentration of 1μg / mL, add 100μL to each well, and incubate at 25°C overnight.

[0185] Day 3:

[0186] ERα concentration determination:

[0187] 1. Prepare the standard curve solution: Dilute the standard curve stock solution (110 ng / mL) 6-fold using buffer #8 (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, pH 7.2-7.4) to obtain a solution with a concentration of 18.3 ng / mL. Then, further serially dilute the standard using buffer #3 (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, 1 M Urea, pH 7.2-7.4).

[0188] 2. Wash the ELISA plate three times with 270 μL of washing buffer (1X PBS containing 0.05% Tween) per well.

[0189] 3. Add 300 μL of blocking solution (1X PBS containing 1% BSA) to each well and incubate at 25°C for 2 hours;

[0190] 4. Pre-cool 1X PBS. After the compound incubation is complete, remove the supernatant and wash the plate with 250 μL per well of pre-cooled 1X PBS. Then add 30 μL of cell lysis buffer (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, 6 M Urea, 1 mM activated Sodium Orthovanadate, 2.5 mM Sodium Pyrophosphate, 1X protease inhibitors, pH 7.2-7.4) per well and lyse on ice for 15 minutes.

[0191] 5. Remove the blocking solution from the ELISA plate, wash it, and repeat step 3;

[0192] 6. After cell lysis, add 150 μL of buffer #8 (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, pH 7.2-7.4) to each well of the cell plate. Dilute the cell lysate 6-fold, pipette to mix, and transfer 100 μL of the solution to each well of the ELISA plate.

[0193] 7. At the same time, transfer 100 μL of Standard per well to the ELISA plate and incubate at 25°C overnight;

[0194] BCA protein concentration determination:

[0195] 1. Preparation of standard curve solution: dilute the BSA standard in 2-fold gradient using PBS;

[0196] 2. Take 20 μL of standard and test sample and add them to the microplate;

[0197] 3. Add 200 μL of BCA working solution to each well and incubate at 37°C for 30 minutes;

[0198] 4. After incubation, measure the absorbance at 570 nm on a plate reader.

[0199] Day 4:

[0200] 1. Remove the supernatant and wash three times with 270 μL of washing buffer per well.

[0201] 2. Dilute the Human Total ERα Detection Antibody stock solution (14.4 μg / mL) 36-fold using buffer #1 (1X PBS containing 1% BSA) to a final concentration of 400 ng / mL. Transfer 100 μL / well of the solution to the ELISA plate and incubate at 25°C for 2 hours.

[0202] 3. Wash the plate as in step 2;

[0203] 4. Dilute Streptavidin-HRP A 200-fold in buffer #1 (1X PBS containing 1% BSA), dispense 100 μL / well into the ELISA plate, and incubate at 25°C for 20 minutes.

[0204] 5. Wash the plate as in step 2;

[0205] 6. Add 100 μL of substrate solution (a 1:1 mixture of reagent A (H2O2) and reagent B (tetramethylbenzidine)) to each well of the ELISA plate and incubate at 25°C for 20 minutes.

[0206] 7. Add 50 μL / well of stop solution and read the OD450 absorbance on a plate reader.

[0207] Data Analysis:

[0208] ERα concentration measurement: Calculate the A, B, C, and D values ​​in the four-parameter equation y = (AD) / [1+(x / C)^B]+D based on the raw data from the standard curve, where y is the raw OD450 value and x is the concentration at the corresponding point on the standard curve. Calculate the ERα concentration at the corresponding point based on the four-parameter equation and the raw OD450 readings of the samples.

[0209] BCA protein concentration test: Calculate the linear equation y = a + b * x based on the raw data from the standard curve, where y is the raw OD570 value and x is the concentration at the corresponding point on the standard curve. Calculate the total protein concentration at the corresponding point based on the linear equation and the raw OD570 readings of the samples.

[0210] The data were normalized according to the formula ERα concentration / total protein concentration.

[0211] Then use the equation (Sample-Min) / (Max-Min)*100% to convert the raw data into degradation rate, DC 50 The value can be obtained by four-parameter curve fitting (obtained by log(degrader) vs.response--Variable slope mode in GraphPad Prism).

[0212] Max well: Positive control well reading value is 100nM FUL-treated cell well

[0213] Min well: negative control well reading value is 0.5% DMSO treated cell well

[0214] Test Method 2: Evaluation of Antiproliferative Effects in Human Breast Cancer Cells MCF-7

[0215] Purpose of the experiment:

[0216] In this experiment, the ATP fluorescence activity assay (CellTiter-Glo) was used to detect the inhibitory effect of the test compounds on cell proliferation in human breast cancer cells MCF-7.

[0217] Experimental Materials:

[0218] The cell line MCF-7 was purchased from Pronose, MEM medium was purchased from Wisent, penicillin / streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiter-Glo (cell viability chemiluminescence detection reagent) was purchased from Promega.

[0219] Experimental methods:

[0220] 1) MCF-7 cell anti-proliferation experiment:

[0221] MCF-7 cells were seeded in a white 384-well plate with 45 μL of cell suspension per well, containing 600 MCF-7 cells. The cell plate was cultured overnight in a CO2 incubator. The test compound was serially diluted using a dispenser, and a duplicate well experiment was set up. 38 μL of culture medium was added to the middle plate, and then 2 μL of the serially diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 5 μL of each well was transferred to the cell plate. The cell plate was cultured in a CO2 incubator for 6 days. After the cell plate with the compound added was incubated, 10 μL of cell viability chemiluminescent detection reagent was added to each well of the cell plate and incubated at room temperature for 10 minutes to stabilize the luminescent signal. The readings were read using a multi-label analyzer.

[0222] Data Analysis:

[0223] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (obtained using the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism).

[0224] Max well: Positive control well reading value is 2μM FUL-treated cell well

[0225] Min well: negative control well reading value is 0.5% DMSO treated cell well

[0226] Test method 3: Pharmacokinetic evaluation of compounds in mice

[0227] Purpose of the experiment:

[0228] In this study, C57BL male mice were used as test animals. LC / MS / MS was used to quantitatively determine the drug concentration in the plasma of mice at different time points after intravenous or oral administration of the test compound to evaluate the pharmacokinetic characteristics of the test drug in mice.

[0229] Experimental Materials:

[0230] C57 mice (male, Beijing Weitonglihua).

[0231] Experimental operation:

[0232] Clarified solutions of the test compounds were injected into C57 mice (without fasting) via the tail vein or administered orally (without fasting). The compound was administered in a 10% DMSO / 10% Solutol / 80% H2O vehicle. Approximately 50 μL of blood was collected from the cheek vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intravenous administration. The blood samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 g, 3 min, 2-8°C). Following oral gavage administration, approximately 50 μL of blood was collected from the cheek vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were placed in anticoagulant tubes containing sodium heparin. After collection, the blood samples were placed on ice and centrifuged within 1 h to separate the plasma (centrifugation conditions: 6000 g, 3 min, 2-8°C). Plasma drug concentrations were determined by LC-MS / MS, and pharmacokinetic parameters were calculated using the noncompartmental linear logarithmic trapezoidal method using Phoenix WinNonlin 8.2.0 pharmacokinetic software.

[0233] Test Method 4: Pharmacokinetic Evaluation of Compounds in Rats

[0234] Purpose of the experiment:

[0235] In this study, SD male rats were selected as the test compounds, and the LCMS / MS method was used to quantitatively determine the drug concentration in the plasma of rats at different time points after intravenous or oral administration of the test compounds to evaluate the pharmacokinetic characteristics of the test drugs in rats.

[0236] Experimental Materials:

[0237] SD rats (male, Beijing Weitonglihua).

[0238] Experimental operation:

[0239] The test compound was injected as a clear solution into rats via the tail vein (without fasting) or orally administered to rats (without fasting). The vehicle used for the compound was 10% DMSO / 10% Solutol / 80% H2O. For intravenous administration, approximately 200 μL of blood was collected from the jugular vein at each time point of 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration, and placed in an anticoagulant tube with added sodium heparin. After blood sample collection, it was placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 g, 3 minutes, 2-8 ° C). For oral gavage administration, approximately 200 μL of blood was collected from the jugular vein at each time point of 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration, and placed in an anticoagulant tube with added sodium heparin. After blood sample collection, it was placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 g, 3 minutes, 2-8 ° C). The drug concentration in plasma was determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin8.2.0 pharmacokinetic software with the non-compartmental linear logarithmic trapezoidal method.

