Aromatic compounds, pharmaceutical compositions thereof and uses thereof

Abstract

Aromatic compounds, pharmaceutical compositions thereof, and uses thereof are disclosed. Specifically, a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof is disclosed. The compound has excellent inhibitory activity against tumor cell proliferation. [Case 1] TIFF2024523690000688.tif53168

Description

[Technical Field]

[0001] This application claims the priority of Chinese patent application No. 2021114586244, filed on December 2, 2021, the priority of Chinese patent application No. 2022108642275, filed on July 20, 2022, and the priority of Chinese patent application No. 2022111958466, filed on September 28, 2022. This application cites the above Chinese patent applications in their entirety.

[0002] (Technical field) The present invention relates to aromatic compounds, pharmaceutical compositions thereof and uses thereof. [Background technology]

[0003] Normal tissue cell growth, tissue repair, and remodeling depend on precise regulation and a balanced regulatory system of transcriptional activity. Transcriptional activity is regulated by numerous signaling pathways, one of which is the Hippo signaling pathway. Genetic studies in Drosophila and mammals have demonstrated that the Hippo signaling pathway is a conserved and important signaling pathway consisting of a series of kinases, including MST1 / 2 and LATS1 / 2, which regulate the transcription factors YAP / TAZ.

[0004] When the Hippo signaling pathway is active, YAP / TAZ are either phosphorylated and present in the cytoplasm or degraded. When the Hippo signaling pathway is inactive, YAP / TAZ translocate to the nucleus and bind to other transcription factors, including the so-called TEAD family of proteins, TEAD1, TEAD2, TEAD3, and TEAD4. The YAP / TAZ-TEAD complex promotes the transcription of downstream genes and regulates cell proliferation, death, and differentiation. YAP and TAZ can also bind to other factors, and TEAD is widely considered to be the most important regulator of cell proliferation and tumor-promoting growth (Holder and Cunningham 2018).

[0005] High YAP / TAZ activation, resulting in high activity of the YAP / TAZ-TEAD complex, has been found in many human cancers. Nuclear YAP / TAZ expression and protein levels are increased in cancers such as breast cancer, lung cancer, ovarian cancer, rectal cancer, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, and liver cancer (Steinhardt et al., 2008; Harvey et al., 2015). While genetic mutations in the Hippo signaling pathway are rare in normal tissue cells, they are common in cancer tissue cells. For example, mutations in NF2 and LATS1 / 2 proteins cause these proteins to no longer function normally, increasing YAP-TEAD complex activity. Cell proliferation, particularly in malignant pleural mesothelioma (MPM), is determined by YAP / TAZ-TEAD activity.

[0006] Furthermore, activation of YAP / TAZ-TEAD in tumor cells causes resistance to chemotherapy drugs, resulting in resistance to targeted drugs such as BRAF, MEK, EGFR, and KRAS small molecules (Lin L., et al., 2015). This suggests that inhibiting YAP / TAZ-TEAD activity through combined administration may improve drug efficacy and reduce tumor drug resistance. When combined with small molecule targeted drugs, it can prevent tumor cells from escaping immune surveillance, and inhibiting YAP activity can also activate the immune system (Kim et al., 2018).

[0007] Disruption of the YAP / TAZ-TEAD protein-protein interaction can block the Hippo signaling pathway. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to solve the technical problem of the limited number of conventional compounds that inhibit YAP / TAZ-TEAD, and provides aromatic compounds, pharmaceutical compositions thereof, and uses thereof, which have excellent inhibitory activity against tumor cell proliferation. [Means for solving the problem]

[0009] The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. [ka]

