Estrogen receptor antagonist

Abstract

Provided are indole compounds, and specifically disclosed are compounds of formula (II), their isomers, or pharmaceutically acceptable salts thereof, and their use as estrogen receptor antagonists for the manufacture of a drug for treating estrogen receptor-positive breast cancer. TIFF2022513942000173.tif65145

Description

Cross - reference to related applications

[0001] This application claims the priority and benefits of Chinese Patent Application for Invention No. 201811545117.2 filed with the State Intellectual Property Office of the People's Republic of China on December 17, 2018, Chinese Patent Application for Invention No. 201910611070.3 filed with the State Intellectual Property Office of the People's Republic of China on July 8, 2019, and Chinese Patent Application for Invention No. 201910877339.2 filed with the State Intellectual Property Office of the People's Republic of China on September 17, 2019. All the contents of the above patents are incorporated herein by reference.

Technical Field

[0002] The present invention relates to novel indole compounds, specifically, compounds of formula (II), their isomers or pharmaceutically acceptable salts thereof, and their use for manufacturing therapeutic drugs for estrogen receptor - positive breast cancer as estrogen receptor antagonists.

Background Art

[0003] According to the statistics of the World Health Organization (WHO), breast cancer is the second most common cancer in the world and the most common cancer among women. Through years of research, it has been found that the estrogen - estrogen receptor signaling pathway plays a role in promoting breast cancer, and the estrogen receptor (ER) has been established as the most important biomarker for breast cancer. When the expression of the estrogen receptor is used as a judgment index, breast cancer can be divided into estrogen receptor - positive breast cancer and estrogen receptor - negative breast cancer. Among them, estrogen receptor - positive breast cancer accounts for more than 70% of the total number of breast cancer patients.

[0004] Endocrine therapy (ET) for the estrogen-estrogen receptor signaling pathway in breast cancer cells has become the first choice for the treatment of estrogen receptor-positive breast cancer due to its minor side effects and obvious therapeutic effects. The first choice of endocrine therapy is mainly aromatase inhibitor (AI). Although the aromatase inhibitor letrozole has shown excellent therapeutic effects in the treatment of estrogen receptor-positive breast cancer, the problem of drug resistance to aromatase inhibitors in estrogen receptor-positive breast cancer has emerged when the two drugs are used in combination. Specific mutations have been found in estrogen receptors against aromatase inhibitors, and it has been found from many studies that the Y537X mutation is mainly involved. After mutation, the estrogen receptor maintains an activated conformation even in the absence of estrogen, so it can function as a receptor and promote the growth of breast cancer cells. As the only currently marketed selective estrogen receptor downregulator, fulvestrant has shown excellent effects in the treatment of hormone-resistant breast cancer. However, there are various problems with fulvestrant regarding the treatment of AI-resistant ER mutant breast cancer. First, due to the poor PK characteristics of fulvestrant, its bioavailability can even be zero when administered orally. Second, the plasma clearance of fulvestrant is high. Due to the above two reasons, the drug can only be administered by intramuscular injection. In addition, due to its highly lipophilic structure, there are also major problems with the tissue distribution of fulvestrant when administered by intramuscular injection. Clinically, only about 50% of breast cancer patients using fulvestrant show a response. Also, due to its poor PK characteristics, the concentration of fulvestrant in tissues cannot completely degrade ER, especially mutant ER, at the currently approved dosage, so it is not the optimal choice for the treatment of AI-resistant ER mutant breast cancer. Therefore, research and development of drugs suitable for ER mutant breast cancer with improved pharmacokinetic properties are still necessary.

[0005] In Patent Document US20160347717A1, an oral covalent estrogen receptor antagonist H3B-6545 was reported, and a Phase I / II clinical trial of ER-positive breast cancer treatment with this molecule is underway.

Chemical Formula

Summary of the Invention

[0006] The present invention provides a compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical Formula

Chemical Formula

Chemical formula

[0007] In some embodiments of the present invention, X is selected from NH, O and S, Y is selected from CR7, Y1 is CH, Y2 is N, or Y1 is N and Y2 is CH, and L is,

Chemical formula

Chemical formula

[0008] In some embodiments of the present invention, X is selected from NH, Y is selected from CR7, Y1 is N, Y2 is CH, and L is,

Chemical formula

Chemical formula

[0009] In some embodiments of the present invention, X is selected from NH, Y is selected from CR7, Y1 is CH, Y2 is N, and L is,

Chemical formula

[0010] In some embodiments of the present invention, X is selected from NH, Y is selected from N, Y1 is N, Y2 is CH, and L is [Chemical formula] and R 13 is [Chemical formula] and the definitions of the present invention apply to other variables.

[0011] In some embodiments of the present invention, each of the said Rs is independently selected from F, Cl, Br, and I.

[0012] In some embodiments of the present invention, the said R a , R b , R c , R d , R e , R f and R g are each independently selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group, and cyclopropyl group, and the said C 1-6 alkyl group, C 1-6 heteroalkyl group, and cyclopropyl group are optionally substituted by one, two, or three Rs, and the definitions of the present invention apply to other variables.

[0013] In some embodiments of the present invention, the said R a , R b , R c , R d , R e , Rf and R g are each independently selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, Me, Et, CF3, CHF2, CH2F, NHCH3, and N(CH3)2, and the definitions of the present invention apply to other variables.

[0014] In some embodiments of the present invention, said R a , R b , R c , R d , R e , R f and R g are each independently selected from F, Cl, Br, I, Me, Et, CF3, CHF2, and CH2F, and the definitions of the present invention apply to other variables.

[0015] In some embodiments of the present invention, R b is selected from F, Cl, Br, and I, and the definitions of the present invention apply to other variables.

[0016] In some embodiments of the present invention, R d is selected from C 1-6 alkyl groups, said C 1-6 alkyl group is optionally substituted by one, two, or three Rs, said Rs are each independently selected from F, Cl, Br, and I, and the definitions of the present invention apply to other variables.

[0017] In some embodiments of the present invention, R d is selected from methyl groups, said methyl group is optionally substituted by one, two, or three Rs, said Rs are each independently selected from F, and the definitions of the present invention apply to other variables.

[0018] In some embodiments of the present invention, R d is selected from CF3, CHF2, or CH2F, and the definitions of the present invention apply to other variables.

[0019] In some embodiments, R dis selected from CH2F, and the definitions of the present invention apply to other variables.

[0020] In some embodiments, ring A is selected from a phenyl group and a 5- to 6-membered heteroaryl group, and the definitions of the present invention apply to other variables.

[0021] In some embodiments, ring A is selected from a phenyl group, a 5-membered sulfur-containing heteroaryl group, and a 6-membered nitrogen-containing heteroaryl group, and the definitions of the present invention apply to other variables.

[0022] In some embodiments, ring A is selected from a phenyl group, a thienyl group, and a pyridinyl group, and the definitions of the present invention apply to other variables.

[0023] In some embodiments, ring A is a phenyl group,

Chemical formula

[0024] In some embodiments of the present invention, the ring A is selected from a phenyl group and a pyridinyl group, and the definitions of the present invention apply to other variables. In some embodiments of the present invention, the R1 is H, F, Cl, Br, I, CN, COOH, NH2, C 1-3 alkyl group and C 1-3 heteroalkyl group, the C 1-3 alkyl group and C 1-3 heteroalkyl group is optionally substituted by one, two or three R a , and the definitions of the present invention apply to other variables. In some embodiments of the present invention, the R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, Me, Et, CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2, and the definitions of the present invention apply to other variables.

[0025] In some embodiments of the present invention, the R1 is H, F, Cl, Br, I and C 1-6Selected from alkyl groups, and the definitions of the present invention apply to other variables.

[0026] In some embodiments of the present invention, the said R1 is selected from H, F, Cl, Br, I and C 1-3 Selected from alkyl groups, and the definitions of the present invention apply to other variables.

[0027] In some embodiments of the present invention, the said R1 is selected from H, Cl, Br, I and Me, and the definitions of the present invention apply to other variables.

[0028] In some embodiments of the present invention, the said R2 is C 1-3 alkyl groups and C 1-3 heteroalkyl groups, and the said C 1-3 alkyl groups and C 1-3 heteroalkyl groups are optionally substituted by one, two or three R b , and the definitions of the present invention apply to other variables. In some embodiments of the present invention, the said R2 is selected from CF3, CH2CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2, and the definitions of the present invention apply to other variables.

[0029] In some embodiments of the present invention, the said R2 is C 1-6 alkyl groups, and the said C 1-6 alkyl groups are optionally substituted by one, two or three R b , and the definitions of the present invention apply to other variables.

[0030] In some embodiments of the present invention, the said R2 is C 1-6 alkyl groups, and the said C 1-6 alkyl groups are optionally substituted by one, two or three R b , and R b is selected from F, Cl, Br and I, and the definitions of the present invention apply to other variables.

[0031] In some embodiments of the present invention, the said R2 is C 1-3 alkyl groups, and the said C 1-3The alkyl group is optionally substituted by one, two or three Rs b wherein R b is selected from F, and the definitions of the present invention apply to the other variables.

[0032] In some embodiments of the present invention, the R2 is selected from ethyl groups, and the ethyl group is optionally substituted by three Rs b wherein R b is selected from F, and the definitions of the present invention apply to the other variables.

[0033] In some embodiments of the present invention, the R2 is selected from ethyl groups and CH2CF3, and the definitions of the present invention apply to the other variables.

[0034] In some embodiments of the present invention, the R3 is selected from H and C 1-6 alkyl groups, and the definitions of the present invention apply to the other variables.

[0035] In some embodiments of the present invention, the R3 is selected from H and C 1-3 alkyl groups, and the definitions of the present invention apply to the other variables.

[0036] In some embodiments of the present invention, the R3 is selected from H and methyl groups, and the definitions of the present invention apply to the other variables.

[0037] In some embodiments of the present invention, the R3 is selected from H, and the definitions of the present invention apply to the other variables.

[0038] In some embodiments of the present invention, the R4 is selected from COOH, NH2, C 1-6 alkyl groups, -NH-C 1-6 alkyl groups, -N(C 1-6 alkyl)2 groups, -C(=O)-O-C 1-6 alkyl groups, -C(=O)-S-C 1-6 alkyl groups, C 3-6 cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, and phenyl groups, and the C 1-6 alkyl groups, -NH-C1-6 An alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, and a phenyl group are optionally substituted by one, two, or three R d and the definitions of the present invention apply to the other variables. In some embodiments of the present invention, the R4 is COOH, NH2, C 1-3 alkyl group, -NH-C 1-3 alkyl group, -N(C 1-3 alkyl)2 group, -C(=O)-O-C 1-3 alkyl group, -C(=O)-S-C 1-3 alkyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, and a phenyl group, and the C 1-3 alkyl group, -NH-C 1-3 alkyl group, -N(C 1-3 alkyl)2 group, -C(=O)-O-C 1-3 alkyl group, -C(=O)-S-C 1-3 alkyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, and a phenyl group are optionally substituted by one, two, or three R d and the definitions of the present invention apply to the other variables.

[0039] In some embodiments of the present invention, the R4 is -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, and a 3- to 6-membered heterocycloalkyl group, and the -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, and a 3- to 6-membered heterocycloalkyl group are optionally substituted by one, two, or three R d and the definitions of the present invention apply to the other variables.

[0040] In some embodiments of the present invention, the R4 is -NH-C 1-3 alkyl group, -N(C 1-3(Alkyl)2 group and a 4-membered heterocycloalkyl group, and the -NH-C 1-3 alkyl group, -N(C 1-3 (Alkyl)2 group and the 4-membered heterocycloalkyl group are optionally substituted by one, two or three R d and the definitions of the present invention apply to the other variables.

[0041] In some embodiments of the present invention, the R4 is -NH-C 1-3 alkyl group, -N(C 1-3 (Alkyl)2 group, and [Chemical formula] selected from, and the [Chemical formula] is optionally substituted by one, two or three R d and the definitions of the present invention apply to the other variables.

[0042] In some embodiments of the present invention, the R4 is -NH-C 1-3 alkyl group, -N(C 1-3 (Alkyl)2 group, and [Chemical formula] selected from, and the [Chemical formula] is optionally substituted by one, two or three R d and the R d is selected from CF3, CHF2 or CH2F, and the definitions of the present invention apply to the other variables.

[0043] In some embodiments of the present invention, the R4 is [Chemical formula] selected from -NHCH3 and -N(CH3)2, and the definitions of the present invention apply to the other variables.

[0044] In some embodiments of the present invention, R5 is H, C 1-3 Alkyl groups and C 1-3 heteroalkyl groups, 1-3 Alkyl groups and C 1-3 The heteroalkyl group may optionally contain one, two, or three R e and the other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, R5 is selected from H, with the other variables being as defined herein.

[0046] In some embodiments of the present invention, R6, R7, R8, and R9 are each independently selected from H, with the other variables being as defined herein.

[0047] In some embodiments of the present invention, R 10 , R 11 and R 12 are independently H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, and C 1-3 Alkyl groups and C 1-3 heteroalkyl groups, 1-3 Alkyl groups and C 1-3 The heteroalkyl group may optionally contain one, two, or three R g and the other variables are as defined herein. In some embodiments of the present invention, R 10 , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, Me, Et, CF3, OMe, CHF2, CH2F, NHCH3, and N(CH3)2, and all other variables are as defined herein.

[0048] In some embodiments of the present invention, R 10 , R 11 and R 12 are independently H, F, Cl, Br, I, CN, and C 1-6 Alkyl groups and C1-6 Selected from heteroalkyl groups, said C 1-6 alkyl group and C 1-6 The heteroalkyl group is optionally substituted by one, two or three R g and the definitions of the present invention apply to the other variables.

[0049] In some embodiments of the present invention, said R 10 , R 11 and R 12 are each independently H, F, Cl, Br, I, CN, C 1-3 alkyl group and C 1-3 selected from heteroalkyl groups.

[0050] In some embodiments of the present invention, said R 10 , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, CN, Me and OMe, and the definitions of the present invention apply to the other variables.

[0051] In some embodiments of the present invention, said X is selected from NH, and the definitions of the present invention apply to the other variables.

[0052] In some embodiments of the present invention, said Y is selected from N and CH, and the definitions of the present invention apply to the other variables.

[0053] In some embodiments of the present invention, said Y1 is N and Y2 is CH or CF, and the definitions of the present invention apply to the other variables.

[0054] In some embodiments of the present invention, said Y1 is CH and Y2 is CH, and the definitions of the present invention apply to the other variables.

[0055] In some embodiments of the present invention, said structural unit

Chemical formula

Chemical formula

[0056] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

[0057] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

[0058] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

[0059] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

[0060] In some embodiments of the present invention, the R 13 is H,

Chemical formula

[0061] In some embodiments of the present invention, the R 13 is H,

Chemical formula

[0062] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

[0063] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

[0064] In some embodiments of the present invention, the compound, its isomer or its pharmaceutically acceptable salt is

Chemical formula

[0065] In some embodiments of the present invention, the said R 41 and R 42 are each independently selected from H and C 1-3 alkyl groups, and the other variables are subject to the definition of the present invention.

[0066] In some embodiments of the present invention, the said R 41 and R 42 are each independently selected from H and methyl groups, and the other variables are subject to the definition of the present invention.

[0067] In some embodiments of the present invention, the said R 41 is selected from H, R 42 is selected from methyl groups, and the other variables are subject to the definition of the present invention.

[0068] In some embodiments of the present invention, the said compound, its isomers or pharmaceutically acceptable salts thereof are

Chemical formula

[0069] Furthermore, the present invention provides the following compound, its isomer or a pharmaceutically acceptable salt thereof.

Chemical formula

[0070] Furthermore, the present invention provides the following compound, its isomer or a pharmaceutically acceptable salt thereof.

Chemical formula

[0071] The present invention provides a compound of formula (I’), its isomer or a pharmaceutically acceptable salt thereof,

Chemical formula

[0072] In some embodiments of the present invention, in the formula (I’), R a , R b , R c , R d , R e , R f and R g are each independently H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group and cyclopropyl group, and said C 1-6 alkyl group, C 1-6 heteroalkyl group and cyclopropyl group are optionally substituted by one, two or three Rs.

[0073] In some embodiments of the present invention, in the formula (I’), R a , R b , R c , R d , R e , R f and R g are each independently selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, Me, Et, CF3, CHF2, CH2F, NHCH3 and N(CH3)2.

[0074] In some embodiments of the present invention, in the formula (I’), R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, C 1-3 alkyl group and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group is optionally substituted by one, two or three R a .

[0075] In some embodiments of the present invention, in the formula (I’), R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, Me, Et, CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2.

[0076] In some embodiments of the present invention, in the formula (I’), R2 is selected from C 1-3 alkyl group and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group is optionally substituted by one, two or three R b .

[0077] In some embodiments of the present invention, in the formula (I’), R2 is selected from Me, Et, CF3, CH2CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2.

[0078] In some embodiments of the present invention, in the formula (I’), R3 is selected from H.

[0079] In some embodiments of the present invention, in the formula (I’), R4 is selected from COOH, NH2, C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, C 3-6 cycloalkyl-3- to 6-membered heterocycloalkyl group and phenyl group, and the C 1-6 alkyl group, -NH-C 1-6An alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, and a phenyl group are each optionally substituted by one, two, or three R d .

[0080] In some embodiments of the present invention, in the formula (I’), R4 is COOH, NH2, C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, and a phenyl group.

[0081] In some embodiments of the present invention, in the formula (I’), R4 is selected from -NHCH3 and -N(CH3)2.

[0082] In some embodiments of the present invention, in the formula (I’), R5 is H, C 1-3 alkyl group, and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group are each optionally substituted by one, two, or three R e .

[0083] In some embodiments of the present invention, in the formula (I’), R5 is selected from H.

[0084] In some embodiments of the present invention, in the formula (I’), R6, R7, R8, and R9 are each independently selected from H.

[0085] In some embodiments of the present invention, in the formula (I’), R 10 , R 11 , and R 12Each is independently selected from H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, C 1-3 alkyl group and C 1-3 heteroalkyl group, and said C 1-3 alkyl group and C 1-3 heteroalkyl group is optionally substituted by one, two or three R g .

[0086] In some embodiments of the present invention, in the formula (I’), R 10 , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, Me, Et, CF3, OMe, CHF2, CH2F, NHCH3 and N(CH3)2.

[0087] In some embodiments of the present invention, in the formula (I’), ring A is selected from phenyl groups.

[0088] In some embodiments of the present invention, in the formula (I’), the structural unit

Chemical formula

Chemical formula

[0089] In some embodiments of the present invention, in the formula (I’), the structural unit

Chemical formula

Chemical formula

[0090] In some embodiments of the present invention, in the formula (I’), the structural unit

Chemical formula

[0091] [[ID=ll]] In some embodiments of the present invention, the structural unit in the formula (I') [Chemical formula] is selected from [Chemical formula] the following.

[0092] In some embodiments of the present invention, in the formula (I'), R a , R b , R c , R d , R e , R f and R g are each independently selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group and cyclopropyl group, and the C 1-6 alkyl group, C 1-6 heteroalkyl group and cyclopropyl group are optionally substituted by one, two or three Rs, and the definitions of the present invention apply to other variables.

[0093] In some embodiments of the present invention, in the formula (I'), R a , R b , R c , R d , R e , R f and R g are each independently selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, Me, Et, CF3, CHF2, CH2F, NHCH3 and N(CH3)2, and the definitions of the present invention apply to other variables.

[0094] In some embodiments of the present invention, in the formula (I’), R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, C 1-3 alkyl group and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group is optionally substituted by one, two or three R a , and the definitions of the present invention apply to other variables.

[0095] In some embodiments of the present invention, in the formula (I’), R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, Me, Et, CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2, and the definitions of the present invention apply to other variables.

[0096] In some embodiments of the present invention, in the formula (I’), R2 is selected from C 1-3 alkyl group and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group is optionally substituted by one, two or three R b , and the definitions of the present invention apply to other variables.