[0240] Test Method 5: Pharmacokinetic Evaluation of Compounds in Beagle Dogs

[0241] Purpose of the experiment:

[0242] In this study, beagle dogs were selected as the test compounds. The LCMS / MS method was used to quantitatively determine the drug concentration in the plasma of beagle dogs at different time points after intravenous or oral administration of the test compounds to evaluate the pharmacokinetic characteristics of the test drugs in beagle dogs.

[0243] Experimental Materials:

[0244] Beagle dogs (male, Jiangsu Yadong Experimental Animal Research Institute Co., Ltd.).

[0245] Experimental operation:

[0246] The test compound was injected into the beagle dogs via forelimb vein or gavage in a clear solution (the vehicle used for the compound was 10% DMSO / 10% Solutol / 80% H2O). For intravenous administration, approximately 1.0 mL of blood was collected from the forelimb vein at each time point of 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration, and placed in an anticoagulant tube with EDTA-2K. The blood samples were placed on ice after collection and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 g, 3 minutes, 2-8°C). For oral gavage administration, approximately 1.0 mL of blood was collected from the forelimb vein at each time point of 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration, and placed in an anticoagulant tube with EDTA-2K. The blood samples were placed on ice after collection and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 g, 3 minutes, 2-8°C). The drug concentration in plasma was determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin8.2.0 pharmacokinetic software with the non-compartmental linear logarithmic trapezoidal method.

[0247] Test Method 6: In vivo pharmacodynamic study in a BALB / c nude mouse model of subcutaneous xenografts of human breast cancer MCF-7 cells

[0248] Cell culture:

[0249] Human breast cancer MCF-7 cells (ECACC, Catalog No. ECACC-86012803) were cultured as monolayers in EMEM (EBSS) supplemented with 10% fetal bovine serum, 1% anti-antibody, 2 mM glutamine, and 1% non-essential amino acids (NEAA) at 37°C in a 5% CO2 incubator. Twice weekly, cells were routinely digested and passaged using trypsin-EDTA. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0250] animal:

[0251] BALB / c nude mice, female, 6-8 weeks old, weighing 18-23 g.

[0252] Experimental plan:

[0253] Estrogen tablets (0.36 mg / tablet) were subcutaneously inoculated on the left back of each mouse. Three days later, 0.2 mL (1×10 7 MCF-7 cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the dorsal side of the right forelimb of each mouse, and the average tumor volume reached approximately 195 mm3 Dosing began at 1:00 PM. The test compound was administered orally once daily for 21 days in a 10% DMSO / 10% Solutol / 80% H2O vehicle. The doses of the test compound administered orally were 3, 10, and 30 mg / kg. Tumor diameters were measured twice weekly with a vernier caliper. Tumor volume was measured in cubic millimeters and calculated using the following formula: V = 0.5a × b 2 , where a and b represent the major and minor diameters of the tumor, respectively. The anti-tumor efficacy of the test compound was evaluated using the TGI (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) = [1 - (average tumor volume at the end of treatment in a given treatment group - average tumor volume at the start of treatment in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%.

[0254] Technical Effects

[0255] The compound of the present application has a significant downregulating effect on ERα protein levels and exhibits a good cell proliferation inhibitory effect; it exhibits good pharmacokinetic properties and drugability in animals, and shows a good tumor shrinking effect in a subcutaneous xenograft tumor model of human breast cancer MCF-7 cells.

[0256] Definition and Description

[0257] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0258] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0259] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present application, which are prepared by reacting the compounds with specific substituents discovered in the present application with relatively non-toxic acids or bases. When the compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present application contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0260] The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, the compounds in the form of free acid or base are reacted with a stoichiometric amount of a suitable base or acid to prepare.

[0261] A "pharmaceutical composition" refers to a composition containing one or more compounds described herein, their isomers, or pharmaceutically acceptable salts thereof, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0262] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0263] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0264] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0265] In all administration methods of the compounds of formula I described herein, the daily dosage is 0.001 to 2000 mg / kg body weight. The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0266] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0267] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, IAPs, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin conjugating enzymes, cause the attachment of ubiquitin to lysines on target proteins and subsequently target specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin conjugating enzymes, are responsible for the transfer of ubiquitin to target proteins. Generally speaking, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by E3s to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0268] The term "targeting chimera" refers to a bifunctional molecule comprising two small molecule ligands, one with high affinity for a target protein of interest, and a second for recruiting an E3 ligase that ubiquitinates and targets the protein for proteolysis by the 26S proteasome.

[0269] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0270] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0271] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0272] The term "preventing" or "preventing" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0273] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0274] The term "substituted" means that a specific atom or group can be replaced by another specified atom or group. For example, CH2 in CH3CH2CH3 can be replaced by O, S, or NH to obtain CH3OCH3, CH3SCH3, and CH3NHCH3.

[0275] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are within the scope of the present invention.

[0276] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0277] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0278] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0279] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0280] Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups via chemical bonds. The chemical bonds linking the sites to other groups can be represented by straight solid bonds. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy lines in the figure indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group.

[0281] The compounds of the present application may exist in specific tautomers, all of which are included within the scope of the present application. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (such as in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions carried out by the reorganization of some bonding electrons. The specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one.

[0282] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0283] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0284] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereoisomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0285] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and extended drug biological half-life. All isotopic variations of the compounds of this application, whether radioactive or not, are included within the scope of this application.

[0286] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0287] The L part in this application can be read from left to right.

[0288] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0289] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0290] The "substituent" described herein includes all substituents mentioned herein, for example, including the following terms "alkyl", "alkylene", "heteroalkyl", "alkoxy", "alkylamino", "dialkylamino", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "heterocyclyl", "heterocyclylalkyl", "aryl", "heteroaryl" and other related groups, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include deuterium atoms, hydroxyl, thiol, halogen, amino , nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio , heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., which are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0291] In some embodiments herein, the substituent is selected from a deuterium atom, a hydroxyl group, a sulfhydryl group, a halogen group, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1- 12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 ester groups, oxo and thio groups, etc., wherein the substituents are optionally substituted by one or more substituents selected from the following: deuterium atoms, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1- 12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0292] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0293] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0294] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the substituent is listed without specifying which atom it is connected to the substituted group, the substituent can be bonded through any atom of the substituent. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0295]

[0026] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0296] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0297] Unless otherwise specified, the term “C 1-5 "Alkylene" refers to a saturated straight or branched chain or cyclic hydrocarbon group consisting of 1 to 5 carbon atoms, which has two residues derived from the same carbon atom or two different carbon atoms of the parent alkane. 1-5 Alkylene includes C 1-5 Alkylene or C 1-3 Alkylene. C 1-5 Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like.

[0298] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0299] The term "alkylamino" refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0300] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0301] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, for example, a "5-6 membered ring" refers to a "ring" having 5-6 atoms arranged around it.

[0302] Unless otherwise specified, the term "cycloalkyl" refers to a carbon ring that is fully saturated and can exist as a monocyclic, fused, bridged, or spirocyclic ring. 3-12 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, wherein the C 3-12 Cycloalkyl groups include C 3-10 、C 3-8 、C 3-6 and C 5-6 Cycloalkyl, etc.; which may be monovalent, divalent or polyvalent. "C 3-10 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, wherein the C 3-10 Cycloalkyl groups include C 3-8 、C 3-6 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent; it may be a monocyclic, fused, bridged or spirocyclic ring. 3-10Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0303] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycloalkyl group is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered or 4- to 6-membered ring containing 1, 2 or 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0304] The term "4-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, cyclic and bridged rings. In addition, with respect to the "4-8 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 4-8 membered heterocycloalkyl includes 4-6 membered, 4-7 membered, 4-8 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0305] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0306] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7, or 5 to 6 rings. Preferred heteroaryls have a single 4 to 8-membered ring, especially a 5 to 6-membered ring, or a plurality of fused rings containing 5 to 14, especially 5 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0307] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 3. C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0308] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any connectable site on the benzene ring can be connected to other groups through one chemical bond, including at least These 4 connection methods.

[0309] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0310] The compounds of the present disclosure can be prepared by those skilled in the art of organic synthesis via Scheme 1, wherein R2, R3, E1, E2, E3, T2, T3, T4 and m are as defined in the present disclosure.