[0010] however, [ka] is a single or double bond, Y is CH or N; W is O or CH-R W and R W is H, OH, C1-C6 alkoxy, -C1-C6 alkyl-OR W-1 or C1-C6 alkyl, R W-1 is H or C1-C6 alkyl, Z is CH, O, S or NH; R2 is H or halogen; R6 is H, CN, -CONHR 6-1 , -NHR 6-2 or C1-C6 alkoxy substituted by one, two or three NH2 or OH; R 6-1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," substituted with one, two, or three C1-C6 alkyl; R 6-2 is a C1-C6 alkyl substituted by one, two or three NH2 or OH; R1, R3, R4, X, A and Q are defined as described in any one of the following schemes: Scheme 1: Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with one, two or three R 1-1-2 C1-C6 alkoxy substituted by -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 and R 1-1-2 are each independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11 are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1 "a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; When X is N or CH, R1 is -(CH2) m1 -O-(CH2) m2 -OR 1-6 m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," Scheme 2: Q is "a 3- to 15-membered monocyclic or bicyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-2 "3-15 membered monocyclic or bicyclic heteroaryl, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" substituted by one, two or three R Q-5 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by [ka] and where R Q-3 , R Q-4 together with the atoms to which they are attached, form a 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocyclic ring, one, two or three R Q-1 a 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocyclic ring substituted with one, two or three R Q-2and forming a "3-15 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" substituted by R Q-1 and R Q-2 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; R Q-5 are independently oxo (=O), methylene (=CH2), or C2-C6 alkenyl, Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with one, two or three R 1-1-2 C1-C6 alkoxy substituted by -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 and R 1-1-2 are each independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Scheme 3: A is one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is substituted by [ka] Instead, R A-1 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O), and at least one R A-1 is C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O), R A-2are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with one, two or three R 1-1-2 C1-C6 alkoxy substituted by -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 and R 1-1-2 are each independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1 "a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 4: R4 is NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4"3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with one, two or three R 1-1-2 C1-C6 alkoxy substituted by -(CH2)n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 and R 1-1-2 are independently OH, NH or halogen; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1 "a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 5: R3 is C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 , wherein the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three, and the 3- to 6-membered heteroaryl is -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with one, two or three R 1-1-2 C1-C6 alkoxy substituted by -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 and R 1-1-2 are each independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11 are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1"a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH2.

[0011] In one embodiment, [ka] is a single or double bond, Y is CH or N; W is O or CH-R W and R W is H, OH, C1-C6 alkoxy, -C1-C6 alkyl-OR W-1 or C1-C6 alkyl, R W-1 is H or C1-C6 alkyl, Z is CH, O, S or NH; R2 is H or halogen; R6 is H, CN, -CONHR 6-1 , -NHR 6-2 or C1-C6 alkoxy substituted by one, two or three NH2 or OH; R 6-1is H, C1-C6 alkyl, C3-C6 cycloalkyl, "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," substituted with one, two, or three C1-C6 alkyl; R 6-2 is a C1-C6 alkyl substituted by one, two or three NH2 or OH; R1, R3, R4, X, A and Q are defined as described in any one of the following schemes: Scheme 1: Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is -(CH2) m1 -O-(CH2) m2 -OR 1-6 m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2-O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1 "a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 2: Q is "a 3- to 15-membered monocyclic or bicyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-2 "3-15 membered monocyclic or bicyclic heteroaryl, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" substituted by one, two or three R Q-5 "3- to 6-membered heterocycloalkyl, wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three," substituted by [ka] and where R Q-3 , R Q-4 together with the atoms to which they are attached, form a 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocyclic ring, one, two or three R Q-1 a 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocyclic ring substituted with one, two or three R Q-2 and forming a "3-15 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" substituted by R Q-1 and R Q-2 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; R Q-5 are independently oxo (=O), methylene (=CH2), or C2-C6 alkenyl, Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4"3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2-O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Scheme 3: A is one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is substituted by [ka] Instead, R A-1 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O), and at least one R A-1 is C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O), R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NRX2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11 are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1 "a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 4: R4 is NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1 "a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 5: R3 is C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or -(CH) m1 -O-(CH2) m2 -OR 1-6and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11 are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocyclic ring in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-1"a 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C3-C6 cycloalkyl or one, two or three R Q-1 is a C3-C6 cycloalkyl substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH2.