[0097] In some embodiments of the present invention, in the formula (I’), R2 is selected from Me, Et, CF3, CH2CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2.

[0098] In some embodiments of the present invention, in the formula (I’), R3 is selected from H, and the definitions of the present invention apply to other variables.

[0099] In some embodiments of the present invention, in the formula (I’), R4 is COOH, NH2, C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, C 3-6Selected from a cycloalkyl-3- to 6-membered heterocycloalkyl group and a phenyl group, wherein the C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group and phenyl group are optionally substituted by one, two or three R d and the definitions of the present invention apply to the other variables.

[0100] In some embodiments of the present invention, in the formula (I’), R4 is COOH, NH2, C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, azetidinyl group and phenyl group, and the definitions of the present invention apply to the other variables.

[0101] In some embodiments of the present invention, in the formula (I’), R4 is selected from -NHCH3 and -N(CH3)2, and the definitions of the present invention apply to the other variables.

[0102] In some embodiments of the present invention, in the formula (I’), R5 is H, C 1-3 alkyl group and C 1-3 heteroalkyl group, wherein the C 1-3 alkyl group and C 1-3 heteroalkyl group are optionally substituted by one, two or three R e and the definitions of the present invention apply to the other variables.

[0103] In some embodiments of the present invention, in the formula (I’), R5 is selected from H, and the definitions of the present invention apply to the other variables.

[0104] In some embodiments of the present invention, in the formula (I’), R6, R7, R8 and R9 are each independently selected from H, and the definitions of the present invention apply to other variables.

[0105] In some embodiments of the present invention, in the formula (I’), R 10 , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, C 1-3 alkyl group and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group are optionally substituted by one, two or three R g , and the definitions of the present invention apply to other variables.

[0106] In some embodiments of the present invention, in the formula (I’), R 10 , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, Me, Et, CF3, OMe, CHF2, CH2F, NHCH3 and N(CH3)2, and the definitions of the present invention apply to other variables.

[0107] In some embodiments of the present invention, in the formula (I’), ring A is selected from phenyl groups, and the definitions of the present invention apply to other variables.

[0108] In some embodiments of the present invention, in the formula (I’), the structural unit

Chemical formula

Chemical formula

[0109] In some embodiments of the present invention, in the formula (I’), the structural unit [Chemistry] is [Chemistry] selected from, and the definitions of the present invention apply to other variables.

[0110] In some embodiments of the present invention, the structural unit in the formula (I’) [Chemistry] is [Chemistry] selected from, and the definitions of the present invention apply to other variables.

[0111] In some embodiments of the present invention, the structural unit in the formula (I’) [Chemistry] is [Chemistry] selected from, and the definitions of the present invention apply to other variables.

[0112] In some embodiments of the present invention, the compound, its isomer or its pharmaceutically acceptable salt is [Chemistry] selected from wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are defined according to the present invention.

[0113] In some embodiments of the present invention, the compound, its isomer or its pharmaceutically acceptable salt is [Chemistry] selected from wherein R1, R2, R3, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are subject to the definition of the present invention, R 41 and R 42 are each independently selected from H and C 1-6 alkyl groups, and the C 1-6 alkyl groups are optionally substituted by one, two or three R d 's, R d is subject to the definition of the present invention.

[0114] The present invention provides a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, [Chemical formula] wherein TIFF0007716980000061.tif9157 is a single bond or a double bond, X is selected from NH, O and S, Y1 is CH and Y2 is N, or Y1 is N and Y2 is CH, ring A is selected from a C 6-10 aryl group and a 5- to 10-membered heteroaryl group, R1 is H, halogen, CN, COOH, NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group and a 3- to 6-membered heterocycloalkyl group, and the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group and a 3- to 6-membered heterocycloalkyl group are optionally substituted by one, two or three R a 's, R2 is a C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6Selected from a cycloalkyl group and a 3- to 6-membered heterocycloalkyl group, the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, and 3- to 6-membered heterocycloalkyl group are optionally substituted by one, two, or three R b . R3 is H, halogen, CN, NO2, OH, COOH, NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, or 3- to 6-membered heterocycloalkyl group, and the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, and 3- to 6-membered heterocycloalkyl group are optionally substituted by one, two, or three R c . R4 is COOH, NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, phenyl group, or 5- to 6-membered heteroaryl group, and the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, phenyl group, and 5- to 6-membered heteroaryl group are optionally substituted by one, two, or three R d . R5 is H, C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, or 3- to 6-membered heterocycloalkyl group, and the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, and 3- to 6-membered heterocycloalkyl group are optionally substituted by one, two, or three R e . R6, R7, R8, and R9 are each independently H, halogen, CN, NO2, OH, COOH, NH2, C 1-6 alkyl group, C 1-6A heteroalkyl group, C 3-6 selected from a cycloalkyl group and a 3- to 6-membered heterocycloalkyl group, wherein the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group and 3- to 6-membered heterocycloalkyl group are optionally substituted by one, two or three R f ; R 10 , R 11 and R 12 are each independently H, halogen, CN, NO2, OH, COOH, NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, wherein the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group are optionally substituted by one, two or three R g ; R a , R b , R c , R d , R e , R f and R g are each independently H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, C 1-8 alkyl group, C 1-8 heteroalkyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 cycloalkyl-C 1-3 alkyl-group, wherein the C 1-8 alkyl group, C 1-8 heteroalkyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 cycloalkyl-C 1-3 alkyl-group is optionally substituted by one, two or three R; R is independently selected from F, Cl, Br, I, OH, CN, NH2, COOH, Me, Et, CF3, CHF2, CH2F, NHCH3, and N(CH3)2, said C 1-6 The heteroalkyl group, 3- to 6-membered heterocycloalkyl group, and 5- to 6-membered heteroaryl group each contain one, two, three, or four heteroatoms or heteroatomic groups independently selected from -NH-, -O-, -S-, -O-N=, -C(=O)-O-, -C(=O)-S-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and N.

[0115] In some embodiments of the present invention, in the formula (I), R a , R b , R c , R d , R e , R f and R g are each independently H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group, and cyclopropyl group, and said C 1-6 alkyl group, C 1-6 heteroalkyl group, and cyclopropyl group are optionally substituted by one, two, or three Rs.

[0116] In some embodiments of the present invention, in the formula (I), R a , R b , R c , R d , R e , R f and R g are each independently selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, Me, Et, CF3, CHF2, CH2F, NHCH3, and N(CH3)2.

[0117] In some embodiments of the present invention, in the formula (I), R1 is H, F, Cl, Br, I, CN, COOH, NH2, C 1-3 alkyl group, and C 1-3heteroalkyl groups, 1-3 Alkyl groups and C 1-3 The heteroalkyl group may optionally contain one, two, or three R a is replaced by

[0118] In some embodiments of the present invention, in formula (I), R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, Me, Et, CF3, CHF2, CH2F, -NHCH3, and -N(CH3)2.

[0119] In some embodiments of the present invention, in formula (I), R2 is C 1-3 Alkyl groups and C 1-3 heteroalkyl groups, 1-3 Alkyl groups and C 1-3 The heteroalkyl group may optionally contain one, two, or three R b is replaced by

[0120] In some embodiments of the present invention, in formula (I) above, R2 is selected from Me, Et, CF3, CH2CF3, CHF2, CH2F, -NHCH3, and -N(CH3)2.

[0121] In some embodiments of the present invention, R3 is selected from H in formula (I) above.

[0122] In some embodiments of the present invention, in formula (I), R4 is COOH, NH2, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, -N(C 1-6 alkyl)2 groups, -C(=O)-OC 1-6 Alkyl group, -C(=O)-SC 1-6 Alkyl group, C 3-6 cycloalkyl-3 to 6-membered heterocycloalkyl group and phenyl group, 1-6 Alkyl group, -NH-C 1-6 Alkyl group, -N(C 1-6 alkyl)2 groups, -C(=O)-OC 1-6 Alkyl group, -C(=O)-SC 1-6 Alkyl group, C3-6 The cycloalkyl group, 3- to 6-membered hetero cycloalkyl group, and phenyl group are each optionally substituted by one, two, or three Rs d as follows.

[0123] In some embodiments of the present invention, in the formula (I), R4 is COOH, NH2, C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, and phenyl group.

[0124] In some embodiments of the present invention, in the formula (I), R4 is selected from -NHCH3 and -N(CH3)2.

[0125] In some embodiments of the present invention, in the formula (I), R5 is H, C 1-3 alkyl group, and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group are each optionally substituted by one, two, or three Rs e as follows.

[0126] In some embodiments of the present invention, in the formula (I), R5 is selected from H.

[0127] In some embodiments of the present invention, in the formula (I), R6, R7, R8, and R9 are each independently selected from H.

[0128] In some embodiments of the present invention, in the formula (I), R 10 , R 11 and R 12 are each independently H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, C 1-3 alkyl group, and C 1-3 heteroalkyl group, and the C 1-3An alkyl group and C 1-3 The heteroalkyl group is optionally substituted by one, two or three R g .

[0129] In some embodiments of the present invention, in the formula (I), R 10 , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, Me, Et, CF3, OMe, CHF2, CH2F, NHCH3 and N(CH3)2.

[0130] In some embodiments of the present invention, in the formula (I), ring A is selected from phenyl groups.

[0131] In some embodiments of the present invention, in the formula (I), the structural unit

Chemical formula

Chemical formula

[0132] In some embodiments of the present invention, in the formula (I), the structural unit

Chemical formula

Chemical formula

[0133] In some embodiments of the present invention, in the formula (I), the structural unit

Chemical formula

Chemical formula

[0134] In some embodiments of the present invention, the structural unit in the formula (I)

Chemical formula

Chemical formula

[0135] In some embodiments of the present invention, in the formula (I), R a , R b , R c , R d , R e , R f and R g are each independently H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, C 1-6 alkyl group, C 1-6 heteroalkyl group and cyclopropyl group, and the C 1-6 alkyl group, C 1-6 heteroalkyl group and cyclopropyl group are optionally substituted by one, two or three Rs, and the definitions of the present invention apply to other variables.

[0136] In some embodiments of the present invention, in the formula (I), R a , R b , R c , R d , R e , R f and R g are each independently selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, Me, Et, CF3, CHF2, CH2F, NHCH3 and N(CH3)2, and the definitions of the present invention apply to other variables.

[0137] In some embodiments of the present invention, in the formula (I), R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, C 1-3 alkyl group and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3The heteroalkyl group is optionally substituted by one, two or three Rs a and the definitions of the present invention apply to the other variables.

[0138] In some embodiments of the present invention, in the formula (I), R1 is selected from H, F, Cl, Br, I, CN, COOH, NH2, Me, Et, CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2, and the definitions of the present invention apply to the other variables.

[0139] In some embodiments of the present invention, in the formula (I), R2 is selected from a C 1-3 alkyl group and a C 1-3 heteroalkyl group, and the C 1-3 alkyl group and the C 1-3 heteroalkyl group are optionally substituted by one, two or three Rs b and the definitions of the present invention apply to the other variables.

[0140] In some embodiments of the present invention, in the formula (I), R2 is selected from Me, Et, CF3, CH2CF3, CHF2, CH2F, -NHCH3 and -N(CH3)2.

[0141] In some embodiments of the present invention, in the formula (I), R3 is selected from H, and the definitions of the present invention apply to the other variables.

[0142] In some embodiments of the present invention, in the formula (I), R4 is selected from COOH, NH2, a C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, a C 3-6 cycloalkyl-3- to 6-membered heterocycloalkyl group and a phenyl group, and the C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C1-6 An alkyl group, C 3-6 The cycloalkyl group, 3- to 6-membered heterocycloalkyl group, and phenyl group are each optionally substituted by one, two, or three Rs d and the definitions of the present invention apply to the other variables.

[0143] In some embodiments of the present invention, in the formula (I), R4 is COOH, NH2, C 1-6 alkyl group, -NH-C 1-6 alkyl group, -N(C 1-6 alkyl)2 group, -C(=O)-O-C 1-6 alkyl group, -C(=O)-S-C 1-6 alkyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, and phenyl group, and the definitions of the present invention apply to the other variables.

[0144] In some embodiments of the present invention, in the formula (I), R4 is selected from -NHCH3 and -N(CH3)2, and the definitions of the present invention apply to the other variables.

[0145] In some embodiments of the present invention, in the formula (I), R5 is H, C 1-3 alkyl group, and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group are each optionally substituted by one, two, or three Rs e and the definitions of the present invention apply to the other variables.

[0146] In some embodiments of the present invention, in the formula (I), R5 is selected from H, and the definitions of the present invention apply to the other variables.

[0147] In some embodiments of the present invention, in the formula (I), R6, R7, R8, and R9 are each independently selected from H, and the definitions of the present invention apply to the other variables.

[0148] In some embodiments of the present invention, in the formula (I), R 10 , R 11and R 12 is each independently H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, C 1-3 alkyl group and C 1-3 heteroalkyl group, and the C 1-3 alkyl group and C 1-3 heteroalkyl group is optionally substituted by one, two or three R g and the definitions of the present invention apply to the other variables.

[0149] In some embodiments of the present invention, in the formula (I), R 10 , R 11 and R 12 are each independently selected from H, F, Cl, Br, I, CN, NO2, OH, COOH, NH2, Me, Et, CF3, OMe, CHF2, CH2F, NHCH3 and N(CH3)2, and the definitions of the present invention apply to the other variables.

[0150] In some embodiments of the present invention, in the formula (I), ring A is selected from phenyl groups, and the definitions of the present invention apply to the other variables.

[0151] In some embodiments of the present invention, in the formula (I), the structural unit

Chemical formula

Chemical formula

[0152] In some embodiments of the present invention, in the formula (I), the structural unit

Chemical formula

Chemical formula

[0153] In some embodiments of the present invention, the structural unit in the formula (I)

Chemical formula

Chemical formula

[0154] In some embodiments of the present invention, the structural unit in the formula (I)

Chemical formula

Chemical formula

[0155] Some technical solutions of the present invention are composed of arbitrarily combining the above variables.

[0156] Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

[0157] Furthermore, the present invention provides a method for treating estrogen receptor-related diseases and symptoms in mammals, preferably humans, comprising administering a therapeutically effective amount of the compound, its isomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0158] Furthermore, the present invention provides the use of the compound, its isomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for manufacturing a therapeutic drug for estrogen receptor-related diseases and symptoms.

[0159] Furthermore, the present invention provides the use of the compound, its isomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition for treating estrogen receptor-related diseases and symptoms.

[0160] Furthermore, the present invention provides the compound, its isomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition for treating estrogen receptor-related diseases and symptoms.

[0161] Furthermore, the present invention provides the use of the compound, its isomers or pharmaceutically acceptable salts thereof for manufacturing an estrogen receptor inhibitor.

[0162] Furthermore, the present invention provides the use of the composition for manufacturing an estrogen receptor inhibitor.

[0163] In some embodiments of the present invention, the estrogen receptor-related diseases and symptoms are breast cancer.

[0164] In some embodiments of the present invention, the breast cancer is estrogen receptor-positive breast cancer.

[0165] Furthermore, the present invention provides the use of the compound, its isomers or pharmaceutically acceptable salts thereof for manufacturing a therapeutic drug for estrogen receptor-positive breast cancer.

Advantages of the Invention

[0166] The compound of the present invention has an excellent inhibitory effect on cytochrome P450. Clinically, drug combination is expected. The compound of the present invention can be used for treating diseases related to the estrogen signaling pathway, such as breast cancer and other diseases.

[0167] The compound of the present invention generally has excellent anti-proliferative activity against breast cancer cell MCF7.

[0168] The compounds of the present invention have excellent properties in in vitro ADME. They are excellent in hepatic microsomal metabolic stability (PPB) and have a small interspecies difference. They have excellent inhibitory activities against CYP1A2, CYP2C9, CYP2C19, CYP2D6, etc. Clinically, the risk of drug-drug interaction (DDI) is clearly reduced, and they also have excellent permeability.

[0169] Regarding the in vivo PK properties, the compounds of the present invention have excellent pharmacokinetic properties. As can be seen from the PK experimental results of mice and rats, it is suggested from the apparent volume of distribution (Vdss) of the compounds of the present invention that they have a wider tissue distribution. The compounds of the present invention are excellent in terms of oral exposure and bioavailability. In the mouse MCF7 breast cancer efficacy test, it was found that the compounds of the present invention are excellent in tumor shrinkage effect.

[0170] In addition, in the uterine wet weight inhibition experiment of young rats, the results showed that the compounds of the present invention can clearly inhibit the uterine growth of rats. Since the risk of endometrial thickening or endometrial cancer is small, it can be said that the safety is high. "Related Terms and Definitions"

[0171] Unless otherwise specified, the following terms and expressions used in this specification have the following meanings. When a specific term or expression is not specially defined, it is not uncertain or unclear, but is understood in the ordinary sense. When a trade name is described in this specification, it means the corresponding product or its active ingredient.

[0172] As used in this specification, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human or animal tissues, are non-toxic and non-irritating, and are medically determined not to cause allergic reactions, other problems or complications, and for which the benefit-risk is reasonable.

[0173] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention produced with an acid or base that is relatively non-toxic relative to the compounds having the specific substituents according to the present invention. When a functional group that is relatively acidic relative to the compound of the present invention is included, a base addition salt is obtained by contacting the compound with a sufficient amount of a base in a solution free of impurities or a suitable inert solvent.

[0174] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid groups or bases by ordinary chemical methods. Generally, the method for preparing such salts is to react the free acid or free base forms of these compounds with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both.

[0175] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. This class of compounds according to the present invention includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, for example, mixtures rich in enantiomers or diastereomers, and all of these mixtures are included within the scope of the present invention. Substituents such as alkyl groups may have another asymmetric carbon atom. All of the above isomers and their mixtures are included within the scope of the present invention.

[0176] 1] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

[0177] Unless otherwise specified, the terms "cis / trans isomer" or "geometric isomer" are caused by the fact that the double bond or the single bond of the ring-forming carbon atoms cannot rotate freely.

[0178] Unless otherwise specified, the term "diastereomer" refers to stereoisomers having two or more chiral centers and whose molecules are non-mirror images of each other.

[0179] Unless otherwise specified, “(+)” represents dextrorotation, “(-)” represents levorotation, and “(±)” represents a racemate.

[0180] Unless otherwise specified, a wedge-shaped solid line bond ( TIFF0007716980000078.tif8158) and a wedge-shaped dashed line bond ( TIFF0007716980000079.tif8158) are used to represent the absolute configuration of a chiral center, a linear solid line bond ( TIFF0007716980000080.tif8158) and a linear dashed line bond ( TIFF0007716980000081.tif8158) are used to represent the relative configuration of a chiral center, a wavy line ( TIFF0007716980000082.tif8158) is used to represent a wedge-shaped solid line bond ( TIFF0007716980000083.tif8158) or a wedge-shaped dashed line bond ( TIFF0007716980000084.tif8158), or a wavy line ( TIFF0007716980000085.tif8158) is used to represent a linear solid line bond ( TIFF0007716980000086.tif8158) and a linear dashed line bond ( TIFF0007716980000087.tif8158).

[0181] Unless otherwise specified, when a compound has a double bond structure such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond has two different substituents attached (for a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is regarded as a substituent attached to it), for the compound, the atoms on the double bond and their substituents are connected by a wavy line ( Connected by (TIFF0007716980000088.tif8158) represents the (Z)-isomer, (E)-isomer or a mixture of two isomers of the said compound. For example, the said compound represented by the following formula (A) exists as either of the isomers of formula (A-1) or formula (A-2) or as a mixture of two isomers of formula (A-1) and formula (A-2). The said compound represented by the following formula (B) exists as either of the isomers of formula (B-1) or formula (B-2) or as a mixture of two isomers of formula (B-1) and formula (B-2). The said compound represented by the following formula (C) exists as either of the isomers of formula (C-1) or formula (C-2) or as a mixture of two isomers of formula (C-1) or formula (C-2). [Chemical formula] [Chemical formula] [Chemical formula]

[0182] Specific tautomers or tautomeric forms may exist for the compounds of the present invention. Unless otherwise specified, the terms "tautomer" or "tautomeric form" refer to isomers of different functional groups that are in a state of dynamic balance at room temperature and can be rapidly converted from one to the other. When tautomers are recognized (e.g., in a solution), a chemical equilibrium is established between the tautomers. For example, proton tautomers (also called prototropic tautomers) include interconversions made by the transfer of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions made by the recombination of some of the electrons forming the bonds. A specific example of keto-enol interconversion is the conversion between the tautomer pentane-2,4-dione and 4-hydroxy-3-penten-2-one.

