Tricyclic tetrahydroisoquinoline derivatives, their preparation method and their medical applications

Abstract

The present disclosure relates to tricyclic tetrahydroisoquinoline derivatives, their preparation methods, and their pharmaceutical applications. In particular, the present disclosure relates to tricyclic tetrahydroisoquinoline derivatives represented by general formula (I), their preparation methods, pharmaceutical compositions containing the derivatives, and their use as estrogen receptor modulators and in the preparation of drugs for treating estrogen receptor-mediated or dependent diseases or disorders. wherein, each substituent in general formula (I) is as defined in the specification. TIFF2023509944000122.tif5353

Description

[Technical Field]

[0001] This application claims priority from Chinese patent application CN202010025118.5, filed January 10, 2020, Chinese patent application CN202010036802.3, filed January 14, 2020, Chinese patent application CN202010273891.3, filed April 9, 2020, Chinese patent application CN202010680491.4, filed July 15, 2020, Chinese patent application CN202010819555.4, filed August 14, 2020, and Chinese patent application CN202010971693.4, filed September 16, 2020. The entire texts of the above Chinese patent applications are incorporated herein by reference.

[0002] The present disclosure belongs to the pharmaceutical field and relates to tricyclic tetrahydroisoquinoline derivatives, their preparation methods and pharmaceutical applications. In particular, the present disclosure relates to tricyclic tetrahydroisoquinoline derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as estrogen receptor modulators for treating estrogen receptor-mediated or dependent diseases or disorders, particularly preferably breast cancer. [Background technology]

[0003] Through long-term basic research and clinical monitoring, it has been found that diseases such as breast cancer, ovarian cancer, osteoporosis, schizophrenia, and Alzheimer's disease are closely related to abnormalities in the estrogen signaling pathway. Estrogen is a steroid hormone secreted by the endocrine system and plays an important role in the reproductive system, bone tissue, cardiovascular system, immune system, and central nervous system. The estrogen signaling pathway plays an important role in regulating cell proliferation, differentiation, and apoptosis. The development and progression of estrogen-dependent tumors, such as breast cancer, ovarian cancer, and endometrial cancer, are all closely related to estrogen. Currently, the main chemotherapy for breast cancer uses antiestrogens, such as tamoxifen, which exhibits estrogen agonist properties in the uterus and has a stimulatory effect on uterine cancer cells. These serious side effects have made it imperative to seek new, safe, and effective treatment methods.

[0004] One of the key proteins in the estrogen signaling pathway is the estrogen receptor (ER). ER is a steroid hormone receptor and a ligand-activated transcription factor in the nuclear receptor superfamily. It contains two isoforms, ERα (discovered in 1950) and ERβ (discovered in 1996), encoded by different genes. Erα and Erβ share a high degree of amino acid similarity, with DNA-binding domains reaching up to 97% similarity and ligand-binding domains reaching up to 56%, but only a low degree of homology of 24% at the N-terminus. The ER contains six domains (A-F) and four major functional regions. The N-terminal A / B domain functional region contains the ligand-independent transcription activation functional region AF-1. AF-1 has constitutive activation activity and activates target gene transcription by interacting with basal transcription factors, reactivators, and other transcription factors. This region contains multiple phosphorylation sites, and the activity of AF-1 has been reported to depend on protein phosphorylation. The DNA-binding domain (DBD), consisting of the C domain, is highly conserved and contains two zinc finger domains, allowing specific binding to target DNA. This domain also plays a key role in receptor dimerization. The D domain, a hinge region connecting the DBD and the ligand domain (LBD), is less conserved (only 30% homology between the two isoforms). The C-terminal E domain constitutes the ligand-binding domain (LBD), which determines the specific binding of ER to ligands such as estrogen, SERMs (selective estrogen receptor modulators), and SERDs (selective estrogen receptor downregulators). The LBD contains the ligand-dependent transcriptional activation domain AF-2, which synergizes with AF-1 to activate the transcription of target genes. At the same time, the LBD possesses a strong dimerization interface and remains functional even in the absence of ligand, making it a critical site for receptor dimerization.

[0005] Erα is primarily distributed in the uterus, ovaries, testes, pituitary gland, kidneys, epididymis, and adrenal glands, while Erβ is primarily distributed in the prostate, ovaries, lungs, bladder, brain, and blood vessels. SERMs need to be studied because both full agonists and full antagonists have serious side effects. Their "selectivity" means that SERMs act as agonists in some tissues, such as bone, liver, and ERβ-rich areas of the cardiovascular system, but as antagonists in other tissues, such as the mammary gland. They may be either agonists or antagonists in the uterus (where Erα is prominent). Currently available SERMs include tamoxifen, raloxifene, bazedoxifene, and toremifene, but research has found that currently available SERMs have serious side effects, such as long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps, and endometrial cancer, while common side effects of raloxifene include hot flashes, leg pain, breast swelling, and venous thrombosis. Therefore, the research and development of new compounds has become a problem to be solved.

[0006] Tamoxifen, a member of a class of compounds called selective estrogen receptor modulators (SERMs), stabilizes Erα and slightly upregulates ERα receptor levels. Conversely, fulvestrant induces rapid degradation of Erα, promoting blockage of the ER receptor signaling pathway. These compounds are called selective estrogen receptor downregulators (SERDs). The differences in the mechanisms of action of these SERMs and SERDs appear to be the mechanisms underlying resistance to these compounds. Many tumors that are tamoxifen-resistant but remain ER-positive remain sensitive to fulvestrant. Based on clinical findings, SERDs such as fulvestrant can effectively treat some ERα-positive, tamoxifen-resistant breast cancers. Therefore, compounds that induce Erα degradation can be used to extend the duration of successful anti-estrogen therapy in breast cancer patients (potentially using different SERMs, aromatase inhibitors, and SERDs in sequence).

[0007] Patent applications that disclose selective estrogen receptor-mediated modulators include WO2014165723, WO2014151899, WO2014141292, WO2014191726, WO2015092634, WO2014135834, WO2014106848, and EP1113007. Summary of the Invention

[0008] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, as well as a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows: [ka] Among them, Ring A is a heterocyclyl group; Z is an O atom, an S atom, or an NR7 and CR 9 R 10 is selected from G 1 , G 2 , G 3 and G 4 are homologous or different and each independently represent CR 8 or a N atom, R 1a and R 1b are identical or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3are selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5 are selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a halogen atom, a carboxy group, an aldehyde group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R7 are selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, a propargyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group; n is 1, 2 or 3; s is 0, 1 or 2, and p is 0, 1, 2 or 3.

[0009] In some embodiments of the present disclosure, there is provided a compound represented by general formula (I) or its tautomers, meso-isomers, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, [ka] Among them, R 1aand R 1b are identical or different and are each independently selected from H atoms, deuterium atoms, halogens, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, carboxy groups, aldehyde groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from halogens, alkyl groups, alkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; Ring A is a heterocyclyl group; Z is an O atom, an S atom, or an NR 7 and CR 9 R 10 is selected from G 1 , G 2 , G 3 and G 4 are homologous or different and each independently represent CR 8 or a N atom, R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3are selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5 are selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a halogen atom, a carboxy group, an aldehyde group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R7 are selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, a propargyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group; n is 1, 2 or 3; s is 0, 1 or 2, and p is 0, 1, 2 or 3.

[0010] In some embodiments of the present disclosure, in the compound represented by general formula (I) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, and a pharmaceutically acceptable salt thereof, ring A is a 3- to 6-membered heterocyclyl group, and the heterocyclyl group contains 1 to 3 heteroatoms selected from N atoms, O atoms, and S atoms, and is preferably selected from an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group, more preferably a pyrrolidinyl group or a piperidinyl group.

[0011] In another embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof, wherein G 1 , G 2 , G 3 and G 4 are all CR 8 or G 1 , G 2 , G 3 and G 4 One of them is a N atom and the others are CR 8 and preferably, G 1 , G 2 , G 3 and G 4 are all CR 8 or G 1 is N and G 2 , G 3 and G 4 is CR 8 and R 8 is as defined in general formula (I), preferably R 8 are the same or different and each independently represents a hydrogen atom or a halogen atom.

[0012] In some embodiments of the present disclosure, the compound represented by general formula (I) or its tautomer, meso-isomer, racemic form, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salts thereof is a compound represented by general formula (II): [ka] Among them, r is 0, 1, 2 or 3; q is 1, 2 or 3; t is 1 or 2, Z, G 1 , R 1a , R 1b , R 2 ~R 6 , R 8 , n and s are as defined in general formula (I).

[0013] In some embodiments of the present disclosure, the compound represented by general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture form thereof, and pharmaceutically acceptable salts thereof is a compound represented by general formula (IIG) or general formula (IIGa): [ka] Among them, R 11a and R 11b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; k is an integer from 1 to 6, q is 1, 2 or 3; t is 1 or 2, r is 0, 1, 2 or 3; G 1 , Z, R 1a , R 1b , R 2 ~R 4 , R 6 , R 8 , n and s are as defined in general formula (I).

[0014] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), and general formula (IIGa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, and a pharmaceutically acceptable salt thereof, Z is NR 7 or O atom, R 7 is as defined in general formula (I).

[0015] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), and general formula (IIGa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, and a pharmaceutically acceptable salt thereof, Z is NR 7 and R 7 is as defined in general formula (I).

[0016] In another embodiment of the present disclosure, in the compounds represented by general formula (II), general formula (IIG), and general formula (IIGa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, and a pharmaceutically acceptable salt thereof, q is 2 and t is 1, or q is 2 and t is 2.

[0017] In another embodiment of the present disclosure, n is 1 in the compounds represented by general formula (I), general formula (II), general formula (IIG), and general formula (IIGa), or in the form of a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, and a pharmaceutically acceptable salt thereof.

[0018] In some embodiments of the present disclosure, the compound represented by general formula (I) or its tautomer, meso-isomer, racemic form, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salts thereof is a compound represented by general formula (III) or general formula (IIIa): [ka] Among them, r is 0, 1, 2 or 3; G 1 , R 1a , R 1b , R 2 ~R 8 and s are as defined in general formula (I).

[0019] In some embodiments of the present disclosure, the compound represented by general formula (I) or its tautomer, meso-isomer, racemic form, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salts thereof is a compound represented by general formula (IV) or general formula (IVa): [ka] Among them, r is 0, 1, 2 or 3; G 1 , R 1a , R 1b , R 2 ~R 8 and s are as defined in general formula (I).

[0020] In another embodiment of the present disclosure, in the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, G 1 is CR 8 and R 8 is as defined in general formula (I).

[0021] In another embodiment of the present disclosure, in the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, G 1 is N.

[0022] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 7 is a hydrogen atom.

[0023] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 1a and R 1b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, and a haloalkyl group.

[0024] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 1a and R 1b are the same or different and each independently represent a H atom, a deuterium atom, a fluorine atom, and C 1-6 alkyl groups, preferably R 1a and R 1b is a deuterium atom.

[0025] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 1a and R 1b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group and a haloalkyl group, preferably R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a fluorine atom, and C 1-6 The alkyl group is selected from the group consisting of:

[0026] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 2 is a hydrogen atom.

[0027] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 3 is a hydrogen atom.

[0028] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 4is a hydrogen atom or an alkyl group, preferably C 1-6 It is an alkyl group, more preferably a methyl group.

[0029] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof, R 5 is an alkyl group, said alkyl group being optionally further substituted with one or more substituents selected from halogen, amino, cyano, hydroxy, alkoxy, carboxyl and cycloalkyl groups, preferably R 5 is an alkyl group, optionally substituted by one or more substituents selected from halogen and hydroxyl groups, more preferably -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH2OH, -CH2-CF2-CH3 or -CH2-CF(CH3)2, and most preferably -CH2-CF3 or -CH2-CF2-CH2OH.

[0030] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof, R 5 is an alkyl group or a haloalkyl group, wherein the alkyl group is optionally further substituted with one or more substituents selected from halogen, amino group, cyano group, hydroxy group, alkoxy group, carboxyl group, and cycloalkyl group, and is preferably an alkyl group or a haloalkyl group, more preferably -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, or -CH2-CF(CH3)2, and most preferably -CH2-CF3.

[0031] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 6 is a hydrogen atom or a haloalkyl group.

[0032] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 6 is a haloalkyl group, preferably haloC 1-6 It is an alkyl group, more preferably -CH2-CH2-CH2F, -CH2-CH2-CF3 or -CH2-CH2-CH2-CF3, and more preferably -CH2-CH2-CH2F.

[0033] In another embodiment of the present disclosure, in the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (IIGa), general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, and a pharmaceutically acceptable salt thereof, R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a cyano group, and are preferably a hydrogen atom or a halogen.

[0034] In another embodiment of the present disclosure, the compound represented by general formula (II) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof, wherein G 1 is CR 8or an N atom, preferably an N atom, and Z is NR 7 or O atom, R 1a and R 1b are the same or different and are each independently selected from a H atom or a deuterium atom; R 2 is a hydrogen atom, and R 3 is a hydrogen atom, and R 4 is a methyl group, and R 5 is C 1-6 is an alkyl group, 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and hydroxyl groups, R 6 Halo C 1-6 is an alkyl group, and R 7 is a hydrogen atom, and R 8 are the same or different and each independently represents a hydrogen atom or a halogen; r is 0, 1 or 2; n is 1; q is 1 or 2; and t is 1.

[0035] In another embodiment of the present disclosure, the compounds represented by general formula (III), general formula (IIIa), general formula (IV) and general formula (IVa) or their tautomers, meso-isomers, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, 1 is CR 8 or a N atom, preferably a N atom, and R 1a and R 1b are the same or different and are each independently selected from a H atom or a deuterium atom; R 2 is a hydrogen atom, and R 3 is a hydrogen atom, and R 4 is a methyl group, and R 5 is C 1-6 is an alkyl group, 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and hydroxyl groups, and R 6 Halo C 1-6 is an alkyl group, and R 7 is a hydrogen atom, and R 8are the same or different and each independently represents a hydrogen atom or a halogen atom; and r is 0, 1, or 2.

[0036] Exemplary compounds of the present disclosure include, but are not limited to: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0037] Another aspect of the present disclosure provides a compound represented by general formula (IA), or its tautomeric, meso-, racemic, enantiomeric, diastereomeric, mixtures thereof, and pharmaceutically acceptable salts thereof: [ka] Among them, X is Br, G 1 , G 2 , G 3 and G 4 are homologous or different and each independently represent CR 8 or a N atom, R 1a and R 1bare the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3 are selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4are selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5 are selected from alkyl, haloalkyl and cycloalkyl groups, wherein said alkyl and cycloalkyl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; n is 1, 2, or 3, and s is 0, 1 or 2. The compounds of general formula (IA) are intermediates for preparing the compounds of general formula (I).