[0311] Route 1

[0312] Each product obtained by the reaction in the above-mentioned route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to, Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this disclosure can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0313] The structures of the compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0314] The solvents used in this application are commercially available.

[0315] Compounds are named according to the conventional nomenclature in the art or using The software named the commercially available compounds using the supplier's catalog name.

[0316] This application uses the following abbreviations: DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; MeOH stands for methanol; M stands for mol / L; Boc stands for tert-butyloxycarbonyl; Bn stands for benzyl; Pd / C stands for palladium-carbon catalyst; EDTA stands for ethylenediaminetetraacetic acid; prep-HPLC stands for preparative high-performance liquid chromatography; and Tf stands for trifluoromethanesulfonyl.

[0317] The present invention is described in detail below by way of examples, but this is not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0318] Reference Example 1

[0319] Step 1: Synthesis of intermediate 1-Cb

[0320] Intermediate 1-Ca (50 g) and trimethyl orthoformate (107.28 g) were dissolved in methanol (450 mL), and p-toluenesulfonic acid monohydrate (3.85 g) was added with stirring. The mixture was stirred at 25°C under a nitrogen atmosphere for 3 hours. After the reaction, saturated sodium carbonate solution was added to the reaction solution until the pH reached 7-8. 500 mL of dichloromethane and 500 mL of water were added, and the mixture was stirred for 10 minutes. The layers were allowed to stand and separate. The aqueous phase was extracted with dichloromethane (300 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 1-Cb.

[0321] 1 H NMR (400MHz, CDCl3) δ = 7.37-7.27 (m, 5H), 5.11 (s, 2H), 4.20 (br s, 2H), 4.01 (d, J = 6.8Hz, 1H), 3.34 (s, 6H), 2.73 (br s, 2H), 1.82-1.67 (m, 3H), 1.22 (br d, J=10.5Hz, 2H).

[0322] Step 2: Synthesis of intermediate 1-Cc

[0323] Intermediate 1-Cb (63 g) was dissolved in methanol (1000 mL), and wet Pd / C (7 g) was added. The mixture was stirred at 25°C under a hydrogen atmosphere for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filter cake was washed with methanol (100 mL x 5), and the organic phase was concentrated under reduced pressure to yield Intermediate 1-Cc.

[0324] 1 H NMR (400MHz, DMSO-d6) δ = 4.05 (br s, 1H), 4.00 (d, J = 6.8Hz, 1H), 3.24 (s, 6H), 2.97 (br d, J=12.3Hz, 2H), 2.51-2.50 (m, 1H), 2.47-2.43 (m, 1H), 1.70-1.60 (m, 1H), 1.58 (br d, J=13.3Hz, 2H), 1.14 (dq, J=3.9, 12.3Hz, 2H).

[0325] Step 3: Synthesis of intermediate 1-Cd

[0326] Intermediate 1-Cc (34.40 g) and p-chloroiodobenzene (46 g) were dissolved in dimethyl sulfoxide (500 mL). L-proline (8.88 g), cuprous iodide (7.35 g), and potassium carbonate (53.32 g) were added with stirring. The mixture was stirred at 110°C under a nitrogen atmosphere for 4 hours. After the reaction, the reaction mixture was cooled to below 50°C and added to 2.5 L of water with stirring. The mixture was stirred for 10 minutes and filtered. The filter cake was washed with 1 L of water and collected. 480 mL of methyl tert-butyl ether was added and the mixture was washed with ammonia (28%):water = 1:2 (200 mL*2). The organic phase was washed with saturated brine (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Take 20 g of the crude product and add 15 mL of methyl tert-butyl ether. Heat until all the product is dissolved, then cool to room temperature naturally. Stir for 30 min and filter. Wash the filter cake with methyl tert-butyl ether (2 mL*3). Collect the filter cake and dry it to obtain the intermediate 1-Cd.

[0327] 1 H NMR (400MHz, CDCl3) δ = 7.22-7.14 (m, 2H), 6.85 (d, J = 8.9Hz, 2H), 4.08 (d, J = 7.3Hz, 1H), 3.64 (br d, J=12.3Hz, 2H), 3.37 (s, 6H), 2.65 (dt, J=2.3, 12.3Hz, 2H), 1.84 (br d, J=13.1Hz, 2H), 1.75 (tdt, J=3.7, 7.6, 11.4Hz, 1H), 1.51-1.38 (m, 2H).

[0328] Step 4: Synthesis of Intermediate 1-C

[0329] Intermediate 1-Cd (1 g) and bis(bis(dibenzoyl)pyridinol) borate (1.48 g) were dissolved in methoxycyclopentane (20 mL). Tris(dibenzylideneacetone)dipalladium (339.45 mg), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (353.43 mg), and potassium acetate (1.09 g) were added and stirred at 110°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with methoxycyclopentane (10 mL x 5). The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (ethyl acetate: 0-5%, ethyl acetate / petroleum ether) to obtain Intermediate 1-C.

[0330] 1H NMR (400MHz, CDCl3) δ=7.69 (d, J=8.5Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 4.06 (d, J=6.8Hz, 1H), 3.82 (br d, J=12.5Hz, 2H), 3.36 (s, 6H), 2.79-2.67 (m, 2H), 1.87-1.80 (m, 2H), 1.80-1.72 (m, 1H), 1.49-1.39 (m, 2H), 1.32 (s, 12H).

[0331] Step 5: Synthesis of Intermediate 1-B

[0332] Intermediate 1-A (10 g) was dissolved in dichloromethane (100 mL), pyridine (6.24 g) was added at 0°C, and trifluoromethanesulfonic anhydride (37.08 g) was slowly added dropwise. The mixture was stirred at 15°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was added to water (200 mL) and extracted with dichloromethane (100 mL*2). The organic phase was washed with saturated sodium bicarbonate solution (50 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude intermediate 1-B.

[0333] Step 6: Synthesis of Intermediate 1-D

[0334] Intermediate 1-B (300 mg) and Intermediate 1-C (369.33 mg) were dissolved in 1,4-dioxane (12 mL). Tetrakis(triphenylphosphine)palladium (95.95 mg) and 1M sodium bicarbonate solution (2.39 mL) were added with stirring. The mixture was rapidly heated to 80°C and stirred for 2 hours under a nitrogen atmosphere. After the reaction, the reaction solution was cooled to room temperature and filtered through celite. The filter cake was washed with methyl tert-butyl ether (30 mL*5). 80 mL of water was added to the organic phase, stirred for 10 minutes, and the layers were separated by standing. The aqueous phase was extracted with methyl tert-butyl ether (20 mL*3). The organic phases were combined and washed with saturated brine (50 mL*1). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate percentage: 0-5%, ethyl acetate / petroleum ether) to obtain Intermediate 1-D.

[0335] 1H NMR (400MHz, CDCl3) δ=7.17 (d, J=8.5Hz, 2H), 6.97 (d, J=8.5Hz, 1H), 6.87 (br d, J=6.3Hz, 2H), 6.82 (d, J=2.8Hz, 1H), 6.73 (dd, J=2.8, 8.5Hz, 1H), 6.29 (t, J=7.3Hz, 1H), 4.09 (d, J=7.3Hz, 1H), 3.83 (s, 3H), 3.71 (br d, J=12.3Hz, 2H), 3.37 (s, 6H), 2.74-2.58 (m, 4H), 2.14 (quin, J=7.0Hz, 2H), 1.94 (q, J=7.2Hz, 2H), 1.85 (br d, J=12.3Hz, 2H), 1.80-1.70 (m, 1H), 1.53-1.39 (m, 2H).

[0336] Step 7: Synthesis of Intermediate 1

[0337] Intermediate 1-D (943.6 mg) was dissolved in dichloromethane (21 mL), and pyridinium tribromide (777.51 mg) was added at -5 to 0°C. The mixture was stirred at this temperature for 0.5 hours. After the reaction was completed, 2M sodium bisulfate solution was added to the reaction solution until the color of the mixed solution no longer lightened. The mixture was stirred for 15 minutes, and dichloromethane (20 mL) was added. The mixture was allowed to stand for separation. The aqueous phase was extracted with dichloromethane (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. 5 mL of n-heptane was added to the crude product, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain Intermediate 1.