[0183] Unless otherwise specified, the terms "containing a large amount of isomers", "containing a large amount of enantiomers", "containing a large amount of enantiomers", or "containing a large amount of enantiomers" mean that the content of a specific isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more, and less than 100%.

[0184] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" relate to the difference in the relative percentage content of two isomers or two enantiomers. For example, when the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80%.

[0185] Optically active (R)- and (S)-isomers, and D- and L-isomers can be synthesized by asymmetric synthesis, asymmetric reagents or other conventional techniques. To obtain the enantiomers of a specific compound of the present invention, it may be synthesized by asymmetric synthesis or induction with an asymmetric auxiliary. The diastereomeric mixture of the product is separated, and the auxiliary functional group is removed to obtain the pure product of the desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxy group), an optically active appropriate acid or base is formed with the salt of the diastereomer, and then the diastereomers are resolved by a conventional method well known in the art to obtain a pure enantiomer. In addition, the separation of enantiomers and diastereomers is generally carried out by chromatography, and a chiral stationary phase is used for chromatography, which may be optionally combined with a chemical induction method (e.g., carbamate formation from an amine). The compounds of the present invention may contain isotopes of the atoms in the compound at a non-natural ratio in one or more atoms constituting the compound. For example, the compound is tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14It may be labeled with radioisotopes such as C). Alternatively, hydrogen may be replaced with deuterium to form a deuterated drug. The bond composed of deuterium and carbon is more robust than the normal bond composed of hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reduced toxicity and side effects, improved drug stability and therapeutic effect, and extended biological half-life of the drug. Variants containing isotopes of the compounds of the present invention are all included in the scope of the present invention regardless of whether they are radioactive. The term "optional" or "optionally" means that the matters or situations described subsequently may occur but do not necessarily occur, and the description includes both the cases where the said events or situations occur and the cases where the said matters or situations do not occur.

[0186] The term "substituted" means that any one or more hydrogen atoms (including deuterium and variants of hydrogen) on the atom are substituted by a substituent on the condition that the valence of the specific atom is normal and the compound after substitution is stable. When the substituent is oxygen (=O), two hydrogen atoms will be substituted. Oxygen substitution is not performed on aryl groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and quantity of the substituent are not limited within the chemically achievable range.

[0187] When a specific variable (e.g., R) appears one or more times in the composition or structure of a compound, an independent definition is used each time it appears. Therefore, for example, when a functional group is substituted by 0 to 2 Rs, the said functional group may optionally be substituted by up to 2 Rs, and moreover, each R is independently selected. Also, the combination of substituents and / or their variants is recognized only when a stable compound is formed by the said combination.

[0188] For example, when the number of connecting functional groups is 0 as in -(CRR)0-, it means that the said connecting functional group is a single bond.

[0189] When a variable is a single bond, it represents that two functional groups connected through it are directly connected. For example, when L is a single bond in A-L-Z, it represents that the structure is A-Z.

[0190] When a substituent is not shown, it represents that the substituent does not exist. For example, when X is not shown in A-X, it represents that the structure is A.

[0191] When one substituent is cross-linked to two or more atoms of a ring through a bond, the substituent may be bonded to any atom of the ring. For example, for the structural unit

Chemical formula

[0192] When it is not specified which atom of a specific substituent is connected to the target functional group through, the substituent may be bonded through any of its atoms. For example, a pyridyl substituent may be connected to the target functional group through any one carbon atom of the pyridine ring.

[0193] When the connection direction is not indicated by the described connecting functional group, it is connected in any direction. For example,

Chemical formula

Chemical formula

Chemical formula

[0194] Unless otherwise specified, when a target group has one or more connectable sites, any one or more sites of the group can be connected to other groups via a chemical bond. The chemical bond connecting to other groups at the site can be represented by a linear solid bond ( TIFF0007716980000096.tif8158), a linear dashed bond ( TIFF0007716980000097.tif8158), or a wavy line ( TIFF0007716980000098.tif8158). For example, in -OCH3, the linear solid bond represents that it is connected to other groups through the oxygen atom of the group.

Chemical formula

Chemical formula

[0195] Unless otherwise defined, the number of atoms in a ring is defined as the ring member number. For example, "5- to 7-membered ring" means a "ring" composed of 5 to 7 atoms arranged in a ring.

[0196] Unless otherwise specified, the term "C 1-8 alkyl group" represents a straight-chain or branched saturated hydrocarbon group consisting of 1 to 8 carbon atoms. The C 1-8 alkyl group is C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4, including C8, C7, C6, C5 alkyl groups, etc., may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). C 1-8 Examples of alkyl groups include, but are not limited to, methyl group (Me), ethyl group (Et), propyl group (including n-propyl group and isopropyl group), butyl group (including n-butyl group, isobutyl group, s-butyl group, t-butyl group), pentyl group (including n-pentyl group, isopentyl group, neopentyl group), hexyl group, heptyl group, octyl group, etc.

[0197] Unless otherwise specified, the term "C 1-6 alkyl group" refers to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The above C 1-6 alkyl group may be C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , including C6, C5 alkyl groups, etc., may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). C 1-6 Examples of alkyl groups include, but are not limited to, methyl group (Me), ethyl group (Et), propyl group (including n-propyl group and isopropyl group), butyl group (including n-butyl group, isobutyl group, s-butyl group, t-butyl group), pentyl group (including n-pentyl group, isopentyl group, neopentyl group), hexyl group, etc.

[0198] Unless otherwise specified, the term "C 1-3 alkyl group" refers to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The above C 1-3 alkyl group may be C 1-2 , C 2-3 alkyl group, etc., may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). C 1-3Examples of alkyl groups include, but are not limited to, methyl group (Me), ethyl group (Et), propyl group (including n-propyl group and isopropyl group), etc. Unless otherwise specified, "C 2-8 alkenyl group" means a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond and consisting of 2 to 8 carbon atoms, and the carbon-carbon double bond may be at any position of the group. The C 2-8 alkenyl group is C 2-6 、C 2-4 、C 2-3 、C4, C3, C2 alkenyl groups, etc., and may be monovalent, divalent or polyvalent. Examples of C 2-8 alkenyl groups include, but are not limited to, ethenyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, m-butadienyl group, m-pentadienyl group, m-hexadienyl group, etc.

[0199] The term "heteroalkyl group", alone or in combination with another term, represents a stable straight-chain or branched alkyl group atom group or a combination thereof consisting of a predetermined number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, and among them, nitrogen atoms and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Also in some embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 heteroalkyl group, and in some embodiments, the heteroalkyl group is C 1-3It is a heteroalkyl group. The heteroatom or heteroatomic group may be located at any position within the heteroalkyl group, such as the connection position to the remaining part of the molecule of the alkyl group. The terms "alkoxy group", "alkylamino group" and "alkylthio group (also called thioalkoxy group)" are conventional expressions, each referring to an alkyl functional group connected to the remaining part of the molecule via one oxygen atom, amino group or sulfur atom. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH-A-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3. The maximum number of connected heteroatoms is two, for example, -CH2-NH-OCH3.

[0200] Unless otherwise specified, the term "halo" or "halogen" represents a fluorine atom, chlorine atom, bromine atom or iodine atom, either by itself or as part of another substituent.

[0201] Unless otherwise specified, "C 3-6 cycloalkyl group" represents a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. The C 3-6 cycloalkyl group is C 3-5 、C 4-5 、C 5-6 cycloalkyl groups, etc., and may be monovalent, divalent or polyvalent. Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.

[0202] Unless otherwise specified, "C 3-5The "cycloalkyl group" represents a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, and the said C 3-5 The cycloalkyl group is C 3-4 , C 4-5 including cycloalkyl groups etc., and may be monovalent, divalent or polyvalent. C 3-5 Examples of the cycloalkyl group include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group etc.

[0203] Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl group", by itself or in combination with other terms, represents a saturated cyclic group consisting of 3 to 6 ring atoms, one, two, three or four of which are independently heteroatoms selected from O, S and N, and the rest are carbon atoms. Among them, the nitrogen atom may be optionally quaternized, and the nitrogen atom and sulfur atom may be optionally oxidized (i.e., NO, S(O) pwherein p is 1 or 2). It includes monocyclic and bicyclic ring systems, among which the bicyclic ring system includes spiro rings, fused rings, and bridged rings. For the "3- to 6-membered heterocycloalkyl group", the heteroatom may be located at a position connected to the remaining part of the heterocycloalkyl group molecule. The 3- to 6-membered heterocycloalkyl group includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, 6-membered heterocycloalkyl groups, etc. Examples of the 3- to 6-membered heterocycloalkyl group include azetidinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, tetrahydrothienyl group (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl group (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl group, piperidinyl group (including 1-piperidinyl group, 2-piperidinyl group, 3-piperidinyl group, etc.), piperazinyl group (including 1-piperazinyl group, 2-piperazinyl group, etc.), morpholinyl group (including 3-morpholinyl group, 4-morpholinyl group, etc.), dioxane group, dithiane group, isoxazolidinyl group, isothiazolidinyl group, 1,2-oxazinyl group, 1,2-thiazinyl group, hexahydropyridazinyl group, homopiperazinyl group, homopiperidinyl, etc., and is not limited thereto.

[0204] Unless otherwise specified, in the present invention, the term "C" 6-10 aromatic ring" and "C" 6-10 aryl group" can be used interchangeably. The term "C" 6-10 aromatic ring" or "C" 6-10 aryl group" represents a cyclic hydrocarbon group having a conjugated π-electron system consisting of 6 to 10 carbon atoms, which may be monocyclic, fused bicyclic, or fused tricyclic ring systems, and each ring is an aromatic ring. It may be monovalent, divalent, or polyvalent. The C 6-10 aryl group includes C 6-9 , C9, C 10 , C6 aryl groups, etc. Examples of the C 6-10 aryl group include phenyl group, naphthyl group (including 1-naphthyl group, 2-naphthyl group, etc.), and is not limited thereto.

[0205] Unless otherwise specified, in the present invention, the terms "5- to 10-membered heteroaromatic ring" and "5- to 10-membered heteroaryl group" can be used interchangeably. The term "5- to 10-membered heteroaryl group" represents a cyclic group having a conjugated π electron system consisting of 5 to 10 ring atoms, one, two, three, or four of which are independently heteroatoms selected from O, S, and N, and the rest are carbon atoms. It may be a monocyclic, fused bicyclic, or fused tricyclic ring system, and each ring is an aromatic ring. Among them, the nitrogen atom may be optionally quaternized, and the nitrogen atom and sulfur atom may be optionally oxidized (i.e., NO, S(O) pwherein p is 1 or 2). The 5- to 10-membered heteroaryl group may be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5- to 10-membered heteroaryl group includes 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered, 6-membered heteroaryl groups, etc. Examples of the 5- to 10-membered heteroaryl group include a pyrrolyl group (including an N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, etc.), a pyrazolyl group (including a 2-pyrazolyl group, 3-pyrazolyl group, etc.), an imidazolyl group (including an N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, etc.), an oxazolyl group (including a 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, etc.), a triazolyl group (including a 1H-1,2,3-triazolyl group, 2H-1,2,3-triazolyl group, 1H-1,2,4-triazolyl group, 4H-1,2,4-triazolyl group, etc.), a tetrazolyl group, an isoxazolyl group (including a 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, etc.), a thiazolyl group (including a 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, etc.), a furyl group (including a 2-furyl group, 3-furyl group, etc.), a thienyl group (including a 2-thienyl group, 3-thienyl group, etc.), a pyridinyl group (including a 2-pyridinyl group, 3-pyridinyl group, 4-pyridinyl group, etc.), a pyrazinyl group, a pyrimidinyl group (including a 2-pyrimidinyl group, 4-pyrimidinyl group, etc.), a benzothiazolyl group (including a 5-benzothiazolyl group, etc.), a purinyl group, a benzimidazolyl group (including a 2-benzimidazolyl group, etc.), a benzoxazolyl group, an indolyl group (including a 5-indolyl group, etc.), an isoquinolinyl group (including a 1-isoquinolinyl group, 5-isoquinolinyl group, etc.), a quinoxalinyl group (including a 2-quinoxalinyl group, 5-quinoxalinyl group, etc.), a quinolinyl group (including a 3-quinolinyl group, 6-quinolinyl group, etc.), and are not limited thereto.

[0206] Unless otherwise specified, in the present invention, the terms "5- or 6-membered heteroaromatic ring" and "5- or 6-membered heteroaryl group" can be used interchangeably. The term "5- or 6-membered heteroaryl group" represents a monocyclic group having a conjugated π-electron system consisting of 5 or 6 ring atoms, one, two, three, or four of which are independently heteroatoms selected from O, S, and N, and the rest are carbon atoms. Among them, the nitrogen atom can be optionally quaternized, and the nitrogen atom and sulfur atom can be optionally oxidized (i.e., NO, S(O) p where p is 1 or 2). The 5- or 6-membered heteroaryl group can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5- or 6-membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5- or 6-membered heteroaryl group include pyrrolyl groups (including N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, etc.), pyrazolyl groups (including 2-pyrazolyl group, 3-pyrazolyl group, etc.), imidazolyl groups (including N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, etc.), oxazolyl groups (including 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, etc.), triazolyl groups (including 1H-1,2,3-triazolyl group, 2H-1,2,3-triazolyl group, 1H-1,2,4-triazolyl group, 4H-1,2,4-triazolyl group, etc.), tetrazolyl groups, isoxazolyl groups (including 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, etc.), thiazolyl groups (including 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, etc.), furyl groups (including 2-furyl group, 3-furyl group, etc.), thienyl groups (including 2-thienyl group, 3-thienyl group, etc.), pyridinyl groups (including 2-pyridinyl group, 3-pyridinyl group, 4-pyridinyl group, etc.), pyrazinyl groups or pyrimidinyl groups (including 2-pyrimidinyl group, 4-pyrimidinyl group, etc.), and are not limited thereto.

[0207] Unless otherwise specified, C n-n+m or C n -C n+m includes any numerical value among n to n + m carbons. For example, C 1-12includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 and includes any range from n to n + m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , C 9-12 and so on. Similarly, n to n + m members represent that the number of ring atoms is from n to n + m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and includes any range from n to n + m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, a 6- to 10-membered ring, and so on.

[0208] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, typical leaving groups include trifluoromethanesulfonate, chlorine, bromine, iodine, sulfonic acid ester groups (e.g., methanesulfonic acid ester, toluenesulfonic acid ester, p-bromobenzenesulfonic acid ester, p-toluenesulfonic acid ester, etc.), and acyloxy groups (e.g., acetoxy group, trifluoroacetoxy group, etc.).

[0209] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group", and "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen site of an amino group. Representative amino protecting groups include, but are not limited to, formyl group, acyl group (e.g., alkanoyl group (e.g., acetyl group, trichloroacetyl group, trifluoroacetyl group)), alkoxycarbonyl group (e.g., t-butoxycarbonyl group (Boc)), arylmethyloxycarbonyl group (e.g., benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl group (Fmoc)), arylmethyl group (e.g., benzyl group (Bn), trityl group (Tr), 1,1-di-(4'-methoxyphenyl)methyl), silyl group (e.g., trimethylsilyl group (TMS), t-butyldimethylsilyl group (TBS)), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of a hydroxy group. Representative hydroxy protecting groups include, but are not limited to, alkyl group (e.g., methyl group, ethyl group, t-butyl group), acyl group (e.g., alkanoyl group (e.g., acetyl group)), arylmethyl group (e.g., benzyl group (Bn), p-methoxybenzyl group (PMB), 9-fluorenylmethyl group (Fm), diphenylmethyl group (DPM)), silyl group (e.g., trimethylsilyl group (TMS), t-butyldimethylsilyl group (TBS)), etc.

[0210] The compounds of the present invention can be synthesized by various synthetic methods well known to those skilled in the art, including the following specific embodiments, embodiments combined with other chemical synthesis methods, and alternative replacement forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0211] The compounds in the present invention are named based on the ordinary naming rules in this field or using ChemDraw®. Commercially available compounds conform to the names in the catalogs provided by the manufacturers.

Embodiments for Carrying out the Invention

[0212] Next, the present invention will be described in detail using examples. This is not intended to impose any limitation on the present invention.

[0213] As those skilled in the art will understand, in each reaction process for synthesizing the compounds of the present invention, the order of steps may be interchanged. This is included within the scope of the present invention.

[0214] (Example 1) [Chemical formula] [Chemical formula]

[0215] In Step A, under -75°C and nitrogen protection, n-butyllithium (2.5 M, 428.40 mL, 1.05 eq) was slowly added dropwise to a solution of Compound 1-1 (100.00 g, 1.02 mol, 140.85 mL, 1.00 eq) in tetrahydrofuran (500 mL) over 1 hour. After raising the temperature of the reaction solution to 0°C and stirring for 10 minutes, the temperature was lowered to -75°C, and then hexamethylphosphoric triamide (201.06 g, 1.12 mol, 197.12 mL, 1.10 eq) was added over 1 hour. After stirring the reaction solution at -75°C for 1 hour, ethyl iodide (198.86 g, 1.27 mol, 101.98 mL, 1.25 eq) was added over 1 hour, and then the temperature was raised to 20°C and reacted for 10 hours. Then, 400 mL of water was added, and the layers were separated. The organic phase was washed three times with 400 mL of water, dried over anhydrous sodium sulfate, filtered, and distilled to obtain Product 1-2.

[0216] In Step B, dimethylaminopyridine (3.65 g, 29.88 mmol, 0.10 eq) and Boc2O (68.46 g, 313.70 mmol, 72.07 mL, 1.05 eq) were added to a solution of Compound 1-3 (35.00 g, 298.76 mmol, 1.00 eq) in dichloromethane (400 mL). After reacting the reaction solution at 20°C for 12 hours, it was extracted twice with 400 mL of ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Product 1-4.

[0217] In step C, under -75°C and nitrogen protection, lithium diisopropylamide (2M, 75.95 mL, 1.10 eq) was slowly added dropwise to a solution of compound 1-4 (30.00 g, 138.08 mmol, 1.00 eq) in tetrahydrofuran (400 mL). After stirring the reaction solution at -75°C for 30 minutes, cyanogen bromide (55.40 g, 523.04 mmol, 38.47 mL, 3.79 eq) was added. Then, the temperature was raised to 15°C and reacted for 12 hours. 400 mL of water was added, and liquid separation was performed. The organic phase was washed three times with 300 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 50:1, v / v) to obtain product 1-5.

[0218] In step D, cesium carbonate (85.81 g, 263.38 mmol, 2.00 eq), cuprous iodide (1.25 g, 6.58 mmol, 0.05 eq), palladium acetate (1.48 g, 6.58 mmol, 0.05 eq), and 1,1'-bis(diphenylphosphino)ferrocene (3.65 g, 6.58 mmol, 0.05 eq) were added to a solution of product 1-5 (39.00 g, 131.69 mmol, 1.00 eq) in N,N-dimethylacetamide (300 mL). Then, under nitrogen protection, compound 1-2 (33.26 g, 263.38 mmol, 2.00 eq) was added. After reacting the reaction solution at 80°C for 12 hours, 1 L of ethyl acetate and 1 L of water were added, filtered and separated by liquid separation. The organic layer was extracted three times with 1 L of water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 30:1, v / v) to obtain product 1-6.