[0038] Another aspect of the present disclosure provides a compound represented by general formula (IA), or its tautomeric, meso-, racemic, enantiomeric, diastereomeric, mixtures thereof, and pharmaceutically acceptable salts thereof: [ka] Among them, R 1a and R 1b are identical or different and are each independently selected from H atoms, deuterium atoms, halogens, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, carboxy groups, aldehyde groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from halogens, alkyl groups, alkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; X is Br, G 1 , G 2 , G 3 and G 4 are homologous or different and each independently represent CR 8 or a N atom, R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3are selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5 are selected from alkyl, haloalkyl and cycloalkyl groups, wherein said alkyl and cycloalkyl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; n is 1, 2, or 3, and s is 0, 1 or 2. The compounds of general formula (IA) are intermediates for preparing the compounds of general formula (I).

[0039] Another aspect of the present disclosure provides a compound represented by general formula (IA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, [ka] Among them, X is Br, r is 0, 1, 2 or 3; G 1 , R 1a , R 1b , R 2 ~R 5 , R 8 , n and s are as defined in general formula (IA). Compounds of general formula (IIA) are intermediates for preparing compounds of general formula (II).

[0040] Another aspect of the present disclosure provides a compound represented by general formula (IA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIIA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, [ka] Among them, X is Br, r is 0, 1, 2 or 3; G 1 , R 1a , R 1b , R 2 ~R 5 , R 8and s are as defined in general formula (IA). Compounds of general formula (IIIA) are intermediates for preparing compounds of general formula (III).

[0041] Another aspect of the present disclosure provides a compound represented by general formula (IA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIIaA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, [ka] Among them, X is Br, r is 0, 1, 2 or 3; G 1 , R 1a , R 1b , R 2 ~R 5 , R 8 and s are as defined in general formula (IA). Compounds of general formula (IIIaA) are intermediates for preparing compounds of general formula (IIIa).

[0042] Another aspect of the present disclosure provides a compound represented by general formula (IA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIGA) or general formula (IIGaA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, [ka] Among them, R w is a hydroxy protecting group, preferably [ka] and Z is an O atom, an S atom, or an NR 7 and CR 9 R 10 is selected from G 1 is CR 8 or a N atom, R 1a and R 1b are identical or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3is selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 is selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a halogen atom, a carboxy group, a carboxylic acid ester group, an aldehyde group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, a propargyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 8are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group; R 11a and R 11b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; k is an integer from 1 to 6, q is 1, 2 or 3; t is 1 or 2, n is 1, 2 or 3; r is 0, 1, 2 or 3, and s is 0, 1 or 2.

[0043] Another aspect of the present disclosure provides a compound represented by general formula (IA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIGA) or general formula (IIGaA), or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, [ka] Among them, R 1a and R 1b are identical or different and are each independently selected from H atoms, deuterium atoms, halogens, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, carboxy groups, aldehyde groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups are optionally substituted with one or more substituents selected from halogens, alkyl groups, alkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups; R w is a hydroxy protecting group, preferably [ka] and Z is an O atom, an S atom, or an NR 7 and CR 9 R 10 is selected from G 1 is CR 8 or a N atom, R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3 is selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 is selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a halogen atom, a carboxy group, a carboxylic acid ester group, an aldehyde group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, a propargyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a carboxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cyano group, a cycloalkyl group, and a heterocyclyl group; R 11a and R 11b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxy group, an aldehyde group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; k is an integer from 1 to 6, q is 1, 2 or 3; t is 1 or 2, n is 1, 2 or 3; r is 0, 1, 2 or 3, and s is 0, 1 or 2.

[0044] Exemplary intermediate compounds of the present disclosure include, but are not limited to, the following: [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0045] Another aspect of the present disclosure provides a process for preparing a compound of general formula (I) or any of its tautomeric, meso, racemic, enantiomeric, diastereomeric forms, mixtures thereof, and pharmaceutically acceptable salts thereof, the process comprising: [ka] a step of coupling a compound of general formula (IA) with a compound of general formula (IB) to obtain a compound of general formula (I), Among them, X is Br, Ring A, Z, G 1 , G 2 , G 3 , G 4 , R 1a , R 1b , R 2 ~R 6 , p, n and s are as defined for compounds of general formula (I).

[0046] Another aspect of the present disclosure provides a method for preparing a compound represented by general formula (II), or a tautomeric, meso, racemic, enantiomeric, diastereomeric or mixture thereof, as well as a pharmaceutically acceptable salt thereof, the method comprising: [ka] a step of coupling a compound of general formula (IIA) with a compound of general formula (IIB) to obtain a compound of general formula (II), Among them, X is Br, G 1 , Z, R 1a , R 1b , R 2 ~R 6 , R 8 , r, q, t, n and s are as defined for compounds of general formula (II).

[0047] Another aspect of the present disclosure provides a method for preparing a compound represented by general formula (III), or a tautomeric, meso, racemic, enantiomeric, diastereomeric or mixture thereof, as well as a pharmaceutically acceptable salt thereof, the method comprising: [ka] a step of coupling a compound of general formula (IIIA) with a compound of general formula (IIIB) to obtain a compound of general formula (III), Among them, X is Br, G 1 , R 1a , R 1b , R 2 ~R 8 , r and s are as defined for compounds of general formula (III).

[0048] Another aspect of the present disclosure provides a method for preparing a compound represented by general formula (IIIa), or any of its tautomeric, meso, racemic, enantiomeric, diastereomeric forms, mixtures thereof, and pharmaceutically acceptable salts thereof, the method comprising: [ka] a step of coupling a compound of general formula (IIIaA) with a compound of general formula (IIIB) to obtain a compound of general formula (IIIa), Among them, X is Br, G 1 , R 1a , R 1b , R 2~R 8 , r and s are as defined for compounds of general formula (IIIa).

[0049] Another aspect of the present disclosure provides a process for preparing a compound of general formula (IIG) or general formula (IIGa), or a tautomeric, meso, racemic, enantiomeric, diastereomeric or mixture thereof, as well as a pharmaceutically acceptable salt thereof, the process comprising: [ka] [ka] removing the hydroxy protecting group from a compound of general formula (IIGA) to obtain a compound of general formula (IIG); removing the hydroxy protecting group from the compound of general formula (IIGaA) to obtain a compound of general formula (IIGa), Among them, R w is a hydroxy protecting group, preferably [ka] and Z, G 1 , R 1a , R 1b , R 2 ~R 4 , R 6 , R 8 , R 11a , R 11b , q, t, k, r, n and s are as defined for compounds of general formula (IIG).

[0050] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The present disclosure further relates to a method for preparing the pharmaceutical composition, which comprises mixing a compound represented by each general formula or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, diluent, or excipient.

[0051] Another aspect of the present disclosure relates to the use of a compound represented by general formula (I) or its tautomers, meso-isomers, racemates, enantiomers, diastereomers, mixtures thereof, pharmaceutically acceptable salts thereof, and pharmaceutical compositions protecting the same, in the preparation of an estrogen receptor modulator, preferably an estrogen receptor downregulator (SERD).

[0052] Another aspect of the present disclosure relates to the use of a compound represented by general formula (I) or its tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, pharmaceutically acceptable salt thereof, and pharmaceutical compositions containing them in the preparation of a medicament for preventing and / or treating cancer, wherein the cancer is preferably selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian mass, hemophilia, and leukemia, preferably selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer, more preferably breast cancer.

[0053] Another aspect of the present disclosure relates to the use of a compound represented by general formula (I) or its tautomers, meso-isomers, racemates, enantiomers, diastereomers, mixtures thereof, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them in a medicament for preventing and / or treating an estrogen receptor-mediated or dependent disease or disorder, wherein the estrogen receptor-mediated or dependent disease or disorder is preferably selected from cancer, central nervous system defects, circulatory system defects, blood system defects, immune and inflammatory diseases, susceptibility to infectious diseases, metabolic defects, neurological defects, mental defects, and reproductive defects. The cancer is preferably selected from breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, hemophilia, and leukemia, more preferably selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer, and most preferably breast cancer; the central nervous system (CNS) defect may be alcoholism or migraine; the circulatory defect may be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, or hypertension; the blood system defect may be deep vein thrombosis; and the immune disease and inflammation. The disease may be Graves' disease, arthritis, multiple sclerosis, or cirrhosis of the liver; the infection susceptibility may be hepatitis B or chronic liver disease; the metabolic defect may be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, or osteoporosis; the neurological defect may be Alzheimer's disease, Parkinson's disease, migraine, or vertigo; the mental defect may be anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, or psychosis; and the reproductive defect may be age at menarche, endometriosis, or infertility, etc.

[0054] Another aspect of the present disclosure relates to a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) of the present disclosure or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The method shows excellent efficacy and few side effects. The cancer is preferably selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian prolapse, hemophilia, and leukemia, preferably selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer, and more preferably breast cancer.

[0055] Another aspect of the present disclosure relates to a method for treating an estrogen receptor-mediated or dependent disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) of the present disclosure or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the method shows excellent efficacy and few side effects, and the estrogen receptor-mediated or dependent disease or disorder is preferably selected from cancer, central nervous system defect, circulatory defect, blood system defect, immune and inflammatory disease, susceptibility to infectious diseases, metabolic defect, neurological defect, mental defect, and reproductive defect. The cancer is preferably selected from breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, hemophilia, and leukemia, more preferably selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer, and most preferably breast cancer; the central nervous system (CNS) defect may be alcoholism or migraine; the circulatory defect may be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, or hypertension; the blood system defect may be deep vein thrombosis; and the immune disease and inflammation. The disease may be Graves' disease, arthritis, multiple sclerosis, or cirrhosis of the liver; the infection susceptibility may be hepatitis B or chronic liver disease; the metabolic defect may be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, or osteoporosis; the neurological defect may be Alzheimer's disease, Parkinson's disease, migraine, or vertigo; the mental defect may be anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, or psychosis; and the reproductive defect may be age at menarche, endometriosis, or infertility, etc.

[0056] Another aspect of the present disclosure relates to a compound represented by general formula (I) of the present disclosure or a tautomer, meso form, racemic form, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a drug.

[0057] Another aspect of the present disclosure relates to a compound represented by general formula (I) of the present disclosure or its tautomer, meso form, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof, as well as a pharmaceutical composition containing the same, as a drug for treating cancer, wherein the cancer may be selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian mass, hemophilia, and leukemia, preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, more preferably breast cancer.

[0058] Another aspect of the present disclosure relates to a compound represented by general formula (I) of the present disclosure or its tautomer, meso-isomer, racemate, enantiomer, diastereomeric form, or mixture thereof, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutical composition containing the same, as a drug for treating an estrogen receptor-mediated or dependent disease or disorder, wherein the estrogen receptor-mediated or dependent disease or disorder is preferably selected from cancer, central nervous system defect, circulatory defect, blood system defect, immune disease and inflammatory disease, susceptibility to infectious diseases, metabolic defect, neurological defect, mental defect, and reproductive defect. The cancer is preferably selected from breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, hemophilia, and leukemia, more preferably selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer, and most preferably breast cancer; the central nervous system (CNS) defect may be alcoholism or migraine; the circulatory defect may be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, or hypertension; the blood system defect may be deep vein thrombosis; and the immune disease and inflammation. The disease may be Graves' disease, arthritis, multiple sclerosis, or cirrhosis of the liver; the infection susceptibility may be hepatitis B or chronic liver disease; the metabolic defect may be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, or osteoporosis; the neurological defect may be Alzheimer's disease, Parkinson's disease, migraine, or vertigo; the mental defect may be anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, or psychosis; and the reproductive defect may be age at menarche, endometriosis, or infertility, etc.

[0059] The active compound can be in a form suitable for administration by any suitable route, and is preferably in a unit dose form or a form that the patient can self-administer as a single dose. The unit dose presentation of the compounds or compositions of the present disclosure may be in the form of tablets, capsules, cachets, bottled liquids, powders, granules, pills, suppositories, reconstituted powders, or liquid preparations.

[0060] The dose of the compound or composition used in the therapeutic methods of the present disclosure will generally vary depending on the severity of the disease, the weight of the patient, and the relative efficacy of the compound, although as a general guideline, a suitable unit dose may be between 0.1 and 1000 mg.

[0061] In addition to the active compound, the pharmaceutical composition according to the present disclosure may contain one or more additives selected from fillers (diluents), adhesives, wetting agents, disintegrants, excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0062] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as a tablet, a sugar-coated tablet, a tablet, an aqueous or oily suspension, a dispersible powder or granules, an emulsion, a hard or soft capsule, or a syrup or elixir. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a visually appealing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for mixing to prepare tablets.

[0063] Aqueous suspensions contain the active substances and excipients suitable for the manufacture of aqueous suspensions. Aqueous suspensions may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0064] Oily suspensions may be prepared by suspending the active ingredient in vegetable oil. Oily suspensions may contain thickening agents. In order to provide a palatable preparation, the above-mentioned sweeteners and flavoring agents may be added.

[0065] Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water can provide the active ingredient and a dispersing or wetting agent for mixing, a suspending agent, or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be exemplified above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions are preserved by adding an antioxidant, such as ascorbic acid.

[0066] Pharmaceutical compositions according to the present disclosure may also be in the form of oil-in-water emulsions.

[0067] The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable preparations may also be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in the oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion can be infused into the patient's bloodstream via local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant, cyclical concentration of the compounds of the present disclosure. To maintain such a constant concentration, a continuous intravenous administration device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0068] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be prepared using the above-mentioned suitable dispersing or wetting agents and suspending agents according to known techniques. The sterile injectable preparation may be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent. Sterile fixed oils can be conveniently used as a solvent or suspending medium.

[0069] The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, thereby dissolving in the rectum and releasing the drug. Such materials include cocoa butter, glycerol gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0070] As is well known to those skilled in the art, the dosage of a drug is determined by many factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the composition of the drug, etc. In addition, the optimal treatment method, such as the treatment mode, the daily dose of the compound of general formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment plans.