[0338] 1 H NMR (400MHz, CDCl3) δ = 7.17 (br d, J=8.5Hz, 2H), 7.05-6.86 (m, 2H), 6.80-6.76 (m, 2H), 6.69-6.64 (m, 1H), 4.12 (d, J=7.3Hz, 1H), 3.82 (s, 3H), 3.77 (br d, J=12.3Hz, 2H), 3.40 (s, 6H), 2.76 (br t, J=7.0Hz, 4H), 2.59 (t, J=6.9Hz, 2H), 2.30 (quin, J=7.0Hz, 2H), 1.90 (br d, J=11.0Hz, 2H), 1.79 (br s, 1H), 1.65 (br s, 2H)

[0339] Reference Example 2

[0340] Step 1: Synthesis of Intermediate 2-B

[0341] Intermediate 2-A (37 g) and N-Boc piperazine (32.34 g) were dissolved in dioxane (450 mL), and tris(dibenzylideneacetone)dipalladium (15.90 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (10.05 g) and potassium phosphate (73.74 g) were added under stirring. Stirred for 17 hours at 90-100° C. under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature and filtered and concentrated to obtain a crude product. Ethyl acetate (200 mL) and n-heptane (200 mL) were added, stirred and slurried at 15-20° C. for 1 hour, filtered, and the filter cake was dried under vacuum to obtain intermediate 2-B.

[0342] 1 H NMR (400MHz, CDCl3) δ = 7.77-7.75 (m, 1H), 6.99 (br dd, J=2.0, 8.6Hz, 1H), 6.80 (s, 1H), 5.21 (s, 2H), 3.62-3.59 (m, 4H), 3.40-3.35 (m, 4H), 1.49 (s, 9H).

[0343] Step 2: Synthesis of Intermediate 2-C

[0344] Intermediate 2-B (43 g) was dissolved in tetrahydrofuran (150 mL), methanol (150 mL) and water (150 mL), and sodium hydroxide (21.61 g) was added under stirring. The mixture was stirred at 15-25°C for 16 hours. After the reaction was completed, 1M hydrochloric acid solution was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Ethyl acetate (125 mL) and n-heptane (250 mL) were added, stirred and slurried at 15-20°C for 2 hours, filtered, and the filter cake was dried under vacuum to obtain intermediate 2-C.

[0345] 1 H NMR (400MHz, DMSO-d6) δ = 7.79-7.77 (m, 1H), 7.35 (br d, J = 5.8Hz, 1H), 7.21 (br s, 1H), 6.82 (br dd, J = 2.4, 8.9Hz, 1H), 4.79 (s, 2H), 3.45 (br s, 4H), 3.30-3.28 (m, 4H), 1.46-1.39 (m, 9H).

[0346] Step 3: Synthesis of intermediate 2-D

[0347] Intermediate 2-C (15 g) was dissolved in methanol (90 mL) and ethyl acetate (90 mL). A 2M hexane solution of trimethylsilyldiazomethane (45 mL) was added at -10 to 0°C and stirred for 1 hour. A 2M hexane solution of trimethylsilyldiazomethane (10 mL) was added at -10 to 0°C and stirred at 0 to 5°C for 3 hours. A small amount of acetic acid was added dropwise to quench the reaction. Water (450 mL) was added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (120 mL). The organic layers were combined, washed with saturated sodium carbonate solution (140 mL) and saturated brine (140 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 2-D.

[0348] Step 4: Synthesis of Intermediate 2-E

[0349] Intermediate 2-D (15 g) was dissolved in tetrahydrofuran (85 mL), and triphenylphosphine (16.84 g) and carbon tetrabromide (21.29 g) were added. The mixture was stirred at 15-25°C for 12 hours. 65 mL of petroleum ether / ethyl acetate = 3 / 1 was added, stirred, filtered, and the filtrate was concentrated. 320 mL of petroleum ether / ethyl acetate = 3 / 1 was added, stirred, filtered, and the filtrate was concentrated. 320 mL of petroleum ether / ethyl acetate = 3 / 1 was added, stirred, filtered, and the filtrate was concentrated to obtain Intermediate 2-E.

[0350] 1 H NMR (400MHz, DMSO-d6) δ=7.81 (d, J=8.8Hz, 1H), 7.10 (d, J=2.8Hz, 1H), 6.92 (dd, J=2.6, 8 .9Hz, 1H), 5.00(s, 2H), 3.78(s, 3H), 3.46-3.43(m, 4H), 3.35-3.29(m, 4H), 1.41(s, 9H).

[0351] Step 5: Synthesis of Intermediate 2-G

[0352] Intermediate 2-E (19.2 g) was dissolved in acetonitrile (385 mL), and Intermediate 2-F (16.63 g) and N,N-diisopropylethylamine (30.02 g) were added. The mixture was stirred at 75-80°C for 24 hours. Water (260 mL) was added, and the mixture was extracted with ethyl acetate (2 x 195 mL). The mixture was washed with saturated brine (195 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product Intermediate 2-G. MS m / z: 525.3 [M+Na] + .

[0353] Step 6: Synthesis of the trifluoroacetate salt of intermediate 2

[0354] Intermediate 2-G (25 g) was dissolved in acetonitrile (375 mL), and benzenesulfonic acid (15.74 g) was added. The mixture was stirred at 75-80°C for 16 hours. The mixture was filtered, and the filter cake was purified by preparative HPLC (column: Phenomenex luna C18 250*80 mm*10 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile percentage: 0%-15.5%, 18.5 min) to obtain the trifluoroacetate salt of Intermediate 2.

[0355] 1 H NMR (400MHz, DMSO-d6) δ = 10.96 (s, 1H), 8.92-8.75 (m, 1H), 7.63-7.53 (m, 1H), 7.18-7. 08 (m, 2H), 5.05 (dd, J=5.0, 13.3Hz, 1H), 4.38-4.23 (m, 2H), 3.55-3.44 (m, 4H), 3.25 (br s, 4H), 2.96-2.84 (m, 1H), 2.64-2.54 (m, 1H), 2.41-2.31 (m, 1H), 2.02-1.91 (m, 1H).

[0356] Example 1

[0357] Step 1: Synthesis of compound 1-A

[0358] To a solution of Intermediate 1 (0.30 g) in 1,4-dioxane (10 mL) and water (2 mL) were added 3,6-dihydro-2H-pyran-4-boronic acid naphthalene ester (142.52 mg), tetrakis(triphenylphosphine)palladium (142.53 mg), and sodium carbonate (196.10 mg). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 100°C for 2 hours. After the reaction, the reaction mixture was cooled to room temperature and concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate %: 0-15%, ethyl acetate / petroleum ether) to obtain Compound 1-A. MS m / z: 490.2 [M+H] + .

[0359] 1 H NMR (400MHz, CDCl3) δ = 7.14-6.55 (m, 7H), 5.56 (br s, 1H), 4.21-4.04 (m, 3H), 3.83 (s, 3H), 3.77-3.67 (m, 4H), 3.41 (s, 6H), 2.68 (br t, J=6.2Hz, 3H), 2.19-2.04(m, 6H), 1.96-1.70(m, 3H), 1.53-1.23(m, 3H).

[0360] Step 2: Synthesis of Compound 1-B

[0361] To a solution of compound 1-A (120 mg) in methanol (100 mL) was added wet palladium hydroxide (25.67 mg, 20% purity). The reaction was stirred at 25°C, 30 psi for 24 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filter cake was rinsed with methanol (10 mL x 3), and the organic phase was concentrated under reduced pressure to obtain crude compound 1-B. MS m / z: 492.2 [M+H] + .

[0362] Step 3: Synthesis of Compound 1-C

[0363] Boron tribromide (214.01 mg) was added to a solution of compound 1-B (84 mg) in dichloromethane (5 mL) at 0°C, and the reaction was stirred at 25°C for 1 hour. After the reaction, the reaction solution was added to 30 mL of water and stirred for 5 minutes. The layers were separated by standing. The aqueous phase was extracted with dichloromethane (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 1-C. MS m / z: 450.0 [M+H+H2O] + .