[0219] In step E, potassium carbonate (69.27 g, 501.25 mmol, 5.00 eq) was added to a solution of methanol (300 mL) and water (15 mL) containing product 1-6 (27.00 g, 100.25 mmol, 1.00 eq). After reacting the reaction solution at 70 °C for 12 hours, it was filtered and concentrated, 300 mL of ethyl acetate was added, and it was extracted twice with 300 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 - 30:1, v / v) to obtain product 1-7. MS[ESI,M+1]: 170.1.

[0220] In step F, bis(pinacolato)diboron (600.25 mg, 2.36 mmol, 1.00 eq) and (T-4)-tetrakis(triphenylphosphine)platinum (58.82 mg, 47.28 μmol, 0.02 eq) were added to a solution of product 1-7 (400 mg, 2.36 mmol, 1.00 eq) in 2-methyltetrahydrofuran (5 mL). After reacting the reaction solution at 85 °C under nitrogen protection for 7 hours, it was cooled to room temperature to obtain compound 1-8, which was used directly in the next step reaction without purification. MS[ESI,M+1]: 424.3.

[0221] In step G, compound 1-9 (791 mg, 1.66 mmol, 0.7 eq, for the synthesis method of this compound, refer to US20160347717A1), cesium carbonate (1.08 g, 3.33 mmol, 2.00 eq) and bis(triphenylphosphine)palladium(II) dichloride (58.41 mg, 83.21 μmol, 0.05 eq) were added to a solution of compound 1-8 (1.0 g, 2.36 mmol, 1.00 eq) in 2-methyltetrahydrofuran (5 mL) at room temperature. The reaction system was replaced with nitrogen three times and water (0.2 mL) was added. The reaction solution was reacted at 30 °C under nitrogen protection for 12 hours to obtain product 1-10, which was used directly in the next step reaction without purification. MS[ESI,M+1]: 645.5.

[0222] In step H, to a solution of compound 1-10 (1.07 g, 1.66 mmol, 1.00 eq) in 2-methyltetrahydrofuran (5 mL) were added 2-chloro-4-fluorobenzene iodide (510.81 mg, 1.99 mmol, 1.2 eq) and potassium hydroxide solution (4 M, 2.9 mL, 7.00 eq), and the reaction system was replaced with nitrogen three times. After reacting the reaction solution at 85 °C under nitrogen protection for 6 hours, bis(triphenylphosphine)palladium(II) dichloride (58.25 mg, 83 μmol, 0.05 eq) was added to the reaction system, and the reaction was continued at 85 °C under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature, 10 mL of water and 10 mL of ethyl acetate were added, the aqueous phase was extracted three times with 10 mL of ethyl acetate, and the combined organic phases were extracted once with 50 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1, v / v) to obtain compound 1-11. MS[ESI,M+1]: 647.2.

[0223] In step I, N-chlorosuccinimide (171.83 mg, 1.29 mmol, 1.2 eq) was added to a solution of compound 1-11 (694 mg, 1.07 mmol, 1.00 eq) in dichloromethane (40 mL). The reaction solution was reacted at 25 °C for 1 hour. The reaction solution was washed twice with 30 mL of saturated sodium bisulfite, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 1-12. MS[ESI,M+1]: 681.1.

[0224] In step J, 8 mL of trifluoroacetic acid (TFA) was added to a solution of product 1-12 (621 mg, 911.06 μmol, 1.00 eq) in dichloromethane (8 mL). The reaction solution was reacted at 25 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) to obtain compound 1. MS[ESI,M+1]: 581.1. 11H NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 7.77 - 7.69 (m, 1H), 7.69 - 7.61 (m, 1H), 7.35 (dd, J = 2.4, 8.8 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.25 - 7.11 (m, 3H), 7.07 (dd, J = 2.4, 8.4 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.60 - 6.55 (m, 2H), 6.51 - 6.44 (m, 1H), 5.81 (br s, 2H), 4.39 (br s, 2H), 3.70 (br d, J = 4.4 Hz, 2H), 3.28 (br s, 2H), 2.97 (s, 3H), 2.92 (s, 3H), 2.68 - 2.48 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H).

[0225] (Example 2) [Chemical formula]

[0226] In Step A, to a solution of Compound 1-10 (1.07 g, 1.66 mmol, 1.00 eq) in 2-methyltetrahydrofuran (5 mL) were added 2-iodobenzonitrile (760.3 mg, 3.32 mmol, 2 eq), an aqueous solution of potassium hydroxide (4 M, 2.90 mL, 7 eq), and bis(triphenylphosphine)palladium(II) dichloride (58.25 mg, 83 μmol, 0.05 eq), and the mixture was purged with nitrogen three times. The reaction was carried out under nitrogen protection at 85 °C for 8 hours. Bis(triphenylphosphine)palladium(II) dichloride (58.25 mg, 83 μmol, 0.05 eq) was added to the reaction system, and the reaction was continued at 85 °C for 24 hours. The reaction solution was diluted with 5 mL of water and 15 mL of ethyl acetate, and extracted three times with ethyl acetate, using 15 mL each time. The combined organic phases were washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (PE:EA = 5:1 to 1:2) to obtain Compound 2-1. MS [ESI, M+1]: 620.4.

[0227] In step B, N-chlorosuccinimide (152.55 mg, 1.14 mmol, 1.2 eq) was added to a solution of compound 2-1 (590 mg, 952 μmol, 1.00 eq) in dichloromethane (10 mL). The reaction mixture was reacted at 25 °C for 2 hours. The reaction mixture was washed twice with 10 mL of saturated sodium bisulfite, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 2-2. MS[ESI,M+1]: 654.3.

[0228] In step C, 7 mL of trifluoroacetic acid was added to a solution of product 2-2 (584 mg, 892.70 μmol, 1.00 eq) in dichloromethane (7 mL). The reaction mixture was reacted at 25 °C for 1 hour. The reaction mixture was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.05% ammonium hydroxide, v / v) / acetonitrile system) to obtain compound 2. MS[ESI,M+1]: 554.3. 1 H NMR(400MHz,CDCl3) 8.54(br s,1H), 7.62 - 7.56(m,2H), 7.49 - 7.48(m,2H), 7.35(br d,J = 7.2Hz,1H), 7.27 - 7.22(m,2H), 7.19 - 7.13(m,3H), 6.75 - 6.71(m,1H), 6.40 - 6.30(m,2H), 4.18(br s,2H), 3.34(br d,J = 3.6Hz,2H), 2.96(br s,3H), 2.91(br s,3H), 2.85(br s,2H), 2.71 - 2.42(m,2H), 0.92(br t,J = 6.8Hz,3H).

[0229] (Example 3)

Chemical Structure

[0230] In step A, under a nitrogen atmosphere, 54.44 mg (77.57 μmol, 0.1 eq) of bis(triphenylphosphine)palladium(II) dichloride was added to a 10 mL solution of 2-methyltetrahydrofuran and 3 mL of aqueous solution containing Compound 1-10 (500 mg, 775.67 μmol, 1.00 eq), iodobenzene (205.71 mg, 1.01 mmol, 112.41 μL, 1.3 eq) and potassium hydroxide (261.12 mg, 4.65 mmol, 6 eq), and the mixture was purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours under nitrogen protection. The reaction solution was diluted with 20 mL of water to cause stratification, and extracted three times with ethyl acetate, using 50 mL each time. The combined organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.1% formic acid, v / v) / acetonitrile system) to obtain Compound 3-1. MS[ESI,M+1]: 595.3.

[0231] In step B, under nitrogen protection, N-chlorosuccinimide (17.96 mg, 134.51 μmol, 1 eq) was added to a dichloromethane (5 mL) solution of Compound 3-1 (80 mg, 134.51 μmol, 1 eq). The reaction solution was reacted at 20 °C for 1 hour. The reaction solution was quenched with 2 mL of saturated sodium bisulfite to cause stratification, and the aqueous phase was extracted three times with ethyl acetate, using 20 mL each time. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Product 3-2. MS[ESI,M+1]: 629.3.

[0232] In step C, under a nitrogen atmosphere, 1 mL of trifluoroacetic acid was added to a dichloromethane (5 mL) solution of Product 3-2 (90 mg, 143.04 μmol, 1 eq). The reaction solution was reacted at 20 °C for 10 minutes. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) and then (water (0.05% ammonium hydroxide, v / v) / acetonitrile system) to obtain Compound 3. MS[ESI,M+1]: 529.1. 1 1H NMR (400 MHz, methanol-d4) δ = 7.67 (d, J = 2.4 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 - 7.09 (m, 8H), 6.77 (td, J = 5.6, 15.2 Hz, 1H), 6.59 - 6.50 (m, 2H), 4.25 (br t, J = 4.8 Hz, 2H), 3.43 (br dd, J = 2.0, 4.0 Hz, 2H), 3.07 (d, J = 2.0 Hz, 3H), 2.96 (d, J = 0.8 Hz, 3H), 2.94 - 2.88 (m, 2H), 2.55 (q, J = 7.6 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0233] The pH of Compound 3 was adjusted to 3 with 1 M hydrochloric acid solution, and the solvent was removed under reduced pressure to obtain the monohydrochloride of Compound 3. 1 1H NMR (400 MHz, DMSO-d6) 11.57 (s, 1H), 9.43 (br s, 2H), 7.67 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.27 - 7.11 (m, 6H), 6.83 (d, J = 15.2 Hz, 1H), 6.67 - 6.53 (m, 2H), 4.39 (t, J = 5.2 Hz, 2H), 3.77 (br d, J = 5.2 Hz, 2H), 3.28 - 3.19 (m, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 2.48 - 2.42 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0234] (Example 4) [Chemical formula]

[0235] In step A, under a nitrogen atmosphere, 10 mL of 2-methyltetrahydrofuran and 3 mL of aqueous solution containing compound 1-10 (500 mg, 775.67 μmol, 1.00 eq), 1-bromo-3-methoxybenzene (188.60 mg, 1.01 mmol, 127.43 μL, 1.3 eq) and potassium hydroxide (261.12 mg, 4.65 mmol, 6 eq) were added with bis(triphenylphosphine)palladium(II) dichloride (54.44 mg, 77.57 μmol, 0.1 eq), and the mixture was purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours under nitrogen protection. The reaction solution was diluted with 20 mL of water to form layers, and extracted three times with ethyl acetate, 50 mL each time. The combined organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.1% formic acid, v / v) / acetonitrile system) to obtain compound 4-1. MS[ESI,M+1]: 625.3.

[0236] The operations of steps B and C refer to steps B and C in the synthesis of compound 3, and compound 4-2 (MS[ESI,M+1]: 625.3) and crude product 4 were obtained respectively. The crude product was separated by preparative HPLC (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) and (water (0.05% ammonium hydroxide, v / v) / acetonitrile system) to obtain compound 4. MS[ESI,M+1]: 559.1. 11H NMR (400 MHz, DMSO-d6) δ = 11.45 (br s, 1H), 7.70 - 7.60 (m, 1H), 7.50 (br d, J = 7.8 Hz, 1H), 7.39 (br d, J = 7.8 Hz, 1H), 7.34 - 7.06 (m, 5H), 6.83 - 6.72 (m, 2H), 6.66 - 6.54 (m, 2H), 6.53 - 6.44 (m, 1H), 4.16 (br t, J = 5.2 Hz, 2H), 3.69 (s, 3H), 3.30 (br d, J = 4.4 Hz, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 2.80 - 2.73 (m, 2H), 2.45 (br d, J = 7.2 Hz, 2H), 2.06 (br d, J = 13.2 Hz, 1H), 0.91 (br t, J = 7.2 Hz, 3H).

[0237] The crude product was separated by preparative HPLC (water (0.05% hydrochloric acid, v / v) / acetonitrile system) to obtain the monohydrochloride of Compound 4. MS [ESI, M+1]: 559.3. 1 1H NMR (400 MHz, DMSO-d6) δ = 11.59 (s, 1H), 9.54 (br s, 2H), 7.73 - 7.66 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.26 (br d, J = 2.4 Hz, 1H), 7.23 - 7.17 (m, 2H), 7.16 - 7.09 (m, 1H), 6.88 - 6.80 (m, 1H), 6.80 - 6.72 (m, 2H), 6.66 (d, J = 8.4 Hz, 1H), 6.63 - 6.55 (m, 1H), 4.51 - 4.31 (m, 2H), 3.78 (br d, J = 5.6 Hz, 2H), 3.69 (s, 3H), 3.25 (br s, 2H), 3.02 (s, 3H), 2.85 (s, 3H), 2.45 (br d, J = 7.2 Hz, 2H), 0.96 - 0.84 (m, 3H).

[0238] (Example 5)

Chemical Structure

[0239] In step A, a solution of compound 5-1 (5 g, 42.32 mmol, 1 eq) in N,N-dimethylformamide (50 mL) was cooled to 0 °C, and sodium hydride (2.54 g, 63.49 mmol, purity 60%, 1.5 eq) was added to the solution in several portions. The reaction mixture was stirred at 0 °C for 30 minutes, compound 5-2 (8.22 g, 46.56 mmol, 5.96 mL, 1.1 eq) was added, and then the temperature was raised to 20 °C and reacted for 1 hour. Then, 50 mL of saturated ammonium chloride solution was added, and the mixture was separated. The aqueous phase was extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 5-3. MS[ESI,M+1]: 259.1.

[0240] In step B, under nitrogen protection at -70 °C, lithium diisopropylamide (2 M, 6.39 mL, 1.1 eq) was slowly added dropwise to a solution of compound 5-3 (3 g, 11.61 mmol, 1 eq) in tetrahydrofuran (20 mL). The reaction mixture was stirred at -70 °C for 30 minutes, iodine (4.42 g, 17.42 mmol, 3.51 mL, 1.5 eq) was added, and then the temperature was raised to 25 °C and reacted for 2 hours. 20 mL of aqueous saturated ammonium chloride solution and 20 mL of aqueous saturated sodium sulfite solution were added, and the mixture was separated. The aqueous phase was extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 - 3:1, v / v) to obtain product 5-4. MS[ESI,M+1]: 384.9.

[0241] In step C, cesium carbonate (8 (3.39 g, 10.41 mmol, 2 eq)), cuprous iodide (49.57 mg, 260.29 μmol, 0.05 eq), palladium acetate (58.44 mg, 260.29 μmol, 0.05 eq) and 1,1'-bis(diphenylphosphino)ferrocene (144.30 mg, 260.29 μmol, 0.05 eq) were added to a solution of compound 5-4 (2 g, 5.21 mmol, 1 eq) in N,N-dimethylacetamide (10 mL). Then, compound 5-5 (1.31 g, 10.41 mmol, 2 eq) was added under nitrogen protection. The reaction mixture was reacted at 80 °C for 12 hours, 20 mL of ethyl acetate and 20 mL of water were added, filtered and separated, the aqueous phase was extracted three times with 20 mL of ethyl acetate, the organic phases were combined, washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1, v / v) to obtain product 5-6. MS[ESI,M+1]: 311.1.

[0242] In step D, sodium hydroxide (4 M, 708.83 μL, 4 eq) was added to a 10 mL solution of product 5-6 (220 mg, 708.83 μmol, 1 eq). The reaction mixture was reacted at 60 °C for 2 hours, 10 mL of water was added and extracted three times with 50 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain product 5-7. MS[ESI,M+1]: 171.2.

[0243] In step E, compound 5-8 (164.11 mg, 646.26 μmol, 1 eq) and (T-4)-tetrakis(triphenylphosphine)platinum (16.08 mg, 12.93 μmol, 0.02 eq) were added to a solution of product 5-7 (110 mg, 646.26 μmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction mixture was reacted at 85 °C under nitrogen protection for 12 hours and cooled to room temperature to obtain product 5-9, which was used directly in the next step reaction without purification.

[0244] In step F, to a solution of product 5-9 (274.11 mg, 646.26 μmol, 1 eq) in 2-methyltetrahydrofuran (10 mL) at room temperature were added compound 5-10 (215.03 mg, 452.38 μmol, 0.7 eq), cesium carbonate (421.13 mg, 1.29 mmol, 2 eq), and bis(triphenylphosphine)palladium(II) dichloride (22.68 mg, 32.31 μmol, 0.05 eq). The reaction system was purged with nitrogen three times and water (2.5 mL) was added. The reaction solution was reacted at 30 °C under nitrogen protection for 12 hours to obtain product 5-11.

[0245] In step G, to a solution of product 5-11 (417.22 mg, 646.26 μmol, 1 eq) in 2-methyltetrahydrofuran (10 mL) were added compound 5-12 (131.84 mg, 646.26 μmol, 72.04 μL, 1 eq), potassium hydroxide solution (4 M, 1.13 mL, 7 eq), and bis(triphenylphosphine)palladium(II) dichloride (22.68 mg, 32.31 μmol, 0.05 eq). The reaction was continued at 85 °C under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, 20 mL of water and 20 mL of ethyl acetate were added. The aqueous phase was extracted three times with 20 mL of ethyl acetate, and the combined organic phases were extracted once with 20 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by reverse-phase column chromatography (water (0.1% formic acid, v / v) / acetonitrile system) to obtain compound 5-13. MS[ESI,M+1]: 596.3.

[0246] In step H, N-chlorosuccinimide (6.72 mg, 50.36 μmol, 1.2 eq) was added to a solution of compound 5-13 (25 mg, 41.97 μmol, 1 eq) in dichloromethane (5 mL). The reaction solution was reacted at 25 °C for 12 hours. The reaction solution was quenched with 10 mL of saturated sodium bisulfite, separated, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were extracted twice with 20 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 5-14. MS [ESI, M+1]: 630.3.

[0247] In Step I, 0.1 mL of trifluoroacetic acid was added to a solution of Compound 5-14 (20 mg, 31.74 μmol, 1 eq) in dichloromethane (2 mL). The reaction mixture was reacted at 25 °C for 1 hour. The reaction mixture was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (10 mM ammonium bicarbonate) / acetonitrile system, 45% - 75%) to obtain Compound 5. MS [ESI, M+1]: 530.3. 1 H NMR (400 MHz, methanol-d4) δ = 8.28 (dd, J = 1.6, 4.8 Hz, 1H), 8.01 (dd, J = 1.6, 8.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.33 - 7.20 (m, 7H), 6.78 (td, J = 5.6, 15.2 Hz, 1H), 6.60 - 6.53 (m, 2H), 4.26 (t, J = 5.4 Hz, 2H), 3.44 (dd, J = 1.5, 5.6 Hz, 2H), 3.09 (s, 3H), 2.98 (s, 3H), 2.96 - 2.88 (m, 2H), 2.59 - 2.50 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0248] (Example 6) [Chemical formula]

[0249] In Step A, to a solution of Compound 1-8 (1.50 g, 3.54 mmol, 1.42 eq) in 2-methyltetrahydrofuran (10 mL) at room temperature, Compound 6-1 (1.15 g, 2.49 mmol, 1 eq), cesium carbonate (1.62 g, 4.99 mmol, 2 eq) and bis(triphenylphosphine)palladium(II) dichloride (87.49 mg, 124.65 μmol, 0.05 eq) were added. The reaction system was purged with nitrogen three times and 1 mL of water was added. The reaction mixture was reacted at 30 °C under nitrogen protection for 12 hours to obtain Product 6-2, which was used directly in the next step reaction without purification.

[0250] In step B, to a solution of product 6-2 (1.07 g, 1.66 mmol, 1.00 eq) in 2-methyltetrahydrofuran (10 mL) were added 1-bromo-3-methoxybenzene (558.81 mg, 2.99 mmol, 377.57 μL, 1.2 eq), potassium hydroxide solution (4 M, 4.36 mL, 7 eq), and bis(triphenylphosphine)palladium(II) dichloride (87.38 mg, 124.49 μmol, 0.05 eq). The reaction system was purged with nitrogen three times. After reacting the reaction solution at 85 °C under nitrogen protection for 12 hours, the reaction solution was cooled to room temperature, 30 mL of water was added, the aqueous phase was extracted three times with 50 mL of ethyl acetate, and the combined organic phases were extracted twice with 50 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 4:5, v / v) to obtain compound 6-4. MS[ESI,M+1]: 611.3.