[0012] In one embodiment, [ka] is a single or double bond, Y is CH or N; W is O or CH-R W and R W is H, OH, C1-C6 alkoxy, -C1-C6 alkyl-OR W-1 or C1-C6 alkyl, R W-1 is H or C1-C6 alkyl, Z is CH, O, S or NH; R2 is H or halogen; R6 is H, CN, -CONHR 6-1 , -NHR 6-2 or C1-C6 alkoxy substituted by one, two or three NH2 or OH; R 6-1is H, C1-C6 alkyl, C3-C6 cycloalkyl, "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three," or "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three," substituted with one, two, or three C1-C6 alkyl; R 6-2 is a C1-C6 alkyl substituted by one, two or three NH2 or OH; R1, R3, R4, X, A and Q are defined as described in any one of the following schemes: Scheme 1: Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is -(CH2) m1 -O-(CH2) m2 -OR 1-6 m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2-O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R Q-1 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 2: Q is "a 3- to 15-membered monocyclic or bicyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," and one, two, or three R Q-2 "3-15 membered monocyclic or bicyclic heteroaryl, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" substituted by one, two or three R Q-5 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by [ka] and where R Q-3 , R Q-4together with the atoms to which they are attached, form a 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocyclic ring, one, two or three R Q-1 a 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocyclic ring substituted with one, two or three R Q-2 and forming a "3-15 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" substituted by R Q-1 and R Q-2 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; R Q-5 are independently oxo (=O), methylene (=CH2), or C2-C6 alkenyl, Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or -(CH) m1-O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Scheme 3: A is one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is substituted by [ka] Instead, R A-1are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O), and at least one R A-1 is C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O), R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R Q-1 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 4: R4 is NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or -(CH) m1 -O-(CH2) m2-OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NR X2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R3 is halogen, CN, C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; A is C6~C10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10 monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11 are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R Q-1 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2, C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4 C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH; Scheme 5: R3 is C2-C6 alkynyl, NH2, OH or C1-C6 alkoxy; Concatenated with X [ka] is a double bond, X is N, CH or CR X1 and When X is N or CH, R1 is H, OH, halogen, -L1-R 1-4 "3-6 membered heteroaryl, wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or -(CH) m1 -O-(CH2) m2 -OR 1-6 and L1 is absent, -O-, -NH-, -S- or -S(O)2-; R 1-4 is C1-C6 alkyl or one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5are independently OH, halogen, COOH, C3-C6 cycloalkyl, "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", "3- to 6-membered heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", C1-C6 alkoxy, or -S(O)2-C1-C6 alkyl; m1 is 0, 1 or 2, m2 is 1 or 2, and R 1-6 is a C3-C6 cycloalkyl or "a 3- to 6-membered heterocycloalkyl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," X is CR X1 If R X1 , R1 together with the atoms to which they are connected form ring B, i.e. [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with Concatenated with X [ka] is a single bond, X is NRX2 and R X2 , R1 together with the atoms to which they are connected form a ring C, i.e. [ka] teeth, [ka] and ring C is "a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R 1-3 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 , R 1-2 and R 1-3 are independently oxo (=O), OH, NH, halogen, -S(O)-C1-C6 alkyl, CN, C1-C6 alkyl, one, two or three R 1-1-1 C1-C6 alkyl substituted with -(CH2) n1 -O-(CH2) n2 -O-C3-C6 cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R 1-1-1 are independently OH, NH or halogen; R4 is halogen, NH2, CN, OH, C1-C6 alkoxy, C1-C6 alkyl substituted with one hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one, two or three halogens or C2-C6 alkynyl; A is C6~C 10 Monocyclic or bicyclic aryl, one, two or three R A-1 C6-C substituted by 10monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R A-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R A-1 and R A-2 are independently halogen, C1-C6 alkoxy, NH2, CN, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one hydroxy, or oxo (=O); Q is -CR7R8-NR9-R 10 or R 11 and R7, R8 and R9 are independently H or C1-C6 alkyl; R 10 is H, C1-C6 alkyl or -(CH2) 0-2 -R 10-1 and R 10-1 is C1-C6 alkyl, C1-C6 alkoxy or R substituted by one, two or three OH groups. 10-2 and R 10-2 and R 11 are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R Q-1 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R Q-1 are independently OH, halogen, and NR Q-1-1 R Q-1-2 , C1-C6 alkyl, one, two or three R Q-1-3 C1-C6 alkyl, C1-C6 alkoxy, substituted by one, two or three R Q-1-4C1-C6 alkoxy, oxo (=O), methylene (=CH2) or C2-C6 alkenyl substituted by R Q-1-1 and R Q-1-2 are independently H or C1-C6 alkyl, R Q-1-3 and R Q-1-4 are independently halogen, OH or NH2.

[0013] In some preferred embodiments of the present invention, specific groups in the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof are as defined below, and groups not mentioned are as described in any one of the schemes of the present invention (abbreviated as "in any one of the embodiments of the present invention"), and each C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0014] In any one embodiment of the present invention, each C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy or ethoxy.

[0015] In any one embodiment of the present invention, each halogen is independently F, Cl, Br or I, for example F or Cl.

[0016] In any one embodiment of the present invention, each C3-C6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl.

[0017] In any one embodiment of the present invention, each "5- to 6-membered monocyclic heteroaryl in which the heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" is independently "5- or 6-membered monocyclic heteroaryl in which the heteroatom is selected from one or two of N and O, and the number of heteroatoms is one, two or three", for example, [ka] is.