[0071] Detailed Description of the Invention Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0072] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, Examples of alkyl groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available attachment site, and are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0073] The term "alkenyl group" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. It is a straight-chain or branched-chain group containing 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 2 to 6 carbon atoms. The alkenyl group may be substituted or unsubstituted; if substituted, the substituents are preferably one or more groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0074] The term "alkynyl group" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. It is a straight-chain or branched-chain group containing 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups include, but are not limited to, -C≡CH, -CHC≡CH, -CHC≡CCH, -C≡CCHCH, -CHC≡CCHCH, -C≡CCH(CH), -C(CH)C≡CH, -C(CH)C≡CCH, and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0075] The term "alkylene group" refers to a saturated, straight-chain or branched-chain aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkylene group containing 1 to 6 carbon atoms. 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. The alkylene group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available linkage site, and are preferably one or more groups independently and optionally selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0076] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0077] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 (e.g., 3, 4, 5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene, cyclooctyl, and the like, preferably cycloalkyl groups, and polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0078] The term "spirocycloalkyl group" refers to a polycyclic group in which 5- to 20-membered monocyclic rings share one carbon atom (referred to as a spiro atom) and may contain one or more double bonds. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered (e.g., 7, 8, 9, and 10-membered). Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include: [ka] Includes.

[0079] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and one or more rings may contain one or more double bonds. It is preferably 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, and 10 members). Depending on the number of rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic or tricyclic, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include: [ka] Includes.

[0080] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly linked, and may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, and 10 members). Depending on the number of rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka] Includes.

[0081] The cycloalkyl ring includes the above-mentioned cycloalkyl groups (e.g., monocyclic, fused, spirocyclic, and bridged cycloalkyl groups) fused to an aryl group, heteroaryl group, or heterocycloalkyl group, in which the ring connected to the parent structure is a cycloalkyl group. Non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptane group, etc., and preferably an indanyl group or a tetrahydronaphthyl group.

[0082] A cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0083] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O) and S(O)2, but excluding the -OO-, -OS- or -SS- ring moieties, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, in which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms, preferably 3 to 8 ring atoms, in which 1 to 3 are heteroatoms, and preferably 3 to 6 ring atoms, in which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuran, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazole, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., with tetrahydropyranyl, piperidinyl, and pyrrolidinyl being preferred. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyl groups.

[0084] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group in which 5- to 20-membered monocyclic rings share one atom (referred to as a spiro atom), where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O), and S(O)2, and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, and 10-membered). Depending on the number of spiro atoms shared by the rings, spiroheterocyclyl groups are classified as monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups, with monospiroheterocyclyl groups and bisspiroheterocyclyl groups being preferred. A 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl group is more preferred. Non-limiting examples of spiroheterocyclyl groups are [ka] Includes.

[0085] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings optionally containing one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O) and S(O)2, and the remaining ring atoms are carbon. Preferably, the group has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 and 10 members). Depending on the number of rings, fused heterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0086] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O) and S(O)2, and the remaining ring atoms are carbon. It is preferably 6-14 membered, more preferably 7-10 membered (e.g., 7, 8, 9 and 10 members). Depending on the number of rings, bridged heterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, and are preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0087] The heterocyclyl rings include heterocyclyl groups (e.g., monocyclic, fused, spiro, and bridged cycloalkyl groups) fused to an aryl, heteroaryl, or cycloalkyl group, wherein the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] Includes:

[0088] Heterocyclyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0089] The term "aryl group" refers to a 6- to 20-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably 6-membered, such as phenyl and naphthyl groups. The aryl ring includes an aryl group fused to a heteroaryl ring, heterocyclyl ring, or cycloalkyl ring, in which the ring connected to the parent structure is an aryl group, non-limiting examples of which are: [ka] Includes.

[0090] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0091] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, and 10-membered) and contain 1 to 3 heteroatoms, more preferably 5 or 6-membered and contain 1 to 3 heteroatoms. Non-limiting examples include pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazolyl, and pyrazinyl groups. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl group, where the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include: [ka] Includes.

[0092] Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0093] The cycloalkyl, heterocyclyl, aryl, and heteroaryl groups have one residue derived by removing one hydrogen atom from a ring atom of the parent moiety, or two residues derived by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent moiety.

[0094] The term "alkylthio group" refers to -S-(alkyl group) and -S-(unsubstituted cycloalkyl group), where alkyl group is as defined above. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio. An alkylthio group may be optionally substituted or unsubstituted; if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0095] The term "cycloalkoxy group" refers to an -O-cycloalkyl group, wherein the cycloalkyl group is as defined above.

[0096] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0097] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above. The term "haloalkoxy group" refers to an alkoxy group substituted with a halogen, wherein alkoxy is as defined above.

[0098] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl group is as defined above.

[0099] The term "halohydroxyalkyl group" refers to a hydroxyalkyl group substituted with one or more halogens, where hydroxyalkyl group is as defined above. The term "hydroxy group" refers to an -OH group.

[0100] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0101] The term "amino group" refers to -NH2.

[0102] The term "cyano group" refers to -CN.

[0103] The term "nitro group" refers to -NO2.

[0104] The term "aldehyde group" refers to -C(O)H.

[0105] The term "carboxy group" refers to -C(O)OH.

[0106] The term "aldehyde group" refers to -C(O)H.

[0107] The term "carboxylic acid ester group" refers to -C(O)O(alkyl group) or -C(O)O(cycloalkyl group), where alkyl group and cycloalkyl group are as defined above.

[0108] The term "hydroxy protecting group" refers to a group known in the art that is suitable for protecting a hydroxyl group, and is described in the literature ("Protective Groups in Organic Synthesis", 5 ThSee the hydroxy protecting groups in Ed. TW Greene & P. ​​G M Wuts. For example, preferably, the hydroxy protecting group is a (C 1-10 C alkyl or aryl group) or a silyl group, such as a methyl group, a tert-butyl group, an allyl group, a benzyl group, a methoxymethyl group (MOM), an ethoxyethyl group, a 2-tetrahydropyranyl group (THP), etc. 1-10 an alkyl group or a substituted alkyl group, preferably an alkyl group substituted with an alkoxy group or an aryl group, more preferably C 1-6 C substituted with alkoxy groups 1-6 C substituted with alkyl or phenyl groups 1-6 Alkyl groups, most preferably C 1-4 C substituted with alkoxy groups 1-4 It may be an alkyl group, for example, a formyl group, an acetyl group, a benzoyl group, etc. (C 1-10 alkyl or aryl) acyl group, (C 1-6 Alkyl or C 6-10 (aryl)sulfonyl group, (C 1-6 Alkoxy or C 6-10 The term "optionally" or "optionally" means that the subsequently described event or circumstance may occur, but is not necessarily so, and the phrase includes cases where the event or circumstance occurs and cases where it does not occur. For example, the phrase "heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may be present, but is not necessarily so, and the phrase includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0109] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group, are independently replaced with a corresponding number of substituents, each of which has an independent option (i.e., the substituents may be identical or different). Needless to say, substituents are located only at chemically feasible sites, and those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino group or hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0110] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients, which facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert their biological activity.

[0111] A "pharmaceutically acceptable salt" refers to a salt of a compound according to the present disclosure, which is safe and effective when used in a mammalian body and possesses the desired biological activity.

[0112] The compounds of the present disclosure include their isotopic derivatives. The term "isotopic derivative" refers to a compound having a structure according to the present disclosure, but differing only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure according to the present disclosure, but where hydrogen has been replaced by "deuterium" or "tritium", or fluorine has been replaced by "isotopic derivative". 18 F-fluorine labeling ( 18 F isotope) or carbon atoms are replaced by 11 C-, 13 C-, or 14 C-rich carbon ( 11 C-, 13 C- or 14 C-carbon label, 11 C-, 13 C- or 14C-isotope) are within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in bioassays, or as imaging tracers for in vivo diagnosis of disease, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies.

[0113] In the various deuterated forms of the compounds of formula (I) disclosed herein, each available hydrogen atom bonded to a carbon atom can be independently replaced with deuterium, and unless otherwise specified, when a position is specifically designated as D or deuterium, it is understood that the position has an abundance of deuterium at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation). Those skilled in the art can synthesize deuterated forms of the compounds of formula (I) by referring to relevant literature. When preparing deuterated forms of the compounds of formula (I), commercially available deuterated starting materials may be used, or the compounds may be synthesized by conventional techniques using deuterated reagents, including, but not limited to, deuterated borane, tritiated borane in tetrahydrofuran, deuterated lithium aluminum, deuterated iodoethane, deuterated iodomethane, and the like.

[0114] The term "therapeutically effective amount" of a drug or pharmacologically active agent refers to a sufficient dose of the drug or agent to produce the desired effect while being non-toxic. The effective amount is determined by the individual and depends on the age and general condition of the recipient, as well as the specific active substance, but an appropriate effective amount for an individual can be determined by one skilled in the art through routine testing.

[0115] Methods for synthesizing compounds according to the present disclosure To achieve the objectives of this disclosure, this disclosure adopts the following technical solutions.

[0116] Technical proposal 1 The compound represented by general formula (I) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, as well as a pharmaceutically acceptable salt thereof, can be produced by the following method: [ka] a step of coupling a compound of general formula (IA) with a compound of general formula (IB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (I); Among them, X is Br, Ring A, Z, G 1 , G 2 , G 3 , G 4 , R 1a , R 1b , R 2 ~R 6 , p, n and s are as defined in general formula (I).

[0117] Technical proposal 2 The compound represented by general formula (II) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, as well as a pharmaceutically acceptable salt thereof, can be prepared by the following method: [ka] a step of coupling a compound of general formula (IIA) with a compound of general formula (IIB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (II); Among them, X is Br, G 1 , Z, R 1a , R 1b , R 2 ~R 6 , R 8 , r, q, t, n and s are as defined in general formula (II).

[0118] Technical proposal 3 The compound represented by general formula (III) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, as well as a pharmaceutically acceptable salt thereof, can be prepared by the following method: [ka] a step of coupling a compound of general formula (IIIA) with a compound of general formula (IIIB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (III); Among them, X is Br, G 1 , R 1a , R 1b , R 2 ~R 8 , r and s are as defined in general formula (III).

[0119] Technical proposal 4 The compound represented by general formula (IIIa) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, as well as a pharmaceutically acceptable salt thereof, can be prepared by the following method: [ka] a step of coupling a compound of general formula (IIIaA) with a compound of general formula (IIIB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (IIIa); Among them, X is Br, G 1 , R 1a , R 1b , R 2 ~R 8 , r and s are as defined in general formula (IIIa).

[0120] Technical proposal 5 The method for preparing the compound represented by general formula (IIG) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, and a pharmaceutically acceptable salt thereof, is as follows: [ka] removing the hydroxy protecting group from a compound of general formula (IIGA) in the presence of a phase transfer catalyst (preferably n-tetrabutylammonium fluoride) to obtain a compound of general formula (IIG), Among them, R w is a hydroxy protecting group, preferably [ka] and Z, G 1 , R 1a , R 1b , R 2 ~R 4 , R 6 , R 8 , R 11a , R 11b , q, t, k, r, n and s are as defined in general formula (IIG).

[0121] Technical plan 6 The compound represented by general formula (IIGa) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, as well as a pharmaceutically acceptable salt thereof, can be prepared by the following method: [ka] removing the hydroxy protecting group from a compound of general formula (IIGaA) in the presence of a phase transfer reagent (preferably n-tetrabutylammonium fluoride) to obtain a compound of general formula (IIGa); Among them, R w is a hydroxy protecting group, preferably [ka] and Z, G 1 , R 1a , R 1b , R 2 ~R 4 , R6 , R 8 , R 11a , R 11b , q, t, k, r, n and s are as defined in general formula (IIGa).

[0122] In the above synthesis schemes 1 to 4, the reagents that provide basic conditions include organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, or cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide, preferably sodium tert-butoxide.

[0123] In the above synthesis schemes 1 to 4, the catalyst includes, but is not limited to, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenylyl)[2-(2'-amino-1,1'-biphenylyl)]palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 1,1'-bis(dibenzylphosphorus)dichlorodipentylironpalladium, or tris(dibenzylideneacetone)dipalladium.

[0124] The phase transfer reagent in the above synthesis schemes 5 and 6 includes, but is not limited to, benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide, tetrabutylammonium chloride, n-tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate (TBAB), trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, preferably n-tetrabutylammonium fluoride.

[0125] The reaction is preferably carried out in a solvent, and the solvents used include, but are not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, acetonitrile, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, or N,N-dimethylformamide, and mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION

[0126] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. [Example]

[0127] The structures of compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are expressed in units of 10-6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0128] For MS measurements, a liquid chromatograph mass spectrometer Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS) is used. Waters ACQuity UPLC-QD / SQD (Manufacturer: Waters, MS Model: Waters ACQuity Qda Detector / Waters SQ Detector) THERMO Ultimate 3000- Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

[0129] For high performance liquid chromatography (HPLC) analysis, high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 are used. For chiral HPLC analysis, a high performance liquid chromatograph Agilent 1260 DAD is used. For preparative high performance liquid chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 are used. For chiral separation, a preparative chromatograph Shimadzu LC-20AP is used. As a CombiFlash high-speed preparative chromatograph, Combiflash Rf200 (TELEDYNE ISCO) is used. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography. The silica gel plate specifications for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and those for separating and purifying products by thin-layer chromatography are 0.4 mm to 0.5 mm. Silica gel column chromatography generally uses 200-300 mesh silica gel manufactured by Yantai Yellow Sea Silica Gel Co., Ltd. as a carrier.

[0130] The mean kinase inhibition rate and IC50 value are measured using a microplate reader NovoStar (BMG, Germany).

[0131] Known starting materials according to the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0132] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere. The argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L. The hydrogen atmosphere means that a hydrogen balloon with a capacity of about 1 L is connected to the reaction flask.

[0133] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenator and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenator are used.

[0134] The hydrogenation reaction is generally carried out by evacuating the reactor and injecting hydrogen, and repeating this procedure three times.

[0135] For microwave reactions, a CEM Discover-S 908860 microwave reactor is used.

[0136] In the examples, unless otherwise specified, the solutions are aqueous solutions.

[0137] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20°C to 30°C.

[0138] Thin layer chromatography (TLC) was used to monitor the progress of the reactions in the examples. The developing solvents used in the reactions, the eluent system of column chromatography used to purify the compounds, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system, and the volume ratio of the solvents may be adjusted depending on the polarity of the compounds, or may be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0139] Example 1 (S)-1-(3-fluoropropyl)-N-(4-((5R,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)pyrrolidin-3-amine 1 [ka] [ka]

[0140] Step 1 (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate tert-butyl ester 1b (S)-Pyrrolidin-3-ylcarbamate tert-butyl ester 1a (1.86 g, 10 mmol, Shaoyuan) was dissolved in N,N-dimethylformamide (20 mL), diisopropylethylamine (1.55 g, 12 mmol), and 1-fluoro-3-iodopropane (207 mg, 11 mmol) were added dropwise. The mixture was stirred for 12 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with water (50 mL × 2), and washed with saturated sodium chloride solution (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 1b (1.92 g) in 78% yield.