[0251] In step C, N-chlorosuccinimide (314.84 mg, 2.36 mmol, 1.2 eq) was added to a solution of compound 6-4 (1.2 g, 1.96 mmol, 1 eq) in dichloromethane (20 mL). The reaction solution was reacted at 25 °C for 12 hours. The reaction solution was washed with 5 mL of saturated sodium bisulfite, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 6-5. MS[ESI,M+1]: 645.2.

[0252] In step D, 5 mL of trifluoroacetic acid was added to a solution of product 6-5 (450 mg, 697.47 μmol, 1 eq) in dichloromethane (5 mL). The reaction solution was reacted at 25 °C for 1 hour under a nitrogen atmosphere. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.05% hydrochloric acid, v / v) / acetonitrile system) to obtain compound 6. MS[ESI,M+1]: 545.2. 11H NMR (400 MHz, DMSO-d6) δ = 11.93 - 11.15 (m, 1H), 9.43 (br s, 2H), 8.24 (br d, J = 4.8 Hz, 1H), 7.77 - 7.62 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.25 (d, J = 3.2 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.22 - 7.17 (m, 2H), 7.15 - 7.08 (m, 1H), 6.84 - 6.78 (m, 1H), 6.76 (br d, J = 2.8 Hz, 1H), 6.19 (d, J = 15.4 Hz, 1H), 4.47 - 4.34 (m, 2H), 3.73 (br d, J = 5.6 Hz, 2H), 3.69 (s, 3H), 3.22 (br s, 2H), 2.64 (d, J = 4.8 Hz, 3H), 2.47 - 2.40 (m, 2H), 1.12 - 0.72 (m, 3H).

[0253] (Example 7) [Chemical formula] [Chemical formula]

[0254] In Step A, sodium carbonate (2.41 g, 22.72 mmol, 5 eq) was added to a solution of 10 mL of dichloromethane and 1 mL of N,N-dimethylformamide containing compound 7-1 (1.2 g, 4.54 mmol, 1 eq). The reaction system was reacted at 25 °C for 15 minutes and then cooled to 0 °C. Acryloyl chloride (1.23 g, 13.63 mmol, 1.11 mL, 3 eq) was added and the reaction was carried out at 25 °C for 11 hours and 45 minutes. 10 mL of water was added to the reaction system, and the mixture was extracted three times with 20 mL of a mixed solution of dichloromethane and methanol (10:1, v / v). The combined organic phases were washed once with 10 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product 7-2. MS [ESI, M+1]: 318.9.

[0255] In Step B, Pd(PPh3)2Cl2 (73.01 mg, 104.01 μmol, 0.05 eq) and Cs2CO3 (1.36 g, 4.16 mmol, 2 eq) were added to a solution of compound 1-8 (1.25 g, 2.95 mmol, 1.42 eq) and crude product 7-2 (661.75 mg, 2.08 mmol, 1 eq) in 2-methyltetrahydrofuran (5 mL). The reaction system was purged with nitrogen three times, and 0.2 mL of water was added. The reaction solution was reacted at 30 °C for 12 hours to obtain product 7-3, which was used directly in the next step without purification. MS[ESI,M+1]: 488.3.

[0256] In Step C, potassium hydroxide solution (4 M, 4.36 mL, 7 eq) and bis(triphenylphosphine)palladium(II) dichloride (72.72 mg, 103.61 μmol, 0.05 eq) were added to a solution of product 7-3 (1.01 g, 2.07 mmol, 1 eq) and 2-chloro-4-fluorobenzene iodide (637.69 mg, 2.49 mmol, 1.2 eq) in 2-methyltetrahydrofuran (5 mL), and the reaction system was purged with nitrogen three times. The reaction solution was reacted at 85 °C under nitrogen protection for 12 hours. 30 mL of water was added to the reaction system, and the mixture was extracted three times with 50 mL of ethyl acetate. The combined organic phases were extracted twice with 50 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 2:3, v / v) to obtain compound 7-4 (360 mg, 734.74 μmol). MS[ESI,M+1]: 490.2.

[0257] In Step D, N-chlorosuccinimide (52.33 mg, 391.86 μmol, 1.2 eq) was added to a solution of Compound 7-4 (160 mg, 326.55 μmol, 1 eq) in dichloromethane (10 mL). The reaction system was replaced with nitrogen three times. The reaction solution was reacted at 25 °C for 12 hours. The reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.225% formic acid)-acetonitrile system, v / v) to obtain Compound 7. MS[ESI,M+1]: 524.2. 1 H NMR(400 MHz, DMSO-d6) δ = 11.47 (s, 1H), 8.24 (br t, J = 5.3 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.68 - 7.54 (m, 1H), 7.52 - 7.34 (m, 3H), 7.26 - 7.11 (m, 4H), 6.61 (d, J = 8.7 Hz, 1H), 6.20 (dd, J = 10.0, 17.1 Hz, 1H), 6.06 (dd, J = 2.3, 17.1 Hz, 1H), 5.58 - 5.54 (m, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.47 - 3.36 (m, 2H), 2.48 - 2.39 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H).

[0258] (Example 8)

Chemical Structure

[0259] In step A, a solution of indolin-2-one (Compound 8-1, 10 g, 75.10 mmol, 1 eq) and triethylamine (22.80 g, 225.31 mmol, 31.36 mL, 3 eq) in dichloromethane (100 mL) was purged with nitrogen three times and cooled to -70 °C. Trifluoromethanesulfonic anhydride (46.62 g, 165.23 mmol, 27.26 mL, 2.2 eq) was added dropwise to the reaction system while controlling the temperature of the reaction system to be below -60 °C. After the addition was complete, the reaction was carried out at -60 °C for 2 hours. 1 M hydrochloric acid was slowly added dropwise to the reaction system. When the pH dropped to 1, the temperature of the reaction system was maintained below 30 °C. The reaction system was washed twice with 100 mL of 0.5 M hydrochloric acid and once with 100 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product 8-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.86 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.35 - 7.40 (m, 2H), 6.61 (s, 1H).

[0260] In step B, Pd(PPh3)4 (4.36 g, 3.78 mmol, 0.1 eq) and cuprous iodide (719.09 mg, 3.78 mmol, 0.1 eq) were added to a solution of crude product 8-2 (15 g, 37.76 mmol, 1 eq) in triethylamine (150 mL). The reaction system was purged with nitrogen three times and trimethylsilylacetylene (18.54 g, 188.80 mmol, 26.15 mL, 5 eq) was added. Under nitrogen protection, the reaction system was reacted at 65 °C for 12 hours. The reaction system was quenched with 100 mL of water and extracted three times with 150 mL of ethyl acetate. The combined organic phases were washed twice with 100 mL of saturated brine and dried over sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1, v / v) to obtain Compound 8-3. 1 H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.37 - 7.44 (m, 2H), 7.07 (s, 1H), 0.31 (s, 9H).

[0261] In Step C, potassium carbonate (6.72 g, 48.64 mmol, 2 eq) was added to a methanol (50 mL) solution of compound 8-3 (8.4 g, 24.32 mmol, 1 eq), and the temperature of the reaction system was raised to 70 °C and reacted for 30 minutes. After cooling to room temperature, it was quenched with 100 mL of water, and the reaction system was extracted 3 times with 150 mL of dichloromethane. The combined organic phases were washed twice with 100 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 8-4 was obtained. 1 H NMR (400 MHz, CDCl3) ppm 8.19 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.17 - 7.19 (m, 1H), 7.06 - 7.08 (m, 1H), 6.75 (s, 1H), 3.24 (s, 1H).

[0262] In Step D, Pd2(dba)3 (648.67 mg, 708.37 μmol, 0.05 eq), bis[2-(diphenylphosphino)phenyl]ether (DPEphos, 1.53 g, 2.83 mmol, 0.2 eq) and DABCO (3.18 g, 28.33 mmol, 3.12 mL, 2 eq) were added to a dry reaction flask. The reaction tube was purged with nitrogen three times, and under a nitrogen atmosphere, crude product 8-4 (2 g, 14.17 mmol, 1 eq), 2-iodo-1,1,1-trifluoroethane (2.97 g, 14.17 mmol, 1.39 mL, 1 eq) and 20 mL of toluene were added to the reaction system. The reaction system was reacted at 80 °C for 12 hours. The reaction system was filtered and washed with 50 mL of ethyl acetate, and the organic phase was concentrated to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 - 5:1, v / v) to obtain compound 8-5. MS [ESI, M+1]: 224.1.

[0263] In step E, (T-4)-tetrakis(triphenylphosphine)platinum (55.75 mg, 44.80 μmol, 0.02 eq) was added to 10 mL of 2-methyltetrahydrofuran containing compound 8-5 (0.5 g, 2.24 mmol, 1 eq) and bis(pinacolato)diboron (568.87 mg, 2.24 mmol, 1 eq). The reaction system was reacted at 85 °C for 12 hours under nitrogen protection and then cooled to room temperature to obtain product 8-6, which was directly used in the next-step reaction without purification.

[0264] In step F, compound 1-9 (532.97 mg, 1.12 mmol, 0.50 eq), Pd(PPh3)2Cl2 (78.70 mg, 112.13 μmol, 0.05 eq) and cesium carbonate (1.46 g, 4.49 mmol, 2 eq) were added to a solution of product 8-6 (1.07 g, 2.24 mmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction system was replaced with nitrogen three times and 2.5 mL of water was added. The reaction solution was reacted at 30 °C for 12 hours to obtain product 8-7, which was directly used in the next-step reaction without purification.

[0265] In step G, compound 8-8 (649.89 mg, 2.70 mmol, 1.2 eq), potassium hydroxide solution (4 M, 3.93 mL, 7 eq) and Pd(PPh3)2Cl2 (78.87 mg, 112.37 μmol, 0.05 eq) were added to a solution of product 8-7 (1.57 g, 2.25 mmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction system was replaced with nitrogen three times, the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When it cooled to room temperature, the reaction system was diluted with 10 mL of water and 10 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by silica gel column chromatography to obtain compound 8-9. MS[ESI,M+1]: 686.2.

[0266] In step H, a dichloromethane (5 mL) solution containing compound 8-9 (500 mg, 729.20 μmol, 1 eq) and N-chlorosuccinimide (116.84 mg, 875.04 μmol, 1.2 eq) was reacted at 20 °C for 12 hours. The reaction solution was quenched with 10 mL of water, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 8-10 was obtained. MS[ESI,M+1]: 720.4.

[0267] In step I, trifluoroacetic acid (71.25 mg, 624.89 μmol, 46.27 μL, 1 eq) was added to a dichloromethane (5 mL) solution of crude product 8-10 (450 mg, 624.89 μmol, 1 eq). The reaction solution was reacted at 20 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system), silica gel plate (petroleum ether:ethyl acetate = 0:1, v / v), and preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system) to obtain compound 8. MS[ESI,M+1]: 620.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (s, 1H) 8.50 - 8.60 (m, 2H) 8.23 (s, 1H) 7.85 (d, J = 2.4 Hz, 1H) 7.56 (d, J = 7.6 Hz, 1H) 7.34 - 7.47 (m, 2H) 7.12 - 7.29 (m, 2H) 6.70 (d, J = 8.4 Hz, 1H) 6.55 - 6.63 (m, 1H) 6.46 - 6.53 (m, 1H) 4.18 (t, J = 5.6 Hz, 2H) 3.50 - 3.63 (m, 2H) 3.31 - 3.32 (m, 2H) 2.97 (s, 3H) 2.83 - 2.87 (m, 3H) 2.77 (t, J = 5.6 Hz, 2H).

[0268] (Example 9)

Chemical formula

[0269] In Step A, 2-chloro-4-fluorobenzene (692.40 mg, 2.70 mmol, 1.2 eq), potassium hydroxide solution (4 M, 3.93 mL, 7 eq) and Pd(PPh3)2Cl2 (78.87 mg, 112.37 μmol, 0.05 eq) were added to a solution of compound 8-7 (1.57 g, 2.25 mmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction system was replaced with nitrogen three times, and the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When it cooled to room temperature, the reaction system was diluted with 10 mL of water and 10 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by silica gel column chromatography to obtain compound 9-1. MS[ESI,M+1]: 701.2.

[0270] In Step B, a solution of compound 9-1 (200 mg, 285.25 μmol, 1 eq) and N-chlorosuccinimide (45.71 mg, 342.30 μmol, 1.2 eq) in dichloromethane (10 mL) was reacted at 20 °C for 12 hours. The reaction solution was quenched with 10 mL of water, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 9-2 was obtained. MS[ESI,M+1]: 735.1.

[0271] In Step C, trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 132.47 eq) was added to a solution of crude product 9-2 (150 mg, 203.92 μmol, 1 eq) in dichloromethane (2 mL). The reaction solution was reacted at 20 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system) twice to obtain compound 9. MS[ESI,M+1]: 635.2. 11H NMR (EW16419-73-P1A, 400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H) 7.79 (d, J = 2.00 Hz, 1H) 7.53 (d, J = 7.6 Hz, 1H) 7.42 - 7.49 (m, 3H) 7.21 - 7.33 (m, 3H) 7.13 - 7.19 (m, 1H) 6.55 - 6.67 (m, 2H) 6.46 - 6.53 (m, 1H) 4.16 (t, J = 5.6 Hz, 2H) 3.41 - 3.62 (m, 2H) 3.30 - 3.31 (m, 2H) 2.97 (s, 3H) 2.83 (s, 3H) 2.77 (t, J = 5.6 Hz, 2H).

[0272] (Example 10) [Chemical formula]

[0273] In Step A, o-iodobenzonitrile (104.22 mg, 572.59 μmol, 1 eq), potassium hydroxide solution (4 M, 715.74 μL, 5 eq), and Pd(PPh3)2Cl2 (20.10 mg, 28.63 μmol, 0.05 eq) were added to a 10 mL solution of 2-methyltetrahydrofuran containing compound 8-7 (400 mg, 572.59 μmol, 1 eq) and 2.5 mL of an aqueous solution. The reaction system was purged with nitrogen three times, the temperature of the reaction solution was raised to 85 °C, and the reaction was carried out for 12 hours. When the temperature dropped to room temperature, the reaction system was diluted with 10 mL of water and 10 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, the organic phases were combined, washed with 20 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated on a silica gel plate to obtain compound 10-1. MS [ESI, M+1]: 674.2.

[0274] In step B, a dichloromethane (5 mL) solution containing compound 10-1 (35 mg, 51.95 μmol, 1 eq) and N-chlorosuccinimide (8.32 mg, 62.34 μmol, 1.2 eq) was reacted at 20 °C for 12 h. The reaction mixture was quenched with 10 mL of saturated sodium bisulfite, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 10-2 was obtained. MS[ESI,M+1]: 708.2.

[0275] In step C, trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL, 159.41 eq) was added to a dichloromethane (3 mL) solution of crude product 10-2 (30 mg, 42.36 μmol, 1 eq). The reaction mixture was reacted at 20 °C for 1 h. The reaction mixture was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system), and further separated by preparative HPLC (water (0.05% ammonium hydroxide, v / v) / acetonitrile system) to obtain compound 10. MS[ESI,M+1]: 608.3. 1 H NMR (EW16419-216-P1A, 400 MHz, DMSO-d6) δ = 11.59 (s, 1H), 7.81 - 7.68 (m, 4H), 7.60 - 7.42 (m, 3H), 7.32 - 7.12 (m, 3H), 6.66 - 6.43 (m, 3H), 4.21 - 4.11 (m, 2H), 3.47 - 3.43 (m, 2H), 3.48 - 3.41 (m, 2H), 2.96 (s, 3H), 2.89 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H).

[0276] (Example 11)

Chemical formula

[0277] In step A, 1 mL of trifluoroacetic acid was added to a dichloromethane (1 mL) solution of compound 11-1 (100 mg, 154.52 μmol, 1 eq). The reaction solution was reacted for 1 hour at 25 °C under nitrogen protection. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.225% formic acid, v / v) / acetonitrile system) to obtain compound 11. MS[ESI,M+1]: 547.3. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H) 8.90 (br s, 2H) 7.74 (d, J = 2.45 Hz, 1H) 7.57 (d, J = 7.46 Hz, 1H) 7.26 - 7.41 (m, 4H) 7.18 (m, 1H) 7.08 (t, J = 7.23 Hz, 1H) 7.01 (t, J = 7.04 Hz, 1H) 6.81 (d, J = 15.16 Hz, 1H) 6.67 (d, J = 8.68 Hz, 1H) 6.52 - 6.60 (m, 2H) 4.37 (t, J = 5.07 Hz, 2H) 3.81 (br d, J = 4.40 Hz, 2H) 3.04 (s, 3H) 2.88 (s, 3H) 2.59 - 2.75 (m, 2H) 2.31 - 2.44 (m, 2H) 1.01 (t, J = 7.52 Hz, 3H).

[0278] (Example 12)

Chemical formula

[0279] In step A, N-bromosuccinimide (33.00 mg, 185.42 μmol, 1.2 eq) was added to a dichloromethane (3 mL) solution containing compound 11-1 (100 mg, 154.52 μmol, 1 eq). The reaction system was replaced with nitrogen three times and reacted at 25 °C for 2 hours. 10 mL of dichloromethane was added to the reaction solution, and the organic phase was washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 12-1 was obtained. MS[ESI,M+1]: 804.9.

[0280] In Step B, 1 mL of trifluoroacetic acid was added to a dichloromethane (1 mL) solution of crude product 12-1 (140.00 mg, 173.92 μmol, 1 eq). The reaction solution was reacted for 1 hour at 25 °C under nitrogen protection. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) to obtain Compound 12. MS[ESI,M+1]: 627.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (s, 1H) 8.91 (br s, 2H) 7.78 (d, J = 2.02 Hz, 1H) 7.31 - 7.38 (m, 1H) 7.35 - 7.28 (m, 2H) 7.25 - 7.18 (m, 2H) 7.12 - 7.27 (m, 2H) 7.19 (d, J = 13.28 Hz, 1H) 6.79 (d, J = 15.18 Hz, 1H) 6.68 (d, J = 8.54 Hz, 1H) 6.54 (m, 1H) 4.35 (br t, J = 4.96 Hz, 2H) 3.97 (br s, 2H) 3.79 (br d, J = 5.14 Hz, 2H) 3.02 (s, 3H) 2.87 (s, 3H) 2.36 - 2.47 (m, 2H) 0.90 (t, J = 7.56 Hz, 3H).

[0281] (Example 13)

Chemical Structure

[0282] In Step A, N-iodosuccinimide (83.43 mg, 370.84 μmol, 1.2 eq) was added to a dichloromethane (10 mL) solution containing Compound 11-1 (200 mg, 309.03 μmol, 1 eq). The reaction system was replaced with nitrogen three times and reacted at 25 °C for 2 hours. The reaction solution was quenched with 5 mL of an aqueous saturated sodium sulfite solution, 10 mL of dichloromethane was added to the reaction solution, the organic phase was washed twice with 20 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 13-1 was obtained. MS[ESI,M+1]: 773.3.

[0283] In Step B, 3 mL of trifluoroacetic acid was added to a dichloromethane (3 mL) solution of crude product 13-1 (200 mg, 258.71 μmol, 1 eq). The reaction solution was reacted for 1 hour under nitrogen protection at 25 °C. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) to obtain Compound 13. MS[ESI,M+1]: 673.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (s, 1H) 8.86 (br s, 2H) 7.81 (m, 1H) 7.47 (d, J = 8.84 Hz, 1H) 7.39 - 7.42 (m, 1H) 7.30 - 7.37 (m, 1H) 7.27 - 7.29 (m, 2H) 7.17 - 7.26 (m, 1H) 7.11 - 7.15 (m, 1H) 6.88 (d, J = 15.18 Hz, 1H) 6.78 (d, J = 15.16 Hz, 1H) 6.68 (d, J = 8.66 Hz, 1H) 6.54 (m, 1H) 4.36 (t, J = 5.02 Hz, 2H) 3.72 - 3.98 (m, 2H) 3.19 - 3.44 (m, 2H) 3.02 (s, 3H) 2.87 (s, 3H) 2.30 - 2.48 (m, 2H) 0.90 (t, J = 7.52 Hz, 3H).

