TRICYCLIC TETRAHYDROISOQUINOLINE DERIVATIVE, METHOD OF PREPARATION THEREOF AND APPLICATION THEREOF IN MEDICINE

Abstract

The present invention relates to a tricyclic tetrahydroisoquinoline derivative, a method for preparing the same, and a medical application thereof. In particular, the present invention relates to a tricyclic tetrahydroisoquinoline derivative represented by general formula (I), a method for preparing the same, and a pharmaceutical composition comprising said derivative, its use as an estrogen receptor modulator, and its use in the preparation of a drug for treating estrogen receptor-mediated or dependent diseases or disorders. The substituents in general formula (I) are the same as those defined in the invention. (See Formula).

Description

TRICYCLIC TETRAHYDROISOQUINOLINE DERIVATIVE, METHOD OF PREPARATION THE SAME AND APPLICATION OF THE SAME IN MEDICINE LRnonn / zznz / e / YiAi The present application claims the priority of Chinese Patent Application CN202010025118.5 filed on January 10, 2020, the Chinese Patent Application CN202010036802.3 filed on January 14, 2020, Chinese Patent Application CN202010273891.3 filed on April 9, 2020, Chinese Patent Application CN202010680491.4 filed on July 15, 2020, Chinese Patent Application CN202010819555.4 filed on August 14, 2020 and Chinese Patent Application CN202010971693.4 filed on September 16, 2020, which are incorporated herein by reference in their entirety. Field of Invention The present invention belongs to the field of the pharmaceutical industry and refers to tricyclic tetrahydroisoquinoline derivatives, a method of preparation thereof and their use in the pharmaceutical industry. In particular, the present invention relates to a tricyclic tetrahydroisoquinoline derivative of general formula (I), a method of preparation thereof, a pharmaceutical composition comprising the derivative and its use as an estrogen receptor modulator to treat a disease mediated or estrogen receptor dependent. or condition, wherein the disease is particularly preferably breast cancer. Background of the Invention After long-term basic research and clinical follow-up, it is found that diseases such as breast cancer, ovarian cancer, osteoporosis, schizophrenia, senile dementia, etc. They are closely associated with the abnormality of the estrogen signaling pathway. Estrogen is a steroid hormone secreted by the endocrine system. It plays an important role in the reproductive system, bone tissue, cardiovascular system, immune system and central nervous system. The estrogen signaling system plays an important role in regulating cell growth, differentiation and apoptosis. The development and progression of estrogen-dependent tumors, such as breast cancer, ovarian cancer, endometrial cancer, etc., are closely related to estrogen. Currently, the main chemotherapy for breast cancer is the use of antiestrogens such as tamoxifen; However, tamoxifen acts as an estrogen agonist in the uterus, having a stimulating effect on cancer cells in the uterus. Due to these serious side effects, it is imperative to find new safe and effective treatments. An important protein in the estrogen signaling pathway is the estrogen receptor (ER). ER is a spheroid hormone receptor and is a ligand-activated transcription factor that belongs to the nuclear receptor superfamily. It includes two subtypes: ERa (found in 1950) and ERp (found in 1996), each encoded by a different gene. ERa and ERp are very similar at the amino acid level: they are up to 97% similar in the DNA binding domain and up to 56% similar in the ligand binding domain. However, they only have 24% homology at the N-terminus, which is considered low. The ER comprises 6 domains (A-F), which form 4 main functional regions. The N-terminal A / B domain functional region includes an AF-1 ligand-independent transcriptional activation functional region, which has constitutive activation activity and activates transcription of a target gene by acting with basal transcription factors, reactivation factors. and other transcription factors, factors The region has a plurality of phosphorylation sites. The action of AF-1 is reported to depend on protein phosphorylation. The DNA binding domain (DBD) formed from the C domain is highly conserved and comprises two zinc finger domains capable of specifically binding to target DNA. The domain also plays an important role in receptor dimerization. The D domain is a hinge region that links the DBD and the ligand binding domain (LBD). It is poorly conserved (two subtypes are only 30% homologous). The C-terminal E domain forms the ligand-binding domain (LBD), which determines the specific binding of the ER to ligands such as estrogen, SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader ) and the like. The LBD includes a functional region of AF-2 ligand-dependent transcriptional activation, which acts synergistically with AF-1 to allow the ER to activate transcription of the target gene. Furthermore, the LBD has a powerful dimerization interface and can still function without a ligand; therefore, the LBD is a critical site for receptor dimerization. ERa is mainly distributed in the uterus, ovaries, testes, pituitary gland, kidneys, epididymis and adrenal glands, while RPE is mainly distributed in the prostate, ovaries, lungs, bladder, brain and blood vessels. Since full agonists or antagonists have serious side effects, effort is being focused on SERM research. By "selective" it is meant that SERMs act as agonists in certain tissues such as bones, liver and the RPE-concentrated region of the cardiovascular system, while as antagonists in some other tissues such as the mammary gland. They can act as agonists or antagonists in the uterus (region where ERa predominates). SERMs currently available in the market include tamoxifen, raloxifene, bazedoxifene, toremifene, etc. Without LRnonn / zznz / e / YiAi However, SERMs currently available on the market have been shown to still have serious side effects; For example, long-term use of tamoxifen and toremifene may cause endometrial hyperplasia, polyps, endometrial carcinoma, etc., and raloxifene has common side effects including hot flashes, leg pain, breast swelling and pain, venous embolism , etc. Therefore, the research and development of new compounds is still a problem to be solved. Tamoxifen belongs to a class of compounds called selective estrogen receptor modulators (SERMs). It can stabilize ERa and slightly increase the level of ERa receptors. In contrast, fulvestrant may cause rapid degradation of ERa and enhanced blockade of ER signaling pathways; Such compounds are called selective estrogen receptor degraders (SERDs). The differences in the mechanisms of action of these SERMs and SERDs also appear to be the mechanism responsible for resistance to these compounds. Many tumors that are resistant to tamoxifen but remain ER positive remain sensitive to fulvestrant. SERDs such as fulvestrant have been clinically found to be effective in the treatment of some tamoxifen-resistant and ERa-positive breast cancers. Therefore, compounds that cause ERa degradation can be used to extend the time period within which antiestrogen therapy (different SERMs, aromatase inhibitors, and SERDs can be used in sequence) is effective in treating patients with breast cancer. Disclosed patent applications regarding selective estrogen receptor-mediated modulators include WO2014165723, WO2014151899, WO2014141292, WO2014191726, WO2015092634, WO2014135834, WO2014106848 and EP1113007. LRnonn / zznz / e / YiAi Summary of the Invention The present invention aims to provide a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (I) has a structure like the one shown below: where: ring A is heterocyclyl; Z is selected from the group consisting of one O atom, one S atom, NR7, and CR9R10; G1, G2, G3, and G4 are identical or different and each is independently GR8 or an N atom; R1a and R1b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl , heterocyclyl, aryl and heteroaryl; R2 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of the hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group that consists of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R5 is selected from the group consisting of the hydrogen atom, alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano , amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; LRnonn / zznz / B / YiAi R6 are identical or different and each is independently selected from the group consisting of the hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, amino, nitro, halogen, carboxyl, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, in wherein alkyl, cycloalkyl and heterocyclyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R7 is selected from the group consisting of the hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl, where alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R9 and R10 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl; n is 1,2 or 3; s is 0, 1 or 2; and p is 0, 1,2 or 3. In some embodiments of the present invention, in a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof z G'^G' G4^.G1 GO;\ ( l i ικηοηη / ζζηζ / Β / γίΛΐ R1a and R1b are identical or different and each is independently selected from the group consisting of H atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl , heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; ring A is heterocyclyl; Z is selected from the group consisting of one O atom, one S atom, NR7, and CR9R10; G1, G2, G3, and G4 are identical or different and are each independently CR8o an N atom; R2 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, in wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of the hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro , hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of the hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group that consists of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R5 is selected from the group consisting of the hydrogen atom, alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano , amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R6 are identical or different and each is independently selected from the group consisting of the hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, LRnonn / zznz / e / YiAi amino, nitro, halogen, carboxyl, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R7 is selected from the group consisting of the hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl, where alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R9 and R10 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl; n is 1,2 or 3; s is 0, 1 or 2; and p is 0, 1,2 or 3. In some embodiments of the present invention, in a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, ring A has 3 6-membered, heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of an N atom, an O atom and an S atom, and is preferably selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl, and is more preferably pyrrolidinyl or piperidinyl. In other embodiments of the present invention, in a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, G1, G2, G3 and G4 are all GR8, or one of G1, G2, G3, and G4 is an N atom, and the others are CR8; preferably, G1, G2, G3 and G4 are all CR8, or G1 is N, and G2, G3 and G4 are CR8; R8 are as defined in the general formula (I); LRnonn / zznz / e / YiAi preferably, R8 are identical or different and each is independently a hydrogen or halogen atom. LRnonn / zznz / e / YiAi In some embodiments of the present invention, a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (I). H): ^N'Ré I (Rsi- R;!where: r is 0, 1.2 or 3; q is 1,2 or 3; t is 1 or 2; Z, G1, R1a, R1b, R2-R6, R8, n and s are as defined in general formula (I). In some embodiments of the present invention, a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (I). IIG) or (IIGa): (HG) (IIGa) where: Rila and Riif are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 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; G1, Z, R1a, R1b, R2-R4, R6, R8, n and s are as defined in general formula (I). In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG) and (IIGa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or salts pharmaceutically acceptable thereof, Z is NR7 or an O atom; R7is as defined in general formula (I). In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG) and (IIGa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or salts pharmaceutically acceptable thereof, Z is NR7; R7is as defined in general formula (I). In some other embodiments of the present invention, in compounds of general formulas (II), (IIG) and (IIGa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts of the themselves, q is 2, and t is 1; or q is 2, and t is 2. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG) and (IIGa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or salts pharmaceutically acceptable thereof, n is 1. In some embodiments of the present invention, a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (I). III) or (Illa): LRnonn / zznz / e / YiAi LRnonn / zznz / B / YiAi where: r is 0, 1.2 or 3; G1, R1a, R1b, R2-R8and s are as defined in general formula (I). In some embodiments of the present invention, a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (I). IV) or (IVa): (R?)s n 1 d O - _ > I R1b'bJ (IVa) where: r is 0, 1.2 or 3; G1, R1a, R1b, R2-R8and s are as defined in general formula (I). In some other embodiments of the present invention, in the above compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, G1es CR8; R8 is as defined in the general formula (I). In some other embodiments of the present invention, in the above compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, G1es N. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R7 is a hydrogen atom. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R1a and R1b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl and haloalkyl . In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R1a and R1b are identical or different and each is independently selected from the group consisting of an H atom, a deuterium atom, a of fluorine and Ci-6 alkyl; preferably, R1a and R1b are deuterium atoms. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R1a and R1b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl and haloalkyl ; preferably, R1a and R1b are identical or different and each is independently selected from the group consisting of the hydrogen atom, a fluorine atom and Ci-6 alkyl. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R2 is a hydrogen atom. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, LRnonn / zznz / e / YiAi enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R3 is a hydrogen atom. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R4 is a hydrogen atom or alkyl, preferably Ci-6 alkyl and more preferably methyl. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R5 is alkyl optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, cyano, hydroxy, alkoxy, carboxyl and cycloalkyl; R5 is preferably alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy, more preferably -CH2-CF3, CH2-CHF2, -CH2-CF2-CH2OH, -CH2-CF2-CH3 or -CH2-CF( CH3)2, and more preferably -CH2-CF3or -CH2-CF2-CH2OH. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R5 is alkyl or haloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, cyano, hydroxy, alkoxy, carboxyl and cycloalkyl, and It is preferably alkyl or haloalkyl, more preferably -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3o -CH2-CF(CH3)2, and most preferably -CH2-CF3. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R is a hydrogen or haloalkyl atom. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, CH2-CF3, and more preferably -CH2-CH2-CH2F. In some other embodiments of the present invention, in compounds of general formulas (I), (II), (IIG), (IIGa), (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, LRnonn / zznz / e / YiAi enantiomers or diastereomers thereof or mixtures thereof, or pharmaceutically acceptable salts thereof, R8 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl , alkoxy, haloalkyl and cyano, and are preferably hydrogen or halogen atoms. In some other embodiments of the present invention, in a compound of general formula (II) or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, G1 is CR8 or an atom of N, preferably an N atom; Z is NR7o an O atom; R1a and R1b are identical or different and each is independently selected from the group consisting of one H atom and one deuterium atom; R2 is a hydrogen atom; R3 is a hydrogen atom; R4 is methyl; R5 is C1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy; R6 is haloalkyl Ci-6! R7 is a hydrogen atom; R8 are identical or different and each is independently a hydrogen atom or a halogen; r is 0, 1 or 2; n is 1; q is 1 or 2; and t is 1 In some other embodiments of the present invention, in compounds of general formulas (III), (Illa), (IV) and (IVa) or tautomers, mesomers, racemates, enantiomers or diastereomers thereof or mixtures thereof, or salts pharmaceutically acceptable ones thereof, G1 is CR8o an N atom, preferably an N atom; R1a and R1b are identical or different and each is independently selected from the group consisting of one H atom and one deuterium atom; R2 is a hydrogen atom; R3 is a hydrogen atom; R4 is methyl; R5 is Ci-6alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy; R6is haloalkyl Ci-e; R7 is a hydrogen atom; R8 are identical or different and each is independently a hydrogen atom or a halogen; and r is 0, 1 or 2. Typical compounds described herein include, but are not limited to: LRnonn / zznz / B / YiAi 2 HN*^7 χΊ F^y'^F □^-^Χ^Χ, F 2 (S)-N-(3,5-difluoro-4-((5S,7R)-7-methyl-6- (2,2,2-trifluoroethyl)-5,6,7,8tetrahydro-[1,3]dioxolo[4,5-g]¡soquinolin-5-¡l)phen¡l)-1 -(3fluoropropyl )pyrrolídin-3-amine 2 3 HN^ 0 <ΎηΎ'ΟΗ 3 2,2-difluoro-3-((5R,7R)-5-(4-(((S)-1- (3-fluoropropyl)pyrrolidin-3¡l)amino)phen¡l)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinol ¡n-6(5H)yl)propan-1-ol 3 4 FÍI <°ΤΓι j^T^oh 4 2,2-difluoro-3-((5S,7R)-5-(5-(((S )-1 -(3-f luoropropyl)pyrrolidi n-3yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin6 (5H)-yl)propan-1-ol 4 5 0^0 Μ τ y T / “Π 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1 -(3-fluoropropyl)pyrrolidin-3yl)amino)phenyl)-7-methyl-7, 8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)2,2 -difluoropropan-1-ol 5 LRnonn / zznz / e / γΐΛΐ 6 r>^-F ρϊι <°X¿NA^ 6 N-((S)-1-(3-fluoropropyl)pyrrolídin-3-H)-6-((5S,7R)-7-metH- 6-(2,2,2trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3amine 6 7 Π .71 0 ^0 M -n Ay TI (S)-N-(4-((5S,7R)-2,2-difluoro-7-methyl-6-(2,2,2-trifluoroethyl)-5,6 ,7,8tetrahydro-[1,3]dioxolo[4,5-g]¡soquinolín-5-¡l)-3,5-difluorophen¡l)-1-(3fluoropropyl)pyrrolídin -3-amine 7 8 71 7Π 0^0 b and “Π 6-((5S,7R)-2,2-difluoro-7-methyl-6-(2,2,2-trifluoroeth¡ l)-5,6,7,8-tetrahydro[1,3]dioxolo[4, 5-g]isoquinolin-5-¡l)-N-((S)-1 -(3-fluoropropyl )pyrro¡din-3¡l)pyrro¡din-3-am¡na 8 9 O^O M m b TI 5-Fluoro-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-íl)-6-((5S,7R)-7-met ¡l-6-(2,2,2trifluoroethyl)- 5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]¡soquinol¡n-5-¡l)p¡ radin-3amine 9 10 XX 10 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolyl) n-3¡l)amino)phenyl)-2,2,7-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinol¡n6(5H)-yl)-2, 2-difluoropropan-1 -ol 10 11 hn'z^ / -(3-fluoropropyl)pyrrolidin-3yl)amino)pyridin-2-lo)-7-methyl-7,8-dihydro-[1,3 ]dioxolo[4,5-g]¡soquinol¡n6(5H)-yl)propan-1-ol 11 12 ) T / o z U-Λ—u. Χλ / \ CN o ° 0 Q^Q ικηοηη / ζζηζ / Β / γίΛΐ 2,2-difluoro-3-((5S,7R)-5-(5-(((S)-1 -(3-fluoropropyl)pyrrolidin-3yl)amino)pyridin-2 -yl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinol¡n6(5H)-¡l-2,2-d2)propan-1-ol 12 13 HN pil VXjO'X'0H 13 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyrídin-2yl )-7-methyl-7, 8-dihydro-[1,3]dioxolo[4,5-g]¡soquinolin-6(5H)-¡l-2,2d2)propan-1-ol 13 14 HN MI OMmMoh 14 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluorOprop¡l)azetidin-3-¡l)amino)pyr¡d ¡n-2yl)-7-methyl-7, 8-dihydro-[1,3]dioxolo[4,5-g]¡soquinolin-6(5H)-¡l)propan-1-ol 14 15e Γ NH XX <οιΧα 15e (5S,7R)-5-(2,6-difluoro-4-(((S)-pyrrOl¡din-3-yl)oxy)phen¡l)-7 -methyl-6-(2,2,2trifluoroethyl)- 5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 15e 15 A V— / v / \ 10 yXV? O 0^0 (5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoroprop¡l)pyrrolidin-3-¡l)ox ¡)phenyl)-7methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]¡soquinoline¡ne LRnonn / zznz / e / γΐΛΐ -(3-Fluoropropyl)-N-(4-((5R,7R)-7-methyl-6-(2,2,2-tnfluoroethyl)-5,6,7,8tetrahydro-[1,3 ] dioxolo[4,5-g]¡soquinol¡n-5-¡l)phen¡l)azet¡din-3-am¡na 16 LRnonn / zznz / e / YiAi N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((5S,7Fl)-7-metH-6-(2,2,2-tnfluoroethH)5,6,7,8 - tetrahydro-[ 1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin-3-amine 17 2,2-difluoro-3-((5R,7R)-5-(4-((1-(3-fluoroprop¡l)azet¡din-3-¡l)amino)phenyl)-7methyl-7 ,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-íl)propan-1 -ol 18 2,2-difluoro-3-((5R,7R)-5-(4-(((S)-1 -(3-fluoropropyl)pyrrolidin-3yl)amino)phenyl)-7-methyl-7, 8-dihydro-[1,3]dioxolo[4,5-g]isoquinol¡n-6(5H)-yl2,2-d2)propan-1-ol 19 Another aspect of the present invention provides a compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof. LRnonn / zznz / e / YiAi X is Br; G1, G2, G3, and G4 are identical or different and each is independently GR8 or an N atom; R1a and R1b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl , heterocyclyl, aryl and heteroaryl; R2 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of the hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro , hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of the hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group that consists of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R5 is selected from the group consisting of alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl, wherein alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 1,2 or 3; and s is 0, 1 or 2. The compound of general formula (IA) is an intermediate for the preparation of the compound of general formula (I). Another aspect of the present invention provides a compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof. x G '' ^G ¿G4^G1 Rl:·’' i IA ) where: R1a and R1b are identical or different and each is independently selected from the group consisting of H atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl , heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; LRnonn / zznz / e / YiAi X is Br; G1, G2, G3, and G4 are identical or different and are each independently CR8o an N atom; R2 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of the hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro , hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of the hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group that consists of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R5 is selected from the group consisting of alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl, wherein alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 1,2 or 3; and s is 0, 1 or 2. The compound of general formula (IA) is an intermediate for the preparation of the compound of general formula (I). Another aspect of the present invention provides a compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture LRnonn / zznz / e / YiAi thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (HA) or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or a mixture thereof, or a salt pharmaceutically acceptable thereof, x l. ÍIVΎ O(R;), T or V- XR- T T T R7. <ΙΙΛ’ where: X is Br; r is 0, 1.2 or 3; G1, R1a, R1b, R2-R5, R8, n and s are as defined in the general formula (IA). The compound of general formula (HA) is an intermediate for the preparation of the compound of general formula (II). Another aspect of the present invention provides a compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (IA). IHA) or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, x L (Rs). LRnonn / zznz / B / YiAi í ΙΙΙΛ j where: X is Br; r is 0, 1.2 or 3; G1, R1a, R1b, R2-R5, R8and s are as defined in the general formula (IA). The compound of general formula (IIIA) is an intermediate for the preparation of the compound of general formula (III) Another aspect of the present invention provides a compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (IA). 11laA) or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, xíRsK. O'o. - . .1ΛΛΠ j ITwhere:(IllaA X is Br; r is 0, 1.2 or 3; G1, R1a, R1b, R2-R5, R8and s are as defined in the general formula (IA). The compound of general formula (IllaA) is an intermediate for the preparation of the compound of general formula (Illa). Another aspect of the present invention provides a compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (IA). IIGA) or (IIGaA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, LRnonn / zznz / e / YiAi is a hydroxy protecting group, and is preferably Z is selected from the group consisting of one O atom, one S atom, NR7, and CR9R10; G1 is CR8o an N atom; R1a and R1b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R2 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of the hydrogen atom, alkyl and cycloalkyl, where the alkyl and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl , alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R6 is selected from the group consisting of hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, amino, nitro, halogen, carboxyl, carboxylate group, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, where alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R7 is selected from the group consisting of the hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, where the alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy , cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; LRnonn / zznz / e / YiAi R8 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl, where alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R9 and R10 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl; RUa and ri w are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl ; 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. Another aspect of the present invention provides a compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (IA). IIGA) or (IIGaA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, LRnonn / zznz / e / YiAi ; IIGA i í IIGiiA ) where: R1a and R1b are identical or different and each is independently selected from the group consisting of H atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl , heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q Rwes a hydroxy protecting group, and is preferably Z is selected from the group consisting of one O atom, one S atom, NR7, and CR9R10; G1 is CR8o an N atom; R2 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of the hydrogen atom, alkyl and cycloalkyl, where the alkyl and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl , alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R6 is selected from the group consisting of hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, amino, nitro, halogen, carboxyl, carboxylate group, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, where alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the ικηοηη / ζζηζ / Β / γίΛΐ group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R7 is selected from the group consisting of the hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, where the alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy , cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of the hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl, where alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R9 and R10 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl; R11ay are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl ; 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. Typical intermediate compounds described herein include, but are not LRnonn / zznz / e / YiAi limited to: Example Structure and Name of the Compound 1h Br 0 1h (5R,7R)-5-(4-bromophenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrah¡ dro- [1,3]dioxolo[4,5 -g]isoquinoline 1h 2b Br / A F^F <Χ0Ύ 2b (5S,7R)-5-(4-bromo-2,6-difluorophenyl)-7-methyl- 6-(2,2,2-trifluoroethyl)-5,6,7,8tetrahydro-[1,3 ]dioxolo[4,5-g]isoquinol¡ne 2b 6b Br or <°:CÓ^ 6b (5S,7R )-5-(5-bromopyridín-2-yl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8tetrahydro-[1 ,3]dioxolo [4,5-g]isoquinoline 6b 9b Br fJÓn O ' , F 9b (5S,7R)-5-(5-bromo-3-fluoropindin-2-yl)-7-methyl -6-(2,2,2-trifluoroethyl)- 5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 9b LRnonn / zznz / e / γΐΛΐ 3e i—\ / N^ / \ HN^ / ·. or tere-butyl (S)-3-((4-((5R,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2difluoropropyl) - 7-metH-5,6,7, 8-tetrahydro-[ 1,3]dioxolo[4,5-g]isoquinolin-5¡l)phenyl)amino)pyrrolidine-1 -carboxylate 3e 3f / NH HN*^^ .....' Ó (S) -N-(4-((5R,7R)-6-(3-((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-met ¡l5,6,7,8-tetrahydro -[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)pyrrolidin-3-amine 3f 3g F N— / . ' or (S)-N-(4-((5R,7R)-6-(3-((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-d¡fluoroprop¡l )-7-methyl5,6,7,8-tetrahydro -[1,3]dioxolo[4,5-g]¡soquinolin-5-¡l)phen¡l)-1 -(3fluoropropyl)pyrrole ¡d¡n-3-am¡na 3g 4c I—λ hn^^N^o i 0 <:χώ>¥< . or tere-butyl (S)-3-((6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2difluoropropyl)-7-metH-5,6, 7,8-tetrahydro-[ 1,3]dioxolo[4,5-g]isoquinolin-5¡l)pyridin-3-yl)amino)pyrrolidine-1-carboxylate 4c LRnonn / zznz / e / γΐΛΐ 4d Γ NH HN^^ Ψ O . or 6-((5S,7R)-6-(3-((tert-butyldiphen¡lsil¡l)oxy)-2,2-difluoroprop¡l)-7-methyl-5,6,7,8tetrahydro -[1,3]dioxolo [4,5-g]isoquinol¡n-5-yl)-N-((S)-pyrrolidin-3-¡l)piñdin-3amine 4d 4e IL f λ / =\ zx 0 0^,0 6-((5S,7R)-6-(3-((tert-butyldiphen¡lsilyl)ox¡)-2,2-difluoropropyl)-7-methyl -5,6,7,8tetrahydro-[1,3]dioxolo [4,5-g]isoquinolin-5-¡l)-N-((S)-1 -(3fluoropropyl)pyrrolidin-3-yl)pyridin- 3-amine 4e 5c 1—λ o—Z / N—7 \ f'x f Q or 5c tere-butyl (S)-3-((4-((5S,7R)-6-(3- ((tert-butyldiphenylsHyl)oxy)-2,2difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[ 1,3]dioxolo[4,5-g]isoquinolin-5-yl)3 , 5-difluorophenyl)amino)pyrrolidine-1 -carboxylate 5d Γ NH HN*^ / F 0 <οΌ0ΝΊΖ0Χ< ..... ¿ (S)-N-(4-((5S,7R)-6-(3 -((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4 ,5-g]isoquinolin-5-yl)-3,5difluorophenyl)pyrrolidin-3-amine LRnonn / zznz / e / γΐΛΐ 5e F N~y ΗΙ\Τ τ'F 0 <°χό^κ . or (S)-N-(4-((5S,7R)-6-(3-((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-d¡fluoroprop¡l) -7-met¡l5,6,7,8-tetrahydro -[1,3]dioxolo[4,5-g]¡soquinol¡n-5-¡l)-3,5-difluorophen¡l )-1 -(3fluoropropyl)pyrrolídin-3-amine 11c 1—λ o— / 1 N—Z \ .jS..... 11c tere-butyl (S)-3-((6 -((5S,7R)-6-(3-((tert-butyldiphenylsilyl)ox¡)-2,2difluoropropyl)-7-methyl-5,6,7,8-tetrahydro-[ 1,3]dioxolo[4 ,5-g]isoquinol¡n-5-¡l)5-fluorop¡ridin-3-yl)amino)pyrrolidine- 1 -carboxylate 11c 11d / NH Q °^· or 11d 6-((5S,7R)- 6-(3-((tert-butyld¡phenyls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-methyl-5,6,7,8tetrahydro-[1,3 ]dioxolo [4,5-g]isoquinolin-5-yl)-5-fluoro-N-((S)-pyrrolidin-3yl)pyrid¡n-3-am¡na 11d 11e i O? U kr-7 °v° 6-((5S,7R)-6-(3-((tert-butyld¡phenyls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7- methyl-5,6,7,8tetrahydro-[1,3]dioxolo [4,5-g]isoquinolin-5-¡l)-5-fluoro-N-((S)-1 -(3fluoropropyl )pyrrolidin-3-yl)pyridin-3-amine 11e LRnonn / zznz / e / γΐΛΐ 12b F Ψ Q DO . or 6-((5S,7R)-6-(3-((tert-but¡ld¡phenyls¡l¡l)ox¡)-2,2-difluoropropyl)-7-methyl¡l-5, 6,7,8tetrahydro-[1,3]dioxolo [4,5-g]isoquinol¡n-5-¡l-2,2-d2)-N-((S)-1 -(3fluoropropyl)pyrrole ¡d¡n-3-¡l)p¡r¡d¡n-3-am¡na 12b 13a hn^'7 Φ 0 DO^ or 13a 6-((5S,7R)-6-(3-( (tert-butyld¡phenyls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-methyl-5,6,7,8tetrahydro-[1,3]dioxolo [4,5 -g]isoquinol¡n-5-¡l-2,2-d2)-N-(1 -(3fluoropropyl)azet¡din-3-¡l)pyr¡d¡n-3-amine 13a 14a oA *£ 0 z CHO -X / \ 3-((6- ((5S, 7R)-6-(3-((tert-butyldiphenylsilyl)oxy) -2,2-difluoropropyl)-7-methyl5,6,7 ,8-tetrahydro) of tere-butyl -[1,3]dioxolo[4,5-g]isoquinolin-5-yl)pyridin3-¡l)amino)azetidine-1 -carboxylate 14a 14b V / o L A X / =- A i vM) °^° N-(azetidin-3-H)-6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2difluoropropyl) - 7-metH-5 ,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5yl)pyridin-3-amine 14b LRnonn / zznz / e / γΐΛΐ 14c HN^7 Y 0 <°WY°# 6-((5S,7R)-6-(3-((tert-butyld¡phenyls¡l¡l)ox¡)-2,2-d¡fluoroprop¡l )-7-methyl-5,6,7,8tetrahydro-[1,3]dioxolo [4,5-g]isoquinolin-5-¡l)-N-(1 -(3-fluoropropyl)azetid ¡n3-¡l)pyrid¡n-3-am¡na 14c 18a Br Ó <ύΛί^°η 18a 3-((5R,7R)-5-(4-bromophenyl)-7-methyl-7, 8-d¡hydro-[1,3]dioxolo[4,5g]isoquinol¡n-6(5H)-¡l)- 2,2-difluoropropan-1-ol 18a 19b F N— / HN^7 Λ YY γ O Dx / ° N z\ I. II j 1 s· 19b [^J] (S)-N-(4-((5R,7R)-6-(3-((tert-but¡ld¡ phenyls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-methyl5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g] ¡soquinolin-5-¡l-2,2-d2)phen¡l)-1 -(3fluoropropyl)pyrro¡din-3-amine 19b ©Ai í ib i i I i LRnonn / zznz / e / YiAi subject a compound of general formula (IA) and a compound of general formula (IB) to a coupling reaction to give the compound of general formula (I), where: X is Br; ring A, Z, G1, G2, G3, G4, R1a, R1b, R2-R6, p, n and s are as defined in the compound of general formula (I). Another aspect of the present invention provides a method for preparing the compound of general formula (II) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, comprising the following passed: subjecting a compound of general formula (HA) and a compound of general formula (IIB) to a coupling reaction to give the compound of general formula (II), where: X is Br; G1, Z, R1a, R1b, R2-R6, R8, r, q, t, n and s are as defined in the compound of general formula (II). Another aspect of the present invention provides a method for preparing the compound of general formula (III) or the tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, comprising the following passed: LRnonn / zznz / e / YiAi subjecting a compound of general formula (IIIA) and a compound of general formula (IIIB) to a coupling reaction to give the compound of general formula (III), where: X is Br; G1, R1a, R1b, R2-R8, r and s are as defined in the compound of general formula (III). Another aspect of the present invention provides a method for preparing the compound of general formula (Illa) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or its pharmaceutically acceptable salt, comprising the following step: i IllaA! (Illa i subject a compound of general formula (IllaA) and a compound of general formula (IIIB) to a coupling reaction to give the compound of general formula (Illa), where: X is Br; G1, R1a, R1b, R2-R8, r and s are as defined in the compound of general formula (Illa). Another aspect of the present invention provides a method for preparing the compound of general formula (IIG) or (IIGa) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, which includes the next step LRnonn / zznz / e / YiAi removing a hydroxy protecting group from a compound of general formula (IIGA) to give the compound of general formula (IIG), or removing a hydroxy protecting group from a compound of general formula (IIGaA) to give the compound of general formula (IIGa), where:;s / / \\ Rwes a hydroxy protecting group, and is preferably Z, G1, R1a, R1b, R2-R4, R6, R8, R11a, R11b, q, t, k, r, n and s are as defined in the compound of general formula (IIG). Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vehicles, diluents or excipients. The present invention also relates to a method for preparing the above pharmaceutical composition, which comprises mixing the compounds of various general formulas or the tautomers, mesomers, racemates, enantiomers or diastereomers thereof or their mixtures, or their pharmaceutically acceptable salts, with the pharmaceutically acceptable vehicles, diluents or excipients. Another aspect of the present invention relates to the use of the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition that It comprises the same in the preparation of an estrogen receptor modulator, preferably in the preparation of a selective estrogen receptor degrader (SERD). Another aspect of the present invention relates to the use of the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in preparing a medicament to prevent and / or treat cancer, wherein the cancer is preferably selected from the group consisting of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer , ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia, more preferably from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer, and most preferably breast cancer. Another aspect of the present invention relates to the use of the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in preparing a medicament to prevent and / or treat a disease or condition mediated or dependent on an estrogen receptor, wherein the disease or condition mediated or dependent on an estrogen receptor is preferably selected from the group consisting of cancer, central nervous system deficit, cardiovascular system deficit, blood system deficit, immune and inflammatory disease, susceptible infection, metabolic deficit, neurological deficit, psychiatric deficit and reproductive deficit; The cancer is preferably selected from the group consisting of breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, hemophilia and leukemia, more preferably from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer, and most preferably breast cancer; central nervous system (CNS) deficit may be alcoholism or migraine; deficit of the cardiovascular system may be aortic aneurysm, susceptibility to myocardial infarction, sclerosis of the aortic valve, cardiovascular disease, coronary artery disease or hypertension; the deficit of the blood system can be a deep vein thrombosis; the illness Immune and inflammatory LRnonn / zznz / e / YiAi may be Graves' disease, arthritis, multiple sclerosis, or liver cirrhosis; susceptibility to infections may be hepatitis B or chronic liver disease; metabolic deficit can be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia or osteoporosis; The neurological deficit may be Alzheimer's disease, Parkinson's disease, migraine or vertigo; psychiatric deficit may be anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder or psychosis; and the reproductive deficit can be age of menarche, endometriosis, infertility, etc. Another aspect of the present invention relates to a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective dose of the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof. or the mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising the same of the present invention. The method has a remarkable therapeutic effect and fewer side effects. The cancer is preferably selected from the group consisting of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia, more preferably from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer, and most preferably breast cancer. Another aspect of the present invention relates to a method of treating an estrogen receptor-dependent or mediated disease, comprising administering to a patient in need thereof a therapeutically effective dose of the compound of general formula (I) or the tautomer, mesomer , racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same of the present invention. The method has a remarkable therapeutic effect and fewer side effects. The estrogen receptor-mediated or dependent disease or condition is preferably selected from the group consisting of cancer, central nervous system deficit, cardiovascular system deficit, blood system deficit, immune and inflammatory disease, susceptible infection, metabolic deficit, neurological deficit , psychiatric deficit, and reproductive deficit. The cancer is preferably selected from the group consisting of breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, hemophilia and leukemia, more preferably from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer, and