[0018] In any one embodiment of the present invention, each "3- to 6-membered heterocycloalkyl in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "5- or 6-membered heterocycloalkyl in which the heteroatom is selected from one or two of N and O, and the number of heteroatoms is one, two, or three", for example, [ka] is.

[0019] In any one embodiment of the present invention, each C2-C6 alkynyl independently represents [ka] For example, [ka] is.

[0020] In any one embodiment of the present invention, each C2-C6 alkenyl independently represents [ka] For example, [ka] is.

[0021] In any one embodiment of the present invention, each of "C6 to C 10 The "monocyclic or bicyclic aryl" is independently phenyl or naphthyl, for example, phenyl.

[0022] In any one embodiment of the present invention, each "8- to 12-membered bicyclic heteroaryl in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "9- or 10-membered bicyclic heteroaryl in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", for example: [ka] is.

[0023] In any one embodiment of the present invention, each "3- to 15-membered monocyclic or bicyclic heteroaryl, in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "5- to 10-membered monocyclic or bicyclic heteroaryl, in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three", for example: [ka] is.

[0024] In any one embodiment of the present invention, each 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring is independently a 5- to 6-membered monocyclic, 6- to 10-membered bicyclic, or 8- to 15-membered tricyclic saturated or unsaturated carbocyclic ring, preferably a 5- to 6-membered monocyclic, 6- to 10-membered bicyclic, or 8- to 15-membered tricyclic saturated carbocyclic ring.

[0025] In any one embodiment of the present invention, each "5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "5- to 6-membered monocyclic, 6- to 10-membered bicyclic, or 8- to 15-membered tricyclic saturated or unsaturated heterocycle in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three."

[0026] In any one embodiment of the present invention, each 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocycle is independently a 3- to 6-membered monocyclic or 6- to 10-membered bicyclic saturated or unsaturated carbocycle, preferably a 3- to 6-membered monocyclic saturated carbocycle or a 6- to 10-membered bicyclic saturated or unsaturated carbocycle.

[0027] In any one embodiment of the present invention, each "3- to 15-membered monocyclic or bicyclic saturated or unsaturated heterocycle in which the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "a 3- to 6-membered monocyclic saturated heterocycle or a 6- to 10-membered bicyclic saturated or unsaturated heterocycle in which the heteroatom is selected from one or two of N and O, and the number of heteroatoms is one or two."

[0028] In any one embodiment of the present invention, Y is CH.

[0029] In any one embodiment of the present invention, R W is H, OH or C1-C6 alkyl.

[0030] In any one embodiment of the present invention, W is CH—R W and R W is H, OH or C1-C6 alkyl, for example CH2, CH-OH or CH-CH3.

[0031] In any one embodiment of the present invention, W is CH2.

[0032] In any one embodiment of the present invention, Z is O.

[0033] In any one embodiment of the present invention, R2 is halogen, preferably F.

[0034] In any one embodiment of the present invention, R 6-1 is H or C1-C6 alkyl.

[0035] In any one embodiment of the present invention, R6 is -CONHR 6-1 For example, [ka] is.

[0036] In any one embodiment of the present invention, R6 is H, CN, [ka] is.

[0037] In any one embodiment of the present invention, R 1-6 is a C3-C6 cycloalkyl.

[0038] In any one embodiment of the present invention, R 1-1 is oxo (=O), OH, NH2, CN, halogen, -S(O)2-C1-C6 alkyl, C1-C6 alkyl or one, two or three R 1-1-2 and C1-C6 alkoxy substituted with.

[0039] In any one embodiment of the present invention, R 1-1-2 is OH.

[0040] In any one embodiment of the present invention, R 1-1is oxo (=O), OH, NH2, CN, halogen, -S(O)2-C1-C6 alkyl, C1-C6 alkyl or one, two or three R 1-1-2 C1-C6 alkoxy substituted with R 1-1-2 is OH.

[0041] In any one embodiment of the present invention, R 1-2 is OH or a halogen.

[0042] In any one embodiment of the present invention, in Scheme 1: [ka] teeth, [ka] and ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 is oxo (=O), OH, NH2, CN, halogen, -S(O)2-C1-C6 alkyl, C1-C6 alkyl or one, two or three R 1-1-2 C1-C6 alkoxy substituted with R 1-2 is OH or a halogen, R 1-1-2 is OH, for example, [ka] TIFF0007774326000114.tif234168TIFF0007774326000115.tif209168TIFF0007774326000116.tif169168 is.