[0284] (Example 14)

Chemical Structure

[0285] In Step A, 1-bromo-2-chlorobenzene (317.20 mg, 1.66 mmol, 193.42 μL, 1.2 eq), potassium hydroxide solution (4 M, 2.42 mL, 7 eq) and Pd(PPh3)2Cl2 (48.45 mg, 69.03 μmol, 0.05 eq) were added to a solution of Compound 1-10 (0.89 g, 1.38 mmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction system was replaced with nitrogen three times, and the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When it cooled to room temperature, the reaction system was diluted with 30 mL of water, the aqueous phase was extracted three times with 50 mL of ethyl acetate, the combined organic phases were washed twice with 50 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by column chromatography to obtain Compound 14-1. MS[ESI,M+1]: 629.3.

[0286] In Step B, N-chlorosuccinimide (43.30 mg, 324.23 μmol, 1.2 eq) was added to a solution of Compound 14-1 (170 mg, 270.19 μmol, 1 eq) in dichloromethane (10 mL). The reaction system was replaced with nitrogen three times and reacted at 25 °C for 2 hours. The reaction solution was quenched with 5 mL of an aqueous solution of saturated sodium bisulfite, 10 mL of dichloromethane was added to the reaction solution, the organic phase was washed twice with 20 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 14-2 was obtained. MS[ESI,M+1]: 663.4.

[0287] In Step C, 3 mL of trifluoroacetic acid was added to a solution of crude product 14-2 (200 mg, 301.37 μmol, 1 eq) in dichloromethane (3 mL). The reaction solution was reacted for 1 hour under nitrogen protection at 25 °C. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) to obtain Compound 14. MS[ESI,M+1]: 563.2. 11H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.88 (br s, 2H) 8.75 (m, 1H) 7.81 - 8.53 (m, 1H) 7.77 (m, 2H) 7.40 - 7.65 (m, 4H) 7.22 - 7.35 (m, 1H) 7.12 - 7.21 (m, 1H) 6.78 (d, J = 15.28 Hz, 1H) 6.65 (d, J = 8.40 Hz, 1H) 6.54 (m, 1H) 4.35 (t, J = 5.04 Hz, 2H) 3.58 (br s, 2H) 3.27 (br s, 2H) 3.02 (s, 3H) 2.87 (s, 3H) 2.39 - 2.48 (m, 2H) 0.90 (t, J = 7.52 Hz, 3H).

[0288] (Example 15) [Chemical Structure Diagram]

[0289] In Step A, 1-bromo-2,4-dichlorobenzene (239.70 mg, 1.06 mmol, 1.2 eq), potassium hydroxide solution (4 M, 1.55 mL, 7 eq), and Pd(PPh3)2Cl2 (31.03 mg, 44.21 μmol, 0.05 eq) were added to a solution of Compound 1-8 (0.57 g, 884.26 μmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction system was purged with nitrogen three times, and the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When it cooled to room temperature, the reaction system was diluted with 10 mL of water and 10 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, and the combined organic phases were washed three times with 10 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by reverse-phase HPLC (0.1% trifluoroacetic acid system) to obtain Compound 15-1. MS [ESI, M+1]: 663.3.

[0290] In step B, a dichloromethane (10 mL) solution containing compound 15-1 (125 mg, 188.36 μmol, 1 eq) and N-chlorosuccinimide (30.18 mg, 226.03 μmol, 1.2 eq) was reacted at 20 °C for 1 hour. The reaction mixture was quenched with 10 mL of water, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 15-2 was obtained. MS[ESI,M+1]:697.2.

[0291] In step C, trifluoroacetic acid (24.50 mg, 214.88 μmol, 15.91 μL, 1 eq) was added to a dichloromethane (2 mL) solution of crude product 15-2 (150 mg, 214.88 μmol, 1 eq). The reaction mixture was reacted at 20 °C for 1 hour. The reaction mixture was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system) to obtain compound 15. MS[ESI,M+3]:599.3. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.52(s,1H)8.85(br s,2H)7.77(dd,J=2.4,0.8Hz,1H)7.63(d,J=2.0Hz,1H)7.51(d,J=8.0Hz,1H)7.39-7.46(m,2H)7.31-7.37(m,2H)7.13-7.24(m,2H)6.79(d,J=15.2Hz,1H)6.69(dd,J=8.4,0.61Hz,1H)6.50-6.58(m,1H)4.34-4.39(m,2H)3.80(br d,J=4.8Hz,2H)3.28(br s,2H)3.03(s,3H)2.87(s,3H)2.42-2.47(m,2H)0.90(t,J=7.6Hz,3H).

[0292] (Example 16)

Chemical Structure

[0293] In Step A, 4-bromo-2-methylthiophene (187.88 mg, 1.06 mmol, 1.2 eq), potassium hydroxide (KOH) solution (4 M, 1.55 mL, 7 eq), and Pd(PPh3)2Cl2 (31.03 mg, 44.21 μmol, 0.05 eq) were added to a solution of Compound 1-8 (0.57 g, 884.26 μmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction system was purged with nitrogen three times, and the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When the temperature dropped to room temperature, the reaction system was diluted with 10 mL of water and 10 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, and the combined organic phases were washed three times with 10 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by reverse-phase column chromatography (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) to obtain Compound 16-1. MS[ESI,M+1]: 615.4.

[0294] In Step B, a solution of Compound 16-1 (65 mg, 105.73 μmol, 1 eq) and N-chlorosuccinimide (16.94 mg, 126.87 μmol, 1.2 eq) in dichloromethane (10 mL) was reacted at 20 °C for 12 hours. The reaction solution was quenched with 10 mL of water, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 16-2 was obtained. MS[ESI,M+1]: 649.2.

[0295] In Step C, trifluoroacetic acid (17.56 mg, 154.03 μmol, 11.40 μL, 1 eq) was added to a solution of crude product 16-2 (100 mg, 154.03 μmol, 1 eq) in dichloromethane (2 mL). The reaction solution was reacted at 20 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system) to obtain Compound 16 (10.13 mg, 18.01 μmol). MS[ESI,M+1]: 549.4. 11H NMR (EW16419 - 130 - P1A, 400 MHz, DMSO - d6) δ ppm 11.42 (s, 1H) 7.72 (dd, J = 2.4, 0.67 Hz, 1H) 7.48 (d, J = 7.6 Hz, 1H) 7.34 - 7.39 (m, 1H) 7.23 - 7.28 (m, 1H) 7.09 - 7.20 (m, 2H) 7.04 (d, J = 1.6 Hz, 1H) 6.57 - 6.67 (m, 2H) 6.50 - 6.56 (m, 2H) 4.22 (t, J = 5.6 Hz, 2H) 3.32 - 3.36 (m, 5H) 2.99 (s, 2H) 2.84 (s, 3H) 2.35 - 2.43 (m, 5H) 0.93 - 0.99 (m, 3H).

[0296] (Example 17) [Chemical formula]

[0297] In Step A, to 10 mL of 2 - methyltetrahydrofuran and 2 mL of an aqueous solution containing Compound 1 - 8 (1.14 g, 1.77 mmol, 1 eq) were added 1 - bromo - 2,4 - difluorobenzene (409.57 mg, 2.12 mmol, 1.2 eq), potassium hydroxide solution (4 M, 3.09 mL, 7 eq), and Pd(PPh3)2Cl2 (62.07 mg, 88.43 μmol, 0.05 eq). The reaction system was purged with nitrogen three times, the temperature of the reaction solution was raised to 85 °C, and the reaction was carried out for 12 hours. When the temperature dropped to room temperature, the reaction system was diluted with 10 mL of water and 10 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by reverse - phase column chromatography (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) to obtain Compound 17 - 1. MS[ESI,M + 1]: 631.4.

[0298] In Step B, a dichloromethane (5 mL) solution containing compound 17-1 (287 mg, 455.03 μmol, 1 eq) and N-chlorosuccinimide (72.91 mg, 546.04 μmol, 1.2 eq) was reacted at 25 °C for 1 hour. The reaction mixture was quenched with 10 mL of water, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 17-2 was obtained. MS[ESI,M+1]: 665.2.

[0299] In Step C, trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 29.95 eq) was added to a dichloromethane (5 mL) solution of crude product 17-2 (300 mg, 451.01 μmol, 1 eq). The reaction mixture was reacted at 25 °C for 30 minutes. The reaction mixture was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system) to obtain compound 17. MS[ESI,M+1]: 565.2. 1 H NMR(EW16419-174-P1, 400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H) 8.19 (s, 1H) 7.68 (s, 1H) 7.50 (d, J = 7.82 Hz, 1H) 7.28 - 7.41 (m, 2H) 7.04 - 7.24 (m, 5H) 6.45 - 6.65 (m, 3H) 4.16 (t, J = 5.75 Hz, 2H) 3.32 (br d, J = 4.40 Hz, 2H) 2.98 (s, 3H) 2.83 (s, 3H) 2.78 (t, J = 5.75 Hz, 2H) 2.43 (q, J = 7.30 Hz, 2H) 0.90 (t, J = 7.46 Hz, 3H).

[0300] (Example 18)

Chemical Structure

[0301] In step A, 1-bromo-3-methylbenzene (504.13 mg, 2.95 mmol, 357.54 μL, 1 eq), potassium hydroxide solution (4 M, 20.63 mmol, 5.16 mL, 7 eq), and Pd(PPh3)2Cl2 (103.44 mg, 147.38 μmol, 0.05 eq) were added to a solution of compound 1-8 (1.9 g, 2.95 mmol, 1 eq) in 2-methyltetrahydrofuran (5 mL). The reaction system was purged with nitrogen three times, and the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When it cooled to room temperature, the reaction system was diluted with 20 mL of water and 20 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by reverse-phase HPLC (0.1% trifluoroacetic acid) to obtain compound 18-1. MS[ESI,M+1]: 609.3.

[0302] In step B, N-chlorosuccinimide (71.33 mg, 534.19 μmol, 1.2 eq) was added to a solution of compound 18-1 (271 mg, 445.16 μmol, 1 eq) in dichloromethane (5 mL), and the reaction solution was reacted at 25 °C for 1 hour. The reaction solution was quenched with 10 mL of water, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, crude product 18-2 was obtained. MS[ESI,M+1]: 643.4.

[0303] In step C, trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL, 17.37 eq) was added to a solution of crude product 18-2 (250 mg, 388.67 μmol, 1 eq) in dichloromethane (5 mL). The reaction solution was reacted at 25 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system) to obtain compound 18. MS[ESI,M+1]: 543.3. 11H NMR (400 MHz, DMSO-d6) δ = 11.54 (s, 1H), 9.42 (br s, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.28 - 7.01 (m, 6H), 6.95 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 15.2 Hz, 1H), 6.69 - 6.54 (m, 2H), 4.40 (t, J = 5.2 Hz, 2H), 3.79 - 3.75 (m, 2H), 3.24 (br s, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 2.44 (q, J = 7.2 Hz, 2H), 2.27 (s, 3H), 0.90 (t, J = 7.6 Hz, 3H).

[0304] (Example 19) [Chemical formula] [Chemical formula]

[0305] In Step A, a solution of 2,6-difluoro-3-iodopyridine (Compound 19-1, 10 g, 41.50 mmol, 1 eq) in N,N-dimethylformamide (80 mL) was cooled to 0 °C, and sodium hydride (2.49 g, 62.25 mmol, purity 60%, 1.5 eq) was added to the reaction system in several portions while controlling the temperature of the reaction system below 0 °C. After addition, the reaction was carried out at 0 °C for 30 minutes. A solution of N-Boc-ethanolamine (6.69 g, 41.50 mmol, 6.43 mL, 1 eq) in N,N-dimethylformamide (20 mL) was added dropwise to the reaction system while controlling the temperature of the reaction system below 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 1 hour. The reaction system was quenched with 50 mL of water and extracted 3 times with 50 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated brine and dried over sodium sulfate. Filtration and concentration gave a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1, v / v) to obtain Compound 19-2. 11H NMR (400 MHz, chloroform-d) δ = 7.85 (t, J = 8.4 Hz, 1H), 6.45 - 6.31 (m, 1H), 4.30 - 4.13 (m, 2H), 3.44 (br d, J = 4.8 Hz, 2H), 1.37 (s, 9H).

[0306] In Step B, a hydrochloric acid methanol solution (4 M, 2 mL, 1.50 eq) was added to a solution of Compound 19-2 (2.04 g, 5.34 mmol, 1 eq) in ethanol (20 mL). The reaction system was reacted at 45 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain Compound 19-3. MS [ESI, M+1]: 283.4.

[0307] In Step C, a solution of N,N-dimethylbromocrotonamide (615.03 mg, 3.20 mmol, 0.6 eq) in N,N-dimethylformamide (1 mL) was added dropwise to a solution of Compound 19-3 (1.7 g, 5.34 mmol, 1 eq, HCl) and N,N-diisopropylethylamine (2.07 g, 16.01 mmol, 2.79 mL, 3 eq) in N,N-dimethylformamide (5 mL), and the reaction system was reacted at 25 °C for 12 hours. A solution of (Boc)2O (1.40 g, 6.40 mmol, 1.47 mL, 1.2 eq) in dichloromethane (2 mL) was added dropwise to the reaction system while controlling the temperature of the reaction system below 0 °C, and the reaction system was reacted at 25 °C for 2 hours. The reaction system was diluted with 20 mL of water and 20 mL of ethyl acetate, separated, and the aqueous phase was extracted 3 times with 10 mL of ethyl acetate. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1, v / v) to obtain Compound 19-4. MS [ESI, M+1]: 494.2.

[0308] In step D, to a solution of compound 1-8 (0.63 g, 1.49 mmol, 1 eq) in 2-methyltetrahydrofuran (5 mL) were added compound 19-4 (440.66 mg, 893.28 μmol, 0.6 eq), Pd(PPh3)2Cl2 (52.25 mg, 74.44 μmol, 0.05 eq), and cesium carbonate (970.16 mg, 2.98 mmol, 2 eq). The reaction system was purged with nitrogen three times and 1 mL of water was added. The reaction solution was reacted at 30 °C for 12 hours to obtain product 19-5, which was used directly in the next step reaction without purification. MS[ESI,M+1]: 663.4.

[0309] In step E, to a solution of product 19-5 (986.47 mg, 1.49 mmol, 1 eq) in 2-methyltetrahydrofuran (20 mL) were added 1-bromo-3-methylbenzene (278.68 mg, 1.49 mmol, 188.30 μL, 1 eq), potassium hydroxide solution (4 M, 2.61 mL, 7 eq), and Pd(PPh3)2Cl2 (52.25 mg, 74.50 μmol, 0.05 eq). The reaction system was purged with nitrogen three times, and the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When it cooled to room temperature, the reaction system was diluted with 10 mL of water and 10 mL of ethyl acetate. The aqueous phase was extracted three times with 10 mL of ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by reverse-phase chromatography (0.1% trifluoroacetic acid) to obtain compound 19-6. MS[ESI,M+1]: 643.4.

[0310] In step F, N-chlorosuccinimide (24.93 mg, 186.70 μmol, 1.2 eq) was added to a dichloromethane (5 mL) solution containing compound 19-6 (0.1 g, 155.58 μmol, 1 eq), and the reaction system was reacted at 25 °C for 1 hour. The reaction solution was quenched with 10 mL of saturated aqueous sodium sulfite solution, and the aqueous phase was extracted 3 times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by preparative HPLC (water (0.025% formic acid, v / v) / acetonitrile system) to obtain product 19-7. MS[ESI,M+1]: 677.4.

[0311] In step G, trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL, 228.66 eq) was added to a dichloromethane (3 mL) solution of product 19-7 (20 mg, 29.53 μmol, 1 eq). The reaction solution was reacted at 25 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.05% hydrochloric acid, v / v) / acetonitrile system) to obtain compound 19. MS[ESI,M+1]: 577.3. 1 H NMR (400 MHz, methanol-d4) δ = 7.44 (dd, J = 8.4, 9.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.10 - 6.98 (m, 3H), 6.76 - 6.62 (m, 4H), 6.58 - 6.46 (m, 2H), 4.39 - 4.32 (m, 2H), 3.77 (d, J = 6.4 Hz, 2H), 3.61 (s, 3H), 3.33 - 3.27 (m, 2H), 3.00 (s, 3H), 2.88 (s, 3H), 2.46 (q, J = 7.6 Hz, 2H), 0.89 (t, J = 7.6 Hz, 3H).

[0312] (Example 20)

Chemical formula

[0313] In step A, N-bromosuccinimide (329.55 mg, 1.85 mmol, 1.2 eq) was added to a dichloromethane (20 mL) solution of compound 4-1 (964 mg, 1.54 mmol, 1 eq). The reaction system was purged with nitrogen three times, and the reaction solution was reacted at 25 °C for 1 hour. The reaction solution was quenched with 10 mL of saturated aqueous sodium bisulfite solution, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine and dried over anhydrous sodium sulfate. The product 20-1 was obtained by concentration. MS[ESI,M+1]: 703.3.

[0314] In step B, compound 20-2 (1.07 g, 4.26 mmol, 1.19 mL, 3 eq), cesium carbonate (1.39 g, 4.26 mmol, 3 eq), and Pd(dppf)Cl2·CH2Cl2 (116.06 mg, 142.11 μmol, 0.1 eq) were added to a dioxane (10 mL) solution containing product 20-1 (1 g, 1.42 mmol, 1 eq). The reaction solution was purged with nitrogen three times, the temperature was raised to 110 °C, and the reaction was carried out for 3 hours. When the reaction system cooled to room temperature, it was quenched with 10 mL of water and 10 mL of ethyl acetate, and the aqueous phase was extracted three times with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude product. The crude product was subjected to reverse-phase column chromatography (water (0.1% trifluoroacetic acid, v / v) / acetonitrile system) to obtain compound 20-3. MS[ESI,M+1]: 639.6.

[0315] In step C, trifluoroacetic acid (3.08 g, 27.01 mmol, 2.00 mL, 26.55 eq) was added to a dichloromethane (10 mL) solution of compound 20-3 (650 mg, 1.02 mmol, 1 eq). The reaction solution was reacted at 25 °C for 30 minutes. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.05% hydrochloric acid, v / v) / acetonitrile system) to obtain compound 20. MS[ESI,M+1]: 539.3. 11H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 9.27 - 9.03 (m, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.35 - 7.15 (m, 3H), 7.10 - 6.95 (m, 2H), 6.87 - 6.74 (m, 4H), 6.69 - 6.49 (m, 2H), 4.37 (br t, J = 5.2 Hz, 2H), 3.78 (br d, J = 6.0 Hz, 2H), 3.70 (s, 3H), 3.25 (br s, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 2.45 (br d, J = 7.6 Hz, 2H), 2.24 - 2.18 (m, 3H), 0.87 (t, J = 7.4 Hz, 3H).

[0316] (Example 21) [Chemical formula] [Chemical formula]

[0317] In Step A, a solution of 4-iodophenol 21-1 (10 g, 45.45 mmol, 1 eq), N-Boc-ethanolamine (8.79 g, 54.54 mmol, 8.45 mL, 1.2 eq), and triphenylphosphine (17.88 g, 68.18 mmol, 1.5 eq) in tetrahydrofuran (80 mL) was cooled to 0 °C, and a solution of diethyl azodicarboxylate (11.87 g, 68.18 mmol, 12.39 mL, 1.5 eq) in tetrahydrofuran (10 mL) was added dropwise to the reaction system while controlling the temperature of the reaction system below 0 °C. After addition, the reaction was carried out at 25 °C for 12 hours. The reaction system was quenched with 50 mL of water and 50 mL of ethyl acetate, and extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed with 50 mL of saturated brine and dried over sodium sulfate. Filtration and concentration gave a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5 / 1, v / v) to obtain compound 21-2.