[0364] Step 4: Synthesis of the hydrochloride salt of compound 1

[0365] To a solution of compound 1-C (80 mg) and the trifluoroacetic acid salt of intermediate 2 (131.41 mg) in dichloromethane (2 mL) and methanol (0.4 mL) were added sodium acetate (30.41 mg) and magnesium sulfate (111.57 mg). The reaction was stirred at 25°C for 30 minutes. Sodium acetate borohydride (117.86 mg) was added to the reaction solution, and the reaction was stirred at 25°C for 16 hours. 1 mL of water was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (column: Xtimate C18 150*40mm*5μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; acetonitrile gradient ratio: 10%-40% over 10 minutes) to obtain the hydrochloride salt of compound 1. MS m / z: 744.2 [M+H] +

[0366] 1H NMR (400MHz, DMSO-d6) δppm 10.96(s, 1H), 9.11-9.45(m, 1H), 7.54-7.65(m, 1H), 7.26-7.38(m, 1H), 7.12-7.24(m, 3H), 6.92-7.09(m, 2 H), 6.60-6.69(m, 1H), 6.45-6.52(m, 1H), 6.36-6.44(m, 1H), 5.01-5.13(m, 1H), 4.19-4.43(m, 2H), 4.00(br d, J=13.05Hz, 2H), 3.85(br d, J=7.03Hz, 2H), 3.61-3.74(m, 5H), 3.14(br s, 4H), 2.85-2.92 (m, 1H), 2.52-2.70 (m, 6H), 2.35-2.43 (m, 2H), 1.94-2.13 (m, 6 H), 1.80-1.93(m, 3H), 1.59-1.74(m, 3H), 1.39-1.46(m, 2H), 1.14-1.24(m, 2H).

[0367] Example 2

[0368] Step 1: Synthesis of compound 2-B

[0369] To a solution of compound 2-A (2.00 g) in toluene (40 mL) was added aluminum chloride (3.36 g) and the mixture was allowed to react at 90°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and added to 120 g of ice water. The mixture was stirred for 30 minutes and filtered. The filter cake was rinsed with water (5 mL x 3) and then with isopropyl ether (5 mL x 2). The filter cake was collected and dried under reduced pressure to obtain compound 2-B. 1 H NMR (400MHz, CDCl3) δ=7.74 (d, J=8.3Hz, 1H), 6.75 (dd, J=2.5, 8.5Hz, 1H), 6. 66(d, J=2.5Hz, 1H), 2.92-2.85(m, 2H), 2.77-2.67(m, 2H), 1.93-1.75(m, 4H).

[0370] Step 2: Synthesis of compound 2-C

[0371] Potassium carbonate (2.18 g) was added to a solution of compound 2-B (1.85 g) in acetonitrile (40 mL), followed by benzyl bromide (2.15 g) dropwise, and the mixture was stirred at 80°C for 3 hours. After the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filter cake was rinsed with acetonitrile (20 mL x 5). The organic phase was concentrated under reduced pressure to obtain a crude product. 100 mL of ethyl acetate and 60 mL of water were added to the crude product, and the layers were separated by standing. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-C. MS m / z: 266.9 [M+H] +

[0372] Step 3: Synthesis of compound 2-D

[0373] Dissolve 2-C (2.50 g) in dichloromethane (50 mL), add pyridine (1.11 g) at 0°C, and slowly add trifluoromethanesulfonic anhydride (3.97 g) dropwise. Stir at 25°C for 16 hours. After the reaction, add the reaction solution to water (100 mL) and extract with dichloromethane (30 mL x 3). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 2-D.

[0374] Step 4: Synthesis of compound 2-F

[0375] 2-D (3.30 g) and 2-E (2.30 g) were dissolved in 1,4-dioxane (50 mL). Tetrakis(triphenylphosphine)palladium (736.29 mg) and 1M sodium bicarbonate solution (18.35 mL) were added with stirring. Under a nitrogen atmosphere, the temperature was rapidly raised to 80°C and stirred for 2 hours. After the reaction, the reaction solution was cooled to room temperature and filtered through celite. The filter cake was washed with methyl tert-butyl ether (30 mL x 5). The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether, ethyl acetate %: 0-30%) to obtain compound 2-F. MS m / z: 484.2 [M+H] +

[0376] Step 5: Synthesis of Compound 2-G

[0377] 2-F (2.40 g) was dissolved in dichloromethane (50 mL), and pyridinium tribromide (1.67 g) was added at -5 to 0°C. The mixture was stirred at this temperature for 0.5 hours. After the reaction was completed, saturated sodium bisulfite solution was added to the reaction solution until the color of the mixture no longer lightened. The mixture was stirred for 15 minutes, and dichloromethane (50 mL) was added. The mixture was allowed to stand for separation. The aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether, ethyl acetate %: 0-30%) to obtain compound 2-G. MS m / z: 564.0 [M+H+2]+

[0378] 1 H NMR (400MHz, CDCl3) δ=7.46-7.32 (m, 5H), 7.13 (d, J=8.8Hz, 2H), 6.86 (d, J=8.5Hz, 3H ), 6.80-6.75(m, 1H), 6.73-6.68(m, 1H), 5.04(s, 2H), 4.12(d, J=7.0Hz, 1H), 3.75(br d, J=12.3Hz, 2H), 3.37 (s, 6H), 2.76-2.64 (m, 4H), 2.57 (t, J=6.9Hz, 2H), 2.28 (quin, J=6.9Hz, 2H), 1.85 (br d, J=13.1Hz, 2H), 1.79-1.71 (m, 1H), 1.44 (dq, J=4.0, 12.3Hz, 2H)

[0379] Step 6: Synthesis of compound 2-H

[0380] To a solution of compound 2-G (0.35 g) in 1,4-dioxane (30 mL) and water (6 mL) were added 4,4-difluorocyclohexyl-1-ene-1-boronic acid naphthalene ester (167.05 mg), tetrakis(triphenylphosphine)palladium (143.79 mg), and sodium carbonate (197.84 mg). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 100°C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to obtain a crude product, which was then purified by column chromatography (ethyl acetate / petroleum ether, ethyl acetate %: 0-15%) to obtain compound 2-H. MS m / z: 600.5 [M+H] +

[0381] 1H NMR (400MHz, CDCl3) δ = 7.47-7.42 (m, 2H), 7.39 (t, J = 7.3Hz, 2H), 7.34 (br d, J=7.0Hz, 1H), 6.97 (d, J=8.5Hz, 2H), 6.85 (d, J=2.5Hz, 1H), 6.82-6.77 (m, 3H), 6.76-6.71 (m, 1H), 5.39 (br s, 1H), 5.05 (s, 2H), 4.09 (d, J=7.3Hz, 1H), 3.70 (br d, J=12.3Hz, 2H), 3.37 (s, 6H), 2.71-2.60 (m, 4H), 2.48 (br t, J=13.8Hz, 2H), 2.25(br s, 2H), 2.17-2.05(m, 4H), 1.97-1.88(m, 2H), 1.85(br d, J=13.1Hz, 2H), 1.79-1.68 (m, 1H), 1.45 (dq, J=3.9, 12.4Hz, 2H)

[0382] Step 7: Synthesis of compound 2-I

[0383] To a solution of compound 2-H (300 mg) in methanol (90 mL) was added wet palladium hydroxide (300 mg, 20% purity). The reaction was stirred at 25°C, 35 psi for 24 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filter cake was rinsed with methanol (10 mL x 5), and the organic phase was concentrated under reduced pressure to obtain crude compound 2-I. MS m / z: 512.2 [M+H] +

[0384] Step 8: Synthesis of compound 2-J

[0385] To a solution of compound 2-I (230 mg) in tetrahydrofuran (5 mL) was added 2M sulfuric acid (899.07 μL), and the reaction was stirred at 50°C for 1 hour. After the reaction, the reaction solution was cooled to room temperature and the pH was adjusted to 7-8 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 2-J. MS m / z: 466.4 [M+H] +

[0386] Step 9: Synthesis of the hydrochloride salt of compound 2

[0387] To a solution of compound 2-J (220 mg) and intermediate 2 (334.47 mg) in dichloromethane (10 mL) and methanol (2 mL) were added sodium acetate (77.52 mg) and magnesium sulfate (284.40 mg). The reaction was stirred at 25°C for 30 minutes. Sodium acetate borohydride (300.45 mg) was added to the reaction solution, and the reaction was stirred at 25°C for 16 hours. 1 mL of water was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by prep-HPLC (column: Xtimate C18 150*40mm*5μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; acetonitrile percentage: 18%-48%; 10 minutes) to obtain the hydrochloride salt of compound 2. MS m / z: 778.7 [M+H] +

[0388] 1 H NMR (400MHz, DMSO-d6) δ = 10.97 (s, 2H), 7.59 (br d, J = 7.3Hz, 1H), 7.50-7.26 (m, 1H), 7.21-7.12 (m, 2H), 6.92 (br s, 3H), 6.64 (br s, 1H), 6.54-6.38 (m, 2H), 5.06 (br d, J=12.5Hz, 1H), 4.43-4.19 (m, 2H), 3.97 (br d, J=12.5Hz, 2H), 3.77-3.56 (m, 3H), 3.50 (br s, 6H), 3.11 (br s, 3H), 2.90(br d, J=12.8Hz, 2H), 2.70-2.54(m, 6H), 2.45-2.31(m, 2H), 2.08-2.05(m, 6H), 1.82(br s, 2H), 1.67(br s, 4H), 1.24(br s, 2H).