[0043] In any one embodiment of the present invention, in Scheme 1: [ka] teeth, [ka] TIFF0007774326000119.tif211168TIFF0007774326000120.tif231168TIFF0007774326000121.tif215168TIFF0007774326000122.tif62168 and Preferably [ka] TIFF0007774326000124.tif209168TIFF0007774326000125.tif100168 and More preferably [ka] TIFF0007774326000127.tif240168TIFF0007774326000128.tif33168 and More preferably, [ka] TIFF0007774326000130.tif140168 is.

[0044] In any one embodiment of the present invention, in Schemes 2 to 5: [ka] teeth, [ka] and R1 is -L1-R 1-4 and L1 is -O-; R 1-4 is one, two or three R 1-5 C1-C6 alkyl substituted with R 1-5 are independently OH, Ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, containing one, two, or three R 1-1 a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted with one, two, or three R 1-2 wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, and is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle substituted with R 1-1 is oxo (=O), OH, NH2, CN, halogen, -S(O)2-C1-C6 alkyl, C1-C6 alkyl or one, two or three R 1-1-2 C1-C6 alkoxy substituted with R 1-2 is OH or a halogen, R 1-1-2 is OH, for example, [ka] TIFF0007774326000134.tif234168TIFF0007774326000135.tif208168TIFF0007774326000136.tif203168 is.

[0045] In any one embodiment of the present invention, in Schemes 2 to 5: [ka] is independently [ka] TIFF0007774326000139.tif242168TIFF0007774326000140.tif232168TIFF0007774326000141.tif245168TIFF0007774326000142.tif60168 and Preferably [ka] TIFF0007774326000144.tif243168TIFF0007774326000145.tif30168 and More preferably [ka] TIFF0007774326000147.tif206168 and More preferably, [ka] TIFF0007774326000149.tif76168 is.

[0046] In any one embodiment of the present invention, in Scheme 4, R4 is OH, NH2, C1-C6 alkoxy or C2-C6 alkynyl, for example: [ka] is.

[0047] In any one embodiment of the present invention, in Scheme 4, R4 is [ka] is.

[0048] In any one embodiment of the present invention, in Schemes 1-3 and 5, R4 is independently halogen, OH, NH2, C1-C6 alkoxy or C2-C6 alkynyl, such as F, [ka] is.

[0049] In any one embodiment of the present invention, in Schemes 1-3 and 5, R4 is independently [ka] is.

[0050] In any one embodiment of the present invention, in Scheme 5, R3 is [ka] is.

[0051] In any one embodiment of the present invention, in Schemes 1-4, R3 is independently [ka] For example, [ka] is.

[0052] In any one embodiment of the present invention, in Scheme 3, A is [ka] TIFF0007774326000158.tif52168 is.

[0053] In any one embodiment of the present invention, in Schemes 1-2 and 4-5, A is independently [ka] is.

[0054] In any one embodiment of the present invention, in Scheme 2, Q is [ka] is.

[0055] In any one embodiment of the present invention, in Schemes 1 and 3-5, Q is [ka] TIFF0007774326000162.tif152168 is.

[0056] In any one embodiment of the present invention, the compound represented by formula (I) is as shown below. [ka]

[0057] However, if the carbon atom marked with "*" is a chiral carbon atom, it may be in the S configuration, the R configuration, or a mixture thereof. The definitions of R1, R2, R3, R4, R6, X, Y, W, Z, A and Q are as described in any one of the claims of the present invention.

[0058] In any one embodiment of the present invention, the compound represented by formula (I) is as shown below. [ka]

[0059] wherein R1, R2, R3, R4, R6, X, Y, W, Z, A and Q are defined as described in any one of the aspects of the present invention.

[0060] In any one embodiment of the present invention, the compound represented by formula (I) is as shown below. [ka]

[0061] However, the definitions of ring B, R2, R3, R4, R6, Y, W, Z, A and Q are as defined in any one of the aspects of the present invention.

[0062] In any one embodiment of the present invention, the compound represented by formula (I) is as shown below. [ka]

[0063] However, the definitions of ring B, R2, R3, R4, R6, Y, W, Z, A and Q are as defined in any one of the aspects of the present invention.

[0064] In any one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (ID) or a compound represented by formula (IE). [ka]

[0065] where n1 is 0, 1, 2, or 3, and R 1-1 , R 6-1 and R w is as defined in any one of the claims of the present invention.