[0318] In step B, a hydrochloric acid methanol solution (4 M, 20 mL, 2.08 eq) was added to a methanol (100 mL) solution of compound 21-2 (14 g, 38.55 mmol, 1 eq). The reaction system was reacted at 45 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 21-3. MS[ESI,M+1]: 264.0.

[0319] In step C, a solution of N,N-dimethylbromocrotonamide (4.62 g, 24.04 mmol, 0.6 eq) in N,N-dimethylformamide (10 mL) was added dropwise to a solution of compound 21-3 (12 g, 40.06 mmol, 1 eq, HCl) and N,N-diisopropylethylamine (15.53 g, 120.19 mmol, 20.93 mL, 3 eq) in N,N-dimethylformamide (80 mL), and the reaction system was reacted at 25 °C for 12 hours. A solution of (Boc)2O (10.49 g, 48.07 mmol, 11.04 mL, 1.2 eq) in N,N-dimethylformamide (10 mL) was added dropwise to the reaction system at 0 °C. After the addition was complete, the temperature was raised to 25 °C and the reaction was carried out for 12 hours. When the temperature dropped to room temperature, it was quenched with 100 mL of water, and after liquid separation, the aqueous phase was extracted 3 times with 100 mL of ethyl acetate. The combined organic phases were washed 2 times with 100 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1, v / v) to obtain compound 21-4. MS[ESI,M+1]: 475.1.

[0320] In step D, compound 21-4 (2.52 g, 5.32 mmol, 0.6 eq), Pd(PPh3)2Cl2 (311.01 mg, 443.09 μmol, 0.05 eq), and cesium carbonate (5.77 g, 17.72 mmol, 2 eq) were added to a solution of compound 1-8 (3.75 g, 8.86 mmol, 1 eq) in 2-methyltetrahydrofuran (10 mL). The reaction system was replaced with nitrogen 3 times and 5 mL of water was added. The reaction solution was reacted at 30 °C for 12 hours to obtain product 21-5, which was used directly in the next step reaction without purification.

[0321] In step E, to a solution of product 21-5 (5.7 g, 8.86 mmol, 1 eq) in 2-methyltetrahydrofuran (20 mL) were added 3-iodoanisole (1.66 g, 8.86 mmol, 1.12 mL, 1 eq), potassium hydroxide solution (4 M, 15.51 mL, 7 eq), and Pd(dppf)Cl2 (324.01 mg, 443.00 μmol, 0.05 eq). The reaction system was purged with nitrogen three times, the temperature of the reaction solution was raised to 85 °C, and the mixture was reacted for 12 hours. When the temperature dropped to room temperature, the reaction system was diluted with 20 mL of water and 20 mL of ethyl acetate. The aqueous phase was extracted three times with 20 mL of ethyl acetate, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by reverse-phase chromatography (0.1% trifluoroacetic acid) to obtain compound 21-6. MS[ESI,M+1]: 624.4.

[0322] In step F, N-chlorosuccinimide (387.90 mg, 2.90 mmol, 1.2 eq) was added to a solution of compound 21-6 (1.51 g, 2.42 mmol, 1 eq) in dichloromethane (20 mL), and the reaction system was reacted at 25 °C for 1 hour. The reaction solution was quenched with 10 mL of saturated aqueous sodium sulfite solution, and the aqueous phase was extracted three times with 20 mL of dichloromethane. The combined organic phases were washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 21-7. MS[ESI,M+1]: 658.3.

[0323] In step G, trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL, 29.63 eq) was added to a solution of product 21-7 (1.5 g, 2.28 mmol, 1 eq) in dichloromethane (20 mL). The reaction solution was reacted at 25 °C for 30 minutes. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.05% ammonium hydroxide, v / v) / acetonitrile system) to obtain compound 21. MS[ESI,M+1]: 558.1. 1H NMR(400MHz,DMSO-d6)δ=11.39(s,1H),7.48(d,J=7.6Hz,1H),7.37(d,J=8.0Hz,1H),7.21-7.09(m,3H),6.87-6.70(m,5H), 6.69-6.56(m,3H),6.54-6.46(m,1H),3.92-3.85(m,2H),3.66(s,3H),3.33-3.29(m,2H),2.98(s,3H),2.84(s,3H),2.78(br t,J=5.6Hz,2H),2.45-2.37(m,2H),0.92-0.85(m,3H).

[0324] (Examples 22 and 23) [ka] [ka]

[0325] In Step A, trans-2-pentenoic acid (5 g, 49.94 mmol, 5.05 mL, 1 eq) was dissolved in 50 mL of carbon tetrachloride, and N-bromosuccinimide (11.56 g, 64.92 mmol, 1.3 eq) was added. The reaction mixture was reacted under nitrogen protection at 80 °C for 12 h. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude product 22-1. MS[ESI,M+1]:179.1.

[0326] In step B, 8 mL of thionyl chloride was added to the crude product 22-1 (3 g, 16.76 mmol, 1 eq). The reaction mixture was reacted at 80° C. for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give compound 22-2.

[0327] In step C, dimethylamine (1.33 g, 16.26 mmol, 1.49 mL, 1 eq, hydrochloride) was dissolved in 30 mL of dichloromethane, sodium carbonate (3.45 g, 32.51 mmol, 2 eq) was added to the solution, and compound 22-2 (3.21 g, 16.26 mmol, 1 eq) was dissolved in 12 mL of dichloromethane and added dropwise to the reaction solution at 0 °C. The reaction system was reacted at 25 °C for 2 hours. After diluting the reaction system with 20 mL of water and 20 mL of dichloromethane and separating the layers, the organic phase was washed twice with 30 mL of saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude product 22-3. MS[ESI,M+1]: 206.1.

[0328] In step D, compound 22-4 (6.83 g, 25.88 mmol, 1 eq) was dissolved in 100 mL of DMF, diisopropylethylamine (6.69 g, 51.76 mmol, 9.02 mL, 2 eq) was added, and the crude product 22-3 (3.2 g, 15.53 mmol, 0.6 eq) was dissolved in 50 mL of DMF and added to the reaction solution. The reaction solution was reacted at 25 °C for 12 hours to obtain product 22-5, which was used directly in the next step reaction without purification. MS[ESI,M+1]: 390.0.

[0329] In step E, (Boc)2O (6.78 g, 31.05 mmol, 7.13 mL, 1.2 eq) was added to product 22-5 (10.07 g, 25.87 mmol, 1 eq). The reaction solution was reacted at 25 °C for 2 hours under nitrogen protection. 100 mL of water was added to the reaction system and extracted three times with 200 mL of ethyl acetate. The combined organic phases were washed twice with 200 mL of saturated brine. It was dried over anhydrous sodium sulfate. Filtration and concentration gave a crude product. The crude product was separated by column chromatography to obtain compound 22-6. MS[ESI,M+1]: 490.1.

[0330] In step F, to a solution of compound 1-8 (575.14 mg, 1.36 mmol, 1 eq) in 2-methyltetrahydrofuran (20 mL) were added compound 22-6 (399.06 mg, 815.49 μmol, 0.6 eq), 5 mL of water, cesium carbonate (885.68 mg, 2.72 mmol, 2 eq), and bis(triphenylphosphine)palladium(II) dichloride (47.70 mg, 67.96 μmol, 0.05 eq). The reaction system was purged with nitrogen three times, and the reaction solution was reacted at 30 °C under nitrogen protection for 12 hours to obtain product 22-7.

[0331] In step G, to a solution of product 22-7 (895.19 mg, 1.36 mmol, 1 eq) in 2-methyltetrahydrofuran (20 mL) were added m-bromoanisole (305.05 mg, 1.63 mmol, 206.12 μL, 1.2 eq), potassium hydroxide solution (4 M, 2.38 mL, 7 eq), and bis(triphenylphosphine)palladium(II) dichloride (47.70 mg, 67.96 μmol, 0.05 eq). The reaction system was purged with nitrogen three times, and then continuously reacted at 85 °C under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, the aqueous phase was extracted three times with 30 mL of ethyl acetate, and the combined organic phases were extracted three times with 50 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by reverse-phase column chromatography (water (0.1% formic acid, v / v) / acetonitrile system) to obtain compound 22-8. MS[ESI,M+1]: 639.2.

[0332] In step H, a solution of compound 22-8 (290 mg, 453.98 μmol, 1 eq) and N-chlorosuccinimide (72.75 mg, 544.78 μmol, 1.2 eq) in dichloromethane (5 mL) was reacted at 20 °C for 1 hour. The reaction solution was quenched with 10 mL of saturated sodium bisulfite, separated, the aqueous phase was extracted three times with 20 mL of dichloromethane, and the combined organic phases were extracted twice with 20 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 22-8'. MS[ESI,M+1]: 673.3.

[0333] In Step I, 1 mL of trifluoroacetic acid was added to a dichloromethane (8 mL) solution of product 22-8’ (203 mg, 301.53 μmol, 1 eq). The reaction solution was reacted at 20 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.05% hydrochloric acid, v / v) / acetonitrile system) to obtain product 22-9. MS [ESI, M+1]: 573.2.

[0334] In Step J, product 22-9 (150 mg, 256.78 μmol, 1 eq, HCl) was resolved by supercritical fluid chromatography (SFC) method (chiral IG (water (0.1% ammonium hydroxide, v / v) / methanol)) to obtain compound 22 or 23 (Rt = 2.290, MS [ESI, M+1]: 573.2), and compound 23 or 22 (Rt = 2.474, MS [ESI, M+1]: 573.2). 1 H NMR (400 MHz, chloroform-d) δ = 8.58 (s, 1H), 7.69 - 7.63 (m, 2H), 7.31 - 7.28 (m, 1H), 7.24 - 7.12 (m, 5H), 6.77 - 6.71 (m, 3H), 6.63 - 6.58 (m, 1H), 6.43 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 15.2 Hz, 1H), 4.28 - 4.21 (m, 2H), 3.72 (s, 3H), 3.37 (t, J = 6.8 Hz, 1H), 3.04 (s, 3H), 2.98 (s, 3H), 2.92 - 2.81 (m, 2H), 2.59 - 2.54 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H), 0.99 (t, J = 8.0 Hz, 3H). 11H NMR (400 MHz, chloroform-d) δ = 9.42 (s, 1H), 7.67 - 7.57 (m, 2H), 7.32 - 7.28 (m, 1H), 7.24 - 7.11 (m, 5H), 6.76 - 6.71 (m, 3H), 6.57 - 6.36 (m, 3H), 4.35 (s, 2H), 3.89 (s, 1H), 3.71 (s, 3H), 3.23 - 3.06 (m, 2H), 2.94 (d, J = 2. Hz, 6H), 2.59 - 2.53 (m, 2H), 1.34 (d, J = 6.0 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H).

[0335] (Examples 24, 25) [Chemical formula]

[0336] In Step A, to a solution of Compound 1-8 (4.75 g, 11.23 mmol, 1.42 eq) in 2-methyltetrahydrofuran (30 mL) were added Compound 22-6 (3.48 g, 7.11 mmol, 0.9 eq), Pd(PPh3)2Cl2 (277.42 mg, 395.25 μmol, 0.05 eq), and cesium carbonate (5.15 g, 15.81 mmol, 2 eq). The reaction system was purged with nitrogen three times and 6 mL of water was added. The reaction mixture was reacted at 30 °C for 12 hours to obtain Product 24-7, which was used directly in the next step reaction without purification.

[0337] In step B, to a solution of product 24-7 (5.21 g, 7.91 mmol, 1 eq) in 2-methyltetrahydrofuran (20 mL) were added iodobenzene (1.94 g, 9.49 mmol, 1.06 mL, 1.2 eq), potassium hydroxide solution (4 M, 13.84 mL, 7 eq), and Pd(PPh3)2Cl2 (277.61 mg, 395.52 μmol, 0.05 eq). The reaction system was purged with nitrogen three times, and the temperature of the reaction solution was raised to 85 °C and reacted for 12 hours. When it cooled to room temperature, 30 mL of water was added to the reaction system, and it was extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a crude product was obtained. The crude product was separated by reverse-phase chromatography (0.1% formic acid) to obtain compound 24-8. MS[ESI,M+1]: 609.3.

[0338] In step C, N-chlorosuccinimide (552.76 mg, 4.14 mmol, 1.2 eq) was added to a solution of compound 24-8 (2.1 g, 3.45 mmol, 1 eq) in dichloromethane (25 mL), and the reaction system was reacted at 25 °C for 12 hours. The reaction solution was quenched with 15 mL of an aqueous solution of saturated sodium bisulfite, 30 mL of dichloromethane was added, the organic phase was washed twice with 20 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, product 24-8’ was obtained. MS[ESI,M+1]: 643.3.

[0339] In step D, 10 mL of trifluoroacetic acid was added to a solution of product 24-8’ (1.9 g, 2.95 mmol, 1 eq) in dichloromethane (10 mL). The reaction solution was reacted at 25 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (0.05% hydrochloric acid, v / v) / acetonitrile system) to obtain compound 24-9. MS[ESI,M+1]: 543.3.

[0340] In step E, compound 24-9 (150 mg, 256.78 μmol, 1 eq, HCl) was resolved by SFC method (chiral IG (water (0.1% ammonium hydroxide, v / v) / ethanol)) to obtain compound 24 or 25 (Rt = 2.148, MS[ESI,M+1]: 543.3), and compound 25 or 24 was obtained (Rt = 2.352, MS[ESI,M+1]: 543.3). 1 H NMR (400 MHz, DMSO-d6) δ = 11.46 (s, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.21 - 7.16 (m, 3H), 7.15 - 7.09 (m, 2H), 6.55 (d, J = 8.8 Hz, 1H), 6.43 - 6.39 (m, 2H), 4.15 - 4.08 (m, 2H), 3.30 - 3.25 (m, 1H), 2.96 (s, 3H), 2.82 (s, 3H), 2.74 - 2.62 (m, 2H), 2.45 (br d, J = 7.6 Hz, 2H), 1.06 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.6 Hz, 3H). 1 H NMR (400 MHz, DMSO-d6) δ = 11.61 (s, 1H), 9.51 - 9.18 (m, 2H), 7.64 (d, J = 2.8 Hz, 1H), 7.39 (br d, J = 8.0 Hz, 4H), 7.29 (br s, 2H), 7.18 - 7.18 (m, 2H), 6.78 (d, J = 15.2 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 6.55 - 6.47 (m, 1H), 4.34 (br s, 2H), 4.06 - 3.98 (m, 1H), 3.16 (br s, 2H), 2.99 (s, 3H), 2.84 (s, 3H), 2.44 (br d, J = 7.6 Hz, 2H), 1.35 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H).

[0341] (Example 26) [Chemical formula]

[0342] In Step A, to a solution of 2-methyltetrahydrofuran (15 mL) containing Compound 1-8 (2 g, 4.73 mmol, 1.42 eq) (2-methyltetrahydrofuran solution, theoretical value) and Compound 26-1 (1.59 g, 3.33 mmol, 1 eq), bis(triphenylphosphine)palladium(II) dichloride (116.81 mg, 166.42 μmol, 0.05 eq) and cesium carbonate (2.17 g, 6.66 mmol, 2 eq) were added in this order. The reaction system was purged with nitrogen three times and 1 mL of water was added. The reaction solution was reacted at 30 °C under nitrogen protection for 10 hours and then cooled to room temperature to obtain Product 26-2. It was used directly in the next step reaction without purification. MS[ESI,M+1]: 646.4.

[0343] In Step B, to a solution of 2-methyltetrahydrofuran (10 mL) containing Product 26-2 (2.15 g, 3.33 mmol, 1 eq) and iodobenzene (815.28 mg, 4.00 mmol, 445.51 μL, 1.2 eq), potassium hydroxide solution (4 M, 5.83 mL, 7 eq) and bis(triphenylphosphine)palladium(II) dichloride (116.88 mg, 166.51 μmol, 0.05 eq) were added. The reaction system was purged with nitrogen three times and reacted at 85 °C under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, 25 mL of water was added, the reaction system was extracted three times with 30 mL of ethyl acetate, and the combined organic phases were extracted twice with 30 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by reverse-phase column chromatography (trifluoroacetic acid system) to obtain Compound 26-3. MS[ESI,M+1]: 568.2.

[0344] In step C, N-chlorosuccinimide (342.67 mg, 2.57 mmol, 1.2 eq) was added to a solution of compound 26-3 (1.21 g, 2.14 mmol, 1 eq) in dichloromethane (15 mL). The reaction system was replaced with nitrogen three times, and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was extracted twice with 10 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by preparative HPLC (water (10 mM ammonium bicarbonate)-acetonitrile) to obtain product 26-4. MS[ESI,M+1]: 602.2.

[0345] In step D, N,N-diisopropylethylamine (85.86 mg, 664.32 μmol, 115.71 μL, 2 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (151.56 mg, 398.59 μmol, 1.2 eq) were added to a solution of product 26-4 (200 mg, 332.16 μmol, 1 eq) and trifluoroacetate of azetidineamine (31.08 mg, 332.16 μmol, 36.73 μL, 1 eq, hydrochloride) in N,N-dimethylformamide (10 mL). The reaction system was replaced with nitrogen three times. The reaction solution was reacted at 25 °C for 2 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, and it was extracted three times with 10 mL of ethyl acetate. The combined organic phases were extracted twice with 10 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 26-5. MS[ESI,M+1]: 641.3.

[0346] In step E, trifluoroacetic acid (9.54 g, 83.66 mmol, 6.19 mL, 227.31 eq) was added to a dichloromethane (5 mL) solution of crude product 26-5 (236 mg, 368.06 μmol, 1 eq). The reaction solution was reacted for 1 hour at 25 °C under a nitrogen atmosphere. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC twice (water (0.05% ammonium hydroxide v / v) - acetonitrile, water (10 mM ammonium bicarbonate) - acetonitrile) to obtain compound 26. MS[ESI,M+1]: 541.3. 1 H NMR(400 MHz, methanol-d4) δ = 7.71 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.39 - 7.10 (m, 9H), 6.72 (td, J = 6.4, 15.4 Hz, 1H), 6.64 - 6.59 (m, 1H), 6.35 - 6.26 (m, 1H), 4.42 - 4.38 (m, 2H), 4.30 (t, J = 7.7 Hz, 2H), 4.07 (t, J = 7.8 Hz, 2H), 3.72 (dd, J = 1.3, 6.4 Hz, 2H), 3.25 - 3.22 (m, 2H), 2.56 (q, J = 7.4 Hz, 2H), 2.33 (td, J = 7.8, 15.6 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H).

[0347] (Example 27)

Chemical formula

Chemical formula

Chemical formula

[0348] In step A, N,N-diisopropylethylamine (6.70 g, 51.80 mmol, 9.02 mL, 2 eq) was added to a solution of compound 27-1 (6.84 g, 25.90 mmol, 1 eq) in N,N-dimethylformamide (50 mL). Next, a solution of ethyl bromocrotonate (3 g, 15.54 mmol, 2.14 mL, 0.6 eq) in N,N-dimethylformamide (15 mL) was slowly added dropwise to the reaction system. The reaction solution was reacted at 25 °C for 22 hours and then cooled to 0 °C, and (Boc)2O (5.65 g, 25.90 mmol, 5.95 mL, 1 eq) was added. After raising the temperature to 25 °C and reacting for 2 hours, 20 mL of water was added to the reaction system, and the mixture was extracted 3 times with 25 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to reverse-phase column chromatography (water (0.1% trifluoroacetic acid, v / v)-acetonitrile) to obtain product 26-1. MS[ESI,M+1]:477.1.