[0141] Step 2 (S)-1-(3-fluoropropyl)pyrrolidin-3-amine 1c Compound 1b (1.23 g, 5 mmol) was dissolved in dichloromethane (10 mL), and a 5 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and saturated sodium carbonate solution (25 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1c (702 mg) in a 96% yield.

[0142] Step 3 (R)-1-(3,4-bis(benzyloxy)phenyl)-N-(2,2,2-trifluoroethyl)propan-2-amine 1e (R)-1-(3,4-bis(benzyloxy)phenyl)propan-2-amine 1d (7.0 g, 20.1 mmol, obtained by preparation according to a known method "European Journal of Medicinal Chemistry, 2014, 67(23), 35-36") was dissolved in dioxane (100 mL), and diisopropylethylamine (7.8 g, 60.4 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.4 g, 40.3 mmol, obtained by preparation according to the method disclosed in Example 59 on page 69 of the patent application "US20140249162") were added. The reaction was stirred in an oil bath at 80°C for 20 hours under argon gas protection. The reaction mixture was cooled, concentrated under reduced pressure, added with saturated sodium carbonate solution (50 mL), extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained with developing solvent system B was purified by column chromatography to give the title compound 1e (7.6 g) in a yield of 88%. MS m / z (ESI): 430.3 [M+1]

[0143] Step 4 (R)-4-(2-((2,2,2-trifluoroethyl)amino)propyl)-1,2-hydroquinone 1f Compound 1e (3.3 g, 7.7 mmol) was dissolved in methanol (10 mL), protected with argon gas, and palladium hydroxide on carbon (0.5 g, 3.8 mmol) was added. Hydrogen was introduced using a hydrogen balloon and the mixture was stirred for 3 hours. After that, the stirring was stopped, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1f (1.8 g) in a 96% yield.

[0144] Step 5 (1R,3R)-1-(4-bromophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 1g Compound 1f (3.0 g, 12.0 mmol) was dissolved in toluene (100 mL), and acetic acid (1.4 g, 23.3 mmol) and 4-bromobenzaldehyde (4.4 g, 23.8 mmol) were added. The mixture was stirred in an oil bath at 80 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (100 mL) was added. The aqueous phase was adjusted to pH 8 with saturated sodium carbonate solution (200 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 1g (3.5 g) in 70% yield. MS m / z (ESI): 416.0 [M+1]

[0145] Step 6 (5R,7R)-5-(4-bromophenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 1H Compound 1g (3.5 g, 8.4 mmol) was dissolved in N,N-dimethylformamide (100 mL), and dibromomethane (1.9 g, 10.9 mmol) and cesium carbonate (3.6 g, 11.0 mmol) were added. The mixture was stirred in an oil bath at 70 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 1h (2.4 g) in 67% yield.

[0146] Step 7 (S)-1-(3-fluoropropyl)-N-(4-((5R,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)pyrrolidin-3-amine 1 Compound 1h (600 mg, 1.4 mmol) was dissolved in dioxane (10 mL), and compound 1c (225 mg, 1.5 mmol), 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl (3 mg, 0.007 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), and sodium tert-butoxide (471 mg, 4.9 mmol) were added. The mixture was protected with argon gas and reacted in an oil bath at 105 °C for 16 hours with stirring, after which the reaction was stopped. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give title compound 1 (449 mg) in a 65% yield. MS m / z (ESI): 494.2 [M+1] 1H NMR (400 MHz, CD3OD) 6.84 (d, 2H), 6.49 (s, 1H), 6.43 (d, 2H), 6.20 (s, 1H), 5.75 (d, 2H), 4.64 (s, 1H), 4.45-4.42 (m, 1H), 4.33-4.30 (m, 1H), 3.91-3.87 (m, 1H), 3.18-3.15 (m, 2H), 2.83-2.80 (m, 2H), 2.66-2.40 (m, 8H), 1.85-1.60 (m, 3H), 0.92 (d, 3H).

[0147] Example 2 (S)—N-(3,5-difluoro-4-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine 2 [ka] [ka]

[0148] Step 1 (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 2a Compound 1f (310 mg, 1.2 mmol) was dissolved in toluene (5 mL), and acetic acid (598 mg, 10.0 mmol) and 4-bromo-2,6-difluorobenzaldehyde (384 mg, 1.7 mmol) were added. The mixture was stirred in an oil bath at 80 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (10 mL) was added. The aqueous phase was adjusted to pH 8 with saturated sodium carbonate solution (20 mL). The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 2a (390 mg) in 72% yield. MS m / z (ESI): 451.9 [M+1]

[0149] Step 2 (5S,7R)-5-(4-bromo-2,6-difluorophenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 2b Compound 2a (130 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), and dibromomethane (60 mg, 0.3 mmol) and cesium carbonate (121 mg, 0.4 mmol) were added. The mixture was stirred in an oil bath at 70 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 2b (85 mg) in 61% yield. MS m / z (ESI): 464.0 [M+1]

[0150] Step 3 (S)—N-(3,5-difluoro-4-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine 2 Compound 2b (70 mg, 0.2 mmol) was dissolved in dioxane (10 mL), and compound 1c (29 mg, 0.2 mmol), 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl (2 mg, 0.005 mmol), tris(dibenzylideneacetone)dipalladium (2 mg, 0.002 mmol), and sodium tert-butoxide (43 mg, 0.5 mmol) were added. The mixture was protected with argon gas and reacted for 16 hours at 105 °C in an oil bath with stirring, after which the reaction was stopped. The reaction mixture was cooled, concentrated under reduced pressure, added with saturated sodium carbonate solution (20 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained with developing solvent system B was purified by column chromatography to give the title compound 2 (449 mg) in a yield of 58%. MS m / z (ESI): 530.1 [M+1] 1H NMR (400 MHz, CD3OD) 6.45 (s, 1H), 6.07 (s, 1H), 6.03-6.00 (m, 2H), 5.73 (d, 2H), 4.94 (s, 1H), 4.46-4.43 (m, 1H), 4.34-4.31 (m, 1H), 3.87-3.83 (m, 1H), 3.38-3.35 (m, 1H), 3.13-3.02 (m, 2H), 2.86-2.42 (m, 9H), 1.87-1.63 (m, 3H), 0.92 (d, 3H).

[0151] Example 3 2,2-Difluoro-3-((5R,7R)-5-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 3 [ka] [ka]

[0152] Step 1 (R)—N-(1-(3,4-bis(benzyloxy)phenyl)propan-2-yl))-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine 3a Compound 1d (1.0 g, 3.0 mmol) was dissolved in dioxane (20 mL), diisopropylethylamine (1.2 g, 9.0 mmol), and 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate (1.0 g, 2.0 mmol, prepared by a known method [Bioorganic & Medicinal Chemistry Letters, 2018, 28(14), 2528-2532]) were added, and the reaction mixture was stirred in an oil bath at 80 °C for 20 h under argon gas protection. The reaction mixture was cooled, concentrated under reduced pressure, and saturated sodium carbonate solution (50 mL) was added. Extraction was performed with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 3a (1.7 g) in 84% yield. MS m / z (ESI): 680.2 [M+1]

[0153] Step 2 (R)-4-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)benzene-1,2-diphenol 3b Compound 3a (1.4 g, 2.0 mmol) was dissolved in methanol (10 mL), protected with argon gas, added with palladium hydroxide on carbon (0.2 g), and stirred for 3 hours under hydrogen pressure using a hydrogen balloon. The stirring was stopped, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3b (0.9 g) in a 94% yield.

[0154] Step 3 (1R,3R)-1-(4-Bromophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 3c Compound 3b (0.8 g, 1.6 mmol) was dissolved in toluene (10 mL), and acetic acid (0.2 g, 3.2 mmol) and 4-bromobenzaldehyde (0.6 g, 3.2 mmol) were added. The mixture was stirred in an oil bath at 80 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (10 mL) was added. Saturated sodium carbonate solution (20 mL) was slowly added to adjust the pH of the reaction mixture to approximately 8. The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 3c (0.6 g) in 56% yield. MS m / z (ESI): 666.1 [M+1]

[0155] Step 4 (5R,7R)-5-(4-bromophenyl)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 3d Compound 3c (0.2 g, 0.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), and dibromomethane (0.07 g, 0.4 mmol) and cesium carbonate (0.1 g, 0.4 mmol) were added. The mixture was stirred in an oil bath at 70 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 3d (0.1 g) in 47% yield.

[0156] Step 5 (S)-3-((4-((5R,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester 3e Compound 3d (60 mg, 0.09 mmol) was dissolved in dioxane (10 mL), and (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (19 mg, 0.1 mmol), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (12 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), and sodium tert-butoxide (29 mg, 0.3 mmol) were added. The mixture was protected with argon gas and reacted for 16 hours with stirring in an oil bath at 80 °C, after which the reaction was stopped. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 3e (39 mg) in a yield of 55%. MS m / z (ESI): 784.3 [M+1]

[0157] Step 6 (S)—N-(4-((5R,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)pyrrolidin-3-amine 3f Compound 3e (39 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and a 5 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and saturated sodium carbonate solution (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3f (32 mg) in a 93% yield.

[0158] Step 7 (S)—N-(4-((5R,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine 3g Compound 3f (32 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (5 mL), diisopropylethylamine (4 mg, 0.05 mmol) was added, and 1-fluoro-3-iodopropane (10 mg, 0.05 mmol) was added dropwise. The mixture was stirred for 12 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with water (5 mL × 2), saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 3g (22 mg) in 73% yield.

[0159] Step 8 2,2-Difluoro-3-((5R,7R)-5-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 3 Compound 3g (20 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL), and a 1 M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, saturated sodium carbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give title compound 3 (5 mg) in a 33% yield. MS m / z (ESI): 506.3 [M+1] 1H NMR (400 MHz, CD3OD) 6.84 (d, 2H), 6.49 (s, 1H), 6.45 (d, 2H), 6.17 (s, 1H), 5.75 (s, 2H), 4.67 (s, 1H), 4.45-4.42 (m, 1H), 4.34-4.31 (m, 1H), 3.96-3.93 (m, 1H), 3.72-3.69 (m, 1H), 3.57-3.54 (m, 1H), 2.99-2.89 (m, 2H), 2.70-2.61 (m, 6H), 2.43-2.40 (m, 2H), 1.89-1.67 (m, 5H), 0.91 (d, 3H).

[0160] Example 4 2,2-Difluoro-3-((5S,7R)-5-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 4 [ka] [ka]

[0161] Step 1 (1S,3R)-1-(5-bromopyridin-2-yl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 4a Using the synthetic route of Example 3, and substituting 5-bromopicolinaldehyde for the starting material 4-bromo-benzaldehyde in Step 3, the title compound 4a (256 mg) was prepared in 75% yield. MS m / z(ESI): 667.1 [M+1].

[0162] Step 2 (5S,7R)-5-(5-bromopyridin-2-yl)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 4b Using the synthetic route of Example 3 and substituting compound 4a for compound 3c in step 4, the title compound 4b (163 mg) was prepared in 65% yield.

[0163] Step 3 (S)-3-((6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester 4c Using the synthetic route of Example 3 and substituting compound 4b for compound 3d in step 5, the title compound 4c (40 mg) was prepared in 68% yield. MS m / z(ESI): 785.3 [M+1].

[0164] Step 4 6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-N-((S)-pyrrolidin-3-yl)pyridin-3-amine 4d Using the synthetic route of Example 3 and substituting compound 4c for compound 3e in step 6, the title compound 4d (30 mg) was prepared in 95% yield.

[0165] Step 5 6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine 4e Using the synthetic route of Example 3 and substituting compound 4d for compound 3f in step 7, the title compound 4e (25 mg) was prepared in 75% yield.

[0166] Step 6 2,2-Difluoro-3-((5S,7R)-5-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 4 Using the synthetic route of Example 3 and substituting compound 4e for compound 3g in step 8, the title compound 4 (5 mg) was prepared in 29% yield. MS m / z (ESI): 507.2 [M+1] 1H NMR (400 MHz, CD3OD) 7.84 (s, 1H), 7.05-6.96 (m, 2H), 6.62 (s, 1H), 6.21 (s, 1H), 5.86 (d, 2H), 4.77 (s, 1H), 4.58-4.55 (m, 1H), 4.44-4.43 (m, 1H), 3.74-3.71 (m, 1H), 3.62-3.58 (m, 1H), 3.26-3.24 (m, 2H), 2.97-2.95 (m, 2H), 2.76-2.52 (m, 6H), 1.72-1.64 (m, 4H), 1.45-1.43 (m, 2H), 0.92 (d, 3H).

[0167] Example 5 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-2,2-difluoropropan-1-ol 5 [ka] [ka]

[0168] Step 1 (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 5a Using the synthetic route of Example 3, and substituting 4-bromo-benzaldehyde as the starting material in Step 3 with 4-bromo-2,6-difluorobenzaldehyde, the title compound 5a (3.0 g) was prepared in 47% yield. MS m / z(ESI): 702.0 [M+1].

[0169] Step 2 (5S,7R)-5-(4-bromo-2,6-difluorophenyl)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 5b Using the synthetic route of Example 3 and substituting compound 5a for compound 3c in step 4, the title compound 5b (1.6 g) was prepared in 55% yield.

[0170] Step 3 (S)-3-((4-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-3,5-difluorophenyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester 5c Using the synthetic route of Example 3 and substituting compound 5b for compound 3d in step 5, the title compound 5c (1.5 g) was prepared in 65% yield. MS m / z(ESI): 820.3 [M+1].

[0171] Step 4 (S)—N-(4-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-3,5-difluorophenyl)pyrrolidin-3-amine 5d Using the synthetic route of Example 3 and substituting compound 5c for compound 3e in step 6, the title compound 5d (1.3 g) was prepared in 99% yield.

[0172] Step 5 (S)—N-(4-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine 5e Using the synthetic route of Example 3 and substituting compound 5d for compound 3f in step 7, the title compound 5e (1.2 g) was prepared in 92% yield.