[0066] In any one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds: [ka] TIFF0007774326000169.tif241168TIFF0007774326000170.tif240168TIFF0007774326000171.tif21 6168TIFF0007774326000172.tif210168TIFF0007774326000173.tif226168TIFF0007774326000174.t if217168TIFF0007774326000175.tif229168TIFF0007774326000176.tif241168TIFF00077743260001 77.tif240168TIFF0007774326000178.tif232168TIFF0007774326000179.tif230168TIFF00077743260 00180.tif222168TIFF0007774326000181.tif245168TIFF0007774326000182.tif222168TIFF0007774 326000183.tif240168TIFF0007774326000184.tif241168TIFF0007774326000185.tif210168TIFF000 7774326000186.tif216168TIFF0007774326000187.tif218168TIFF0007774326000188.tif231168TIF F0007774326000189.tif222168TIFF0007774326000190.tif206168TIFF0007774326000191.tif161168

[0067] In one embodiment, the compound represented by formula (I) is any one of the following compounds:

[0068] As a compound with a retention time of 1.89 min under the following conditions, [ka] One stereoisomer of , Chiral column model: Cellulose-SB; Eluent: carbon dioxide / (methanol + 20 mM NH3); Gradient: 10%; Flow rate: 3.0 mL / min;

[0069] As a compound with a retention time of 2.12 min under the following conditions, [ka] One stereoisomer of , Chiral column model: Cellulose-SB; Eluent: carbon dioxide / (methanol + 20 mM NH3); Gradient: 10%; Flow rate: 3.0 mL / min;

[0070] As a compound with a retention time of 6.50 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0071] The compound with a retention time of 7.62 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0072] The compound with a retention time of 4.68 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0073] As a compound with a retention time of 4.20 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0074] As a mixture with retention times of 4.21 min and 4.71 min under the following conditions, [ka] A pair of diastereomers of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min, dr = 54 (4.21 min): 46 (4.71 min);

[0075] As a mixture with retention times of 4.60 min and 6.10 min under the following conditions, [ka] A pair of diastereomers of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min, dr = 48 (4.60 min): 52 (6.10 min);

[0076] As a mixture with retention times of 6.20 min and 6.81 min under the following conditions, [ka] A pair of diastereomers of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min, dr = 8 (6.20 min): 92 (6.81 min);

[0077] As a compound with a retention time of 2.43 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: hexane / IPA; Gradient: isocratic: 7 / 3, Flow rate: 1 mL / min;

[0078] As a compound with a retention time of 3.37 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: hexane / IPA; Gradient: isocratic: 7 / 3, Flow rate: 1 mL / min;

[0079] As a mixture with retention times of 2.86 min and 3.75 min under the following conditions, [ka] A pair of diastereomers of, column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic 8 / 2, flow rate: 1 mL / min, dr = 52 (2.86 min): 48 (3.75 min);

[0080] The compound with a retention time of 8.87 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 7 / 3, flow rate: 1 mL / min;

[0081] As a compound with a retention time of 9.60 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: hexane / IPA; Gradient: isocratic: 7 / 3, Flow rate: 1 mL / min;

[0082] As a compound with a retention time of 4.16 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-C, 100 × 4.6 mm, 5 μm; Eluent: hexane (0.1% DEA)-IPA; Gradient: Isocratic: 4 / 1, Flow rate: 1 mL / min;

[0083] As a compound with a retention time of 2.68 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-C, 100 × 4.6 mm, 5 μm; Eluent: hexane (0.1% DEA)-IPA; Gradient: Isocratic: 4 / 1, Flow rate: 1 mL / min;

[0084] As a compound with a retention time of 4.92 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-C, 100 × 4.6 mm, 5 μm; Eluent: hexane (0.1% DEA)-IPA; Gradient: Isocratic: 4 / 1, Flow rate: 1 mL / min;

[0085] The compound with a retention time of 4.87 min under the following conditions is: [ka] One stereoisomer of , Column model: Celluiose-C, 100 × 4.6 mm, 5 μm; Eluent: hexane (0.1% DEA)-IPA; Gradient: Isocratic: 4 / 1, Flow rate: 1 mL / min;

[0086] As a compound with a retention time of 2.197 min under the following conditions, [ka] One stereoisomer of , Column model: Amylose-C, 100 × 4.6 mm, 5 μm; Eluent: Hexane-IPA; Gradient: Isocratic: 7 / 3, Flow rate: 1 mL / min;