[0389] Example 3

[0390] Step 1: Synthesis of compound 3-A

[0391] To a solution of intermediate 1 (1 g) in 1,4-dioxane (20 mL) and water (4 mL) were added cyclohexene-1-boronic acid naphthalene ester (470.59 mg), tetrakis(triphenylphosphine)palladium (475.11 mg), and sodium carbonate (653.67 mg). The atmosphere was purged with nitrogen three times and the mixture was reacted at 100°C for 2 hours. After the reaction, the reaction mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether, ethyl acetate %: 0-15%) to obtain compound 3-A. MS m / z: 488.1 [M+H] +

[0392] Step 2: Synthesis of compound 3-B

[0393] To a solution of compound 3-A (400 mg) in methanol (100 mL) was added wet palladium hydroxide (400 mg, 20% purity). The reaction was stirred at 25°C, 30 psi for 24 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filter cake was rinsed with methanol (30 mL x 3), and the organic phase was concentrated under reduced pressure to obtain crude compound 3-B. MS m / z: 490.3 [M+H] +

[0394] Step 3: Synthesis of compound 3-C

[0395] Boron tribromide (127.90 mg, 49.19 μL) was added to a solution of compound 3-B (50 mg) in dichloromethane (4 mL) at 0°C. The reaction was stirred at 25°C for 1 hour. After the reaction, the reaction solution was added to 30 mL of water and stirred for 5 minutes. The layers were separated by standing. The aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 3-C. MS m / z: 448.4 [M+H+H2O] +

[0396] Step 4: Synthesis of the hydrochloride salt of compound 3

[0397] Sodium acetate (50.41 mg) and magnesium sulfate (184.93 mg) were added to a solution of compound 3-C (132 mg) and intermediate 2 (184.06 mg) in dichloromethane (3 mL) and methanol (0.6 mL). The reaction was stirred at 25°C for 30 minutes. Sodium acetate borohydride (195.37 mg) was added to the reaction solution, and the reaction was stirred at 25°C for 16 hours. 1 mL of water was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (column: Xtimate C18 150*40mm*5μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; acetonitrile percentage: 7%-37%, 14 min.) to obtain the hydrochloride salt of compound 3. MS m / z: 742.3 [M+H] +

[0398] 1H NMR (400MHz, DMSO-d6) δppm 10.94-10.98(m, 1H), 7.57-7.64(m, 1H), 7.26-7.37(m, 1H), 7.13-7.21(m, 3H), 6.94-7.08(m, 2H), 6.60-6.66(m, 1H), 6.37-6.52(m, 2H), 5.03-5.09( m, 1H), 4.19-4.40 (m, 2H), 3.93-4.07 (m, 2H), 3.52-3.77 (m, 6H), 3.06-3.2 4(m, 6H), 2.84-2.97(m, 2H), 2.27-2.43(m, 3H), 1.89-2.13(m, 6H), 1.87(br d, J=6.53Hz, 2H), 1.49-1.69(m, 6H), 1.32-1.45(m, 3H), 1.17-1.27(m, 2H), 0.97-1.14(m, 3H).

[0399] Biological testing:

[0400] Test Example 1: MCF-7 ERα degradation experiment

[0401] Purpose of the experiment:

[0402] The compounds were tested for their ability to degrade ERα receptors under experimental conditions.

[0403] Experimental Materials:

[0404] Phenol red-free MEM medium was purchased from Wisent, fetal bovine serum was purchased from Biosera, and the Human Total ERα / NR3A1 ELISA kit was purchased from R&D. The BCA protein concentration assay kit was purchased from Yisheng, and the MCF-7 cell line was purchased from Purnosel. The Nivo5 multi-label analyzer was purchased from PerkinElmer.

[0405] Experimental methods:

[0406] Day 1:

[0407] 1. Resuspend MCF-7 cells in culture medium (phenol red-free MEM + 5% Charcoal Dextran Stripped FBS + 1% PS) and seed 20,000 cells per well in 80 μl of a 96-well clear cell culture plate. Incubate the plate in a CO2 incubator overnight.

[0408] the next day:

[0409] 1. Dosing cells: Use a dispenser to perform serial dilutions of the test compound in duplicate. Add 78 μL of culture medium to the middle plate. Transfer 2 μL of the serially diluted compound to each well of the middle plate according to the corresponding position. Mix thoroughly and transfer 20 μL per well to the cell plate. The final DMSO concentration is 0.5%. Incubate at 37°C for 24 hours.

[0410] 2. Coat the ELISA strips, dilute Human Total ERα Capture Antibody with 1X PBS to a final concentration of 1μg / mL, add 100μL to each well, and incubate at 25°C overnight.

[0411] Day 3:

[0412] ERα concentration determination:

[0413] 1. Prepare the standard curve solution: Dilute the standard curve stock solution (110 ng / mL) 6-fold using buffer #8 (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, pH 7.2-7.4) to obtain a solution with a concentration of 18.3 ng / mL. Then, further serially dilute the standard using buffer #3 (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, 1 M Urea, pH 7.2-7.4).

[0414] 2. Wash the ELISA plate three times with 270 μL of washing buffer (1X PBS containing 0.05% Tween) per well.

[0415] 3. Add 300 μL of blocking solution (1X PBS containing 1% BSA) to each well and incubate at 25°C for 2 hours;

[0416] 4. Pre-cool 1X PBS. After the compound incubation is complete, remove the supernatant and wash the plate with 250 μL per well of pre-cooled 1X PBS. Then add 30 μL of cell lysis buffer (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, 6 M Urea, 1 mM activated Sodium Orthovanadate, 2.5 mM Sodium Pyrophosphate, 1X protease inhibitors, pH 7.2-7.4) per well and lyse on ice for 15 minutes.

[0417] 5. Remove the blocking solution from the ELISA plate, wash it, and repeat step 3;

[0418] 6. After cell lysis, add 150 μL of buffer #8 (1X PBS containing 1 mM EDTA, 0.5% Triton X-100, pH 7.2-7.4) to each well of the cell plate. Dilute the cell lysate 6-fold, pipette to mix, and transfer 100 μL of the solution to each well of the ELISA plate.

[0419] 7. At the same time, transfer 100 μL of Standard per well to the ELISA plate and incubate at 25°C overnight;

[0420] BCA protein concentration determination:

[0421] 1. Preparation of standard curve solution: dilute the BSA standard in 2-fold gradient using PBS;

[0422] 2. Take 20 μL of standard and test sample and add them to the microplate;

[0423] 3. Add 200 μL of BCA working solution to each well and incubate at 37°C for 30 minutes;

[0424] 4. After incubation, measure the absorbance at 570 nm on a plate reader.

[0425] Day 4:

[0426] 1. Remove the supernatant and wash three times with 270 μL of washing buffer per well.

[0427] 2. Dilute the Human Total ERα Detection Antibody stock solution (14.4 μg / mL) 36-fold in buffer #1 (1X PBS containing 1% BSA) to a final concentration of 400 ng / mL. Transfer 100 μL / well of the solution to the ELISA plate and incubate at 25°C for 2 hours.

[0428] 3. Wash the plate as in step 2;

[0429] 4. Dilute Streptavidin-HRP A 200-fold in buffer #1 (1X PBS containing 1% BSA), dispense 100 μL / well into the ELISA plate, and incubate at 25°C for 20 minutes.

[0430] 5. Wash the plate as in step 2;

[0431] 6. Add 100 μL of substrate solution (a 1:1 mixture of reagent A (H2O2) and reagent B (tetramethylbenzidine)) to each well of the ELISA plate and incubate at 25°C for 20 minutes.

[0432] 7. Add 50 μL / well of stop solution and read the OD450 absorbance on a plate reader.