[0173] Step 6 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-2,2-difluoro-1-propanol 5 Using the synthetic route of Example 3 and substituting compound 5e for compound 3g in step 8, the title compound 5 (300 mg) was prepared in 36% yield. MS m / z (ESI): 542.2 [M+1]. 1 H NMR (400 MHz, CD3OD) 6.56 (s, 1H), 6.18-6.16 (m, 3H), 5.86-5.84 (m, 2H), 4.99 (s, 1H), 4.59-4.56 (m, 1H), 4.49-4.47 (m, 1H), 4.05 (br, 1H), 3.84-3.71 (m, 2H), 3.55-3.53 (m, 2H), 3.15-3.07 (m, 3H), 2.88-2.68 (m, 4H), 2.53-2.38 (m, 2H), 2.03-1.96 (m, 2H), 1.84 (br, 1H), 1.40-1.31 (m, 1H), 1.06 (d, 3H).

[0174] Example 6 N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-amine 6 [ka] [ka]

[0175] Step 1 (1S,3R)-1-(5-Bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 6a Using the synthetic route of Example 2, and substituting 5-bromopicolinaldehyde for the starting material 4-bromo-2,6-difluorobenzaldehyde in Step 1, the title compound 6a (600 mg) was prepared in 60% yield. MS m / z(ESI): 417.0 [M+1].

[0176] Step 2 (5S,7R)-5-(5-bromopyridin-2-yl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 6b Using the synthetic route of Example 2 and substituting compound 6a for compound 2a in step 2, the title compound 6b (450 mg) was prepared in 73% yield. MS m / z(ESI): 431.0 [M+1].

[0177] Step 3 N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-amine 6 Using the synthetic route of Example 2, and substituting compound 6b for compound 2b in step 2, the title compound 6 (200 mg) was prepared in 44% yield. MS m / z(ESI): 495.2 [M+1]. 1 H NMR (400 MHz, CD3OD) 7.81 (s, 1H), 7.12 (d, 1H), 7.00 (d, 1H), 6.60 (s, 1H), 6.21 (s, 1H), 5.86 (d, 2H), 4.76 (s, 1H), 4.56-4.54 (m, 1H), 4.43-4.41 (m, 1H), 4.01-4.00 (m, 1H), 3.47-3.31 (m, 2H), 3.14-3.11 (m, 1H), 2.94-2.61 (m, 8H), 2.37-2.35 (m, 1H), 1.96-1.90 (m, 2H), 1.88-1.74 (m, 1H), 1.08 (d, 3H).

[0178] Example 7 (S)—N-(4-((5S,7R)-2,2-difluoro-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine 7 [ka]

[0179] Example 8 6-((5S,7R)-2,2-difluoro-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine 8 [ka]

[0180] Example 9 5-Fluoro-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-amine 9 [ka] [ka]

[0181] Step 1 (1S,3R)-1-(5-bromo-3-fluoropyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 9a Using the synthetic route of Example 2, and substituting 5-bromo-3-fluoropyridine-2-carbaldehyde for the starting material 4-bromo-2,6-difluorobenzaldehyde in Step 1, the title compound 9a (115 mg) was prepared in 55% yield.

[0182] Step 2 (5S,7R)-5-(5-bromo-3-fluoropyridin-2-yl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 9b Using the synthetic route of Example 2, and substituting compound 9a for compound 2a in step 2, the title compound 9b (58 mg) was prepared in 58% yield.

[0183] Step 3 5-Fluoro-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-amine 9 Using the synthetic route of Example 2, and substituting compound 9b for compound 2b in step 3, the title compound 9 (18 mg) was prepared in 48% yield. MS m / z (ESI): 513.2 [M+1]. 1 H NMR (400 MHz, CD3OD) 7.66-7.65 (m, 1H), 6.74-6.73 (m, 1H), 6.61 (s, 1H), 6.18 (s, 1H), 5.85 (d, 2H), 4.56-4.54 (m, 1H), 4.46-4.44 (m, 1H), 4.00-3.97 (m, 1H), 3.53-3.51 (m, 1H), 3.32-3.29 (m, 2H), 3.06-3.02 (m, 1H), 2.98-2.92 (m, 2H), 2.79-2.76 (m, 1H), 2.66-2.60 (m, 3H), 2.56-2.51 (m, 2H), 2.36-2.35 (m, 1H), 1.96-1.88 (m, 2H), 1.74-1.73 (m, 1H), 1.07 (d, 3H).

[0184] Example 10 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2,2,7-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-2,2-difluoropropan-1-ol 10 [ka]

[0185] Example 11 2,2-Difluoro-3-((5S,7R)-5-(3-fluoro-5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 11 [ka] [ka]

[0186] Step 1 (1S,3R)-1-(5-bromo-3-fluoropyridin-2-yl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 11a Using the synthetic route of Example 3, and substituting 5-bromo-3-fluoropicolinaldehyde for the starting material 4-bromo-benzaldehyde in Step 3, the title compound 11a (356 mg) was prepared in 71% yield. MS m / z(ESI): 685.1 [M+1].

[0187] Step 2 (5S,7R)-5-(5-bromo-3-fluoropyridin-2-yl)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 11b Using the synthetic route of Example 3 and substituting compound 11a for compound 3c in step 4, the title compound 11b (169 mg) was prepared in 61% yield.

[0188] Step 3 (S)-3-((6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-5-fluoropyridin-3-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester 11c Using the synthetic route of Example 3 and substituting compound 11b for compound 3d in step 5, the title compound 11c (92 mg) was prepared in 69% yield.

[0189] Step 4 6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-5-fluoro-N-((S)-pyrrolidin-3-yl)pyridin-3-amine 11d Using the synthetic route of Example 3 and substituting compound 11c for compound 3e in step 6, the title compound 11d (62 mg) was prepared in 95% yield.

[0190] Step 5 6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-5-fluoro-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine 11e Using the synthetic route of Example 3 and substituting compound 11d for compound 3f in step 7, the title compound 11e (35 mg) was prepared in 71% yield.

[0191] Step 6 2,2-Difluoro-3-((5S,7R)-5-(3-fluoro-5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 11 Using the synthetic route of Example 3 and substituting compound 11e for compound 3g in step 8, the title compound 11 (15 mg) was prepared in 39% yield. MS m / z (ESI): 525.2 [M+1]. 1H NMR (400 MHz, CD3OD) 7.68-7.67 (m, 1H), 6.76-6.73 (m, 1H), 6.60 (s, 1H), 6.15 (s, 1H), 5.85 (d, 2H), 4.56-4.54 (m, 1H), 4.47-4.44 (m, 1H), 4.01-3.98 (m, 1H), 3.75-3.70 (m, 1H), 3.60-3.52 (m, 2H), 3.13-2.95 (m, 4H), 2.80-2.51 (m, 7H), 2.38-2.34 (m, 1H), 1.97-1.88 (m, 2H), 1.76-1.72 (m, 1H), 1.05 (d, 3H).

[0192] Example 12 2,2-Difluoro-3-((5S,7R)-5-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol 12 [ka] [ka]

[0193] Step 1 (5S,7R)-5-(5-bromopyridin-2-yl)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2,2-d212a Compound 4a (350 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and dibromodideuteromethane (277 mg, 1.6 mmol) and cesium carbonate (512 mg, 1.6 mmol) were added. The mixture was stirred in an oil bath at 70 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 12a (170 mg) in 48% yield. MS m / z(ESI): 681.1 [M+1].

[0194] Step 2 6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl-2,2-d2)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine 12b Compound 12a (170 mg, 0.25 mmol) was dissolved in dioxane (10 mL), and compound 1c (44 mg, 0.3 mmol), 2,2'-bis-(diphenylphosphine)-1,1'-binaphthyl (12 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), and sodium tert-butoxide (29 mg, 0.3 mmol) were added. The mixture was protected with argon gas. The reaction was stirred in an oil bath at 80 °C for 16 hours, and then quenched. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with eluent system B was purified by column chromatography to give the title compound 12b (103 mg) in 55% yield.

[0195] Step 3 2,2-Difluoro-3-((5S,7R)-5-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol 12 Compound 12b (103 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and a 1 M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, saturated sodium carbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give title compound 12 (35 mg) in a 49% yield. MS m / z (ESI): 509.1 [M+1]. 1 H NMR (400 MHz, CD3OD) 8.01 (dd, 1H), 7.68 (d, 1H), 7.63 (d, 1H), 6.74 (s, 1H), 6.47 (s, 1H), 5.19 (s, 1H), 4.64-4.62 (m, 1H), 4.54-4.52 (m, 1H), 4.42 (br, 1H), 3.83-3.71 (m, 5H), 3.45-3.41 (m, 5H), 3.09-3.05 (m, 1H), 2.91-2.82 (m, 1H), 2.67-2.62 (m, 1H), 2.21-2.12 (m, 4H), 1.14 (d, 3H).

[0196] Example 13 2,2-Difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol 13 [ka] [ka]

[0197] Step 1 6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl-2,2-d2)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine 13a Compound 12a (86 mg, 0.13 mmol) was dissolved in dioxane (10 mL), and compound 1-(3-fluoropropyl)azetidin-3-amine (44 mg, 0.3 mmol, prepared according to the method disclosed in Example 1 on page 50 of patent application WO2019228443), 2,2'-bis-(diphenylphosphine)-1,1'-binaphthyl (12 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), and sodium tert-butoxide (29 mg, 0.3 mmol) were added. The mixture was protected with argon gas. The reaction was continued for 16 hours with stirring in an oil bath at 80 °C, and then the reaction was stopped. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 13a (47 mg) in a yield of 51%.

[0198] Step 2 2,2-Difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol 13 Compound 13a (39 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and a 1 M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and saturated sodium carbonate solution (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give title compound 13 (11 mg) in a 42% yield. MS m / z (ESI): 495.2 [M+1]. 1 H NMR (400 MHz, CD3OD) 7.80 (d, 1H), 7.04 (d, 1H), 6.94 (dd, 1H), 6.61 (s, 1H), 6.19 (s, 1H), 4.64 (br, 2H), 4.54-4.52 (m, 1H), 4.45-4.42 (m, 1H), 4.15-4.10 (m, 1H), 3.85-3.83 (m, 2H), 3.76-3.68 (m, 1H), 3.64-3.56 (m, 1H), 3.14-2.97 (m, 4H), 2.78-2.68 (m, 3H), 2.59-2.52 (m, 1H), 1.84-1.74 (m, 2H), 1.05 (d, 3H).

[0199] Example 14 2,2-Difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 14 [ka] [ka]

[0200] Step 1 3-((6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-yl)amino)azetidine-1-carboxylic acid tert-butyl ester 14a Compound 4b (1.8 g, 2.65 mmol) was dissolved in toluene (50 mL), and 3-aminoazetidine-1-carboxylic acid tert-butyl ester (0.9 g, 5.21 mmol), 2,2'-bis-(diphenylphosphinyl)-1,1'-binaphthyl (165 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (243 mg, 0.26 mmol), and sodium tert-butoxide (763 mg, 7.95 mmol) were added. The mixture was protected with argon gas and reacted for 16 hours with stirring in an oil bath at 80 °C, after which the reaction was stopped. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 14a (1.2 g) in a yield of 59%. MS m / z(ESI): 771.2 [M+1].

[0201] Step 2 N-(azetidin-3-yl)-6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-amine 14b Compound 14a (1.2 g, 1.56 mmol) was dissolved in dichloromethane (25 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and saturated sodium carbonate solution (15 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 14b (0.85 g) in an 81% yield.

[0202] Step 3 6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine 14c Compound 14b (0.82 g, 1.22 mmol) was dissolved in N,N-dimethylformamide (10 mL), diisopropylethylamine (0.48 mg, 3.68 mmol) was added, and 1-fluoro-3-iodopropane (0.35 mg, 1.84 mmol) was added dropwise. The mixture was stirred for 12 hours. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with water (15 mL × 2), saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 14c (0.7 g) in 78% yield.

[0203] Step 4 2,2-Difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 14 Compound 14c (200 mg, 0.4 mmol) was dissolved in tetrahydrofuran (25 mL), and a 1 M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (2 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, saturated sodium carbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give title compound 14 (50 mg) in a 25% yield. MS m / z (ESI): 493.2 [M+1]. 1 H NMR (400 MHz, CD3OD) 7.80 (d, 1H), 7.05 (d, 1H), 6.93 (dd, 1H), 6.61 (s, 1H), 6.20 (s, 1H), 5.85 (d, 2H), 4.77 (s, 1H), 4.54-4.52 (m, 1H), 4.45-4.43 (m, 1H), 4.15-4.12 (m, 1H), 3.88-3.85 (m, 2H), 3.76-3.57 (m, 3H), 3.14-3.05 (m, 4H), 2.75-2.69 (m, 3H), 2.57-2.53 (m, 1H), 1.84-1.76 (m, 2H), 1.06 (d, 3H).

[0204] Example 15 (5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 15 [ka] [ka]

[0205] Step 1 (1S,3R)-1-(4-(benzyloxy)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diphenol 15a Compound 1f (167 mg, 0.7 mmol) was dissolved in toluene (100 mL), trifluoroacetic acid (115 mg, 1.0 mmol), and 4-(benzyloxy)-2,6-difluorobenzaldehyde (250 mg, 1.0 mmol, prepared by the method described in Example 5 on page 61 of WO2008080001) were added. The mixture was stirred in an oil bath at 80°C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (100 mL) was added. The aqueous phase was adjusted to pH 8 with saturated sodium carbonate solution (200 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 15a (235 mg) in 73% yield. MS m / z (ESI): 480.1 [M+1].

[0206] Step 2 (5S,7R)-5-(4-(benzyloxy)-2,6-difluorophenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 15b Compound 15a (580 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and dibromomethane (421 g, 2.4 mmol) and cesium carbonate (1.2 g, 3.6 mmol) were added. The mixture was stirred in an oil bath at 70 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 15b (458 mg) in 77% yield. MS m / z (ESI): 492.1 [M+1].

[0207] Step 3 3,5-Difluoro-4-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenol 15c Compound 15b (450 mg, 0.9 mmol) was dissolved in methanol (10 mL), protected with argon gas, and palladium hydroxide on carbon (0.1 g) was added. Hydrogen was introduced using a hydrogen balloon and the mixture was stirred for 3 hours. The stirring was stopped, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 15c (0.3 g) in a 93% yield. MS m / z (ESI): 402.1 [M+1].