[0087] As a compound with a retention time of 2.646 min under the following conditions, [ka] One stereoisomer of , Column model: Amylose-C, 100 × 4.6 mm, 5 μm; Eluent: Hexane-IPA; Gradient: Isocratic: 7 / 3, Flow rate: 1 mL / min;

[0088] As a compound with a retention time of 3.14 min under the following conditions, [ka] One stereoisomer of, Column model: Amylose-SA, 100 × 4.6 mm, 5 μm; Eluent: Hexane (0.1% DEA)-IPA; Gradient: Isocratic: 4 / 1, Flow rate: 1 mL / min;

[0089] As a compound with a retention time of 3.04 min under the following conditions, [ka] One stereoisomer of, Column model: Amylose-SA, 100 × 4.6 mm, 5 μm; Eluent: Hexane (0.1% DEA)-IPA; Gradient: Isocratic: 4 / 1, Flow rate: 1 mL / min;

[0090] The compound with a retention time of 3.89 min under the following conditions is: [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: Hexane (0.1% DEA)-IPA; Gradient: Isocratic: 6 / 4, Flow rate: 1 mL / min;

[0091] The compound with a retention time of 3.53 min under the following conditions is: [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: Hexane (0.1% DEA)-IPA; Gradient: Isocratic: 6 / 4, Flow rate: 1 mL / min;

[0092] As a mixture with retention times of 1.95 min and 2.88 min under the following conditions, [ka] A pair of diastereomers of, column model: Amylose-C, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 8 / 2, flow rate: 1 mL / min, dr = 65 (1.95 min): 35 (2.88 min);

[0093] As a compound with a retention time of 5.75 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: Hexane (0.1% DEA)-IPA; Gradient: Isocratic: 9 / 1, Flow rate: 1 mL / min;

[0094] As a compound with a retention time of 4.76 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: Hexane (0.1% DEA)-IPA; Gradient: Isocratic: 9 / 1, Flow rate: 1 mL / min;

[0095] As a compound with a retention time of 3.06 min under the following conditions, [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; Eluent: Hexane (0.1% DEA)-IPA; Gradient: Isocratic: 4 / 1, Flow rate: 1 mL / min;

[0096] As a compound with a retention time of 3.32 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0097] As a compound with a retention time of 3.12 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0098] As a compound with a retention time of 2.67 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0099] For a compound with a retention time of 4.10 min under the following conditions, [ka] Column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane / IPA; gradient: isocratic: 85 / 15; flow rate: 1 mL / min;

[0100] The compound with a retention time of 4.47 min under the following conditions is: [ka] Column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane / IPA; gradient: isocratic: 85 / 15; flow rate: 1 mL / min;

[0101] The compound with a retention time of 5.59 min under the following conditions is: [ka] Column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane / IPA; gradient: isocratic 85 / 15; flow rate: 1 mL / min;

[0102] The compound with a retention time of 4.29 min under the following conditions is: [ka] Column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane / IPA; gradient: isocratic: 85 / 15; flow rate: 1 mL / min;

[0103] As a compound with a retention time of 6.65 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0104] The compound with a retention time of 11.46 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0105] As a compound with a retention time of 5.68 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0106] The compound with a retention time of 6.71 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0107] The compound with a retention time of 6.21 min under the following conditions is: [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 3 μm; Eluent: hexane / IPA; Gradient: isocratic: 8 / 2, Flow rate: 1 mL / min;

[0108] The compound with a retention time of 4.71 min under the following conditions is: [ka] One stereoisomer of , Column model: Celluiose-SB, 100 × 4.6 mm, 3 μm; Eluent: hexane / IPA; Gradient: isocratic: 8 / 2, Flow rate: 1 mL / min;

[0109] As a compound with a retention time of 8.1 min under the following conditions, [ka] One stereoisomer of Xselect CSH Prep Fluoro-Phenyl, 150 × 19 mm, 5 μm; eluent: (0.1% FA) H2O-ACN; gradient: 66%–86%; flow rate: 20 mL / min;

[0110] As a compound with a retention time of 6.5 minutes under the following conditions, [ka] One stereoisomer of Xselect CSH Prep Fluoro-Phenyl, 150 × 19 mm, 5 μm; eluent: (0.1% FA) H2O-ACN; gradient: 66%–86%; flow rate: 20 mL / min;

[0111] As a compound with a retention time of 3.90 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0112] As a compound with a retention time of 3.02 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0113] As a compound with a retention time of 3.35 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0114] The compound with a retention time of 4.57 min under the following conditions is: [ka] One stereoisomer of , column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0115] As a compound with a retention time of 4.97 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0116] As a compound with a retention time of 5.22 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / EtOH; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0117] The compound with a retention time of 7.21 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 85 / 15, flow rate: 1 mL / min;