[0349] In step B, trifluoroacetic acid (8.01 g, 70.23 mmol, 5.20 mL, 66.45 eq) was added to a solution of compound 27-3 (200 mg, 1.06 mmol, 1 eq) in dichloromethane (5.2 mL). The reaction solution was reacted at 25 °C for 1 hour. The reaction solution was concentrated to obtain crude product 27-4. 1 H NMR(EW19918-27-P1,400MHz,DMSO-d6)δ=11.32-10.91(m,1H),9.24-8.78(m,1H),4.61(d,J=4.9Hz,1H),4.49(d,J=4.9Hz,1H),4.09-3.99(m,1H),3.87-3.78(m,1H),3.23-3.05(m,1H).

[0350] In step C, to a solution of 2-methyltetrahydrofuran (15 mL) containing compound 1-8 (1.25 g, 2.95 mmol, 1.42 eq, 2-methyltetrahydrofuran solution, theoretical value) and compound 26-1 (990.84 mg, 2.08 mmol, 1 eq) were added bis(triphenylphosphine)palladium(II) dichloride (73.01 mg, 104.01 μmol, 0.05 eq) and cesium carbonate (1.36 g, 4.16 mmol, 2 eq). The reaction system was replaced with nitrogen three times and 1 mL of water was added. After reacting the reaction solution at 30 °C under nitrogen protection for 8 hours, it was cooled to room temperature to obtain compound 27-5. It was used directly in the next step reaction without purification. MS[ESI,M+1]: 646.4.

[0351] In step D, to a solution of 2-methyltetrahydrofuran (8 mL) containing compound 27-5 (1.34 g, 2.08 mmol, 1 eq) and iodobenzene (508.13 mg, 2.49 mmol, 277.67 μL, 1.2 eq) were added potassium hydroxide solution (4 M, 3.63 mL, 7 eq) and bis(triphenylphosphine)palladium(II) dichloride (72.84 mg, 103.78 μmol, 0.05 eq). The reaction system was replaced with nitrogen three times and then continuously reacted at 85 °C under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, 25 mL of water was added, and it was extracted three times with 30 mL of ethyl acetate. The combined organic phases were extracted twice with 30 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The desired compound was detected by a TLC plate (PE:EA = 5:1). The crude product was separated by column chromatography to obtain compound 27-6. MS[ESI,M+1]: 596.3.

[0352] In step E, N-chlorosuccinimide (154.39 mg, 1.16 mmol, 1.2 eq) was added to a solution of compound 27-6 (574 mg, 963.53 μmol, 1 eq) in dichloromethane (15 mL). The reaction system was purged with nitrogen three times, and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was extracted and diluted with 10 mL of dichloromethane, and the combined organic phases were extracted twice with 20 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 27-7. MS[ESI,M+1]: 630.2.

[0353] In step F, water (10.00 g, 555.0 mmol, 10 mL, 874.49 eq) was added to a solution of crude product 27-7 (400 mg, 634.75 μmol, 1 eq) and lithium hydroxide monohydrate (266.36 mg, 6.35 mmol, 10 eq) in methanol (30 mL). The reaction solution was reacted at 25 °C for 6 hours. The pH of the reaction solution was adjusted to 7 with 3 M hydrochloric acid, 5 mL of water was added, the aqueous phase was extracted three times with 10 mL of ethyl acetate, the combined organic phases were extracted twice with 10 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 27-8. MS[ESI,M+1]: 602.2.

[0354] In step G, N,N-diisopropylethylamine (30.05 mg, 232.51 μmol, 40.50 μL, 2 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (53.04 mg, 139.51 μmol, 1.2 eq) were added to a solution of crude product 27-8 (70 mg, 116.26 μmol, 1 eq) and crude product 27-4 (23.62 mg, 116.26 μmol, 1 eq, trifluoroacetic acid) in N,N-dimethylformamide (3 mL). The reaction system was purged with nitrogen three times. The reaction solution was reacted at 25 °C under nitrogen protection for 4 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, the mixture was extracted three times with 10 mL of ethyl acetate, the combined organic phases were extracted twice with 10 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 27-9. MS [ESI, M+1]: 673.3。

[0355] In Step H, 3 mL of trifluoroacetic acid was added to a solution of crude product 27-9 (120 mg, 178.25 μmol, 1 eq) in 3 mL of dichloromethane. The reaction solution was reacted for 1 hour at 25 °C under a nitrogen atmosphere. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC twice (water (0.05% hydrochloric acid)-acetonitrile, water (0.225% formic acid v / v)-acetonitrile) to obtain Compound 27. MS [ESI, M+1]: 573.1。 1 H NMR (400 MHz, DMSO-d6) δ = 11.49 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.26 - 7.11 (m, 6H), 6.64 - 6.55 (m, 2H), 6.16 (d, J = 15.6 Hz, 1H), 4.62 (d, J = 5.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 1H), 4.27 - 4.17 (m, 3H), 3.98 - 3.89 (m, 2H), 3.71 - 3.63 (m, 2H), 3.49 - 3.46 (m, 2H), 3.01 - 2.87 (m, 2H), 2.47 - 2.43 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0356] Experimental Example 1: MCF-7 Cell Proliferation Inhibition Experiment Experimental Materials: EMEM medium was purchased from Wisent, fetal bovine serum was purchased from Biosera, and Promega CellTiter-Glo reagent was used. The MCF-7 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences' Committee for Type Culture Collection. A Nivo5 multi-label analyzer (PerkinElmer) was used.

[0357] Experimental Method: MCF-7 cells were inoculated into white 384-well plates, with 600 cells per 45 mL of cell suspension in each well. The cell culture plates were placed in a carbon dioxide incubator and cultured overnight.

[0358] On the day of adding the compound, the day 0 plate plated under the same conditions the previous day was taken out, centrifuged to remove the medium, 25 μL of Promega CellTiter-Glo reagent was added to each well, and incubated at room temperature for 10 minutes until the luminescence signal became stable. The results were read using a PerkinElmer Nivo multi-label analyzer and used as the 0% inhibition starting value.

[0359] Using a multi-channel pipette, the test compound was diluted 5-fold to 10 concentrations, i.e., diluted from 2 mmol to 0.1 nmol, and each well was repeated twice. 47.5 μL of medium was added to the middle plate, and 2.5 μL of the serially diluted compound was added to each well of the middle plate at the corresponding position. After uniform mixing, 5 μL was transferred to each well of the cell culture plate. The cell culture plate was placed in a carbon dioxide incubator and cultured for 6 days.

[0360] After incubating the compound for 6 days, it was centrifuged to remove the medium, 25 μL of Promega CellTiter-Glo reagent was added to each well of the cell culture plate, and incubated at room temperature for 10 minutes until the luminescence signal became stable. The results were read using a PerkinElmer Nivo multi-label analyzer.

[0361] Data analysis: The formula % inhibition = ((RFU Cmpd - AVER(RFU Neg.Ctrl )) / ((AVER(RFU Day0 ) - AVER(RFU Neg.Ctrl )) × 100% was used to convert the initial data to the inhibition rate, and fitting was performed to calculate IC 50 .

[0362] Experimental results: Shown in Table 1. Table 1: Results of in vitro MCF-7 cell growth inhibition experiment

Table 1

[0363] Experimental Example 2: Evaluation of DMPK Characteristics (1) Study on Metabolic Stability in Liver Microsomes Experimental Purpose: To measure the metabolic stability of the test compound in liver microsomes of humans, CD-1 mice, and SD rats (the providers are Corning Hun (divided) Co., Ltd., Miaotong Biotechnology Co., Ltd., and Miaotong Biotechnology Co., Ltd., respectively).

[0364] Experimental Procedure: First, eight 96-well plates were set up and named T0, T5, T10, T20, T30, T60, NCF60, and BLANK, respectively. Buffer was added to the BLANK at 10 μL / well, and drug solution was added to each of the other plates at 10 μL / well. The set liver microsomes were added to seven plates (80 μL / well) each, and the T0 plate was excluded. Buffer was added to the NCF60 plate at 10 μL / well, placed in a 37°C water bath pot for incubation, and the timing started. [Table 2]

[0365] Next, the prepared NADPH cofactor standard solution was dispensed into a shallow-bottom 96-well plate as a loading slot, and then dispensed into each plate at 10 μL / well using a 96-channel pipette, placed in a 37°C water bath pot for incubation, and the reaction started. [Table 3]

[0366] At each time point, 300 μL / well of a stop solution (cold acetonitrile containing 100 ng / mL of tolbutamide and 100 ng / mL of labetalol as internal standards) was added to stop the reaction and mixed uniformly. Centrifugation was performed at 4000 rpm for 20 minutes in a centrifuge to precipitate the protein. After centrifugation, the supernatant was taken out with a 96-channel pipette and transferred to a new 96-well plate with 300 μL of HPLC water added to each well at 100 μL / well, and mixed uniformly. An operator performed LC / MS / MS detection. The results are shown in Table 2.

[0367] 2) Cytochrome P450 Isozyme Inhibition Effect Study Experimental Purpose: To measure the inhibitory effect of the test compound on the activities of cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) derived from human liver microsomes (Corning Inc.)

[0368] Experimental Procedure: First, the test compound (10 mM) was serially diluted to prepare standard solutions (100× final concentration), with the concentrations of the standard solutions being 5, 1.5, 0.5, 0.15, 0.05, 0.015, and 0.005 mM, respectively. Also, standard solutions of each positive inhibitor of P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and its specific substrate mixture (including 5 types) were set up. Human liver microsomes frozen in an -80°C refrigerator were thawed on ice. After all the human liver microsomes were dissolved, they were diluted with PB to prepare a standard solution at a predetermined concentration (0.253 mg / mL). 20 μL of the substrate mixture was added to the reaction plate (20 μL of PB was added to the Blank well), and 158 μL of the human liver microsome standard solution was added to the reaction plate, and the reaction plate was placed on ice and waited. At this time, 2 μL of each concentration of the test compound (N = 1) and specific inhibitor (N = 2) were added to the corresponding wells, and the corresponding organic solvent was added to the group without inhibitor (test compound or positive inhibitor) to serve as a control group sample (the test compound control sample was 1:1 DMSO:MeOH, and the positive control sample was 1:9 DMSO:MeOH). After pre-incubating in a 37°C water bath for 10 minutes, 20 μL of the cofactor (NADPH) solution was added to the reaction plate, and it was placed in a 37°C water bath and incubated for 10 minutes. 400 μL of cold acetonitrile solution (the internal standard substances were 200 ng / mL tolbutamide and labetalol) was added to stop the reaction. The reaction plate was placed on a shaker and shaken for 10 minutes. Centrifuged at 4000 rpm for 20 minutes, and 200 μL of the supernatant was added to 100 μL of water to dilute the sample. Finally, it was blocked, shaken, and oscillated to be uniform, and then LC / MS / MS detection was performed. The results are shown in Table 2.

[0369] (3) MDR1-MDCK cell bidirectional permeability evaluation experiment In this study, the MDR1-MDCKII cell line obtained with permission from the Piet Borst Laboratory of the Netherlands Cancer Institute was used as an in vitro model. This cell line is Madin-Darby canine kidney cells transfected with the human multidrug resistance gene (MDR1), and these cells can stably express the efflux transporter P-gp. Therefore, it is suitable for screening P-gp substrates or inhibitors to predict the permeability of compounds at sites where high efflux is expected, such as the duodenum, blood-brain barrier, hepatocyte nuclei, and kidney units. The purpose of this study is to measure the bidirectional permeability of the test compound through the MDR1-MDCK II cell model using MDR1-MDCK II cells.

[0370] Experimental procedure: The standard experimental conditions are as follows. Test concentration: 2 μM (DMSO ≤ 1%). Replicates: n = 2. Direction: Bidirectional transport, including two directions: A→B and B→A. Incubation time: 2.5 hours at each time point. Transport buffer: HBSS buffer containing 10 mM Hepes, with a pH of 7.4. Incubation conditions: 37°C, 5% CO2.

[0371] After the incubation was completed, the sample solutions on the administration side and the receiving side were taken out and immediately mixed with a cold acetonitrile solution containing an internal standard substance. The concentrations of the test compound in all samples (initial administration solution, administration-side and receiving-side samples) were analyzed by LC / MS / MS. Parameters such as the apparent permeability coefficient and efflux ratio were calculated. The results are shown in Table 2. Table 2: Results of in vitro DMPK property evaluation

Table 4

[0372] (4) Mouse in vivo pharmacokinetic study Experimental purpose: Female Balb / c mice were used as the test animals. The plasma drug concentrations at different times after intravenous and intragastric administrations of the test compound to the mice were measured by LC / MS / MS method. The pharmacokinetic behavior of the test compound in the mouse body was investigated to evaluate its pharmacokinetic characteristics.

[0373] Experimental method: Experimental animals: Four healthy female Balb / c mice were divided into 2 groups with individuals of similar body weight. The iv group had 2 mice per group, and the po group had 2 mice per group. The animals were purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0374] Drug preparation: iv group: Appropriate amounts of the sample were weighed respectively, and solutions of 2 mg / mL were prepared, mixed in equal amounts and diluted to 0.5 mg / mL, stirred and ultrasonicated until clear. The solvent was 15% HP-b-CD.

[0375] po group: An appropriate amount of the preparation solution of the iv group was diluted to 0.4 mg / mL with 15% HP-b-CD.

[0376] Administration: After fasting overnight, the iv group was given intravenous administration, and the dosage of the test compound was 1 mg / kg each. The po group was given intragastric administration respectively, and the dosage of the test compound was 2 mg / kg each.

[0377] Experimental procedures: After administering the test compound to each mouse in the intravenous injection group for female Balb / c mice, 30 μL of blood was collected from the supine vein at 0.0833, 0.25, 0.5, 1, 2, 4, 8, and 24 hours respectively, and placed into a blood collection tube containing an anticoagulant with pre-added EDTA-K2. After administering the test compound to each mouse in the intragastric administration group, 30 μL of blood was collected from the supine vein at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours respectively, placed into a blood collection tube containing an anticoagulant with pre-added EDTA-K2, then centrifuged (3200 g, 4 °C, 10 minutes) to extract the plasma. The plasma was transferred to a pre-cooled centrifuge tube, rapidly frozen with dry ice, and stored in an ultra-low temperature freezer at -60 °C or above until LC-MS / MS analysis. Four hours after administration, the animals were allowed to resume normal feeding. The plasma content of the test compound after intravenous and intragastric administration to mice was measured by the LC / MS / MS method. The linear range of this method was 2.00 - 2000 nM. The experimental results are shown in Table 3.

[0378] (5) In Vivo Pharmacokinetics Study in Rats Experimental purpose: Female SD rats were used as the test animals, and the plasma drug concentrations at different times after intravenous and intragastric administration of the test compound to rats were measured by the LC / MS / MS method. The pharmacokinetic behavior of the test compound in the rat body was investigated to evaluate its pharmacokinetic characteristics.

[0379] Experimental method: Experimental animals: Four healthy female SD rats were divided into 2 groups with individuals of similar body weight. The iv group had 2 rats per group, and the po group had 2 rats per group. The animals were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0380] Drug preparation: iv group: Appropriate amounts of the sample were weighed respectively to prepare a 2 mg / mL solution, mixed in equal amounts to 0.5 mg / mL, stirred and sonicated until clear. The solvent was 15% HP-β-CD.

[0381] po group: An appropriate amount of the preparation solution of the iv group was diluted to 0.4 mg / mL with 15% HP-β-CD.

[0382] Administration: After an overnight fast, for the iv group, intravenous administration was performed, and the dosage of the test compound was 1 mg / kg each. For the po group, intragastric administration was performed for each, and the dosage of the test compound was 2 mg / kg each.

[0383] Experimental procedure: After administering the test compound to each female SD rat in the intravenous injection group, 200 μL of blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1, 2, 4, 8, and 24 hours respectively, and placed in a blood collection tube containing an anticoagulant with pre-added EDTA-K2. After administering the test compound to each in the intragastric administration group, 200 μL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours respectively, placed in a blood collection tube containing an anticoagulant with pre-added EDTA-K2, then centrifuged (3200 g, 4 °C, 10 minutes) to extract the plasma, transferred the plasma to a pre-cooled centrifuge tube, rapidly frozen with dry ice, and stored in an ultra-low temperature freezer at -60 °C or above until LC-MS / MS analysis. Four hours after administration, the animals were allowed to resume feeding. The plasma content of the test compound after intravenous and intragastric administration to mice was measured by the LC / MS / MS method. The linear range of this method was 2.00 - 2000 nM. The experimental results are shown in Table 3.

[0384] The results of the in vivo PK property evaluation are as shown in Table 3. Table 3: Results of in vivo PK property evaluation

Table 5

[0385] Experimental Example 3: In vivo efficacy evaluation The purpose of this experiment is to evaluate the antitumor effect of the compound of the present invention in a model of MCF-7 breast cancer cell xenograft BALB / c nude mice (provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., and the number of test animals per experimental group is 7).

[0386] Three days before inoculation, a 0.36 mg estrogen sustained-release tablet for 60 days was subcutaneously inoculated into the left shoulder of the mice. When the cells reached the logarithmic growth phase, the cells were collected and counted, and the cell concentration was 10×10 7Adjusted to cells / mL, inoculated with an equal volume of Matrigel added and uniformly mixed. Each mouse was subcutaneously inoculated with 0.2 mL of MCF-7 tumor cell suspension (10×10 6 ) at the right shoulder. On the 14th day after tumor cell inoculation, they were grouped and administered once daily. The average tumor volume was 200 mm 3 , and the body weight was 22.0 - 23.0 g. After grouping, the tumor volume and body weight were measured twice a week. The tumor growth rate (T / C) and tumor growth inhibition rate (TGI) were calculated from the final measurement data on the 27th day after grouping. The antitumor effect of the compound was evaluated by TGI (%) or relative tumor growth rate T / C (%). TGI (%) is the tumor growth inhibition rate. TGI (%) = [(1 - (average tumor volume at the end of administration in the treatment group - average tumor volume at the start of administration in the treatment group)) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%, relative tumor growth rate T / C (%) = T RTV / C RTV × 100% (T RTV : average RTV of the treatment group, C RTV : average RTV of the negative control group). The relative tumor volume (RTV) was calculated from the tumor measurement results, and the calculation formula is RTV = V t / V0, where V0 is the tumor volume measured at the time of grouped administration (D0), and V t is the tumor volume measured at a specific time. T RTV and C RTV used the data of the same day. The results are as follows. Table 4: Antitumor Effect Analysis

Table 6

[0387] Experimental Example 4: Young Rat Uterine Wet Weight Inhibition Experiment The purpose of this experiment is to evaluate the inhibitory effect on uterine growth of the compound of the present invention in young female rats aged 18 to 21 days after birth (provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., with 5 test animals per experimental group). In this experiment, young female rats at 18 days after birth were orally administered the compound of the present invention at a dose of 10 mg / kg and estradiol at a dose of 0.1 mg / kg for 3 consecutive days, respectively. The control group was orally administered estradiol at a dose of 0.1 mg / kg for 3 consecutive days, and the blank group was not administered any drugs other than the corresponding solvent. Three days after administration, the rats were sacrificed, and the uterine weights of the rats were weighed to observe the inhibitory effect of the test drug on the uterine growth of the rats. Inhibition rate = 100×[(Vehicle EE -Cpd) / (Vehicle EE -Vehicle)], where Vehicle EE is the wet uterine weight of the rats in the control group (oral administration of 0.1 mg / kg of estradiol), Cpd is the wet uterine weight of the rats in the administration group, and Vehicle is the wet uterine weight of the rats in the blank group. The results are as follows.

Table 7

Chemical formula

Chemical formula

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Claims

【Claim 1】 【Fig. 1】 [Chemical] A compound, its stereoisomer or a pharmaceutically acceptable salt thereof. **Claim 2** A pharmaceutical composition comprising a therapeutically effective amount of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient, and a pharmaceutically acceptable carrier. **Claim 3** Use of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 2, for the manufacture of a therapeutic agent for estrogen receptor positive breast cancer.

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