[0208] Step 4 (S)-3-(3,5-difluoro-4-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester 15d (R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (82 mg, 0.4 mmol) was dissolved in dry tetrahydrofuran (5 mL) and tri-n-butylphosphine (240 mg, 1.2 mmol) and 1,1'-(azodicarbonyl)dipiperidine (300 mg, 1.2 mmol) were added in an ice bath. After stirring for 1 h, compound 15c (159 mg, 0.4 mmol) was added and the mixture was stirred under argon gas protection for 3 h. The stirring was stopped, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 15d (153 mg) in 67% yield. MS m / z (ESI): 571.0 [M+1].

[0209] Step 5 (5S,7R)-5-(2,6-difluoro-4-(((S)-pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 15e Compound 15d (240 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL), and a 5 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and saturated sodium carbonate solution (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 15e (220 mg) in a 90% yield.

[0210] Step 6 (5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 15 Compound 15e (200 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (5 mL), diisopropylethylamine (44 mg, 0.4 mmol) was added, and 1-fluoro-3-iodopropane (160 mg, 0.9 mmol) was added dropwise. The mixture was stirred for 12 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with water (5 mL × 2), saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 15 (50 mg) in 22% yield. MS m / z (ESI): 531.1 [M+1]. 1 H NMR (400 MHz, CD3OD) 6.59 (s, 1H), 6.52-6.49 (m, 2H), 6.18 (s, 1H), 5.85 (d, 2H), 5.15 (s, 1H), 4.91-4.89 (m, 1H), 4.56-4.53 (m, 1H), 4.46-4.44 (m, 1H), 3.49-3.47 (m, 1H), 3.20-3.16 (m, 1H), 2.93-2.88 (m, 4H), 2.67-2.63 (m, 2H), 2.56-2.51 (m, 2H), 2.40-2.36 (m, 1H), 1.98-1.89 (m, 4H), 1.08 (d, 3H).

[0211] Example 16 1-(3-Fluoropropyl)-N-(4-((5R,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)azetidin-3-amine 16 [ka] Using the synthetic route of Example 1, compound 1c in step 7 was replaced with 1-(3-fluoropropyl)azetidin-3-amine (obtained by the method disclosed in Example 1 on page 50 of the instruction manual of patent application WO2019228443), to prepare the title compound 16 (27 mg) in a yield of 41%. MS m / z (ESI): 480.1 [M+1]. 1 H NMR (400 MHz, CD3OD) 7.04 (d, 2H), 6.64 (s, 1H), 6.61-6.52 (m, 2H), 6.31 (s, 1H), 5.87 (d, 2H), 4.69-4.61 (m, 2H), 4.53-4.39 (m, 3H), 4.18-4.16 (m, 1H), 3.94-3.90 (m, 1H), 3.48-3.37 (m, 4H), 3.10-3.05 (m, 1H), 2.87-2.82 (m, 1H), 2.61-2.56 (m, 1H), 2.07-1.96 (m, 3H), 1.09 (d, 3H).

[0212] Example 17 N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((5S,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-amine 17 [ka] [ka] Compound 6b (100 mg, 0.2 mmol) was dissolved in dioxane (5 mL), and the compound 1-(3-fluoropropyl)azetidin-3-amine (47 mg, 0.4 mmol, prepared according to the method described in Example 1 on page 50 of the patent application WO2019228443), 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl (3 mg, 0.007 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), and sodium tert-butoxide (48 mg, 0.5 mmol) were added. The mixture was then protected with argon gas. The reaction was continued for 16 hours with stirring in an oil bath at 105 °C, and then the reaction was stopped. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 17 (25 mg) in a yield of 22%. MS m / z (ESI): 481.2 [M+1]. 1 H NMR (400 MHz, CD3OD) 7.78 (s, 1H), 7.14 (d, 1H), 6.98 (d, 1H), 6.60 (s, 1H), 6.20 (s, 1H), 5.83 (d, 2H), 4.76 (s, 1H), 4.54-4.52 (m, 1H), 4.44-4.42 (m, 1H), 4.13-4.09 (m, 1H), 3.84-3.81 (m, 2H), 3.47-3.45 (m, 1H), 3.30-2.90 (m, 4H), 2.71-2.53 (m, 4H), 1.82-1.74 (m, 2H), 1.08 (d, 3H).

[0213] Example 18 2,2-Difluoro-3-((5R,7R)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 18 [ka] [ka]

[0214] Step 1 3-((5R,7R)-5-(4-bromophenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-2,2-difluoropropan-1-ol 18a Compound 3d (300 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL), and a 1 M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (2 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, saturated sodium carbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give title compound 18a (84 mg) in a 43% yield.

[0215] Step 2 2,2-Difluoro-3-((5R,7R)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 18 Compound 18a (150 mg, 0.34 mmol) was dissolved in dioxane (5 mL), and compound 1-(3-fluoropropyl)azetidin-3-amine (90 mg, 0.68 mmol, prepared according to the method disclosed in Example 1 on page 50 of the patent application WO2019228443), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (20 mg, 0.03 mmol), palladium acetate (4 mg, 0.02 mmol), and cesium carbonate (222 mg, 0.68 mmol) were added. The mixture was protected with argon gas. The reaction was continued for 16 hours with stirring in an oil bath at 105 °C, and then the reaction was stopped. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 18 (25 mg) in a 15% yield. MS m / z (ESI): 492.2 [M+1]. 1 H NMR (400 MHz, CD3OD) 6.95 (d, 2H), 6.61 (s, 1H), 6.50 (d, 2H), 6.28 (s, 1H), 5.87 (d, 2H), 4.78 (s, 1H), 4.52-4.51 (m, 1H), 4.44-4.42 (m, 1H), 4.10-4.09 (m, 1H), 3.86-3.78 (m, 3H), 3.71-3.66 (m, 1H), 3.29-3.28 (m, 1H), 3.11-2.98 (m, 3H), 2.75-2.67 (m, 4H), 2.54-2.49 (m, 1H), 1.82-1.74 (m, 2H), 1.04 (d, 3H).

[0216] Example 19 2,2-Difluoro-3-((5R,7R)-5-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol 19 [ka] [ka]

[0217] Step 1 (5S,7R)-5-(4-bromophenyl)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2,2-d219a Compound 3c (2.6 g, 4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and dibromodideuteromethane (2.8 g, 16 mmol) and cesium carbonate (5.1 g, 16 mmol) were added. The mixture was stirred in an oil bath at 70 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 19a (1.3 g) in 49% yield.

[0218] Step 2 (S)—N-(4-((5R,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl-2,2-d2)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine 19b Compound 19a (1.0 g, 1.5 mmol) was dissolved in dioxane (20 mL), and compound 1c (0.26 g, 1.8 mmol), 2,2'-bis-(diphenylphosphine)-1,1'-binaphthyl (0.1 g, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (0.1 g, 0.1 mmol), and sodium tert-butoxide (0.3 g, 3.0 mmol) were added. The mixture was protected with argon gas. The reaction was stirred in an oil bath at 80 °C for 16 hours, and then quenched. The reaction mixture was cooled, concentrated, and saturated sodium carbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give the title compound 19b (0.6 g) in 52% yield.

[0219] Step 3 2,2-Difluoro-3-((5R,7R)-5-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol 19 Compound 19b (0.3 g, 0.4 mmol) was dissolved in dichloromethane (5 mL), and a 1 M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (2 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and saturated sodium carbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with developing solvent system B was purified by column chromatography to give the title compound 19 (63 mg) in a 31% yield. MS m / z (ESI): 508.0 [M+1]. 1H NMR (400 MHz, CD3OD) 6.95 (d, 2H), 6.61 (s, 1H), 6.56 (d, 2H), 6.29 (s, 1H), 4.78 (s, 1H), 4.56-4.54 (m, 1H), 4.47-4.44 (m, 1H), 4.05-4.01 (m, 1H), 3.86-3.64 (m, 3H), 3.11-2.96 (m, 2H), 2.84-2.53 (m, 8H), 2.37-2.32 (m, 1H), 1.99-1.90 (m, 2H), 1.77-1.72 (m, 1H), 1.04 (d, 3H).

[0220] Example 20 (Comparative Example) (7R,9S)-8-(2,2-difluoro-3-hydroxypropyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-h]isoquinoline-1,3(2H)-diketone 20 [ka] [ka]

[0221] Step 1 (1S,3R)-1-(5-bromopyridin-2-yl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-7,8-diphenol 20a Compound 3b (0.8 g, 1.6 mmol) was dissolved in toluene (10 mL), and acetic acid (0.2 g, 3.2 mmol) and 5-bromopicolinaldehyde (0.6 g, 3.2 mmol) were added. The mixture was stirred in an oil bath at 80 °C for 16 hours, after which the reaction was stopped. The mixture was cooled, concentrated under reduced pressure, and water (20 mL) was added. Saturated sodium carbonate solution (20 mL) was slowly added to adjust the pH of the reaction mixture to approximately 8. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 20a (0.3 g) in 28% yield.

[0222] Step 2 (1S,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-7,8-diphenol 20b Compound 20a (300 mg, 0.28 mmol) was dissolved in dioxane (10 mL), and 1-(3-fluoropropyl)azetidin-3-amine (111 mg, 0.84 mmol), 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl (15 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium (56 mg, 0.06 mmol), and sodium tert-butoxide (269 mg, 2.8 mmol) were added. The mixture was then protected with argon gas. The reaction was stirred in an oil bath at 105 °C for 16 hours, and then quenched. The reaction mixture was cooled, concentrated under reduced pressure, added with saturated sodium carbonate solution (20 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained with developing solvent system B was purified by column chromatography to give the title compound 20b (109 mg) in a yield of 54%.

[0223] Step 3 (1S,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-7,8-diylbis(trifluoromethylsulfonate) 20c Compound 20b (400 mg, 0.56 mmol) was dissolved in dichloromethane (25 mL) and triethylamine (170 mg, 1.68 mmol), N,N-dimethylpyridin-4-amine (7 mg, 0.06 mmol), and N-phenylbis(trifluoromethanesulfonimide) (500 mg, 1.40 mmol) were added. The mixture was allowed to react at room temperature for 3 hours, and then quenched. The reaction mixture was cooled, concentrated under reduced pressure, and saturated sodium carbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give title compound 20c (450 mg) in 82% yield.

[0224] Step 4 (1S,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-7,8-dicarbonitrile 20d Compound 20c (30 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (5 mL), and zinc cyanide (11 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium (3 mg, 0.003 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (2 mg, 0.004 mmol) were added. The mixture was protected with argon gas. The reaction was stirred in an oil bath at 100 °C for 3 hours, and then quenched. The reaction mixture was cooled, concentrated under reduced pressure, and saturated sodium carbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using eluent system B was purified by column chromatography to give title compound 20d (16 mg) in 72% yield. MS m / z (ESI): 737.3 [M+1].

[0225] Step 5 (7R,9S)-8-(2,2-difluoro-3-hydroxypropyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-h]isoquinoline-1,3(2H)-diketone 20 Compound 20d (16 mg, 0.02 mmol) was dissolved in sulfuric acid (30 mg, 0.3 mmol) and reacted with stirring in an oil bath at 90°C for 2 hours. The reaction was then quenched. The reaction mixture was cooled, concentrated under reduced pressure, and saturated sodium carbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 20 (3 mg) in a 29% yield. MS m / z (ESI): 518.2 [M+1]. 1H NMR (400 MHz, CD3OD) 7.67 (d, 1H), 7.62 (d, 1H), 7.57 (d, 1H), 7.28 (d, 1H), 6.96 (dd, 1H), 5.93 (s, 1H), 4.53-4.51 (m, 1H), 4.43-4.41 (m, 1H), 4.10-4.05 (m, 1H), 3.94-3.88 (m, 2H), 3.81-3.78 (m, 2H), 3.30-3.26 (m, 2H), 2.98-2.95 (m, 2H), 2.81-2.63 (m, 5H), 1.83-1.77 (m, 2H), 1.13 (d, 3H).

[0226] Example 21 (Comparative Example) (8R,10S)-9-(2,2-difluoro-3-hydroxypropyl)-10-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-2,3,7,8,9,10-hexahydropyrrolo[3,4-f]phthalazine-1,4-diketone 21 [ka] Compound 20 (6 mg, 0.01 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (5 mg, 0.1 mmol) was added, and the mixture was stirred in an oil bath at 80°C for 24 hours. The reaction was then quenched. The reaction mixture was cooled, concentrated under reduced pressure, and saturated sodium carbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained using developing solvent system B was purified by column chromatography to give the title compound 21 (3 mg) in 49% yield. MS m / z (ESI): 533.2 [M+1]. 1H NMR (400 MHz, CD3OD) 8.08 (d, 1H), 7.71 (d, 1H), 7.55 (d, 1H), 7.27 (d, 1H), 6.97 (dd, 1H), 6.65 (s, 1H), 4.55-4.53 (m, 1H), 4.45-4.43 (m, 1H), 4.18-4.11 (m, 1H), 3.97-3.91 (m, 4H), 3.29-3.15 (m, 4H), 2.87-2.81 (m, 4H), 2.71-2.63 (m, 1H), 1.86-1.78 (m, 2H), 1.11 (d, 3H).

[0227] Biological evaluation The present disclosure will be further explained below using test examples, but these examples are not intended to limit the scope of the present disclosure.

[0228] Test Example 1: Inhibitory effect of compounds according to the present disclosure on the binding of E and ER The compounds disclosed herein have an inhibitory effect on the binding of E (estrogen) and ER (estrogen receptor), and therefore inhibit the binding of the E and ER complex to ERE (estrogen response element), further inhibiting the expression of downstream luciferase protein. The inhibitory effect of the compounds disclosed herein on the binding of E and ER was tested by the following method.

[0229] 1. Purpose of the experiment This experiment tested the inhibitory effect of compounds on the binding of E and ER, and measured IC 50 The purpose of this study is to evaluate the in vitro activity of compounds according to the size of the nucleus.

[0230] 2. Experimental method ERE was cloned upstream of the luciferase gene and transfected into MCF-7 (TCHu74, Cell Bank of the Committee for the Deposit of Typical Cultures, Chinese Academy of Sciences) to select MCF-7 / ERE-luciferase monoclonal cells. MCF-7 / ERE-luciferase cells were seeded at a density of 30,000 cells / well in 96-well plates in MEM (Hyclone, SH30024.01B) medium containing 10% charcoal-stripped FBS (Moregate, FBSF), 1% sodium pyruvate (Sigma, S8636), 1% non-essential amino acids (Sigma, M7145), and 500 μg / mL G418. The cells were cultured at 37°C and 5% CO2. Drugs were prepared as 20 mM stock solutions and diluted 10-fold with 100% DMSO, followed by a further 20-fold dilution with culture medium. After 24 hours of culture, the medium was removed, and 0.1 nM estradiol (Sigma, E2758) and 10 μL of drug diluted in culture medium were added to each well. DMSO was added to the control group and gently shaken to mix uniformly. The cells were then cultured in a 37°C, 5% CO2 incubator. After 24 hours, the cell culture medium was removed, and 50 μL / well of prepared luciferase substrate (Promega, E6110) was added. The cells were incubated at room temperature, protected from light, for 10–15 minutes, and the chemiluminescence signal was measured.