most preferably breast cancer; central nervous system (CNS) deficit may be alcoholism or migraine; deficit of the cardiovascular system may be aortic aneurysm, susceptibility to myocardial infarction, sclerosis of the aortic valve, cardiovascular disease, coronary artery disease or hypertension; the deficiency of the blood system can be a thrombosis LRnonn / zznz / e / YiAi deep vein; the immune and inflammatory disease may be Graves' disease, arthritis, multiple sclerosis, or liver cirrhosis; susceptibility to infections may be hepatitis B or chronic liver disease; metabolic deficit can be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia or osteoporosis; The neurological deficit may be Alzheimer's disease, Parkinson's disease, migraine or vertigo; psychiatric deficit may be anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder or psychosis; and the reproductive deficit can be age of menarche, endometriosis, infertility, etc. Another aspect of the present invention relates to the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof described herein, or the pharmaceutical composition comprising the same of the present invention for use as a medicine. Another aspect of the present invention relates to the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof described herein, or the pharmaceutical composition comprising the same of the present invention for use as a medicament for treating cancer, wherein the cancer can be selected from the group consisting of breast cancer, endometrial cancer, cervical cancer, skin cancer , prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia, more preferably from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer , and most preferably breast cancer. Another aspect of the present invention relates to the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same of the present invention for use as a medicament to treat an estrogen receptor-mediated or dependent disease or condition, wherein the estrogen receptor-mediated or dependent disease or condition is preferably selected from the group consisting of cancer, central nervous system deficit, cardiovascular system deficit, blood system deficit, immune and inflammatory disease, susceptible infection, metabolic deficit, neurological deficit, psychiatric deficit and reproductive deficit; The cancer is preferably selected from the group consisting of breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, hemophilia and leukemia, more preferably from the group consisting of breast cancer, ovarian cancer, LRnonn / zznz / e / YiAi endometrium, prostate cancer and uterine cancer, and most preferably breast cancer; central nervous system (CNS) deficit may be alcoholism or migraine; deficit of the cardiovascular system may be aortic aneurysm, susceptibility to myocardial infarction, sclerosis of the aortic valve, cardiovascular disease, coronary artery disease or hypertension; the deficit of the blood system can be a deep vein thrombosis; the immune and inflammatory disease may be Graves' disease, arthritis, multiple sclerosis, or liver cirrhosis; susceptibility to infections may be hepatitis B or chronic liver disease; metabolic deficit can be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia or osteoporosis; The neurological deficit may be Alzheimer's disease, Parkinson's disease, migraine or vertigo; psychiatric deficit may be anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder or psychosis; and the reproductive deficit can be age of menarche, endometosis, infertility, etc. The active compound may be formulated in a form suitable for administration by any suitable route, preferably in unit dose form, or in single dose form that may be self-administered by a patient. The unit dose of the compound or composition of the present invention may be in the form of a tablet, capsule, seal, vial, powder, granule, lozenge, suppository, regenerating powder or liquid formulation. The dosage of the compound or composition used in the treatment method of the present invention will generally vary with the severity of the disease, the weight of the patient and the relative effectiveness of the compound. However, as a general guide, an appropriate unit dose may be 0.1 to 1000 mg. The pharmaceutical composition of the present invention may comprise, in addition to the active compound, one or more auxiliary materials selected from the group consisting of filler (diluent), binder, wetting agent, disintegrant, excipient and the like. Depending on the method of administration, the compositions may comprise from 0.1 to 99% by weight of the active compound. The pharmaceutical composition comprising the active ingredient may be in a form suitable for oral administration, for example, in the form of a tablet, dragee, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard tablet or soft capsule, or syrup or elixir. The oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and may comprise one or more ingredients selected from the group consisting of sweetener, corrector, colorant and preservative, to provide a visually pleasing and pleasant taste. on the palate, pharmaceutical formulation. The tablet comprises the active ingredient and an excipient Non-toxic pharmaceutically acceptable LRnonn / zznz / e / YiAi used for mixing and suitable for tablet preparation. The aqueous suspension comprises an active substance and an excipient which is used for mixing and is suitable for the preparation of the aqueous suspension. The aqueous suspension may also comprise one or more preservatives, for example, ethylparaben or npropylparaben, one or more colorants, one or more correctors and one or more sweeteners. The oil suspension can be formulated by suspending the active ingredient in vegetable oil. The oil suspension may comprise a thickening agent. The sweeteners and correctors described above can be added to provide a palatable formulation. The dispersed powder and granules suitable for the preparation of an aqueous suspension may be allowed to provide the active ingredient and a dispersing or wetting agent, a suspending agent or one or more preservatives for mixing, by adding water. The above invention may be exemplified by suitable dispersants or wetting agents and suspending agents. Other excipients can also be added, such as sweeteners, correctors and colorants. Antioxidants such as ascorbic acid are added to preserve these compositions. The pharmaceutical composition described herein may also be in the form of an oil-in-water emulsion. The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Available and acceptable vehicles or solvents include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated in a mixture of water and glycerol to form a microemulsion. The injection or microemulsion can be injected locally into a patient's bloodstream in large quantities. Alternatively, it may be desirable to administer solutions and microemulsions such that a constant circulating concentration of the compound of the present invention is maintained. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is a Deltec CADD-PLUS. TM. 5400 intravenous injection pump. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to the prior art using the suitable dispersants or wetting agents and suspending agents described above. Sterile injectable formulation LRnonn / zznz / e / YiAi may also be a sterile injection or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. Additionally, a sterile fixed oil can conveniently be used as a solvent or suspending medium. The compound of the present invention can be administered in the form of a suppository for rectal administration. Such a pharmaceutical composition can be prepared by mixing a drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols. As well known to those skilled in the art, the dose of the drug administered depends on a variety of factors, including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health status of the patient , the patient's behavior, the patient's diet, the time of administration, the route of administration, the excretion rate, the combination of drugs and the like. Furthermore, the optimal treatment regimen, such as the mode of administration, the daily dose of the compound of general formula (I) or the type of pharmaceutically acceptable salts, can be verified according to conventional treatment regimens. Detailed description of the invention Unless otherwise indicated, the terms used in the specification and claims have the following meanings. The term alkyl refers to a saturated aliphatic hydrocarbon group that is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably to an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2- dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3methylbutyl, 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, 2,3dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2, 2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n -nonyl, 2- methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2 LRnonn / zznz / e / YiAi diethylhexyl and various side chain isomers thereof, etc. More preferably it is a lower alkyl having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, sec-butyl, n-pentyl , 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2methylpropyl, 1,1,2-trimethylpropyl, 1 ,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available connection site, and the substituent is preferably one or more of the following groups; is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo. The term alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl is a linear or branched 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) atoms. carbon, and more preferably 2 to 6 carbon atoms. The alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents independently selected from the group consisting of hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. The term alkynyl refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl is a linear or branched 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) atoms. carbon, and more preferably 2 to 6 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to -C^CH, -CH2C^CH, -CH2C^CCH3, -C^CCH2CH3, CH2CeCCH2CH3, -CeCCH(CH3)2, -O (OH3)2CeCH, - C(CH3)2CeCCH3and the like. The alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents preferably independently selected from the group consisting of hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. The term alkylene refers to a saturated linear or branched aliphatic hydrocarbon group having 2 residues derived from the parent alkane by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms, which LRnonn / zznz / e / YiAi is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkylene 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 alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene 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 may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available connection site with one or more substituents, preferably independently, optionally selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo. The term alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. The term cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. 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 include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, preferably cycloalkyl. Polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. The term spirocycloalkyl refers to a 5- to 20-membered polycyclic group in which the monocyclic rings share a carbon atom (called the spiro atom), in which the spirocycloalkyl may contain one or more double bonds. Spirocycloalkyl preferably has 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 and 10 members). Depending on the number of spiroatoms shared between the rings, the spirocycloalkyl can be monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and bispirocycloalkyl, more preferably 4 LRnonn / zznz / e / YiAi 4-membered / 4-membered, 4-membered / 5-membered / 6-membered monospirocycloalkyl, 4-membered / 5-membered or 5-membered / 6-membered. Non-limiting examples of spirocycloalkyl include: LRnonn / zznz / e / YiAi The term fused cycloalkyl refers to a 5- to 20-membered polycyclic carbon group in which each ring shares a pair of adjacent carbon atoms with the other rings in the system, in which one or more of the rings may contain one or more double carbon atoms, captivity. The fused cycloalkyl preferably has 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 and 10 members). According to the number of rings formed, the fused cycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic cycloalkyl, preferably bicyclic or tricyclic cycloalkyl, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered. members, 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 4 members, 5 members / 5 members, 5 members / 6-membered bicyclic cycloalkyl, 6 members / 3 members, 6 members / 4 members, 6 members / 5 members and 6 members / 6 members. Non-limiting examples of fused cycloalkyl include: The term bridged cycloalkyl refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two carbon atoms that are not directly connected to each other, in which the bridged cycloalkyl may contain one or more double bonds. The bridged cycloalkyl is preferably 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 and 10 members). Depending on the number of rings formed, the bridged cycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include: The cycloalkyl ring includes those in which the cycloalkyl described above (for example, monocyclic, fused, spiro and bridged cycloalkyl groups) is fused to an aryl, heteroaryl or heterocycloalkyl ring, in which the ring connected to the backbone is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like, preferably indanyl and tetrahydronaphthyl. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo. The term heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen , S, S(O) and S(O)2, excluding a cyclic portion of -0-0-, -O-S- or -S-S-, and the remaining ring atoms are carbon atoms. The heterocyclyl preferably contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2 , 3 and 4) are heteroatoms. Heterocyclyl preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms. Heterocyclyl preferably contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like, preferably tetrahydropyranyl, pipe ridinyl and pyrrolidinyl. Polycyclic heterocyclyl includes spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl. The term spiro heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (referred to as a spiro atom), in which one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, S, S(O) and S(O)2, and the remaining ring atoms are carbon atoms. Spiroheterocyclyl may contain one or more double bonds. Spiroheterocyclyl preferably has 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 and 10 members). Depending on the number of spiroatoms shared between the rings, the spiroheterocyclyl may be monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl and bispiroheterocyclyl, and more preferably 4-membered / 4-membered, 4-membered / 5-4-membered monospiroheterocyclyl. LRnonn / zznz / e / YiAi members / 6 members, 5 members / 5 members or 5 members / 6 members. Non-limiting examples of spiroheterocyclyl include: LRnonn / zznz / e / YiAi i— o— and l The term fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring shares a pair of adjacent atoms with the other rings in the system, in which one or more of the rings may contain one or more double bonds. . . In the fused heterocyclyl, one or more of the ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, S, S(O) and S(O)2, and the remaining ring atoms are carbon atoms. The fused heterocyclyl preferably has 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 and 10 members). According to the number of rings formed, the fused heterocyclyl may be bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, 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, 6-membered / 6-membered bicyclic fused 5-heterocyclyl, 6-membered / 3-membered , 6 members / 4 members, 6 members / 5 members and 6 members / 6 members. Non-limiting examples of fused heterocyclyl include The term bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected to each other, wherein the bridged heterocyclyl may contain one or more double bonds. In bridged heterocyclyl, one or more of the ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, S, S(O) and S(O)2, and the remaining ring atoms are carbon atoms. The bridged heterocyclyl preferably has 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 and 10 members). Depending on the number of rings formed, the bridged heterocyclyl may be bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl include: LRnonn / zznz / e / YiAi The heterocyclyl ring includes those in which the heterocyclyl described above (for example, monocyclic, fused, spiro and bridged heterocyclyl groups) is fused to an aryl, heteroaryl or cycloalkyl ring, in which the ring connected to the original structure is heterocyclyl. Non-limiting examples include: and the like. The heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo. The term aryl refers to a 6- to 20-membered, preferably 6- to 10-membered, and more preferably 6-membered, monocyclic or fused polycyclic group of carbon (i.e., rings sharing a pair of adjacent carbon atoms) that has a conjugated π electron system as phenyl and naphthyl. The aryl ring includes those in which the aryl described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, in which the ring connected to the backbone is an aryl ring. Non-limiting examples include: The aryl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio. The term heteroaryl refers to a heteroaromatic system containing 1 to 4 (e.g., 1,2, 3, and 4) heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl preferably has 5 to 10 members (for example, 5, 6, 7, 8, 9 and 10 members) and contains 1 to 3 heteroatoms. The heteroaryl is more preferably 5 or 6 membered and contains 1 to 3 heteroatoms. Non-limiting examples are pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyridinyl, thiadiazole, pyrazinyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, in which the ring connected to the original structure is heteroaryl. Non-limiting examples include: The heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents preferably independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio. The cycloalkyl, heterocyclyl, aryl and heteroaryl described above have 1 residue derived from the main ring by removing a hydrogen atom from a ring atom, or 2 residues derived from the main ring by removing two hydrogen atoms from the same ring atom. ring or two different ring atoms. The term alkylthio refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio and cyclohexylthio. The alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups; is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio. The term cycloalkyloxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above. The term haloalkyl refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. The term deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above. The term haloalkoxy refers to an alkoxy group substituted with a halogen, wherein the alkoxy group is as defined above. The term hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above. The term halohydroxyalkyl refers to a hydroxyalkyl group substituted with one or more halogens, wherein the hydroxyalkyl group is as defined above. The term hydroxy refers to the -OH group. The term halogen refers to fluorine, chlorine, bromine or iodine. The term amino refers to -NH2. The term cyano refers to -CN. The term nitro refers to -NO2. The term aldehyde refers to -C(O)H. The term carboxyl refers to -C(O)OH. The term aldehyde refers to -C(O)H. LRnonn / zznz / e / YiAi The term carboxylate refers to -C(O)O(alkyl) or -C(0)0(cycloalkyl), where alkyl and cycloalkyl are as defined above. The term hydroxy protecting group is a suitable group known in the art to protect