[0433] Data Analysis:

[0434] ERα concentration measurement: Calculate the A, B, C, and D values ​​in the four-parameter equation y = (AD) / [1+(x / C)^B]+D based on the raw data from the standard curve, where y is the raw OD450 value and x is the concentration at the corresponding point on the standard curve. Calculate the ERα concentration at the corresponding point based on the four-parameter equation and the raw OD450 readings of the samples.

[0435] BCA protein concentration test: Calculate the linear equation y = a + b * x based on the raw data from the standard curve, where y is the raw OD570 value and x is the concentration at the corresponding point on the standard curve. Calculate the total protein concentration at the corresponding point based on the linear equation and the raw OD570 readings of the samples.

[0436] The data were normalized according to the formula ERα concentration / total protein concentration.

[0437] Then use the equation (Sample-Min) / (Max-Min)*100% to convert the raw data into degradation rate, DC 50 The value can be obtained by four-parameter curve fitting (obtained by log(degrader) vs.response--Variable slope mode in GraphPad Prism).

[0438] Max well: Positive control well reading value is 100nM FUL-treated cell well

[0439] Min well: negative control well reading value is 0.5% DMSO treated cell well

[0440] The experimental results are shown in Table 1.

[0441] Table 1 Effects of compounds on ERα degradation of DC 50

[0442] Conclusion: The compounds of the present application have good degradation ability for ERα.

[0443] Test Example 2: Evaluation of anti-proliferative effects in human breast cancer cells

[0444] Purpose of the experiment:

[0445] In this experiment, the ATP fluorescence activity assay (CellTiter-Glo) was used to detect the inhibitory effect of the test compounds on cell proliferation in human breast cancer cells.

[0446] Experimental Materials:

[0447] MEM medium was purchased from Wisent, penicillin / streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega; MCF-7 cell line was purchased from Pronose; MCF-7 ERY537S and MCF7 ERD538G cell lines were purchased from Shanghai WuXi AppTec Pharmaceutical Development Co., Ltd.

[0448] Experimental methods:

[0449] Cell anti-proliferation assay:

[0450] Day 0: Seed the cells in a 96-well plate at a density of 800 cells / well. Place the cell plate in a 37°C, 5% CO2 incubator and culture overnight.

[0451] Day 1: Add the corresponding compounds to the cell plate according to the plate map and return it to the incubator for 6 days.

[0452] Day 7: Discard 100 μL of supernatant from each well, add 50 μL of CTG, shake and mix for 15 minutes, equilibrate for 5 minutes, and read the results using Envision.

[0453] Data Analysis:

[0454] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (obtained using the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism).

[0455] Max well: Positive control well reading value is 2μM FUL-treated cell well

[0456] Min well: negative control well reading value is 0.5% DMSO treated cell well

[0457] The experimental results are shown in Table 2.

[0458] Table 2 Antiproliferative activity of compounds on MCF-7 cells

[0459] Conclusion: The compound of the present application has a good anti-proliferative effect on human breast cancer cells.

[0460] Test Example 3: Pharmacokinetic Test in Mice

[0461] Purpose of the experiment:

[0462] The pharmacokinetics of the test compound in mice under experimental conditions.

[0463] Experimental Materials:

[0464] C57 mice (male, Beijing Weitonglihua).

[0465] Experimental operation:

[0466] Clarified solutions of the test compounds were injected into C57 mice (without fasting) via the tail vein or administered orally (without fasting). The compound was administered in a 10% DMSO / 10% Solutol / 80% H2O vehicle. Approximately 50 μL of blood was collected from the cheek vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intravenous administration. The blood samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 g, 3 min, 2-8°C). Following oral gavage administration, approximately 50 μL of blood was collected from the cheek vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were placed in anticoagulant tubes containing sodium heparin. After collection, the blood samples were placed on ice and centrifuged within 1 h to separate the plasma (centrifugation conditions: 6000 g, 3 min, 2-8°C). Plasma drug concentrations were determined by LC-MS / MS, and pharmacokinetic parameters were calculated using the noncompartmental linear logarithmic trapezoidal method using Phoenix WinNonlin 8.2.0 pharmacokinetic software.

[0467] The experimental results are shown in Table 3.

[0468] Table 3 Pharmacokinetic parameters of the compounds of the present invention in mice

[0469] Conclusion: The compound of the present application has good pharmacokinetic properties in mice.

[0470] Test Example 4: In vivo pharmacodynamic study of a BALB / c nude mouse model with subcutaneous xenografts of human breast cancer MCF-7 cells

[0471] Cell culture:

[0472] Human breast cancer MCF-7 cells (ECACC, Catalog No. ECACC-86012803) were cultured as monolayers in EMEM (EBSS) supplemented with 10% fetal bovine serum, 1% anti-antibody, 2 mM glutamine, and 1% non-essential amino acids (NEAA) at 37°C in a 5% CO2 incubator. Twice weekly, cells were routinely digested and passaged using trypsin-EDTA. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0473] animal:

[0474] BALB / c nude mice, female, 6-8 weeks old, weighing 18-23 g.

[0475] Experimental plan:

[0476] Estrogen tablets (0.36 mg / tablet) were subcutaneously inoculated on the left back of each mouse. Three days later, 0.2 mL (1×10 7 MCF-7 cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the dorsal side of the right forelimb of each mouse, and the average tumor volume reached approximately 235 mm 3 The experimental compound was administered orally once daily for 21 days. The doses of the test compound administered orally were 3, 10, and 30 mg / kg. Tumor diameter was measured twice weekly with a vernier caliper. Tumor volume was measured in cubic millimeters and calculated using the following formula: V = 0.5a × b 2 , where a and b represent the major and minor diameters of the tumor, respectively. The anti-tumor efficacy of the test compound was evaluated using the TGI (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%.

[0477] Experimental results:

[0478] The test results are shown in Table 4.

[0479] Table 4 Antitumor effects of test compounds on human breast cancer MCF-7 cell subcutaneous xenograft tumor model

[0480] Conclusion: The compound of the present application exhibited tumor shrinkage effect in the human breast cancer MCF-7 cell subcutaneous xenograft tumor model.

[0481] Test Example 5: Human Breast Cancer MCF-7 Y537S In vivo pharmacodynamic study of a subcutaneous xenograft tumor model in BALB / c nude mice

[0482] animal:

[0483] BALB / c nude mice, female, 6-8 weeks old, weighing 18-23 g.

[0484] Experimental plan:

[0485] Estrogen tablets (0.36 mg / tablet) were subcutaneously inoculated into the left back of each mouse. Three days later, 0.2 mL (1×107 cells) of MCF-7 Y537S The cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the dorsal side of the right forelimb of each mouse, and the average tumor volume reached approximately 430 mm 3 The experimental compound was administered orally once daily for 28 days. The doses of the test compound administered orally were 3, 10, and 30 mg / kg. Tumor diameter was measured twice weekly with a vernier caliper. Tumor volume was measured in cubic millimeters and calculated using the following formula: V = 0.5a × b 2 , where a and b represent the major and minor diameters of the tumor, respectively. The anti-tumor efficacy of the test compound was evaluated using the TGI (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%.

[0486] Experimental results:

[0487] The test results are shown in Table 5.

[0488] Table 5 Effects of test compounds on human breast cancer MCF-7 Y537S Tumor inhibitory effect in subcutaneous cell xenograft tumor models

[0489] Conclusion: The hydrochloride of the compound of the present application is effective in the treatment of human breast cancer MCF-7 Y537S The cell subcutaneous xenograft tumor model showed significant tumor shrinkage effect.