[0231] 3. Test results The inhibitory effect of the compounds of the present disclosure on the binding of E and ER was measured by the above experiments, and the chemiluminescence signal value and the logarithmic concentration of the compound were plotted using Graphpad Prism to determine the IC 50 The values ​​obtained are shown in Table 1. [Table 13] In conclusion, the compounds claimed in this disclosure have obvious inhibitory effects on the binding of E and ER.

[0232] Test Example 2: Inhibitory effect of compounds according to the present disclosure on the proliferation of MCF-7 cells

[0233] 1. Purpose of the experiment This experiment tested the inhibitory effect of the compounds disclosed herein on the proliferation activity of MCF-7 cells using the ATP method, and determined the IC 50 The purpose of this study is to evaluate the in vitro activity of compounds according to the size of the nucleus.

[0234] 2. Experimental method MCF-7 (TCHu74, Cell Bank of the Committee for the Deposit of Typical Cultures, Chinese Academy of Sciences) cells were seeded in 96-well plates in MEM (Hyclone, SH30024.01B) medium containing 10% FBS (Gibco, 10099-141), 1% sodium pyruvate (Sigma, S8636), and 1% non-essential amino acids (Sigma, M7145) at a seeding density of 4,000 cells / well. The cells were cultured at 37°C and 5% CO. Compounds were prepared as 20 mM stock solutions and diluted in 100% DMSO to a final density of 1000x, followed by a 20-fold dilution in medium containing 2% FBS. After 24 hours of culture, the medium was removed, and 90 μL of medium containing 2% FBS and 10 μL of drug were added to each well. 10 μL of DMSO was added to the control group and gently shaken to mix uniformly. The blank group contained 100 μL of 2% FBS medium alone and was cultured in an incubator at 37°C and 5% CO2. After 72 hours, 50 μL of mixed Cell Titer-Glo (Promega, G7571) was added to each well, shaken to mix uniformly, and left at room temperature for 10 minutes, after which the chemiluminescence signal value was measured.

[0235] 3. Data analysis The chemiluminescence signal values ​​and the logarithmic concentration of the compounds were plotted using Graphpad Prism, and the IC values ​​of the compounds were calculated. 50 The values ​​obtained are shown in Table 2. [Table 14] In conclusion, the compounds claimed in this disclosure have obvious inhibitory effects on the proliferation of MCF-7 cells, while Comparative Examples 20 and 21 show no activity.

[0236] Test Example 3 Biological evaluation of the compounds disclosed herein for inhibiting the proliferation of MCF7 cells expressing ERα mutants

[0237] 1. Purpose of the experiment This experiment aims to measure the inhibitory activity of compounds according to the present disclosure on the proliferation of MCF7 cells expressing ERα mutants.

[0238] 2. Experimental method Site-directed mutagenesis and cell line construction The human estrogen receptor α (ERα) protein mutant, ERαY537S, was obtained by site-directed mutagenesis using double-primer PCR with wild-type ESR1 cDNA (Accession No. NM000125) as a template. The primer sequences used for mutagenesis are as follows (underlined nucleotides indicate the mutation site): Y537S: F-AAG AAC GTG GTG CCC CTC T C T GAC CTG CTG CTG GAG ATG(SEQ ID NO: 1); R-CAT CTC CAG CAG CAG GTC A GA GAG GGG CAC CAC GTT CTT (SEQ ID NO: 2). The mutant ESR1 cDNA was cloned into the target lentiviral vector pCDH-CMV-MCS-EF1-Puro. The lentiviral plasmid containing the mutant ESR1 gene sequence and the lentiviral packaging plasmid were then transfected into HEK-293T cells (ATCC, CRL-3216) using Lipofectamine 3000 Transfection Reagent (ThermoFisher Scientific, Cat# L3000075). Forty-eight hours after transfection, the virus-containing medium supernatant was filtered, and the virus pellet was obtained by ultracentrifugation. The virus was then resuspended and dissolved in an appropriate amount of medium and added to MCF7 cells (ATCC, HTB-22). Polybrene was added to a final concentration of 8 μg / mL and incubated overnight. Two days after transfection, 1 μg / mL puromycin was added to the cell culture medium for resistance screening, and approximately two weeks later, an MCF7 cell line capable of stably expressing the ERαY537S mutant was obtained.

[0239] Cell proliferation inhibition experiment MCF7 cells expressing ERα mutants were cultured in complete MEM medium (GE Healthcare, SH30024.01) containing 10% fetal bovine serum. On the first day of the experiment, cells were seeded into a 96-well plate at a density of 3,000 cells / well using complete medium. Each well was filled with 100 μL of cell suspension and incubated overnight in a cell incubator at 37°C and 5% CO2. The following day, the medium was aspirated and replaced with 135 μL of incomplete MEM medium containing 2% fetal bovine serum. Each well was then added with 15 μL of test compound at different concentrations, prepared in incomplete medium, for nine concentration points, starting from 100 nM, diluted four-fold. A blank control containing 0.5% DMSO was also included, and the cells were incubated in a cell incubator at 37°C and 5% CO2 for 144 hours. On the 8th day, the 96-well cell culture plate was removed, and 150 μL of CellTiter-Glo® Luminescent Cell Viability Assay (Promega, G7573) was added to each well. After leaving the plate at room temperature for 10 minutes, the luminescent signal was read using a multilabel plate reader (PerkinElmer, VICTOR 3). The IC was calculated as the inhibitory activity of the compound based on the compound concentration and luminescent signal using the software Graphpad Prism. 50 The values ​​are shown in Table 3.

[0240] 3. Test results [Table 15] In conclusion, the compounds claimed in this disclosure have obvious inhibitory effects on the proliferation of MCF7 cells expressing ERα mutants.

[0241] Test Example 4 Degradation effect of the compound according to the present disclosure on Erα

[0242] 1. Purpose of the experiment The degrading effect of the compounds according to the present disclosure on Erα is tested, and the method is used to measure the degrading effect of the compounds according to the present disclosure on Erα.

[0243] 2. Experimental method MCF-7 cells, an ERα-positive breast cancer cell line, were cultured in DMEM / F12 medium (HyClone, SH30023.01) containing 10% fetal bovine serum (Corning, 35-010-CV). On the first day of the experiment, the cells were trypsinized and washed once with phenol red-free DMEM / F12 medium (ThermoFisher, 11039-021) containing 5% charcoal-treated fetal bovine serum (BIOSUN, BS-0004-500). The cells were then resuspended and counted to determine a cell density of 1.79 × 10 cells. 5The cell suspension was adjusted to cells / mL. 280 μL of the cell suspension was added to each well of a 48-well plate (Corning, 3548), and the cells were cultured overnight in an incubator at 37°C with 5% CO2. On the second day of the experiment, the compounds were gradient diluted with DMSO and further diluted in phenol red-free DMEM / F12 medium containing 5% charcoal-treated fetal bovine serum. 20 μL of the diluted compounds were added to each well of the 48-well plate, resulting in final concentrations of 3000, 300, 30, 3, 0.3, 0.03, and 0.003 nM, respectively. The 48-well plate was then placed in the incubator for 16–18 hours. A 96-well plate was coated with the capture antibody from the Human ERα / NR3A1 Total Protein Detection Reagent Kit (R&D, DYC5715-5). The capture antibody was diluted to 1 μg / mL in PBS, and 100 μL was added to each well of a 96-well plate (Corning, 3590). The plate was then placed in a 26°C incubator overnight. On day 3 of the experiment, the antibody-coated 96-well plate was washed once with PBS, and 200 μL of 1% BSA in PBS was added to each well. The plate was then incubated in a 37°C incubator for 1.5 hours for blocking. The cell culture supernatant was removed, and the cells were washed once with PBS. 60 μL of cell lysis solution was added to each well. The cell lysis solution was PBS containing 6 M urea, 1 mM EDTA, 0.5% Triton X-100, 1 mM PMSF, and protease inhibitors (Roche, 04693159001). After lysing the cells on ice for 15 minutes, 300 μL of PBS containing 1 mM EDTA and 0.5% Triton X-100 was added per well to dilute urea to 1 M. After blocking, the blocking solution was removed from the 96-well plate, and 100 μL of the diluted cell lysate was added to each well. The plate was then incubated in a 37°C incubator for 2 hours and washed five times with PBS. Biotinylated detection antibodies were diluted to 0.4 μg / mL in PBS containing 1% BSA, and 100 μL of the detection antibodies were added to each well. The plate was then incubated in a 37°C incubator for 1 hour.The well plate was then washed five times, and 100 μL of avidin-HRP diluted 200-fold with 1% BSA in PBS was added to each well. The well plate was then incubated at 37°C for 30 minutes. The well plate was then washed five more times, and 100 μL of TMB substrate was added to each well. The mixture was incubated at room temperature until a blue color appeared. 100 μL of stop solution was then added to each well. OD450 single values ​​were read using a PHERAstar multifunctional microplate reader. The IC50 inhibitory activity of the compounds was calculated using Graphpad Prism software. 50 The value was calculated as follows: The maximum degradation rate of a compound was the ratio of the level of Erα remaining after treating cells with 3000 nM of the compound to the level of Erα remaining after treating cells with 3000 nM of fulvestrant.

[0244] 3. Test results EC measured for the degrading effect of the compounds of the present disclosure on Erα 50 The values ​​are shown in Table 4. [Table 16] In conclusion, the compounds claimed in the present disclosure have obvious decomposition activity on Erα, while Comparative Examples 20 and 21 show no activity.

[0245] Test Example 5 Inhibitory effect of compounds according to the present disclosure on the enzyme activity of the midazolam metabolizing site in human liver microsome CYP3A4 The enzymatic activity of the compounds according to the present disclosure at the midazolam metabolic site of human liver microsomal CYP3A4 was measured by the following experimental method.

[0246] 1. Experimental materials and equipment 1. Phosphate buffer solution (20x PBS, purchased from Seiko), 2.NADPH(ACROS, A2646-71-1), 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor 36), 4. ABI QTrap 4000 liquid chromatograph mass spectrometer (AB Sciex), 5. ZORBAX Extend-C18, 3×50 mm, 3.5 μM (Agilent, USA), 6. CYP probe substrate (midazolam, TRC, M343000 / 3 μM) and positive control inhibitor (ketoconazole, SIGMA, Cat No. K1003-100MG).

[0247] 2. Experimental Procedure A 100 mM PBS buffer solution was prepared, and a 0.25 mg / mL microsome solution, 7.5 mM MgCl2, and 5 mM NADPH solution were prepared using this buffer. The 30 mM stock solution was diluted with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM. These solutions were further diluted 200-fold with phosphate buffer solution (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). A 15 μM midazolam working solution was prepared using PBS. A 40 μL aliquot of 0.25 mg / mL microsome solution prepared with 7.5 mM MgCl2 was mixed with 20 μL each of 15 μM midazolam working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). For the positive control, ketoconazole was used instead of the compound at the same concentration. Simultaneously, the wells were preincubated with 5 mM NADPH solution for 5 minutes at 37°C. After 5 minutes, 20 μL of NADPH was added to each well to initiate the reaction, followed by incubation for 30 minutes. Duplicate samples were prepared for each incubation. After 30 minutes, all samples were mixed with 250 μL of acetonitrile containing the internal standard, mixed thoroughly, shaken at 800 rpm for 10 minutes, and then centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was mixed uniformly with 80 μL of ultrapure water and transferred to LC-MS / MS analysis.

[0248] IC values ​​of drugs at the midazolam metabolizing site of CYP3A4 calculated using Graphpad Prism 50 The values ​​are shown in Table 5. [Table 17] The conclusion is that the compounds claimed in the present disclosure have low inhibitory effects on the midazolam metabolic site of human hepatic microsomal CYP3A4, exhibit higher safety, and do not cause metabolic drug interactions based on the midazolam metabolic site of CYP3A4 metabolism.

[0249] Test Example 6 Inhibitory effect of compounds according to the present disclosure on the enzyme activity of the testosterone metabolism site in human liver microsome CYP3A4 The enzymatic activity of the compounds according to the present disclosure on the testosterone metabolism site of human liver microsomal CYP3A4 was measured by the following experimental method.

[0250] 1. Experimental materials and equipment 1. Phosphate buffer solution (20x PBS, purchased from Seiko), 2.NADPH(ACROS, A2646-71-1), 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 905002, Donor 36), 4. ABI QTrap 4000 liquid chromatograph mass spectrometer (AB Sciex), 5. ZORBAX Extend-C18, 3×50 mm, 3.5 μM (Agilent, USA), 6. CYP probe substrate (testosterone, Wokai, CAS No. [58-22-0] / 75 μM) and positive control inhibitor (ketoconazole, SIGMA, Cat No. K1003-100MG).

[0251] 2. Experimental Procedure A 100 mM PBS buffer solution was prepared, and then a 0.25 mg / mL microsome solution, 7.5 mM MgCl2, and 5 mM NADPH solution were prepared using this buffer. A 30 mM stock solution was diluted with DMSO to prepare a series of solutions I containing 30, 10, 3, 1, 0.3, 0.03, 0.003, and 0 mM. These solutions were then further diluted 200-fold with phosphate buffer solution (PBS) to obtain a series of test solutions II containing 150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM. A 375 μM testosterone working solution was prepared using PBS. A 40 μL aliquot of 0.25 mg / mL microsome solution prepared in 7.5 mM MgCl2 was mixed with 20 μL each of 375 μM testosterone working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). For the positive control, ketoconazole was used instead of the compound at the same concentration. Simultaneously, the wells were preincubated with 5 mM NADPH solution for 5 min at 37°C. After 5 min, 20 μL of NADPH was added to each well to initiate the reaction, followed by incubation for 30 min. After 30 min, all samples were mixed with 250 μL of acetonitrile containing the internal standard, mixed thoroughly, shaken at 800 rpm for 10 min, and then centrifuged at 3700 rpm for 10 min. 100 μL of the supernatant was mixed with 80 μL of ultrapure water and transferred to LC-MS / MS analysis.