hydroxy. See hydroxy protective groups in the literature ( Protective Groups in Organic Synthesis, 5th Ed. T.W.Greene & P.G.M.Wuts). As an example, preferably, the hydroxy protecting group may be (C1-10O alkyl aryl)3silyl such as triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; or perhaps C1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C1-6 alkyl substituted with C1-6 alkoxy or C1-6 alkyl substituted with phenyl, and more preferably C1-4 substituted with C1-alkoxy 4 alkyl such as methyl, tere-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP) and the like; or it may be (C1-10O alkyl aryl)acyl such as formyl, acetyl, benzoyl and the like; or it may be (C1-6O alkyl Ce-wjsulfonyl; or it may also be (C1-6 alkoxy or Ce-ium aryloxy) carbonyl. The term optionally or optionally means that the event or circumstance described below may occur, but not necessarily. The invention includes instances where the event or circumstance occurs or does not occur. For example, a heterocyclyl group optionally substituted with alkyl means that the alkyl may be present, but not necessarily, and that the invention includes cases where the heterocyclyl group is substituted or not with alkyl. Substituted means that one or more, preferably up to 5, more preferably 13 hydrogen atoms in the group are independently substituted with a corresponding number of substituents, where each of the substituents has an independent choice (i.e., the substituents may be identical or different). It goes without saying that a substituent is only in its possible chemical position, and those skilled in the art will be able to determine (experimentally or theoretically) the possible or impossible substitution without undue efforts. For example, it may be unstable when an amino or hydroxy group that has a free hydrogen is attached to a carbon atom that has an unsaturated (e.g., olefinic) bond. The term pharmaceutical composition refers to a mixture containing one or more of the compounds described herein or one of their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components and other components, e.g. physiologically / pharmaceutically acceptable vehicles and excipients. The purpose of the pharmaceutical composition is to promote delivery to an organism, which facilitates the absorption of the active ingredient, thereby exerting biological activities. LRnonn / zznz / e / YiAi The term pharmaceutically acceptable salt refers to salts of the described compounds that are safe and effective for use in the body of a mammal and possess the required biological activities. The compounds described herein include isotopic derivatives thereof. The term isotopic derivative refers to compounds that differ in structure only by having one or more isotopic enriched atoms. For example, compounds having the structure described herein have deuterium or tritium instead of hydrogen, or labeled with 18F fluorine (18F isotope) instead of fluorine, or carbon enriched with 11C, 13C or 14C (11C-, labeled with 13C or 14C carbon ; isotope11C,13C or14C) instead of a carbon atom are within the scope of the present invention. Such a compound can be used as an analytical tool or probe, for example, in a biological assay, or can be used as a marker for imaging of diseases in vivo, or as a marker in a pharmacodynamic, pharmacokinetic or receptor study. Various deuterated forms of the compound of general formula (I) of the present invention are those in which each of the available hydrogen atoms connected to the carbon atoms can be independently replaced by a deuterium atom. Unless otherwise noted, when a position is specifically designated for D or deuterium, that position is interpreted as deuterium having an abundance 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 compound of general formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated forms of the compound of general formula (I), or can be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, hydride of lithium and deuterated aluminum, deuterated iodoethane, deuterated iodomethane and the like. For drugs and active pharmacological agents, the term therapeutically effective amount refers to an amount of a drug or agent that is sufficient to provide the desired effect but that is not toxic. Determining the effective amount varies from person to person. It depends on the age and general condition of the subject, as well as the particular active ingredient used. The appropriate effective amount in a case can be determined by those skilled in the art in light of routine testing. Synthesis of the Compounds of the Present Invention. To achieve the purpose of the present invention, the following technical schemes are adopted in the present invention: LRnonn / zznz / e / YiAi Scheme 1 A method is provided for preparing the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture of the LRnonn / zznz / e / YiAi itself, or the pharmaceutically acceptable salt thereof of the present invention, comprising the following step subjecting a compound of general formula (IA) and a compound of general formula (IB) to a coupling reaction under alkaline conditions in the presence of a catalyst to give the compound of general formula (I), where: X is Br; ring A, Z, G1, G2, G3, G4, R1a, R1b, R2-R6, p, n and s are as defined in general formula (I). Scheme 2 A method is provided for preparing the compound of general formula (II) or the tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof of the present invention, comprising the following step : í HA) (IIB; subjecting a compound of general formula (HA) and a compound of general formula (11B) to a coupling reaction under alkaline conditions in the presence of a catalyst to give the compound of general formula (II), where: X is Br; G1, Z, R1a, R1b, R2-R6, R8, r, q, t, n and s are as defined in general formula (II). LRnonn / zznz / e / YiAi Scheme 3 A method is provided for preparing the compound of general formula (III) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof of the present invention, comprising the following step : R1R(HIA i i HIB i (e subjecting a compound of general formula (HIA) and a compound of general formula (HIB) to a coupling reaction under alkaline conditions in the presence of a catalyst to give the compound of general formula (III), where: X is Br; G1, R1a, R1b, R2-R8, r and s are as defined in general formula (III). Scheme 4 A method is provided for preparing the compound of general formula (Illa) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof of the present invention, comprising the following step : ί ΙΙΙΒ ! ί Illa) LRnonn / zznz / e / YiAi subject a compound of general formula (HlaA) and a compound of general formula (HIB) to a coupling reaction under alkaline conditions in the presence of a catalyst to give the compound of general formula (Illa), where : X is Br; G1, R1a, R1b, R2-R8, r and s are as defined in the general formula (Illa). Scheme 5 A method is provided for preparing the compound of general formula (IIG) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof of the present invention, comprising the following step : HGA । iig ; remove a hydroxy protecting group from a compound of general formula (HGA) in the presence of a phase transfer catalyst (preferably tetrabutylammonium fluoride) to give the compound of general formula (IIG), where: Rwes a hydroxy protecting group, and is preferably '\_ / Z, G1, R1a, R1b, R2-R4, R6, R8, R11a, R11b, q, t, k, r, n and s are as defined in the general formula (IIG). LRnonn / zznz / e / YiAi Scheme 6 A method is provided for preparing the compound of general formula (IIGa) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof of the present invention, comprising the following step R-D? z Z ;R r X iR;h, (IIGaA i (HCJa i remove a hydroxy protecting group from a compound of general formula (IIGaA) in the presence of a phase transfer reagent (preferably tetrabutylammonium fluoride) to give the compound of general formula (IIGa), where Rwes a hydroxy protecting group, and is preferably Z, G1, Rla, Rlh, R2-R4, R6, R8, Rlla, Rllb, q, t, k, r, n and s are as defined in the general formula (IIGa). Reagents that provide alkaline conditions in synthesis schemes 1-4 described above include organic bases including, but not limited to, triethylamine, N,Ndiisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, ether, butoxide and potassium tert-butoxide; and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; and are preferably sodium tert-butoxide. Catalysts in the above synthesis schemes 1-4 described above include, but are not limited to, tetraks(triphenylphosphine)palladium(0), palladium dichloride, palladium acetate, bis(dibenzyldenacetone )palladium, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1-biphenyl)[2-(2'-amino-1,1'-biphenyl) dichloride )]palladium, [1,1'-bis(dibenzylphosphino)ferrocene]palladium(ll), [1,1'-bis(dibenzylphosphino)ferrocene]palladium dichloride or tris( d!benzyl!denacetone)d!palladium(0); Phase transfer reagents in synthesis schemes 5 and 6 described above include, but are not limited to, benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide, tetrabutylammonium chloride, n-tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate (TBAB) , trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride, and are preferably n-tetrabutylammonium fluoride; The above reactions are preferably carried out in solvents including, but 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 Ν,Ν-dimethylformamide, and mixtures thereof. Detailed description of the invention The following examples further illustrate the present invention, but the present invention is not limited thereto. Examples The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectrometry (MS). NMR changes (5) are given in units of 106(ppm). NMR spectra were measured using a Bruker AVANCE-400 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-ds), deuterated chloroform (CDCI3), and deuterated methanol (CD3OD) as determination solvents, with tetramethylsilane (TMS) as a standard. internal. Mass spectra were measured using the Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography mass spectrometry system (manufacturer: Agilent; MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity LJPLC-QD / SQD (manufacturer: Waters; MS model: Waters ACQuity Qda Detector / waters SQ Detector) and THERMO Ultímate 3000-Q Exactive (manufacturer: THERMO; MS model: THERMO Q Exactive). High-performance liquid chromatography (HPLC) was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e26952489 high-pressure liquid chromatography. LRnonn / zznz / e / YiAi Chiral HPLC was performed on Agilent 1260 DAD HPLC. HPLC preparation was performed using Waters 25452767, Waters 2767-SQ Detector, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs. Chiral preparation was performed on a Shimadzu LC-20AP preparative chromatograph. A CombiFlash R1200 system (TELEDYNE ISCO) was used for rapid preparation. Huanghai HSGF254 or Qingdao GF254 silica gel plates with specifications of 0.15 mm to 0.2 mm were adopted for thin layer chromatography (TLC) analysis and 0.4 mm to 0.5 mm for TLC separation and purification. Silica gel column chromatography generally used 200 to 300 mesh silica gel (Huanghai, Yantai) as the carrier. Mean kinase inhibition rates and IC50 values ​​were measured using a NovoStar microplate reader (BMG, Germany). The known starting materials described herein can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Chembee Chemicals and other companies. In the examples, the reactions can be performed in an argon atmosphere or a nitrogen atmosphere unless otherwise specified. Argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon containing approximately 1 L of argon or nitrogen. A hydrogen atmosphere means that the reaction flask is connected to a balloon containing approximately 1 L of hydrogen. The Parr 3916EKX hydrogenator, the Qinglan QL-500 hydrogenator, or the HC2-SS hydrogenator were used in the pressurized hydrogenation reactions. Hydrogenation reactions typically involve 3 cycles of vacuum and hydrogen purge. A CEM Discover-S 908860 microwave reactor was used in the microwave reactions. In the examples, a solution refers to an aqueous solution unless otherwise specified. LRnonn / zznz / e / YiAi In the examples, the reaction temperature was room temperature, i.e., 20°C to 30°C, unless otherwise specified. Monitoring the reaction progress in the examples was done by thin layer chromatography (TLC). The developing solvent for the reactions, the 5-eluent system for purification by column chromatography, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane system / ethyl acetate and C: petroleum ether / ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compound, or by adding a small amount of basic or acidic reagents such as tnethylamine and acetic acid. LRnonn / zznz / e / YiAi 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]¡soquinolin-5-¡l)phen¡l)pyrrolídin¡n-3-amine 1 Step 1 (S)-(1-(3-fluoropropyl)pyrrolidin-3-¡l)tere-butylcarbamate 1b Tere-butyl (S)-pyrrolidin-3-ylcarbamate 1a (1.86 g, 10 mmol, Accela) was dissolved in Ν,Ν-dimethylformamide (20 ml) and diisopropylethylamine (1.55 g, 12 mmol) was added. followed by dropwise addition of 1-fluoro-3-iodopropane (207 mg, 11 mmol). The reaction mixture was stirred for 12 h. Water (50 ml) was added, followed by extraction with ethyl acetate (50 ml x 3) and washing with water (50 ml x 2) and saturated sodium chloride solution (50 ml). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 1b (1.92 g, 78% yield). Step 2 (S)-1-(3-fluoropropyl)pyrrolydin-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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (25 ml) was added, followed by extraction with ethyl acetate (15 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 1c (702 mg, 96% yield). Step 3 (R)-1-(3,4-b¡s(benzyloxy¡)phen¡l)-N-(2,2,2-tñfluoroethyl)propan-2-amine 1e (R)-1-(3,4-bis(benzylox¡)phenyl)propan-2-amine 1d (7.0 g, 20.1 mmol, prepared by the method known in European Journal of Medicinal Chemistry, 2014, 67(23), 35-36) in dioxane (100 ml) and diisopropylethylamine (7.8 g, 60.4 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.4 g, 40.3 mmol, prepared as described in Example 59 on page 69 of the specification of Patent Application US20140249162). The reaction mixture was stirred in an oil bath at 80°C under an argon atmosphere for 20 h. The reaction mixture was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate solution (50 ml) was added, followed by extraction with ethyl acetate (100 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by LRnonn / zznz / e / YiAi column chromatography with developing solvent system B to give the title compound 1e (7.6 g, 88% yield). EM m / z (ESI): 430.3 [M+1], Step 4 (R)-4-(2-((2,2,2-trifluoroethyl)amino)propyl)-1,2-benzenediol 1f Compound 1e (3.3 g, 7.7 mmol) was dissolved in methanol (10 ml) and palladium hydroxide on carbon (0.5 g, 3.8 mmol) was added in an argon atmosphere. The reaction mixture was stirred under a hydrogen balloon for 3 h and filtered. The filtrate was concentrated under reduced pressure to give the title compound 1 f (1.8 g, 96% yield). Step 5 (1 R,3R)-1 -(4-bromophenyl)-3-methyl-2-(2,2,2-tresfluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6 ,7-d¡ol 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-bromo-benzaldehyde (4.4 g, 23.8 mmol) were added. The reaction mixture was stirred in an oil bath at 80 °C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (100 mL) was added and the aqueous phase was adjusted to approximately pH 8 by adding saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 1g (3.5 g, 70% yield). EM m / z (ESI): 416.0 [M+1], Step 6 (5R,7R)-5-(4-bromophenyl)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1 ,3]dioxolo[4.5 gjisoquinoline 1h Compound 1g (3.5 g, 8.4 mmol) was dissolved in Ν,Ν-dimethylformamide (100 ml) and dibromomethane (1.9 g, 10.9 mmol) and cesium carbonate (3.6 g, 11.0 mmol) were added. The reaction mixture was stirred in an oil bath at 70°C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (100 ml) was added, followed by extraction with ethyl acetate (100 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 1h (2.4 g, 67% yield). LRnonn / zznz / e / YiAi 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-l)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-di¡cyclohex¡lphosphine-2',6'- b¡s(N,N-dimethylamino)-1, 1'-biphenyl (3 mg, 0.007 mmol), tris(dibenzyldenacetone)dipalladium(0) (20 mg) were added , 0.02 mmol) and sodium tert-butoxide (471 mg, 4.9 mmol). The reaction mixture was stirred in an oil bath at 105 °C under an argon atmosphere for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Saturated sodium bicarbonate solution (20 ml) was added, followed by extraction with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 1 (449 mg, 65% yield). EM 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). Example 2 (S)-N-(3,5-difluoro-4-((5S,7R)-7-methyl-6-(2,2,2-tñfluoroethyl)-5,6,7, 8-tetrahydro-[1,3]dioxolo[4,5g]isoquinolin-5-yl)phenyl)-1 -(3-fluoropropyl)pyrrolídin-3-amine 2 Step 1 (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-tresfluoroethyl)-1,2,3,4tetrahydroisoquinoline-6, 7- diol 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 reaction mixture was stirred in an oil bath at 80 °C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (10 ml) was added and the aqueous phase was adjusted to approximately pH 8 by adding saturated sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 2a (390 mg, 72% yield). EM m / z (ESI): 451.9 [M+1]. Step 2 (5S,7R)-5-(4-bromo-2,6-difluorophen¡l)-7-methyl-6-(2,2,2-tñfluoroethyl)-5,6, 7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 2b Compound 2a (130 mg, 0.3 mmol) was dissolved in Ν,Ν-dimethylformamide (10 ml) and dibromomethane (60 mg, 0.3 mmol) and cesium carbonate (121 mg, 0.4 mmol) were added. The reaction mixture was stirred in an oil bath at 70°C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Water (10 ml) was added, followed by extraction with ethyl acetate (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 2b (85 mg, 61% yield). EM m / z (ESI): 464.0 [M+1]. 