Claims

The compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, in, represents a single bond or a double bond; T1 is selected from C, CH or N; T2, T3 and T4 are each independently selected from CH or N; E1, E2 and E3 are each independently selected from O or CH2, wherein, At most one of E1, E2 and E3 is selected from O; R1 is selected from OH, C 1-6 Alkoxy or COOH; R2 is selected from C 1-12 Alkyl, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 1-12 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by one or more R a Replace; each R a Each independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, or -O-(3-12 membered heterocycloalkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl and -O-(3-12 membered heterocycloalkyl) are optionally substituted with one or more R aa Replace; each R aa Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-12 The cycloalkyl group and the 3-12 membered heterocycloalkyl group are each independently optionally substituted with one or more R b Replace; each R b Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; each R3 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; m is selected from 0, 1 or 2; said T1, T2, T3, T4, E1, E2, E3, R1, R aa 、R b and R3 is optionally substituted with one or more substituents. The compound represented by formula (I) according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: At least one of T2, T3 and T4 is selected from CH; or at least two of T2, T3 and T4 are selected from CH; or T2 is selected from CH, T3 is selected from CH, and T4 is selected from CH; or T2 is selected from N, T3 is selected from CH, and T4 is selected from CH; or T2 is selected from CH, T3 is selected from N, and T4 is selected from CH; or T2 is selected from CH, T3 is selected from CH, and T4 is selected from N; or T2 is selected from N, T3 is selected from N, and T4 is selected from CH; or T2 is selected from N, T3 is selected from CH, and T4 is selected from N; or T2 is selected from CH, T3 is selected from N, and T4 is selected from N. The compound represented by formula (I) according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: E1 is selected from O, E2 and E3 are selected from CH2; or, E2 is selected from O, E1 and E3 are selected from CH2; or, E3 is selected from O, E1 and E2 are selected from CH2; or, E1, E2 and E3 are selected from CH2. The compound represented by formula (I) according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: Said R2 is selected from C 1- 8 alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-8 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more R a Substituted; or, said R2 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted by one or more R a Substituted; or, said R2 is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are optionally substituted by one or more R a or R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl is optionally replaced by one or more R a or, R2 is selected from isopropyl, isobutyl, cyclobutyl, cyclohexyl, cyclopentyl or tetrahydropyranyl, wherein the isopropyl, isobutyl, cyclobutyl, cyclohexyl, cyclopentyl or tetrahydropyranyl is optionally replaced by 1, 2 or 3 R a Substituted; or, said R2 is selected from described or optionally one or more R a Substituted; or, said R2 is selected from The compound according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: Each R a Each independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-10 Cycloalkyl, -OC 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, or -O-(3-10 membered heterocycloalkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-10 Cycloalkyl, -OC 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or -O-(3-10 membered heterocycloalkyl) optionally substituted by one or more R aa Substituted; or, each of said R a Each independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, or -O-(4-8 membered heterocycloalkyl), the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl or -O-(4-8 membered heterocycloalkyl) optionally substituted by one or more R aa Substituted; or, each of said R a Each independently selected from deuterium, halogen, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, or -O-(4-7 membered heterocycloalkyl), the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl or -O-(4-7 membered heterocycloalkyl) optionally substituted by one or more R aa Substituted; or, each of said R a Each is independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)H, =O, -NO2, -S(O)2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, alkyl, -O-tetrahydrofuranyl, -O-piperidinyl, or -O-tetrahydropyranyl, the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl or -O-tetrahydropyranyl optionally substituted by one or more R aa Substituted; or, each of said R a Each independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, azetidinyl, or oxetanyl, wherein the methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, azetidinyl or oxetanyl is optionally replaced by one or more R aa Substituted; or, each of said R a Each independently selected from deuterium, -F, -Cl, -OH, -NH2, -CN, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, or -O-cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl or -O-cyclopropyl is optionally replaced by one or more R aa Substituted; or, each of said R a are each independently selected from deuterium, -F, -Cl, -OH, methyl, isopropyl, methoxy, cyclopropyl, or -O-cyclopropyl, wherein the methyl, isopropyl, methoxy, cyclopropyl, or -O-cyclopropyl is optionally substituted by one or more R aa Substituted; or, each of said R a Each independently selected from deuterium, -F, -Cl, -OH, -NH2, methyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, or -O-cyclopropyl; or, each R a Each is independently selected from deuterium, -F, -Cl, -OH, or methyl. The compound represented by formula (I) according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-10 Cycloalkyl and 3-10 membered heterocycloalkyl are each independently optionally substituted with one or more R b Substituted; or, said L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-8 Cycloalkyl or 4-8 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-8 Cycloalkyl and 4-8 membered heterocycloalkyl are each independently optionally substituted with one or more R b Substituted; or, said L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl group replacement, the C 1-5 Alkylene, C 3-6 The cycloalkyl group and the 4-7 membered heterocycloalkyl group are each independently optionally substituted with one or more R b Substituted; or, said L is selected from C 1-4 Alkylene, the C 1-4 1, 2, 3 or 4 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl group replacement, the C 1-4 Alkylene, C 3-6 The cycloalkyl group and the 4-7 membered heterocycloalkyl group are each independently optionally substituted with one or more R b Substituted; or, said L is selected from C 1-3 Alkylene, the C 1-3 1, 2 or 3 CH2 on the alkylene group are each independently optionally selected from O, NH, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl group replacement, the C 1-3 Alkylene, C 3-6 The cycloalkyl group and the 4-7 membered heterocycloalkyl group are each independently optionally substituted with one or more R b Substituted; or, said L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, tetrahydrothiophenyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, and the C 1-5 Alkylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, tetrahydrothiophenyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by one or more R b Substituted; or, said L is selected from C 1-5 Alkylene, the C 1-5 1, 2, 3, 4 or 5 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, piperidinyl, or piperazinyl, wherein the C 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with one or more R b Substituted; or, said L is selected from C 1-5 Alkylene, the C 1-5 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, piperidinyl, or piperazinyl, wherein the C 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R b Substituted; or, said L is selected from C 1-3 Alkylene, the C 1-3 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by a group selected from O, NH, piperidinyl, or piperazinyl, wherein the C 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2 or 3 R b Substituted; or, said L is selected from C 1-5 Alkylene, the C 1-5 1 or 2 CH2 on the alkylene group are each independently optionally replaced by a group selected from piperidinyl or piperazinyl, wherein 1-5 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R b Substituted; or, said L is selected from C 1-3 Alkylene, the C 1-3 1 or 2 CH2 on the alkylene group are each independently optionally replaced by a group selected from piperidinyl or piperazinyl, wherein 1-3 Alkylene, piperidinyl and piperazinyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R b Substituted; or, said L is selected from The compound according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: Each R b Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1- 4 alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino; or, each of said R b Each independently selected from deuterium, =O, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1- 3-alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino; or, each of said R b are each independently selected from deuterium, =O, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino; or, each R b are each independently selected from deuterium, -F, -Cl, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy; or, each R b Each is independently selected from deuterium, -F, -Cl, -OH, -NH2, or -CN. The compound according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: L is selected from the structure shown in formula (L-1): wherein ring B and ring C are independently selected from C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl; n is selected from 1 and 2; or, the ring B and ring C are independently selected from C 3-10 Cycloalkyl and 3-10 membered heterocycloalkyl; or, the ring B and ring C are independently selected from C 3-8 Cycloalkyl and 4-8 membered heterocycloalkyl; or, the ring B and ring C are independently selected from C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl; or, the ring B and ring C are each independently selected from a 4-7 membered heterocycloalkyl, the heterocycloalkyl containing 1 or 2 N atoms; or, the ring B and ring C are each independently selected from a cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl; or, the ring B and ring C are each independently selected from a piperidinyl, piperazinyl or morpholinyl. The compound according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, wherein: Each R3 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino; or, each R3 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino; or, each R3 is independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino; or, each R3 is independently selected from deuterium, -F, -Cl, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy; or, each R3 is independently selected from deuterium, -F or -Cl. The compound represented by formula (I) according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, which is selected from the compound represented by formula (I-1) or (I-2) or (I-1a) or (I-2a) or (I-2aa) or (I-2ab), its stereoisomers and pharmaceutically acceptable salts thereof: in, E1, E2, R2, R3 and m are as defined in claim 1. The compound represented by formula (I) according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, which are selected from the compounds represented by formula (II) or (III) or (II-1) or (III-1), their stereoisomers and pharmaceutically acceptable salts thereof: in, E1, E2, R2, R3, R a , and m as defined in claim 1; Ring A is selected from C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl; p is selected from 0, 1, 2, or 3; or, the ring A is selected from C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; or, the ring A is selected from C 3-8 Cycloalkyl or 4-8 membered heterocycloalkyl; or, the ring A is selected from C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; Alternatively, the ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; Alternatively, the ring A is selected from cyclobutyl, cyclohexyl, cyclopentyl or tetrahydropyranyl; Alternatively, the ring A is selected from Alternatively, the structural unit Selected from The following compounds, their stereoisomers and pharmaceutically acceptable salts, Alternatively, the following compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof, Alternatively, the following compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof, A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound according to any one of claims 1 to 12, its stereoisomers, and pharmaceutically acceptable salts thereof; further, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Use of the compound according to any one of claims 1 to 12, its stereoisomers and pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 13 in treating or preventing a disease.

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