[0252] IC values ​​of drugs for the testosterone metabolizing site of CYP3A4 calculated using Graphpad Prism 50 The values ​​are shown in Table 6. [Table 18] In conclusion, the compounds claimed in the present disclosure have low inhibitory effects on the testosterone metabolism site of human liver microsomal CYP3A4, demonstrating higher safety.

[0253] Test Example 7 Time-dependent inhibition of the enzyme activity of the midazolam metabolizing site in human liver microsome CYP3A4 by the compounds of the present disclosure. The time-dependent CYP enzyme activity inhibitory effect of the compounds according to the present disclosure on the midazolam metabolic site of human liver microsomal CYP3A4 was measured by the following experimental method.

[0254] 1. Experimental materials and equipment 1. Phosphate buffer solution (20x PBS, purchased from Seiko), 2.NADPH(ACROS, A2646-71-1), 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor 36), 4. ABI QTrap 4000 liquid chromatograph mass spectrometer (AB Sciex), 5. ZORBAX Extend-C18, 3×50 mm, 3.5 μM (Agilent, USA), 6. CYP probe substrate (midazolam, TRC, M343000 / 3 μM) and positive control inhibitor (verapamil, Adamas Reagent Co, Ltd, Cat No. 25904A).

[0255] 2. Experimental Procedure A 100 mM PBS buffer solution was prepared, and a 0.25 mg / mL microsome solution, 7.5 mM MgCl2, and 5 mM NADPH solution were prepared using this buffer. The 30 mM stock solution was diluted with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.1 mM, 0.03 mM, and 0 mM. The above series of solutions I was further diluted 200-fold with phosphate buffer solution (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.5, 0.15, and 0 μM). A 15 μM midazolam working solution was prepared using PBS. The prepared solutions were thoroughly shaken, and 20 μL of each was dispensed into the corresponding reaction plates (+NADPH, TO, and -NADPH groups) to set up three parallel groups. 40 μL of liver microsome working solution was added to each 96-well plate, 20 μL of the corresponding substrate solution was added to the TO plate, and 20 μL of NADPH was added to the TO plate and the +NADPH group, respectively. Time recording was then initiated, and the plates were placed in a water bath and incubated at 37°C. After 30 minutes of incubation, the TO plate was removed and the reaction was stopped with 250 μL of ACN solution containing the internal standard. 20 μL of the corresponding substrate solution was added to the +NADPH group, and 20 μL of the corresponding substrate solution and 20 μL of NADPH were added to the -NADPH group. Time recording was then initiated, and the plates were placed in a water bath and incubated at 37°C. After 30 minutes of incubation, the plates were removed and the reaction was stopped with 250 μL of ACN solution containing the internal standard. The mixture was then shaken at 800 rpm for 10 minutes and centrifuged at 4000 rpm for 15 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water and then transferred to LC-MS / MS analysis.

[0256] IC values ​​of drugs at the midazolam metabolizing site of CYP3A4 calculated using Graphpad Prism 50 The values ​​are shown in Table 7. [Table 19] The conclusion is that the compounds claimed in the present disclosure have low inhibitory effects on the midazolam metabolic site of human hepatic microsomal CYP3A4, exhibit higher safety, and do not cause metabolic drug interactions based on the midazolam metabolic site of CYP3A4 metabolism.

[0257] Test Example 8 Time-dependent inhibitory effect of the compound of the present disclosure on the enzyme activity of the testosterone metabolism site in human liver microsome CYP3A4 The time-dependent inhibitory effect of the compounds according to the present disclosure on the enzyme activity of the testosterone metabolizing site in human liver microsome CYP3A4 was measured by the following experimental method.

[0258] 1. Experimental materials and equipment 1. Phosphate buffer solution (20x PBS, purchased from Seiko), 2.NADPH(ACROS, A2646-71-1), 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 905002, Donor 36), 4. ABI QTrap 4000 liquid chromatograph mass spectrometer (AB Sciex), 5. ZORBAX Extend-C18, 3×50 mm, 3.5 μM (Agilent, USA), 6. CYP probe substrate (testosterone, Wokai, CAS No. [58-22-0] / 75 μM) and positive control inhibitor (verapamil, Adamas Reagent Co Ltd, Cat No. 25904A).

[0259] 2. Experimental Procedure A 100 mM PBS buffer solution was prepared, and a 0.25 mg / mL microsome solution, 7.5 mM MgCl2, and 5 mM NADPH solution were prepared using this buffer. The 30 mM stock solution was diluted with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.1 mM, 0.03 mM, and 0 mM. The above series of solutions I was further diluted 200-fold with phosphate buffer solution (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.5, 0.15, and 0 μM). A 15 μM midazolam working solution was prepared using PBS. The prepared solutions were thoroughly shaken, and 20 μL of each was dispensed into the corresponding reaction plates (+NADPH, TO, and -NADPH groups) to set up three parallel groups. 40 μL of liver microsome working solution was added to each 96-well plate, 20 μL of the corresponding substrate solution was added to the TO plate, and 20 μL of NADPH was added to the TO plate and the +NADPH group, respectively. Time recording was then initiated, and the plates were placed in a water bath and incubated at 37°C. After 30 minutes of incubation, the TO plate was removed and the reaction was stopped with 250 μL of ACN solution containing the internal standard. 20 μL of the corresponding substrate solution was added to the +NADPH group, and 20 μL of the corresponding substrate solution and 20 μL of NADPH were added to the -NADPH group. Time recording was then initiated, and the plates were placed in a water bath and incubated at 37°C. After 30 minutes of incubation, the plates were removed and the reaction was stopped with 250 μL of ACN solution containing the internal standard. The mixture was then shaken at 800 rpm for 10 minutes and centrifuged at 4000 rpm for 15 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water and then transferred to LC-MS / MS analysis.

[0260] IC values ​​of drugs for the testosterone metabolizing site of CYP3A4 calculated using Graphpad Prism 50 The values ​​are shown in Table 8. [Table 20] The conclusion is that the compounds claimed in this disclosure have low inhibitory effects on the testosterone metabolism site of human hepatic microsomal CYP3A4, suggesting greater safety and no CYP3A4-based metabolic drug interactions.

[0261] Test Example 9 1. Purpose of the experiment The blocking effect of compounds according to the present disclosure on hERG potassium current was tested in a stable cell line transfected with the hERG potassium channel using automated patch clamp.

[0262] 2. Experimental method 2.1 Experimental materials and equipment 2.1.1 Experimental materials: [Table 21]

[0263] 2.1.2 Experimental equipment: [Table 22]

[0264] 2.2 Fully automated patch clamp experiment steps HEK293-hERG stable cell lines were subcultured at a density of 1:4 in MEM / EBSS medium (10% FBS, 400 μg / mL G418, 1% MEM non-essential amino acid solution (100x), 1% sodium pyruvate solution) and fully automated patch clamp experiments were performed within 48–72 hours of culture. On the day of the experiment, cells were treated with 0.25% trypsin, harvested by centrifugation, and resuspended in extracellular solution (140 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 5 mM dextrose monohydrate, 10 mM Hepes, pH 7.4, 298 mOsmol) to prepare a cell suspension. The cell suspension was placed in the cell bank of the Patchliner instrument, which then placed the cells onto a chip (NPC-16) using a negative pressure controller. Single cells were then aspirated into the chip wells by negative pressure. After forming the whole-cell configuration, the device acquired hERG currents according to the set hERG current-voltage program, and then the device automatically perfused compounds from low to high concentrations. Data collection and analysis were performed using a HEAK Patchmaster, a HEAK EPC10 patch clamp amplifier (Nanion), and Pathliner software and Pathcontrol HT software to analyze the currents under each compound concentration and the blank control current.

[0265] 2.3 Test Results The blocking effect of the compounds of the present disclosure on the hERG potassium current was measured by the above test, and the measured IC 50 The values ​​are shown in Table 9. [Table 23] In conclusion, the compounds claimed in this disclosure have no inhibitory activity against hERG, demonstrating greater safety.

Claims

1. A compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R 1a and R 1b are the same or different and are each independently selected from an H atom, a deuterium atom, a halogen, and a C 1-6 alkyl group; Ring A is a 3- to 8-membered heterocyclyl group; Z is selected from an O atom and NR 7 ; G 1 , G 2 , G 3 and G 4 are homologous or different, and each independently represents CR 8 or a N atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom or a C 1-6 alkyl group, R 5 is a C 1-6 alkyl group, said C 1-6 alkyl group being optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl groups and hydroxy groups; R 6 is a hydrogen atom or a C 1-6 haloalkyl group, R 7 is a hydrogen atom, R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; n is 1, s is 0, 1 or 2, and p is 0, 1, 2 or 3; A compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

2. Ring A is selected from an azetidinyl group and a pyrrolidinyl group; and / or G1, G 2 , G 3 and G 4 All are CR 8 or G 1 is N and G 2 , G 3 and G 4 is CR 8 and R 8 are the same or different and each independently represents a hydrogen atom or a halogen atom; A compound represented by the general formula (I) according to claim 1, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

3. A compound represented by general formula (II): 【Chemistry 2】 During the ceremony, r is 0, 1, 2 or 3; q is 1, 2 or 3; t is 1 or 2; Z, G 1 , R 1a , R 1b , R 2 ~R 6 , R 8 , n and s are as defined in claim 1; A compound represented by the general formula (I) according to claim 1, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

4. A compound represented by general formula (IIG) or general formula (IIGa), 【Chemistry 3】 During the ceremony, R 11a and R 11b are identical or different and each independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; k is an integer from 1 to 6, q is 1, 2 or 3; t is 1 or 2; r is 0, 1, 2 or 3; G 1 , Z, R 1a , R 1b , R 2 ~R 4 , R 6 , R 8 , n and s are as defined in claim 1; A compound represented by general formula (I) according to claim 1 or 3, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

5. A compound represented by general formula (IV) or general formula (IVa): 【Chemistry 4】 During the ceremony, r is 0, 1, 2 or 3; G 1 , R 1a , R 1b , R 2 ~R 8 and s is as defined in claim 1; A compound represented by general formula (I) according to claim 1 or 3, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

6. G 1 is a N atom; or G 1 is CR 8 R 8 is the same or different, and each independently represents a hydrogen atom or a halogen atom; A compound represented by general formula (I) according to any one of claims 1, 3 to 5, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

7. R 1a and R 1b are identical or different and are each independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; A compound represented by the general formula (I) according to claim 1, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

8. R 1a and R 1b are identical or different and each independently represent a H atom, a deuterium atom, a fluorine atom, and C 1-6 and / or R 4 is C 1-6 and / or R is an alkyl group; 6 is C 1-6 is a haloalkyl group, A compound represented by general formula (I) according to any one of claims 1 to 6, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

9. R 1a and R 1b are deuterium atoms. A compound represented by general formula (I) according to any one of claims 1 to 6, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

10. The compound: 【Chemistry 5】 【Chemistry 6】 Selected from the group consisting of: A compound represented by general formula (I) according to any one of claims 1 to 9, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

11. A compound represented by the general formula (IA) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 7】 During the ceremony, R 1a and R 1b are identical or different and each independently selected from an H atom, a deuterium atom, a halogen, and a C 1-6 alkyl group; X is Br; G 1 , G 2 , G 3 and G 4 are homologous or different, and each independently represents CR 8 or a N atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom or a C 1-6 alkyl group, R 5 is a C 1-6 alkyl group, said C 1-6 alkyl group being optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl groups and hydroxy groups; R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; n is 1, and s is 0, 1 or 2; A compound represented by the general formula (IA) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof.

12. A compound represented by general formula (IIGA) or general formula (IIGaA), or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 8】 During the ceremony, R 1a and R 1b are identical or different and each independently selected from an H atom, a deuterium atom, a halogen, and a C 1-6 alkyl group; R w teeth, 【Chemistry 9】 and Z is an O atom and NR 7 is selected from G 1 CR 8 or a N atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom or a C 1-6 alkyl group, R 6 is a hydrogen atom or a C1-6 haloalkyl group, R 7 is a hydrogen atom, R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; R 11a and R 11b are identical or different and each independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; k is an integer from 1 to 6, q is 1, 2 or 3; t is 1 or 2; n is 1, r is 0, 1, 2 or 3, and s is 0, 1 or 2; A compound represented by general formula (IIGA) or general formula (IIGaA), or a tautomer, meso isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

13. The compound: 【Chemistry 10】 【Chemistry 11】 【change】 【Chemistry 12】 or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

14. A method for preparing a compound represented by general formula (I) according to claim 1 or a tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, comprising the steps of: 【Chemistry 13】 The method includes a step of coupling a compound of general formula (IA) with a compound of general formula (IB) to obtain a compound of general formula (I), In the above formula, X is Br; Ring A, Z, G 1 , G 2 , G 3 , G 4 , R 1a , R 1b , R 2 ~R 6 , n, p and s are as defined in claim 1; method.

15. A process for preparing a compound of general formula (IIG) or general formula (IIGa) according to claim 4 or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, comprising: 【Chemistry 14】 【Chemistry 15】 Removal of Rw from a compound of general formula (IIGA) to obtain a compound of general formula (IIG); removing Rw from the compound of general formula (IIGaA) to obtain a compound of general formula (IIGa); In the above formula, R w teeth, 【Chemistry 16】 and Z, G 1 , R 1a , R 1b , R 2 ~R 4 , R 6 , R 8 , R 11a , R 11b , q, t, k, r, n and s are as defined in claim 4; method.

16. A therapeutically effective amount of a compound represented by general formula (I) according to any one of claims 1 to 10, or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents or excipients. Pharmaceutical compositions.

17. A compound represented by general formula (I) according to any one of claims 1 to 10, or in the form of a tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, for use as an estrogen receptor modulator, or a pharmaceutical composition according to claim 16.

18. A compound represented by general formula (I) according to any one of claims 1 to 10, or in the form of a tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use as a selective estrogen receptor degrader (SERD).

19. 17. The compound of formula (I) according to any one of claims 1 to 10, or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, for preventing and / or treating an estrogen receptor mediated or dependent disease or disorder, wherein the estrogen receptor mediated or dependent disease or disorder is selected from the group consisting of cancer, central nervous system defect, circulatory system defect, blood system defect, immune and inflammatory disease, susceptibility to infectious diseases, metabolic defect, neurological defect, mental defect, and reproductive defect, and the cancer is selected from the group consisting of breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, hemophilia, and leukemia; or a pharmaceutical composition according to claim 16.

20. The compound or pharmaceutical composition of claim 19, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer.

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