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[4,5g]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-dicyclohexylphosphine-2',6'-bis(N,N-dimethyl). lamino)-1, 1'-biphenyl (2 mg, 0.005 mmol), trls(dibenzylidenacetone)dipalladium(0) (2 mg, 0.002 mmol) and sodium tert-butoxide (43 mg, 0.5 mmol). The reaction mixture was stirred in an oil bath at 105°C under an argon atmosphere for 16 hours and the reaction was terminated. The reaction mixture was cooled LRnonn / zznz / e / YiAi and concentrated under reduced pressure. Saturated sodium bicarbonate solution (20 ml) was added, followed by extraction with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give title compound 2 (449 mg, 58% yield). EM 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), 3.133.02 (m, 2H), 2.86-2.42 (m, 9H), 1.87-1.63 (m, 3H), 0.92 (d, 3H). Example 3 2,2-difluoro-3-((5R,7R)-5-(4-(((S)-1 -(3-fluoropropyl)pyrrolidin-3-¡l)amino)phenyl) -7-methyl-7, 8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1 -ol 3. LRnonn / zznz / e / YiAi H.N. F Step 1 (R)-N-(1-(3,4-b¡s(benzyloxy¡)phen¡l)piOpan-2-yl)-3-((tert-but¡ld¡phen¡ls¡ l¡l)ox¡)-2,2difluoropropan-1-amine 3a Compound 1d (1.0 g, 3.0 mmol) was dissolved in dioxane (20 ml) and diisopropylethylamine (1.2 g, 9.0 mmol) and 3-((tert-butyld¡phen¡ls¡l¡l)ox¡ )-2,2-difluoropropyltrifluoromethanesulfonate (1.0 g, 2.0 mmol, prepared using the well-known method in Bioorganic & Medicinal Chemistry Letters, 2018, 28(14), 2528-2532). The reaction mixture was stirred in an oil bath at 80 °C under an argon atmosphere for 20 h. The reaction mixture was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate solution (50 ml) was added, followed by extraction with ethyl acetate (100 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 3a (1.7 g, 84% yield). EM m / z (ESI): 680.2 [M+1]. Step 2 (R)-4-(2-((3-((tert-but¡ld¡phenylsil¡l)oxy)-2,2-difluoroprop¡l)amino)propyl)benzene- 1,2-diol 3b Compound 3a (1.4 g, 2.0 mmol) was dissolved in methanol (10 ml) and palladium hydroxide on carbon (0.2 g) was added in an argon atmosphere. The reaction mixture was stirred under a hydrogen balloon for 3 h and filtered. The filtrate was concentrated under reduced pressure to give the title compound 3b (0.9 g, 94% yield). Step 3 (1 R,3R)-1 -(4-bromophenyl)-2-(3-((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-difluoroprop¡l)-3 -methyl-1,2,3,4tetrahydroisoquinoline-6,7-diol 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-bromo-benzaldehyde (0.6 g, 3.2 mmol) were added. The reaction mixture was stirred in an oil bath at 80°C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (10 ml) was added and the reaction mixture was adjusted to approximately pH 8 by slowly adding saturated sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 3c (0.6 g, 56% yield). EM m / z (ESI): 666.1 [M+1], LRnonn / zznz / e / YiAi Step 4 (5R,7R)-5-(4-bromophen¡l)-6-(3-((tert-but¡ld¡phen¡ls¡l¡l)ox¡)-2,2-d¡fluoropropyl )-7-methyl-5,6,7,8tetrahydro-[ 1,3]dioxolo[4,5-g]isoquinoline 3d Compound 3c (0.2 g, 0.3 mmol) was dissolved in Ν,Ν-dimethylformamide (10 ml) and dibromomethane (0.07 g, 0.4 mmol) and cesium carbonate (0.1 g, 0.4 mmol) were added. The reaction mixture was stirred in an oil bath at 70°C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (10 ml) was added, followed by extraction with ethyl acetate (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 3d (0.1 g, 47% yield). Step 5 tere-butyl (S)-3-((4-((5R,7R)-6-(3-((tert-butyldiphen¡ls¡l¡l)oxy)-2,2-d¡ fluoroprop¡l)-7-methyl-5,6,7,8tetrahydro-[1,3]dioxolo[4,5-g]¡soquinol¡n-5-¡l)phenyl)amino)p¡ rrolidin-1-carboxylate 3e Compound 3d (60 mg, 0.09 mmol) was dissolved in dioxane (10 ml) and tere-butyl (S)-3aminopyrrolidine-1-carboxylate (19 mg, 0.1 mmol), 2,2'-bis-(d¡ Phenylphosphine )-1,1'-binaphthyl (12 mg, 0.02 mmol), tris(dibenzyl acetone)dipalladium(0) (20 mg, 0.02 mmol) were added. and sodium tert-butoxide (29 mg, 0.3 mmol). The reaction mixture was stirred in an oil bath at 80°C under an argon atmosphere for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 3e (39 mg, 55% yield). EM m / z (ESI): 784.3 [M+1]. Step 6 (S)-N-(4-((5R,7R)-6-(3-((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-d¡fluoroprop¡l )-7-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)pyrrolydin-3- am¡na 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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (5 ml) was added, followed by extraction with ethyl acetate (5 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (5 ml), dried over sodium sulfate LRnonn / zznz / e / YiAi anhydrous and filtered. The filtrate was concentrated under reduced pressure to give the title compound 3f (32 mg, 93% yield). Step 7 (S)-N-(4-((5R,7R)-6-(3-((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-d¡fluoroprop¡l )-7-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]¡soquinolin-5-yl)phen¡l)-1 -(3-fluoropropyl )pyrrolidin-3-amine 3g Compound 3f (32 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (5 ml) and diisopropylethylamine (4 mg, 0.05 mmol) was added, followed by dropwise addition of 1-fluoro-3-iodopropane ( 10 mg, 0.05 mmol). The reaction mixture was stirred for 12 h. Water (5 ml) was added, followed by extraction with ethyl acetate (5 ml x 3). The organic phases were combined, washed with water (5 mL x 2) and saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 3g (22 mg, 73% yield). Step 8 2,2-difluoro-3-((5R,7R)-5-(4-(((S)-1 -(3-fluoropropyl)pyrrolidin-3-íl)amino) pheníl)-7-methyl-7, 8-dihydro[1,3]dioxolo[4,5-g]isoquinolín-6(5H)-íl)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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (5 ml) was added, followed by extraction with ethyl acetate (5 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (5 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 3 (5 mg, 33% yield). EM m / z (ESI): 506.3 [M+1]. Ή 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, 1 H), 4.34-4.31 (m, 1 H), 3.96-3.93 (m, 1 H), 3.72-3.69 (m, 1 H), 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). Example 4 2,2-difluoro-3-((5S,7R)-5-(5-(((S)-1 -(3-fluoroprop¡l)pyrro¡din-3-¡l)amino) p¡r¡din-2-¡l)-7- methyl-7,8dihydro-[1,3]dioxolo[4,5-g]isoquinolín-6(5H)-yl)propan- 1 -ol 4 LRnonn / zznz / e / YiAi LRnonn / zznz / e / YiAi Step 1 (1S ,3R)-1 -(5-bromopyridin-2-yl)-2-(3-((tert-butyldiphenylsi lil)oxy)-2,2-difluoropropyl)-3-methyl-1, 2,3,4 tetrahydroisoquinoline-6,7-diol 4a Title compound 4a (256 mg, 75% yield) was obtained following the synthesis scheme of Example 3 with the starting material 4-bromo-benzaldehyde in step 3 replaced by 5-bromopyridylaldehyde. MS m / z(ESI): 667.1 [M+1], Step 2 (5S,7R)-5-(5-bromopyr¡din-2-¡l)-6-(3-((tert-but¡ld¡phenyls¡l¡l)ox¡)- 2,2-difluoropropyl)-7-methyl-5,6,7,8 tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 4b Title compound 4b (163 mg, 65% yield) was obtained following the synthesis scheme of Example 3 with compound 3c in step 4 replaced by compound 4a. Step 3 tere-butyl (S)-3-((6-((5S,7R)-6-(3-((tert-butyl¡ld¡phen¡ls¡lyl)ox¡)-2,2-d ¡fluoroprop¡l)-7-methyl¡l-5,6,7,8tetrahydro-[1,3]dioxolo[4,5-g]¡soquinol¡n-5-yl)pyrid¡ n-3-l)amino)pyrrolidin-1-carboxylate 4c Title compound 4c (40 mg, 68% yield) was obtained following the synthesis scheme of Example 3 with compound 3d in step 5 replaced by compound 4b. MS m / z(ESI): 785.3 [M+1]. 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]isoquinol¡n-5-yl)-N-((S)-pyrrolídin-3-¡l)pyridin-3-amine 4d Title compound 4d (30 mg, 95% yield) was obtained following the synthesis scheme of Example 3 with compound 3e in step 6 replaced by compound 4c. Step 5 6-((5S,7R)-6-(3-((tert-butyldiphen¡ls¡l¡l)ox¡)-2,2-difluoropropyl)-7-methyl-5,6,7 ,8-tetrahydro-[1,3]dioxolo[4,5-g]¡soquinol¡n-5-¡l)-N-((S)-1-(3-fluoroprop¡l)pyrrole ¡din-3-¡l)pir¡d¡n-3-am¡na 4e Title compound 4e (25 mg, 75% yield) was obtained following the synthesis scheme of Example 3 with compound 3f in step 7 replaced by compound 4d. Step 6 2,2-difluoro-3-((5S,7R)-5-(5-(((S)-1 -(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridín-2-yl )-7-methyl-7,8dihydro-[1,3]dioxolo[4,5-g]isoquinolín-6(5H)-yl)propan-1 -ol 4 Title compound 4 (5 mg, 29% yield) was obtained following the synthesis scheme of Example 3 with compound 3g in step 8 replaced by compound 4e. 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, 1 H), 4.58-4.55 (m, 1 H), 4.44-4.43 (m, 1 H), 3.74-3.71 (m, 1 H), 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). Example 5 LRnonn / zznz / e / YiAi 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1 -(3-fluoroprop¡l)pyrrolídin-3-¡l)amino) phen¡l)-7-methyl¡l-7, 8-dihydro[1,3]dioxolo[4,5-g]¡soquinolin-6(5H)-¡l)-2,2-difluoropropan-1 -ol 5 LRnonn / zznz / e / YiAi Step 1 (1 S,3R)-1 -(4-bromo-2,6-difluorophen¡l)-2-(3-((tert-but¡ld¡phen¡ls¡l¡l)ox¡ )-2,2-difluoropropyl)-3-methyl1,2,3,4-tetrahydro¡soquinoline-6,7-diol 5a Title compound 5a (3.0 g, 47% yield) was obtained following the synthesis scheme of Example 3 with the starting material 4-bromo-benzaldehyde in step 3 replaced by 4-bromo-2,6- difluorobenzaldehyde. MS m / z(ESI): 702.0 [M+1]. Step 2 (5S,7R)-5-(4-bromo-2,6-difluorophen¡l)-6-(3-((tert-but¡ld¡phen¡ls¡l)ox¡) -2,2-difluoropropyl)-7-methyl5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 5b Title compound 5b (1.6 g, 55% yield) was obtained following the synthesis scheme of Example 3 with compound 3c in step 4 replaced by compound 5a. LRnonn / zznz / e / YiAi Step 3 tere-butyl (S)-3-((4-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl) -7-met¡l-5,6,7,8tetrahydro-[1,3]dioxolo[4,5-g]¡soquinolin-5-yl)-3,5-difluorophen¡l) amino)pyrrolidin-1-carboxylate 5c Title compound 5c (1.5 g, 65% yield) was obtained following the synthesis scheme of Example 3 with compound 3d in step 5 replaced by compound 5b. EM m / z(ESI): 820.3 [M+1], Step 4 (S)-N-(4-((5S,7R)-6-(3-((tert-but¡ld¡phen¡ls¡l¡l)ox¡)-2,2-d¡fluoropropyl )-7-methyl-5,6,7,8-tetrahydro 5d Title compound 5d (1.3 g, 99% yield) was obtained following the synthesis scheme of Example 3 with compound 3e in step 6 replaced by compound 5c. Step 5 (S)-N-(4-((5S,7R)-6-(3-((tert-but¡ld¡phenyls¡l¡l)ox¡)-2,2-d¡fluoroprop¡l )-7-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]soquinolin-5-yl)-3,5-di fluorophen¡l)-1-(3-fluoroprop¡l)pyrrolídin-3-amine 5e Title compound 5e (1.2 g, 92% yield) was obtained following the synthesis scheme of Example 3 with compound 3f in step 7 replaced by compound 5d. Step 6 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1 -(3-fluoropropyl)pyrrolídin-3-yl)amino)phenyl)-7- methyl-7, 8-dihydro [1,3]dioxolo[4,5-g]¡soquinolin-6(5H)-¡l)-2,2-difluoro-1 -propanol 5 Title compound 5 (300 mg, 36% yield) was obtained following the synthesis scheme of Example 3 with compound 3g in step 8 replaced by compound 5e. EM m / z (ESI): 542.2 [M+1], Ή 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), 1.401.31 (m, 1H), 1.06 (d, 3H). 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]¡soquinol¡n-5-yl)pyr¡din-3-am¡na 6 LRnonn / zznz / e / YiAi H.N. 1'”.L Step 1 (1S,3R)-1-(5-bromopyridín-2-yl)-3-methyl-2-(2,2,2-tresfluoroethyl)-1,2,3, 4-tetrahydroisoquinoline-6,7diol 6a Title compound 6a (600 mg, 60% yield) was obtained following the synthesis scheme of Example 2 with the starting material 4-bromo-2,6-difluorobenzaldehyde in step 1 replaced by 5-bromopyridylaldehyde. EM m / z(ESI): 417.0 [M+1], Step 2 (5S,7R)-5-(5-bromopyridin-2-¡l)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8 -tetrahydro-[1,3]dioxolo [4.5g]isoquinoline 6b Title compound 6b (450 mg, 73% yield) was obtained following the synthesis scheme of Example 2 with compound 2a in step 2 replaced by compound 6a. EM m / z(ESI):431.0 [M+1], Step 3 N-((S)-1-(3-fluoropropyl)pyrrolídin-3-¡l)-6-((5S,7R)-7-methyl-6-(2,2,2- trifluoroethyl)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]¡soquinolin-5-¡l)pyrdin-3-am 6 Title compound 6 (200 mg, 44% yield) was obtained following the synthesis scheme of Example 2 with compound 2b in step 2 replaced by compound 6b. MS m / z(ESI):495.2 [M+1],1H 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), 3.473.31 (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), 1.881.74 (m , 1H), 1.08 (d, 3H). LRnonn / zznz / e / YiAi 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[4.5g]isoquinolin-5-yl)-3,5-difluorophenyl)-1 -(3-fluoropropyl)pyrrole d¡n-3-am¡na 7 Example 8 6-((5S,7R)-2,2-difluoro-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,3] dioxolo[4, 5g]isoquinol¡n-5-¡l)-N-((S)-1 -(3-fluoropropyl)pyrrolídin-3-yl)pyridin-3-amine 8 Example 9 5-Fluoro-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-íl)-6-((5S,7R)-7-methyl-6-( 2,2,2-trifluoroethyl)- 5,6,7,8tetrahydro-[1,3]dioxolo[4,5-g]isoquinol¡n-5-¡l)pyridín -3-amine 9 LRnonn / zznz / e / YiAi Step 1 (1 S,3R)-1 -(5-bromo-3-fluoropyrídin-2-¡l)-3-methyl-2-(2,2,2-trifluoroethyl)-1, 2,3,4tetrahydroisoquinoline-6, 7-diol 9a Title compound 9a (115 mg, 55% yield) was obtained following the synthesis scheme of Example 2 with the starting material 4-bromo-2,6-difluorobenzaldehyde in step 1 replaced by 5-bromo-3- fluoropyridyl-2-aldehyde. Step 2 (5S,7R)-5-(5-bromo-3-fluorop¡r¡din-2-¡l)-7-methyl-6-(2,2,2-tnfluoroethyl) -5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 9b Title compound 9b (58 mg, 58% yield) was obtained following the synthesis scheme of Example 2 with compound 2a in step 2 replaced by compound 9a. Step 3 5-Fluoro-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((5S,7R)-7-methyl-6-(2 ,2,2-trifluoroethyl)- 5,6,7,8tetrahydro-[1,3]dioxolo[4,5-g]¡soquinol¡n-5-¡l)pyrid¡n-3-am 9 Title compound 9 (18 mg, 48% yield) was obtained following the synthesis scheme of Example 2 with compound 2b in step 3 replaced by compound 9b. MS m / z (ESI): 513.2 [M+1],1H 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). Example 10 3-((5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoroprop¡l)pyrrolídin-3-¡l)am¡ no)phenyl)-2,2,7- trimethyl-7,8d i h id ro-[ 1,3]dioxolo[4,5-g]isoquinolin-6(5H)-íl)-2,2- difluoropropan-1 -ol 10 LRnonn / zznz / e / YiAi Example 11 2,2-difluoro-3-((5S,7R)-5-(3-fluoro-5-(((S)-1-(3-fluoropropyl)pyrrolidin-3 -¡l)amino)pyr¡din-2-¡lo )-7methyl-7,8-dih¡dro-[1,3]dioxolo[4,5-g]¡soquinol¡n-6( 5H)-¡l)propan-1 -ol 11 Step 1 (1 S,3R)-1 -(5-bromo-3-fluoropyridin-2-¡l)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoroprop¡l) -3-methyl1,2,3,4-tetrahydroisoquinoline-6,7-diol 11a Title compound 11a (356 mg, 71% yield) was obtained following the synthesis scheme of Example 3 with the starting material 4-bromo-benzaldehyde in step 3 replaced by 5-bromo-3-fluoropyridylaldehyde. EM m / z(ESI): 685.1 [M+1], Step 2 (5S,7R)-5-(5-bromo-3-fluorop¡r¡d¡n-2-¡l)-6-(3-((tert-but¡ldiphen¡ls¡l¡l) oxy¡)-2,2-difluoroprop¡l)-7-methyl¡l5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]¡soquinol¡ne 11b Title compound 11b (169 mg, 61% yield) was obtained following the synthesis scheme of Example 3 with compound 3c in step 4 replaced by compound 11a. Step 3 tere-butyl (S)-3-((6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5,6 ,7 ,8tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-5-fluoropyridín-3-yl)amino)pyrrolidine-1 -carboxylate 11c Title compound 11c (92 mg, 69% yield) was obtained following the synthesis scheme of Example 3 with compound 3d in step 5 replaced by compound 11b. Step 4 6-((5S,7R)-6-(3-((tert-but¡ldiphen¡ls¡l¡l)ox¡)-2,2-difluoropropyl)-7-methyl-5,6 ,7,8-tetrahydro-[1,3]dioxolo [4,5-g]¡soquinolin-5-yl)-5-fluoro-N-((S)-pyrrolidin-3-¡l)pyridin- 3-amine 11d Title compound 11d (62 mg, 95% yield) was obtained following the synthesis scheme of Example 3 with compound 3e in step 6 replaced by compound 11c. Step 5 6-((5S,7R)-6-(3-((tert-but¡ldiphen¡ls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-met¡l-5 ,6,7,8-tetrahydro-[1,3]dioxolo [4,5-g]isoquinolin-5-íl)-5-fluoro-N-((S)-1 -(3- fluoroprop¡l)pyrrolidin-3-¡l)pyr¡din-3-amine 11e Title compound 11e (35 mg, 71% yield) was obtained following the synthesis scheme of Example 3 with compound 3f in step 7 replaced by compound 11d. LRnonn / zznz / e / YiAi Step 6 2,2-difluoro-3-((5S,7R)-5-(3-fluoro-5-(((S)-1-(3-fluoropropyl)pyrrolyclin-3-íl) am¡no)pyr¡cl¡n-2-¡lo )-7methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]¡soquinol¡n-6(5H) -l)propan-1 -ol 11 Title compound 11 (15 mg, 39% yield) was obtained following the synthesis scheme of Example 3 with compound 3g in step 8 replaced by compound 11e. LRnonn / zznz / e / YiAi EM 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). Example 12 2,2-difluoro-3-((5S,7R)-5-(5-(((S)-1 -(3-fluoropropyl)pyrrolidin-3-yl)amino)pyridín-2-yl)- 7-methyl-7,8dih hydro-[1,3]dioxolo[4,5-g]isoquinolín-6(5H)-íl-2,2-d2)propan-1 -ol 12 Step 1 (5S,7R)-5-(5-bromopyridin-2-¡l)-6-(3-((tert-butyldiphenylsilyl)ox¡)-2,2-difluoropropyl)-7-methyl-5 ,6,7,8 tetrahydro-[1,3]dioxolo[4,5-g]isoquinol¡na-2,2-d2 12a Compound 4a (350 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (10 ml) and dibromodideuromethane (277 mg, 1.6 mmol) and cesium carbonate (512 mg, 1.6 mmol) were added. The reaction mixture was stirred in an oil bath at 70 °C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (10 ml) was added, followed by extraction with ethyl acetate (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 12a (170 mg, 48% yield). MS m / z(ESI): 681.1 [M+1], Step 2 6-((5S,7R)-6-(3-((tert-but¡ldiphen¡ls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-met¡l-5 ,6,7,8-tetrahydro-[1,3]dioxolo [4,5-g]isoquinolin-5-yl-2,2-d2)-N-((S)-1 -(3 -fluoroprop¡l)pyrrolidin-3-¡l)pyr¡din-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), tns(d¡benzyl¡denacetone)d¡palladium(0) (20 mg, 0.02 mmol) and sodium tert-butoxide (29 mg, 0.3 mmol) were added. The reaction mixture was stirred in an oil bath at 80°C under an argon atmosphere for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 12b (103 mg, 55% yield). Step 3 2,2-difluoro-3-((5S,7R)-5-(5-(((S)-1 -(3-fluoroprop¡l)pyrrolídin-3-¡l)amino) p¡r¡d¡n-2-¡l)-7- methyl-7,8d i h id ro-[ 1,3]dioxolo[4,5-g]isoquinolín-6(5H)-¡ l-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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (5 ml) was added, followed by extraction with ethyl acetate (5 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (5 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 12 (35 mg, 49% yield). LRnonn / zznz / e / YiAi MS m / z (ESI): 509.1 [M+1],1H 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, 1 H), 4.64-4.62 (m, 1H), 4.54-4.52 (m, 1H), 4.42 (br, 1 H), 3.83-3.71 (m, 5H) , 3.453.41 (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). Example 13 LRnonn / zznz / e / YiAi 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoroprop¡l)azetidine-3-l)amino)pyrid¡ n-2-¡l)-7-met¡l-7, 8d i h id ro-[ 1,3]dioxolo[4,5-g]isoquinolín-6(5H)-yl-2,2 -d2)propan-1 -ol 13 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]isoquinol¡n-5-¡l-2,2-d2)-N-(1 -(3-fluoropropyl)azet¡din-3 -¡l)pyr¡d¡n-3-amine 13a Compound 12a (86 mg, 0.13 mmol) was dissolved in dioxane (10 ml) and the compound 1(3-fluoropropyl)azetidine-3-amine (44 mg, 0.3 mmol) was prepared as described in Example 1 on page 50 of the patent application specification WO2019228443), 2,2'bis-(diphenylphosphino)-1,1'-binaphthyl (12 mg, 0.02 mmol), tris(dibenzyl denacetone)dipalladium(0) (20 mg, 0.02 mmol) and sodium tert-butoxide (29 mg, 0.3 mmol). The reaction mixture was stirred in an oil bath at 80 °C under argon atmosphere for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 13a (47 mg, 51% yield). Step 2 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoroprop¡l)azetidin-3-¡l)amino)p¡r¡ d¡n-2-¡l)-7-met¡l-7, 8d i h id ro-[ 1,3]dioxolo[4,5-g]isoquinol¡n-6(5H)-¡l- 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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (5 ml) was added, followed by extraction with ethyl acetate (5 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (5 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 13 (11 mg, 42% yield). EM m / z (ESI): 495.2 [M+1]. 1H 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). Example 14 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-¡l)-7-methyl -7,8dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 14 LRnonn / zznz / e / YiAi H.N. L1 Yo LRnonn / zznz / e / YiAi Step 1 3-((6-((5S,7R)-6-(3-((tert-butyldiphenyls¡l¡l)ox¡)-2,2-difluoroprop¡l)-7-methyl-5,6 ,7,8-tetrahydro) of terebutyl -[1,3]dioxolo[4,5-g]¡soquinolin-5-¡l)pyr¡d¡n-3-¡l)am¡ no)azethina-1-carboxylate 14a Compound 4b (1.8 g, 2.65 mmol) was dissolved in toluene (50 ml) and tere-butyl 3-aminoazetidine-1-carboxylate (0.9 g, 5.21 mmol), 2,2'-bis-(diphenylphosphine). -1, 1 '-Binaphthyl (165 mg, 0.26 mmol), tñs(dibenzyldenacetone)d¡palladium(0) (243 mg, 0.26 mmol) and sodium tert-butoxide (763 mg, 7, 95 mmol). The reaction mixture was stirred in an oil bath at 80 °C under argon atmosphere for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Saturated sodium bicarbonate solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 14a (1.2 g, 59% yield). MS m / z(ESI): 771.2 [M+1], Step 2 N-(azetidin-3-yl)-6-((5S,7R)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5, 6,7,8tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-l)pyrdin-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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (15 ml) was added, followed by extraction with ethyl acetate (15 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 14b (0.85 g, 81% yield). Step 3 6-((5S,7R)-6-(3-((tert-but¡ld¡phen¡ls¡l¡l)oxy)-2,2-difluoropropyl)-7-methyl-5, 6,7,8-tetrahydro-[1,3]dioxolo [4,5-g]isoquinol¡n-5-yl)-N-(1-(3-fluoroprop¡l)azet¡din- 3-yl)pyrin-3-amine 14c Compound 14b (0.82 g, 1.22 mmol) was dissolved in Ν,Ν-dimethylformamide (10 ml) and diisopropylethylamine (0.48 mg, 3.68 mmol) was added, followed by dropwise addition of 1-fluoro3-iodopropane ( 0.35 mg, 1.84 mmol). The reaction mixture was stirred for 12 h. Water (15 ml) was added, followed by extraction with ethyl acetate (15 ml x 3). The organic phases were combined, washed with water (15 ml x 2) and saturated sodium chloride solution (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 14c (0.7 g, 78% yield). Step 4 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoroprop¡l)azet¡din-3-yl)amino)p¡r ¡d¡n-2-¡l)-7-methyl¡l-7, 8dihydro-[1,3]dioxolo[4,5-g]isoquinol¡n-6(5H)-¡l)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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (10 ml) was added, followed by extraction with ethyl acetate (10 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 14 (50 mg, 25% yield). EM m / z (ESI): 493.2 [M+1]. 1H 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, 1 H), 3.883.85 (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), 1,841.76 (m, 2H), 1.06 (d, 3H). LRnonn / zznz / e / YiAi Example 15 (5S,7R)-5-(2,6-difluoro-4-(((S)-1 -(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6 -(2,2,2trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 15 Step 1 (1 S,3R)-1 -(4-(benzyloxy)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4tetrahydroisoquinoline-6 , 7-diol15a Compound 1f (167 mg, 0.7 mmol) was dissolved in toluene (100 ml) and trifluoroacetic acid (115 mg, 1.0 mmol) and 4-(benzyloxy)-2,6-difluorobenzaldehyde (250 mg, 1.0 mmol). , prepared as described in Example 5 on page 61 of the specification of Patent Application WO2008080001). The reaction mixture was stirred in an oil bath at 80 °C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (100 mL) was added and the aqueous phase was adjusted to approximately pH 8 by adding saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 15a (235 mg, 73% yield). EM m / z (ESI): 480.1 [M+1], 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 reaction mixture was stirred in an oil bath at 70°C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (10 ml) was added, followed by extraction with ethyl acetate (100 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 15b (458 mg, 77% yield). MS m / z (ESI): 492.1 [M+1]. Step 3 3,5-difluoro-4-((5S,7R)-7-methyl-6-(2,2,2-tñfluoroethyl)-5,6,7,8-tetrahydro-[1,3] dioxolo[4, 5g]isoquinol¡n-5-¡l)phenol 15c Compound 15b (450 mg, 0.9 mmol) was dissolved in methanol (10 ml) and palladium hydroxide on carbon (0.1 g) was added in an argon atmosphere. The reaction mixture was stirred under a hydrogen balloon for 3 h and filtered. The filtrate was concentrated under reduced pressure to give the title compound 15c (0.3 g, 93% yield). EM m / z (ESI): 402.1 [M+1]. Step 4 Tere-butyl (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]isoquinol¡n-5-yl)phenoxy¡)pyrrolidine-1-carboxylate 15d Tere-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (82 mg, 0.4 mmol) was dissolved in a dry solution of tetrahydrofuran (5 ml), and tri-n-butylphosphine (240 mg, 1.2 mmol) and dipiperimide of azodicarboxylic acid compound (300 mg, 1.2 mmol) were added successively in an ice bath. After stirring for 1 h, compound 15c (159 mg, 0.4 mmol) was added. The LRnonn / zznz / e / YiAi reaction mixture was stirred in an argon atmosphere for another 3 h and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 15d (153 mg, 67% yield). EM m / z (ESI): 571.0 [M+1], Step 5 (5S,7R)-5-(2,6-difluoro-4-(((S)-pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6-(2,2,2 -trifluoroethyl)- 5,6,7,8tetrahydro-[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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (5 ml) was added, followed by extraction with ethyl acetate (5 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (5 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 15e (220 mg, 90% yield). Step 6 (5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolídin-3-¡l)ox¡)phenyl)-7 -methyl-6-(2,2,2trifluoroethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 15 Compound 15e (200 mg, 0.4 mmol) was dissolved in Ν,Ν-dimethylformamide (5 ml) and diisopropylethylamine (44 mg, 0.4 mmol) was added, followed by dropwise addition of 1-fluoro-3-iodopropane (160 mg , 0.9 millimoles). The reaction mixture was stirred for 12 h. Water (5 ml) was added, followed by extraction with ethyl acetate (5 ml x 3). The organic phases were combined, washed with water (5 mL x 2) and saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 15 (50 mg, 22% yield). MS m / z (ESI): 531.1 [M+1],1H 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), 3.203.16 ( 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), 1,981.89 (m, 4H), 1.08 (d, 3H). LRnonn / zznz / e / YiAi Example 16 1-(3-Fluoropropyl)-N-(4-((5R,7R)-7-methyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro- [1,3 ]dioxolo[4,5g]isoquinolin-5-yl)phenyl)azetidin-3-amine 16 LRnonn / zznz / e / YiAi Title compound 16 (27 mg, 41% yield) was obtained following the synthesis scheme of Example 1 with compound 1c in step 7 replaced by 1-(3fluoropropyl)azetidine-3-amine (prepared as described in Example 1 on page 50 of the Patent Application specification WO2019228443). MS m / z (ESI): 480.1 [M+1],1H 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, 1 H), 2.87-2.82 (m, 1H), 2.61 -2.56 (m, 1 H), 2.07-1.96 (m, 3H), 1.09 (d, 3H). Example 17 N-(1-(3-fluoroprop¡l)azet¡din-3-¡l)-6-((5S,7R)-7-methyl-6-(2,2,2-trifluoroeth¡ l)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]¡soquinol¡n-5-¡l)pyr¡d¡n-3-amine 17 6b Compound 6b (100 mg, 0.2 mmol) was dissolved in dioxane (5 ml) and the compound 1-(3fluoropropyl)azetidine-3-amine (47 mg, 0.4 mmol, prepared as described in Example 1 on page 50 of the patent application specification WO2019228443), 2dic¡clohex¡lphosphina-2',6,-b¡s(N,N-dimethylamino)-1,1'-biphenyl (3 mg, 0.007 mmol), tns(dibenzylideneacetone)dípalladium(0) (20 mg, 0.02 mmol), and sodium tert-butoxide (48 mg, 0.5 mmol). The reaction mixture was stirred in an oil bath at 105 °C under an argon atmosphere for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Saturated sodium bicarbonate solution (20 ml) was added, followed by extraction with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 17 (25 mg, 22% yield). MS m / z (ESI): 481.2 [M+1],1H NMR (400 MHz, CD3OD) 7.78 (s, 1H), 7.14 (d, 1H), 6.98 (d, 1H), 6.60 (s, 1H) ), 6.20 (s, 1 H), 5.83 (d, 2H), 4.76 (s, 1 H), 4.54-4.52 (m, 1 H), 4.44-4.42 (m, 1 H), 4.13-4.09 (m , 1 H), 3.843.81 (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). Example 18 2,2-difluoro-3-((5R,7R)-5-(4-((1-(3-fluoropropyl)azetidin-3-¡l)amino)phenyl)-7-methyl-7,8-dihydro [1,3]dioxolo[4,5-g]isoquinolin-6(5H)-íl)propan-1-ol 18 LRnonn / zznz / e / YiAi Step 1 3-((5R,7R)-5-(4-bromophenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin- 6(5H)-¡l)- 2,2difluoropropan-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. After addition, the reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution (10 ml) was added, followed by extraction with ethyl acetate (10 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 18a (84 mg, 43% yield). Step 2 2,2-difluoro-3-((5R,7R)-5-(4-((1-(3-fluoropropyl)azetdin-3-yl)amino)phenyl)- 7-methyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-l)propan-1-ol 18 Compound 18a (150 mg, 0.34 mmol) was dissolved in dioxane (5 ml) and the compound 1(3-fluoropropyl)azetidine-3-amine (90 mg, 0.68 mmol, prepared as described in Example 1 on page 50 of the specification of Patent Application WO2019228443"), 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.03 mmol), acetate Palladium (4 mg, 0.02 mmol) and cesium carbonate (222 mg, 0.68 mmol) were added. The reaction mixture was stirred in an oil bath at 105 °C under an argon atmosphere for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated. Saturated sodium bicarbonate solution (20 ml) was added, followed by extraction with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 18 (25 mg, 15% yield). MS m / z (ESI): 492.2 [M+1],1H 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, 1 H), 4.52-4.51 (m, 1 H), 4.44-4.42 (m, 1 H), 4.1 0-4.09 (m, 1 H), 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). LRnonn / zznz / e / YiAi 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)-íl-2,2-d2)propan-1 -ol 19 LRnonn / zznz / e / YiAi Step 1: (5S,7R)-5-(4-bromophenyl)-6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-7-methyl-5 ,6,7,820 tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2,2-d219a Compound 3c (2.6 g, 4 mmol) was dissolved in Ν,Ν-dimethylformamide (10 ml) and dibromodideuromethane (2.8 g, 16 mmol) and cesium carbonate (5.1 g, 16 mmol) were added. The reaction mixture was stirred in an oil bath at 70°C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (100 ml) was added, followed by extraction with ethyl acetate (100 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 19a (1.3 g, 49% yield). LRnonn / zznz / e / YiAi Step 1 (1S ,3R)-1 -(5-bromopyridin-2-yl)-2-(3-((tert-butyldifenylsi lil)oxy)-2,2-difluoropropyl)-3-methyl-1, 2,3,4 tetrahydroisoquinol¡ne-7,8-d¡ol 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-bromopyridylaldehyde (0.6 g, 3.2 mmol) were added. The reaction mixture was stirred in an oil bath at 80°C for 16 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Water (20 ml) was added and the reaction mixture was adjusted to approximately pH 8 by slowly adding saturated sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 20a (0.3 g, 28% yield). Step 2 (1 S,3R)-2-(3-((tert-butyldiphenylsilyl)ox¡)-2,2-difluoropropyl)-1 -(5-((1 -(3-fluoropropyl)azetidin-3yl )amino)pyrádina -2-¡l)-3-methyl-1,2,3,4-tetrahydroisoquinolína-7,8-diol 20b Compound 20a (300 mg, 0.28 mmol) was dissolved in dioxane (10 ml) and 1-(330 fluoropropyl)azetidine-3-amine (111 mg, 0.84 mmol), 2-dichlorhexylphosphine- 2',6'-b¡s(N,N dimethylamino)-1,1'-biphenyl (15 mg, 0..04 mmol), tns(dibenzyl¡denacetone)d¡palladium(0 ) (56 mg, 0.06 mmol) and sodium tert-butoxide (269 mg, 2.8 mmol) were additional. The reaction mixture was stirred in an oil bath at 105°C under an argon atmosphere for 16 hours and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate solution (20 ml) was added, followed by extraction with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 20b (109 mg, 54% yield). LRnonn / zznz / e / YiAi Step 3 (1S,3R)-2-(3-((tert-butyld¡phen¡ls¡l¡l)ox¡)-2,2-difluoropropyl)-1-(5-((1-( 3-fluoropropyl)azetidin-3¡l)amino)piñdina -2-yl)-3-methyl-1,2,3,4-tetrahydroisoquinol¡na-7,8-d¡l bis(trifluoromethylsulfonate ) 20c Compound 20b (400 mg, 0.56 mmol) was dissolved in dichloromethane (25 ml) and triethylamine (170 mg, 1.68 mmol), N,N-dimethylpiñdin-4-amine (7 mg, 0.06 mmol) and Nfenílbís(tñfluoromethylsulfonímide) (500 mg, 1.40 mmol). The reaction mixture was allowed to react at room temperature for 3 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate solution (20 ml) was added, followed by extraction with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 20c (450 mg, 82% yield). Step 4 (1 S,3R)-2-(3-((tert-butyldiphen¡lsilyl)oxy)-2,2-difluoropropyl)-1 -(5-((1 -(3-fluoropropyl)) azetidin-3¡l)amino)piñdina -2-¡l)-3-met¡ 1-1,2,3,4-tetrahydro¡soquinol¡na-7,8-d¡nitrilo 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(dibenzyldenacetone)dipalladium. o(0) (3 mg, 0.003 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (2 mg, 0.004 mmol) was added. The reaction mixture was stirred in an oil bath at 100°C under an argon atmosphere for 3 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate solution (20 ml) was added, followed by extraction with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 20d (16 mg, 72% yield). EM m / z (ESI): 737.3 [M+1], Step 5 (7R,9S)-8-(2,2-difluoro-3-hydroxy¡propyl)-9-(5-((1-(3-fluoroprop¡l)azet¡din- 3-¡l)amino)pyrrolo[3,4-h]isoquinoline -1,3(2H)-dione 20 Compound 20d (16 mg, 0.02 mmol) was dissolved in sulfuric acid (30 mg, 0.3 mmol). The solution was stirred in an oil bath at 90 °C for 2 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 20 (3 mg, 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, 1 H), 4.53-4.51 (m, 1 H), 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). Example 21 (Comparative Example) (8R,10S)-9-(2,2-dif luoro-3-hydroxypropyl)-10-(5-(( 1-(3-fluoropropyl)azetidin-3-yl)amino )piñdin-2-yl)8 -methyl-2,3,7,8,9,10-hexahydropyrrolo[3,4-f]phthalazine-1,4-dione r-· N UN LRnonn / zznz / e / YiAi Λ.„ A. A F Or r.' '-Y N OH J..F Compound 20 (6 mg, 0.01 mmol) was dissolved in ethanol (5 ml) and hydrazine hydrate (5 mg, 0.1 mmol) was added. The reaction mixture was stirred in an oil bath at 80°C for 24 h and the reaction was terminated. The reaction mixture was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography with developing solvent system B to give the title compound 21 (3 mg, 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). LRnonn / zznz / e / YiAi Biological Evaluation The present invention is further described and explained below with reference to test examples, but these examples are not intended to limit the scope of the present invention. Test Example 1. Inhibition of binding of E to ER by the compounds described herein The compounds of the present invention can inhibit the binding of E (estrogen) to ER (estrogen receptor), thereby blocking the binding of the complex of E and ER to ERE (estrogen response element) and, consequently, the expression of downstream luciferase proteins. The inhibitory effects of the compounds of the present invention on the binding of E to ER were tested using the following method. 1. Objective This experiment is intended to test the inhibitory effects of the compounds on the binding of E to ER and evaluate the in vitro activity of the compounds according to the IC50 values. 2. Method An ERE was cloned upstream of the luciferase gene, and MCF-7 / ERE-luciferase monoclonal cells were selected by MCF-7 transfection (TCHu74, National Authenticated Cell Culture Collection). MCF-7 / ERE-luciferase cells were seeded in a 96-well plate with MEM medium (hyclone, SH30024.01B) containing 10% charcoal-depleted FBS (Moregate, FBSF), 1% sodium pyruvate (sigma, S8636), 1% non-essential amino acids (sigma, M7145) and 500 pg / ml G418 at a density of 30,000 cells / well and cultured at 37°C with 5% CO2. 20 mM stock solutions of the drugs are prepared, serially diluted 10-fold with 100% DMSO, and then diluted 20-fold with the medium. After the cells were cultured for 24 h, the medium was removed. 0.1 nM of estradiol (sigma, E2758) and 10 pL of a drug diluted in medium were added to each well, and DMSO was added to the control group. The mixtures were mixed well by gentle stirring. Cells were cultured in an incubator at 37°C with 5% CO2 for 24 h and then the cell culture liquid was removed, followed by the addition of 50 pL of a luciferase substrate (Promega, E6110) to each well. The plate was allowed to sit at room temperature in the dark for 10 to 15 minutes and chemiluminescence signal values ​​were determined. 3. Results The inhibitory effects of the compounds of the present invention on the binding of E to ER were tested through the above experiment. The chemiluminescence signal value was plotted against compound concentration (log-wise) using Graphpad Prism, and IC50 values ​​of the compounds were obtained. The results are shown in Table 1. Table 1. Inhibitory effects of the compounds described herein on the binding of E to ER LRnonn / zznz / e / YiAi Example IC50 (nM) 1 0.14 2 0.10 3 0.44 4 0.37 5 0.05 6 0.27 9 0.46 11 0.35 12 1.13 13 0.69 14 0.5 15 0.19 16 0.27 17 0.43 18 0.07 1 9 0.07 Conclusion: The compounds claimed by the present invention had significant inhibitory effects on the binding of E to ER. Test Example 2. Inhibitory effects of the compounds described herein on the proliferation of MCF-7 cells 1. Objective This experiment aimed to test the inhibitory effects of the compounds described herein on the proliferation of MCF-7 cells using the ATP method and to evaluate the in vitro activity of the compounds based on IC50 values. 2. Method MCF-7 cells (TCHu74, National Authenticated Cell Culture Collection) were seeded in a 96-well plate with MEM medium (hyclone, SH30024.01 B) containing 10% FBS (Gibco, 10099-141), sodium pyruvate 1% (sigma, S8636) and 1% non-essential amino acids (sigma, M7145) at a density of 4000 cells / well and cultured at 37°C with 5% CO2. 20 mM stock solutions of the compounds are prepared, serially diluted with 100% DMSO to a final concentration of 1000x, and then diluted 20-fold with medium containing 2% FBS. After the cells were cultured for 24 h, the medium was removed. 90 pL of medium containing 2% FBS and 10 pL of a drug were added to each well, and 10 pL of DMSO was added to the control group. The mixtures were mixed well by gentle stirring. The blank group contained only 100 pL of the medium containing 2% FBS. Cells were cultured in an incubator at 37°C with 5% CO2 for 72 h, and then 50 pL of mixed Cell Titer-Glo (Promega, G7571) was added to each well. The mixtures were mixed well by shaking and allowed to stand at room temperature for 10 min and the chemiluminescence signal values ​​were determined. 3. Data Analysis The chemiluminescence signal value was plotted against compound concentration (log-wise) using Graphpad Prism, and IC50 values ​​of the compounds were obtained. Results are shown in table 2. Table 2. Inhibitory effects of the compounds described herein on the proliferation of MCF-7 cells LRnonn / zznz / e / YiAi Example IC50 (nM) 1 0.31 2 0.17 3 0.15 4 0.28 5 0.03 6 0.34 9 0.35 11 0.23 12 1.12 13 0.29 14 0.36 15 0.3 17 0.44 18 0.07 19 0.07 20 >10000 21 >10000 Note: Examples 20 and 21 are comparative examples. LRnonn / zznz / e / YiAi Conclusion: The compounds claimed by the present invention had significant inhibitory effects on the proliferation of MCF-7 cells, and comparative examples 20 and 21 showed no activity. Test Example 3. Biological evaluation of the inhibition of the proliferation of MCF7 cells expressing the ERa mutant by the compounds described herein 1. Objective This experiment was intended to test the inhibitory activity of the compounds described herein against the proliferation of MCF7 cells expressing the ERa mutant. 2. Method Site-directed mutagenesis and construction of cell lines. The human ERa protein Y537S mutant estrogen receptor a (ERa) was obtained by site-directed mutagenesis in a two-primer PCR manner using the wild-type ESR1 gene cDNA (accession no. NM000125) as a template. The sequences of the primers used in the mutation are as follows (underlined nucleotides are the mutation sites): Y537S: F-AAG AAC GTG GTG CCC CTC TCT GAO CTG CTG CTG GAG ATG (SEQ ID NO: 1); R-CAT CTC CAG CAG CAG GTC AGA GAG GGG CAC CAC GTT CTT (SEQ ID NO: 2). The mutant ESR1 cDNA was cloned into the lentiviral vector of interest pCDH-CMVMCS-EF1-Puro. The lentiviral plasmid carrying 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 supernatant of the virus-carrying medium was filtered and ultracentrifuged to obtain a virus pellet, which was then resuspended in an appropriate amount of medium. The suspension was added to MCF7 cells (ATCC, HTB-22), followed by the addition of polybrene to a final concentration of 8 pg / mL. The mixture was incubated overnight. Two days after transfection, 1 pg / mL of puromycin was added to the cell culture liquid for resistance detection. Approximately two weeks later, an MCF7 cell line capable of stably expressing the ERaY537S mutant was obtained. Cell proliferation inhibition assay MCF7 cells expressing the ERa mutant 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 in a 96-well plate with complete medium at a density of 3000 cells / well to form 100 pL of cell suspension per well. The plate was incubated overnight in a cell incubator at 37°C with 5% CO2. The next day the medium was removed and 135 pL of an incomplete MEM medium containing 2% fetal bovine serum and 15 pL of a test compound prepared at different concentrations with the incomplete medium were added to each well. Final compound concentrations were 9 concentration points obtained by 4-fold serial dilution from 100 nM. A blank control containing 0.5% DMSO was established. The plate was incubated in a cell incubator at 37 °C with 5% CO2 for 144 h. On day 8, the 96-well cell culture plate was removed. 150 μl of CelITiter-Glo® Luminescent Cell Viability Assay (Promega, G7573) was added to each well. The plate was allowed to sit at room temperature for 10 min and luminescence signal values ​​were read using a multi-brand microplate reader (PerkinElmer, VICTOR 3). The IC50 values ​​for the inhibitory activity of the compounds were calculated according to the concentrations of the compounds and the luminescence signal values ​​and are shown in Table 3. 3. Results Table 3. IC50 values ​​for the inhibitory effects of the compounds described herein on the proliferation of MCF7 cells expressing ERa mutants. LRnonn / zznz / e / YiAi Example ICso (nM) 1 1.38 2 0.78 3 0.43 4 0.89 5 0.07 6 0.82 9 1.35 11 0.71 12 3.49 13 1.36 14 1.27 15 0.68 17 2.19 18 0.25 19 0.43 Conclusion: The compounds claimed by the present invention had significant inhibitory effects on the proliferation of MCF7 cells expressing ERa mutants. Test Example 4. Degradation of ERa by compounds disclosed in this document 1. Objective This experiment was intended to test the degradation of ERa by the compounds described herein. This method was used to test the degradation of ERa by the compounds described herein. 2. Method ERa-positive breast cancer cell line MCF-7 cells were cultured in DMEM / F12 medium (HyClone, SH30023.01) containing 10% fetal bovine serum (Corning, 35010-CV). On the first day of the experiment, after being digested, the cells were washed once with DMEM / F12 medium without phenol red (ThermoFisher, 11039-021) containing 5% charcoal-stripped fetal bovine serum (BIOSUN, BS-0004-021). 500), then resuspended and counted, and the cell density was adjusted to 1.79 χ 105 cells / mL. 280 pL 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. The next day, the compounds were diluted in señe with DMSO and further diluted with the phenol red-free DMEM / F12 medium containing 5% charcoal-extracted fetal bovine serum. 20 pL of a diluted compound was added to each well of the 48-well plate at final concentrations of 3000, 300, 30, 3, 0.3, 0.03 and 0.003 nM. The 48-well plate was placed in the incubator for 16 to 18 h. A 96-well plate was coated with the capture antibody from the human ERa / NR3A1 total protein assay kit (R&D, DYC5715-5). 1 pg / ml of capture antibody was prepared in PBS and 100 μl of the antibody was added to each well of the 96-well plate (Corning, 3590). The plate was placed in an incubator at 26°C overnight. On day 3, the antibody-coated 96-well plate was washed once with PBS and 200 μl of PBS containing 1% BSA was added to each well. The plate was incubated in an incubator at 37 °C for 1.5 h to block. The supernatant of the cell culture medium was discarded. The cells were washed once with PBS and 60 μL of cell lysis buffer was added to each well. The cell lysis buffer was PBS containing 6 M urea, 1 mM EDTA, 0.5% TritonX-100, 1 mM PMSF, and a protease inhibitor (Roche, 04693159001). The cells were placed on ice for 15 min and 300 μl of PBS containing 1 mM EDTA and 0.5% TritonX-100 was added to each well to dilute the urea to 1 M. The blocking buffer was discarded from the plate. LRnonn / zznz / e / YiAi 100 wells blocked, and 100 pL of diluted cell lysis buffer was added to each well. The plate was incubated in an incubator at 37°C for 2 h and washed 5 times with PBS. A biotinylated test antibody was diluted to 0.4 pg / ml with PBS containing 1% BSA and then 100 pL of the test antibody was added to each well. The plate was incubated in an incubator at 37°C for 1 h. The plate was then washed five more times and 100 μl of avidin-HRP diluted 200 times with PBS containing 1% BSA was added to each well. The plate was incubated at 37°C for 30 min. The plate was washed five more times and 100 pL of TMB substrate was added to each well. The plate was incubated at room temperature until blue color appeared and 100 pL of stop solution was added to each well. OD450 signal values ​​were read using a PHERAstar multimode microplate reader. IC50 values ​​for the inhibitory activity of the compounds were calculated using Graphpad Prism software. The maximum degradation rates of the compounds are the ratios of the level of ERa remaining in the cells after treating them with 3000 nM compounds to the level of ERa remaining in the cells after treating them with 3000 nM Fulvestrant. 3. Results The EC50 values ​​determined for the compounds described herein in the degradation of ERa are shown in Table 4. LRnonn / zznz / e / YiAi Table 4. Degradation of ERa by the compounds described in this document. Example EC50 (nM) (%) Degradation Emax Fulvestrant 0.06 100 1 0.32 94 2 0.24 104 3 0.19 129 4 0.21 115 5 0.04 108 6 0.17 104 9 1.04 107 11 0.45 91 12 0. 15 101 13 0.38 107 14 0.5 92 15 0.15 95 17 1.24 104 18 0.1 106 19 0.13 100 20 >10000 - 21 >10000 - Note: Examples 20 and 21 are comparative examples. 101 Conclusion: The compounds claimed by the present invention significantly degraded ERa, and Comparative Examples 20 and 21 showed no activity. Test Example 5. Inhibition of the enzyme activity of the midazolam metabolism site in the human liver microsome CYP3A4 by the compounds described herein Inhibition of the enzymatic activity of the midazolam metabolism site in the human liver microsome CYP3A4 by the compounds described herein was tested using the following method. I. Materials and instruments 1. Phosphate buffer (20x PBS, purchased from Sangon); 2. NADPH (AGROS, A2646-71-1); 3. Human liver microsome (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor, 36); 4. ABI QTrap 4000 LC-MS system (AB Sciex); 5. ZORBAX Extend-C18.3 χ 50 mm, 3.5 pm (Agilent, USA); 6. CYP probe substrate (midazolam, TRC, M343000 / 3 pM) and positive control inhibitor (ketoconazole, SIGMA, Cat No. K1003-100MG). II. Procedures A 100 mM PBS buffer was prepared. A 0.25 mg / ml microsome solution, a 7.5 mM MgCl2 solution, and a 5 mM NADPH solution were prepared using the buffer. A 30-mM stock solution was diluted with DMSO to obtain 30-mM, 10-mM, 3-mM, 1-mM, 0.3-mM, 0.03-mM, 0.003-mM, and 0-mM serial solutions I, which were further diluted 200-fold with phosphate buffer (PBS) to obtain series II test solutions (150, 50, 15, 5, 1.5, 0.15, 0.015 and 0 pM). A working solution of midazolam was diluted with PBS to 15 pM. 40 pL of a 0.25 mg / mL microsome solution prepared in 7.5 mM MgCl2 and 20 pL of each of the 15 pM midazolam working solutions and the composite working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015 and 0 pM). Ketoconazole at the same concentration was used instead of the compounds as a positive control group. The mixtures were preincubated with 5 mM NADPH solution at 37°C for 5 min at the same time. After 5 minutes, 20 pL of NADPH was added to each well to start the reactions. The mixtures were incubated for 30 min. Samples were placed LRnonn / zznz / e / YiAi 102 duplicates for all incubated samples. After 30 minutes, 250 μΙ of acetonitrile containing the internal standard was added to all samples. The mixtures were mixed well, shaken at 800 rpm for 10 min, and then centrifuged at 3700 rpm for 10 min. 100 pL of the supernatant and 80 pL of ultrapure water were mixed well and subjected to LC-MS / MS analysis. Drug IC50 values ​​for the midazolam metabolism site on CYP3A4 were calculated using Graphpad Prism and are shown in Table 5. Table 5. IC50 values ​​of the compounds described herein for the site of metabolism of midazolam in the human liver microsome CYP3A4 LRnonn / zznz / e / YiAi Example ICso(pM) 1 15.76 2 >30 3 10 12 8.18 13 15.38 Conclusion: The compounds claimed by the present invention had weak inhibitory effects on the metabolism site of midazolam in the human liver microsome CYP3A4, showing better safety, suggesting that a metabolic drug interaction based on the metabolism site of midazolam does not occur. midazolam on CYP3A4. Test Example 6. Inhibition of the enzyme activity of the testosterone metabolism site in the human liver microsome CYP3A4 by the compounds described herein Inhibition of the enzymatic activity of the testosterone metabolism site in the human liver microsome CYP3A4 by the compounds described herein was tested using the following method. I. Materials and instruments 1. Phosphate buffer (20x PBS, purchased from Sangon); 2. NADPH (AGROS, A2646-71-1); 3. Human liver microsome (Corning Gentest, Cat No. 452161, Lot No. 905002, Donor36); 4. ABI QTrap 4000 LC-MS system (AB Sciex); 5. ZORBAX Extend-C18.3 χ 50 mm, 3.5 pm (Agilent, USA); 103 6. CYP probe substrate (testosterone, Vocko, CAS No. [58-22-0] / 75 μΜ) and positive control inhibitor (ketoconazole, SIGMA, Cat No. K1003-100MG). II. Procedures A 100 mM PBS buffer was prepared. A 100 mM PBS buffer was prepared. A 0.25 mg / ml microsome solution, a 7.5 mM MgCl2 solution, and a 5 mM NADPH solution were prepared using the buffer. A 30-mM stock solution was diluted with DMSO to obtain 30-mM, 10-mM, 3-mM, 1-mM, 0.3-mM, 0.03-mM, 0.003-mM, and 0-mM serial solutions I, which were further diluted 200-fold with phosphate buffer (PBS). ) to obtain test solutions in series II (150, 50, 15, 5, 1.5, 0.15, 0.015 and 0 μΜ). A working solution of testosterone was diluted with PBS to 375 μΜ. 40 pL of a 0.25 mg / ml microsome solution prepared in 7.5 mM MgCl and 20 pL of each of the 375 μΜ testosterone working solutions and the compound working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015 and 0 μΜ). Ketoconazole at the same concentration was used instead of the compounds as a positive control group. The mixtures were preincubated with 5 mM NADPH solution at 37°C for 5 min at the same time. After 5 minutes, 20 pL of NADPH was added to each well to start the reactions. The mixtures were incubated for 30 min. After 30 minutes, 250 μl of acetonitrile containing the internal standard was added to all samples. The mixtures were mixed well, shaken at 800 rpm for 10 min, and then centrifuged at 3700 rpm for 10 min. 100 pL of the supernatant and 80 pL of ultrapure water were mixed well and subjected to LC-MS / MS analysis. Drug IC50 values ​​for the site of testosterone metabolism in CYP3A4 were calculated using Graphpad Prism and are shown in Table 6. Table 6. IC50 values ​​of the compounds described herein for the site of testosterone metabolism in the human liver microsome CYP3A4 LRnonn / zznz / e / YiAi Example ICso(pM) 1 7.31 2 >30 3 14.57 4 15.50 12 23.77 13 >30 Conclusion: The compounds claimed by the present invention had weak inhibitory effects on the site of testosterone metabolism in human liver microsome CYP3A4, showing better safety. 104 Test Example 7. Time-dependent inhibition of the enzymatic activity of the midazolam metabolism site in the human liver microsome CYP3A4 by the compounds described herein Time-dependent inhibition of CYP enzymatic activity of the midazolam metabolism site in human liver microsome CYP3A4 by the compounds described herein was tested using the following method. I. Materials and instruments 1. Phosphate buffer (20x PBS, purchased from Sangon); 2. NADPH (ACROS, A2646-71-1); 3. Human liver microsome (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor, 36); 4. ABI QTrap 4000 LC-MS system (AB Sciex); 5. ZORBAX Extend-C18. 3 χ 50 mm, 3.5 pm (Agilent, USA); 6. CYP probe substrate (midazolam, TRC, M343000 / 3 pM) and positive control inhibitor (verapamil, Adamas Reagent Co, Ltd, Cat No. 25904A). II. Procedures A 100 mM PBS buffer was prepared. A 0.25 mg / ml microsome solution, a 7.5 mM MgCl2 solution, and a 5 mM NADPH solution were prepared using the buffer. A 30-mM stock solution was diluted with DMSO to obtain 30-mM, 10-mM, 3-mM, 1-mM, 0.3-mM, 0.1-mM, 0.03-mM, and 0-mM serial solutions I, which were diluted 200-fold. further with phosphate buffer (PBS) to obtain series II test solutions (150, 50, 15, 5, 1.5, 0.5, 0.15 and 0 pM). A working solution of midazolam was diluted with PBS to 15 pM. The serial test solutions prepared above were mixed well by shaking and aliquoted into 20 pL portions into the corresponding reaction plates (NADPH, T0, and -NADPH groups were set). Three parallel tests were established. 40 μl of the liver microsome working solution was added to each 96-well plate. 20 pL of a corresponding substrate solution was added to the T0 plate. 20 pL of NADPH was added to the T0 plate and the +NADPH group. A stopwatch was started and the plates were incubated in a 37°C water bath. After 30 min of incubation, the T0 plate was removed and the reaction was terminated with 250 pL of an ACN solution containing an internal standard. The +NADPH group was supplemented with 20 pL of the solution. LRnonn / zznz / e / YiAi 105 corresponding substrate and the -NADPH group was supplemented with 20 pL of the corresponding substrate solution and 20 pL of NADPH. A stopwatch was started and the plates were incubated in a 37°C water bath. After 30 min of incubation, the plates were removed and the reactions were terminated with 250 pL of an ACN solution containing an internal standard. The plates were then shaken on a shaker at 800 rpm for 10 min and centrifuged at 4000 rpm for 15 min. 100 pL of the supernatant and 80 pL of ultrapure water were mixed well and subjected to LC-MS / MS analysis. Drug IC50 values ​​for the midazolam metabolism site on CYP3A4 were calculated using Graphpad Prism and are shown in Table 7. Table 7. IC50 values ​​and IC50 changes of the compounds described herein for the site of midazolam metabolism in human liver microsome CYP3A4 LRnonn / zznz / e / YiAi Example (+)NADPH I C5o(pM) (-)NADPH ICso(pM) Variation IC50 4 2.43 2.47 1.0 12 9.16 10.17 0.9 13 13.11 19.59 0.7 Conclusion: The compounds claimed by the present invention had weak inhibitory effects on the metabolism site of midazolam in the human liver microsome CYP3A4, showing better safety, suggesting that a metabolic drug interaction based on the metabolism site of midazolam does not occur. midazolam on CYP3A4. Test Example 8. Time-Dependent Inhibition of the Enzymatic Activity of the Testosterone Metabolism Site in the Human Liver Microsome CYP3A4 by the Compounds Described Herein The time-dependent inhibition of the enzyme activity of the site of testosterone metabolism in the human liver microsome CYP3A4 by the compounds described herein was tested using the following method. I. Materials and instruments 1. Phosphate buffer (20x PBS, purchased from Sangon); 2. NADPH (ACROS, A2646-71-1); 3. Human liver microsome (Corning Gentest, Cat No. 452161, Lot No. 905002, Donor36); 106 4. ABI QTrap 4000 LC-MS system (AB Sciex); 5. ZORBAX Extend-C18, 3 χ 50 mm, 3.5 pm (Agilent, USA); 6. CYP probe substrate (testosterone, Vocko, CAS No. [58-22-0] / 75 μΜ) and positive control inhibitor (verapamil, Adamas Reagent Co Ltd, Cat No. 25904A). II. Procedures A 100 mM PBS buffer was prepared. A 0.25 mg / ml microsome solution, a 7.5 mM MgCl2 solution, and a 5 mM NADPH solution were prepared using the buffer. A 30-mM stock solution was diluted with DMSO to obtain 30-mM, 10-mM, 3-mM, 1-mM, 0.3-mM, 0.1-mM, 0.03-mM, and 0-mM serial solutions I, which were further diluted 200-fold with phosphate buffer (PBS). ) to obtain test solutions in series II (150, 50, 15, 5, 1.5, 0.5, 0.15 and 0 μΜ). A working solution of midazolam was diluted with PBS to 15 μΜ. The serial test solutions prepared above were mixed well by shaking and aliquoted into 20 pL portions into the corresponding reaction plates (NADPH, T0, and -NADPH groups were set). Three parallel tests were established. 40 μl of the liver microsome working solution was added to each 96-well plate. 20 pL of a corresponding substrate solution was added to the T0 plate. 20 pL of NADPH was added to the T0 plate and the +NADPH group. A stopwatch was started and the plates were incubated in a 37°C water bath. After 30 min of incubation, the T0 plate was removed and the reaction was terminated with 250 pL of an ACN solution containing an internal standard. The +NADPH group was supplemented with 20 pL of the corresponding substrate solution and the -NADPH group was supplemented with 20 pL of the corresponding substrate solution and 20 pL of NADPH. A stopwatch was started and the plates were incubated in a 37°C water bath. After 30 min of incubation, the plates were removed and the reactions were terminated with 250 pL of an ACN solution containing an internal standard. The plates were then shaken on a shaker at 800 rpm for 10 min and centrifuged at 4000 rpm for 15 min. 100 pL of the supernatant and 80 pL of ultrapure water were mixed well and subjected to LC-MS / MS analysis. Drug IC5o values ​​for the site of testosterone metabolism in CYP3A4 were calculated using Graphpad Prism and are shown in Table 8. Table 8. IC50 values ​​and IC50 changes of the compounds described herein for the site of testosterone metabolism in the human liver microsome CYP3A4 LRnonn / zznz / e / YiAi 107 Example (+)NADPH ICsofpM) (-)NADPH ICso(pM) Change ICso 4 2.4 2.5 1.0 12 11.6 25.2 0.5 13 >30 >30 No TDI LRnonn / zznz / e / YiAi Conclusion: The compounds claimed by the present invention had weak inhibitory effects at the site of testosterone metabolism in the human liver microsome CYP3A4, showing better safety, suggesting that a CYP3A4-based metabolic drug interaction does not occur. Test Example 9 1. Objective Blockade of hERG potassium currents by the compounds described herein was tested in a stable cell strain transfected with hERG potassium channels using an automated patch clamp. 2. Method 2.1. Materials and instruments 2.1.1. Materials: Reagent Supplier Cat. No. FBS GIBCO 10099 sodium pyruvate solution sigma S8636-100ML Non-essential amino acid solution MEM (100*) sigma M7145-100ML G418 sulfate Enzo ALX-380-013-G005 MEM Hyclone SH30024.01B cDNA hERG Synthesized by GENEWIZ Gene sequence NM_000238.4- 2.1.2 Instruments Instrument Supplier Model Patchliner 4 channels nanion 2-03-03100-002 Patchliner nanion cleaning station 2-02-03201-005 patchliner nanion cell bank 2-02-03105-000 Electrodenchlorinator Patchliner nanion 3-02-03533-000 Amplifier HEAKEPC1O patch clamp nanion 1-01-10012-000 Osmometer Gonoter Gonoter 030 pH Meter Mettle Toledo FE20 108 2.2. Automated patch clamp procedures A stable cell strain HEK293-hERG was subcultured in MEM / EBSS medium (10% FBS, 400 pg / mL G418, 1% MEM non-essential amino acid solution (100x), 1% sodium pyruvate solution) at a density of 1:4, and an automated patch clamp experiment was performed between hour 48 and hour 72 after the start of culture. On the day of the experiment, cells were digested with 0.25% trypsin, then centrifuged, collected, and resuspended in extracellular fluid (140 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 5 mM Dglucose monohydrate, Hepes 10 mM, pH 7.4, 298 mOsm) to form a cell suspension. The cell suspension was placed in the cell bank of the Patchliner instrument, which then applied the cells to a chip (NPC-16) using a negative pressure controller. The negative pressure attracted individual cells to the wells of the chip. When a full cell configuration was formed, the instrument received hERG currents according to a set hERG current-voltage schedule and automatically performed a compound perfusion of low to high concentrations. Data were recorded and analyzed using the HEAK Patchmaster, HEAK EPC10 patch-clamp amplifier (Nanion), Pathliner software, and Pathcontrol HT software, and the currents of the compounds at each concentration and the current of the blank control were analyzed. 23. Results The blockade of hERG potassium currents by the compounds described herein was tested by the above assay, and the IC50 values ​​determined are shown in Table 9. Table 9. IC50 of the compounds described herein for blocking hERG potassium currents LRnonn / zznz / e / YiAi Example ICso(pM) 11 >30 12 >30 13 >30 Note: IC50 30 μΜ indicates no inhibitory activity; 30 > IC50 s 10 μΜ indicates weak inhibitory activity; 10 > IC50 1 pM indicates moderate inhibitory activity; IC50 < 1 pM indicates strong inhibitory activity. Conclusion: The compounds claimed by the present invention do not have inhibitory activity against hERG, showing better safety.

Claims

1. A compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, LRnonn / zznz / e / YiAi where: ring A is heterocyclyl; Z is selected from the group consisting of an O atom, an S atom, NR7 and CR9R10; G1, G2, G3 and G4 are either identical or different and are each independently CR8 or an N atom;Ria and pib are either identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R2 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of a hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted each independently with one or more substituents selected from the group consisting of 110 halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R4 is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R5 is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R6 are identical or different and each is independently selected from the group consisting of hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, amino, nitro, halogen, carboxyl, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R7 is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of a hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl atom, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R9 and R10 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl; n is 1, 2 or 3; s is 0, 1 or 2; and LRnonn / zznz / e / YiAi 111 p is 0, 1, 2 or 3.; 2. A compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, z G^'G7 G'1 ^.G1 :R'J. Β'ΆιΑΑνί'ρκι i) where: R1a and R1b are identical or different and each is independently selected from the group consisting of H atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; ring A is heterocyclyl; Z is selected from the group consisting of one O atom, one S atom, NR7 and CR9R10;G1, G2, G3 and G4 are identical or different and each is independently CR8 or an N atom; R2 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl atoms, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R3 is selected from the group consisting of hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; LRnonn / zznz / e / YiAi 112 R4 is selected from the group consisting of hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R5 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R6 are identical or different and each is independently selected from the group consisting of hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, amino, nitro, halogen, carboxyl, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R7 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl atoms, wherein the alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R9 and R10 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl; n is 1, 2 or 3; s is 0, 1 or 2; and LRnonn / zznz / e / YiAi p is 0, 1, 2 or 3. 113; 3. A compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring A has 3 to 6 members, a heterocycle containing 1 to 3 heteroatoms selected from the group consisting of an N atom, an O atom and an S atom, and is preferably selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl.

4. A compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein G1, G2, G3 and G4 are all CR8, or one of G1, G2, G3 and G4 is an N atom, and the others are CR8; preferably, G1, G2, G3 and G4 are all CR8, or G1 is N, and G2, G3 and G4 are CR8; R8 are as defined in claim 1 or 2; preferably, R8 are identical or different and each is independently a hydrogen or halogen atom.

5. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, is a compound of general formula (II), ^nr 2 A· I íRsi. í 'R:i,Y ο V. 1R r'V TN o TR R:i ; II i LRnonn / zznz / e / YiAi where: r is 0, 1, 2 or 3; q is 1, 2 or 3; t is 1 or 2; Z, G1, R1a, R1b, R2-R6, R8, nys are as defined in claim 1 or 2. 114 6. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, is a compound of general formula (IIG) or (IIGa), LRnonn / zznz / e / YiAi (IIG) (IIGa) where: R11a and R11b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 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; G1, Z, R1a, R1b, R2-R4, R6, R8, nys are as defined in claim 1 or 2.

7. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Z is NR7; R7 is as defined in claim 1 or 2.

8. The compound of general formula (II) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 5 to 7, wherein q is 2, yt is 1; or q is 2, yt is 2. 115 9. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein n is 1. LRnonn / zznz / e / YiAi 10. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 7 to 9, wherein the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, is a compound of general formula (III) or (IIIa), (III) (H1a) wherein: r is 0, 1, 2 or 3; G1, R1a, R1b, R2-R8 and s are as defined in claim 1 or 2.

11. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 7 and 9, wherein the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof, is a compound of general formula (IV) or (IVa), (IV) (IVa) 116 wherein: r is 0, 1, 2 or 3; G1, R1a, R1b, R2-R8 and s are as defined in claim 1 or 2.

12. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein G1 is CR8; R8 is as defined in claim 1 or 2.

13. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein G1 is an N atom.

14. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R7 is a hydrogen atom.

15. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R1a and R1b are identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl and haloalkyl.

16. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 2 to 14, wherein R1a and R1b are identical or different and each is independently selected from the group consisting of an H atom, a deuterium atom, a fluorine atom and Ci-e alkyl; preferably, R1a and R1b are deuterium atoms.

17. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R2 is a hydrogen atom.

18. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17, wherein R3 is a hydrogen atom. LRnonn / zznz / e / YiAi 117 19. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R4 is a hydrogen or alkyl atom, preferably Ci-e alkyl.

20. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 7 to 19, wherein R5 is optionally alkyl substituted with one or more substituents selected from the group consisting of halogen, amino, cyano, hydroxy, alkoxy, carboxyl and cycloalkyl; preferably, R5 is optionally alkyl substituted with one or more substituents selected from the group consisting of halogen and hydroxy.

21. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R6 is haloalkyl Cl-6 · LRnonn / zznz / e / YiAi 22. The compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt, is selected from the group consisting of the following compounds 118 and LRnonn / zznz / e / γΐΛΐ 119 23. A compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, LRnonn / zznz / e / YiAi R! i IA ) where: X is Br; G1, G2, G3 and G4 are identical or different and are each independently CR8 or an N atom; R1a and R1b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R2 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of a hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;120 R4 is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R5 is selected from the group consisting of alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R8 are identical or different and each is independently selected from the group consisting of a hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl atom, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 1, 2 or 3; ys is 0, 1 or 2.

24. A compound of general formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, X G3; G' КLRnonn / zznz / e / YiAi Ι IA ) where: Ria and pib are either identical or different and each is independently selected from the group consisting of H atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents 121 selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; X is Br; G1, G2, G3 and G4 are identical or different and are each independently CR8 or an N atom;R2 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of a hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R4 is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R5 is selected from the group consisting of alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, carboxyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R8 are identical or different and each is independently selected from the group consisting of a hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl, and heterocyclyl atom, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; n is 1, 2, or 3; and LRnonn / zznz / e / YiAi s is 0, 1, or 2. 122; 25. The compound of general formula (IA) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 23 or 24, wherein the compound of general formula (IA) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or the pharmaceutically acceptable salt, is selected from the group consisting of LRnonn / zznz / e / YiAi 26. A compound of general formula (IIGA) or (IIGaA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Rw is a hydroxy protecting group, and Z is preferably selected from the group consisting of an O atom, an S atom, NR7 and CR9R10; G1 is CR8 or an N atom;R1a and R1b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R2 are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R3 is selected from the group consisting of a hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R4 is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R6 is independently selected from the group consisting of hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, amino, nitro, halogen, carboxyl, carboxylate group, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and each heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R7 is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more LRnonn / zznz / e / YiAi 124 substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R8 are identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R9 and R10 are identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl;R11a and R11b are identical or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 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.

27. A compound of general formula (IIGA) or (IIGaA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, LRnonn / zznz / e / YiAi; IIGA i { IIGaA i 125 where: R1a and R1b are identical or different and each is independently selected from the group consisting of H atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;Rw is a hydroxy protecting group, and Z is preferably selected from the group consisting of an O atom, an S atom, NR7 and CR9R10; G1 is CR8 or an N atom; R2 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl atoms, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;R3 is selected from the group consisting of a hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R4 is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R6 is independently selected from the group consisting of hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, cyano, amino, nitro, halogen, carboxyl, carboxylate group, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and each heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R7 is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkenyl, propargyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R8 are identical or different and each is independently selected from the group consisting of a hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl atom, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted each independently with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R9 and R10 are identical or different and each is selected independently from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, cyano, cycloalkyl and heterocyclyl; Rila and Riw are identical or different and each is selected independently from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 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.

28. The compound of general formula (IIGA) or (IIGaA) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 26 or 27, wherein the compound of general formula (IIGA) or (IIGaA) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or the pharmaceutically acceptable salt, is selected from the group consisting of the following compounds: LRnonn / zznz / e / YiAi 127 LRnonn / zznz / e / γΐΛΐ 128 LRnonn / zznz / e / YiAi 29. A method for preparing the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising: subjecting a compound of general formula (IA) and a compound of general formula (IB) to a coupling reaction to give the compound of general formula (I), wherein: X is Br; the rings A, Z, G1, G2, G3, G4, R1a, R1b, R2-R6, n, pys are as defined in claim 1 or 2.

30. A method for preparing the compound of general formula (IIG) or (IIGa) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 6, comprising: 129 ;'-\R R3 ( IIGaA i LRnonn / zznz / e / YiAi removing a hydroxy protecting group from a compound of general formula (IIGA) to give the compound of general formula (IIG), or removing a hydroxy protecting group from a compound of general formula (IIGaA) to give the compound of general formula (IIGa), wherein: ' Rw is a hydroxy protecting group, and is preferably \= / ; Z, G1, R1a, R1b, R2-R4, R6, R8, R11a, R11b, q, t, k, r, nys are as defined in claim 6.

31. A pharmaceutical composition comprising a therapeutically effective amount of the compound of general formula (I) or the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, and one or more pharmaceutically acceptable vehicles, diluents or excipients.

32. Use of the compound of general formula (I) or its tautomer, mesomer, racemate, enantiomer or diastereomer or mixture thereof, or its pharmaceutically acceptable salt according to any of claims 1 to 22, or the pharmaceutical composition according to claim 31 in the preparation of an estrogen receptor modulator, preferably in the preparation of a selective estrogen receptor degrader (SERD).

33. Use of the compound of general formula (I) or of the tautomer, mesomer, racemate, enantiomer or diastereomer thereof or of a mixture thereof, or of a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, or of the pharmaceutical composition according to claim 31, in the preparation of a medicament for preventing and / or treating cancer, wherein the cancer is preferably 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. 130 34. Use of the compound of general formula (I) or its tautomer, mesomer, racemate, enantiomer or diastereomer or mixture thereof, or its pharmaceutically acceptable salt according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 31 in the preparation of a medicament for preventing and / or treating a disease or condition mediated or dependent on an estrogen receptor, wherein, preferably, the disease or condition mediated or dependent on an estrogen receptor is selected from the group consisting of cancer, central nervous system deficiency disease, cardiovascular system deficiency, blood system deficiency, immune and inflammatory disease, susceptible infection, metabolic deficiency, neurological deficiency, psychiatric deficiency and reproductive deficiency;Preferably, the cancer is selected from the group consisting of breast cancer, endometrial cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, tumors of the fallopian tubes, hemophilia, and leukemia; more preferably, the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.