[0118] The compound with a retention time of 8.17 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 85 / 15, flow rate: 1 mL / min;

[0119] For the compound with a retention time of 9.45 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0120] As a compound with a retention time of 6.63 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0121] The compound with a retention time of 3.21 min under the following conditions is: [ka] One stereoisomer of, Column model: Amylose-SA, 100 × 4.6 mm, 3 μm; Eluent: hexane (0.1% DEA)-IPA; Gradient: Isocratic: 85 / 15, Flow rate: 1 mL / min;

[0122] The compound with a retention time of 7.29 min under the following conditions is: [ka] One stereoisomer of, Column model: Amylose-SA, 100 × 4.6 mm, 3 μm; Eluent: hexane (0.1% DEA)-IPA; Gradient: Isocratic: 85 / 15, Flow rate: 1 mL / min;

[0123] The compound with a retention time of 5.46 min under the following conditions is: [ka] One stereoisomer of Celluiose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0124] The compound with a retention time of 6.42 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 85 / 15, flow rate: 1 mL / min;

[0125] The compound with a retention time of 4.47 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SB, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 85 / 15, flow rate: 1 mL / min;

[0126] As a mixture with retention times of 4.97 min and 6.09 min under the following conditions, [ka] A pair of diastereomers of, column model: Celluiose-SC, 100 × 4.6 mm, 3 μm; eluent: hexane / IPA; gradient: isocratic: 8 / 2, flow rate: 1 mL / min, dr = 49 (4.97 min): 51 (6.09 min);

[0127] As a compound with a retention time of 3.88 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0128] As a compound with a retention time of 3.52 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0129] The compound with a retention time of 4.91 min under the following conditions is: [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0130] As a compound with a retention time of 5.05 min under the following conditions, [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0131] For compounds with a retention time of 7.00 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0132] As a compound with a retention time of 3.56 min under the following conditions, [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0133] For a compound with a retention time of 3.40 min under the following conditions, [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0134] As a compound with a retention time of 3.45 min under the following conditions, [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0135] The compound with a retention time of 3.53 min under the following conditions is: [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0136] The compound with a retention time of 7.48 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0137] The compound with a retention time of 7.48 min under the following conditions is: [ka] One stereoisomer of , column model: Celluiose-SC, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0138] The compound with a retention time of 5.91 min under the following conditions is: [ka] One stereoisomer of, column model: Amylose-C, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0139] As a compound with a retention time of 4.72 min under the following conditions, [ka] One stereoisomer of, column model: Amylose-C, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0140] As a compound with a retention time of 2.09 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0141] As a compound with a retention time of 4.03 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0142] As a compound with a retention time of 2.92 min under the following conditions, [ka] One stereoisomer of , column model: Amylose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA) / IPA; gradient: isocratic: 8 / 2, flow rate: 1 mL / min;

[0143] As a compound with a retention time of 4.62 min under the following conditions, [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 5 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0144] As a compound with a retention time of 5.32 min under the following conditions, [ka] One stereoisomer of, column model: Amylose-SA, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 9 / 1, flow rate: 1 mL / min;

[0145] As a compound with a retention time of 3.26 min under the following conditions, [ka] One stereoisomer of , column model: Celluiose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min;

[0146] As a compound with a retention time of 2.90 min under the following conditions, [ka] Column model: Celluiose-C, 100 × 4.6 mm, 3 μm; eluent: hexane (0.1% DEA)-IPA; gradient: isocratic: 4 / 1, flow rate: 1 mL / min.

[0147] The test conditions for the retention time do not limit the compounds. As long as the retention time measured under the test conditions is the same as or within the error range, and the compound is one stereoisomer of the compound defined by the retention time, it falls within the scope of protection of the present invention.

[0148] The present invention further comprises: (1) A compound represented by formula (I) according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; (2) pharmaceutically acceptable adjuvants; The present invention provides a pharmaceutical composition comprising:

[0149] The present invention further provides use of the compound represented by formula (I) described in any one of the above, a pharmaceutically acceptable salt thereof, a solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the manufacture of a medicament used in the prevention and / or treatment of cancer.

[0150] The present invention further provides a method for preventing and / or treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I) according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof.

[0151] The above-mentioned preferred conditions can be arbitrarily combined to obtain each preferred embodiment of the present invention, provided that this does not violate common knowledge in the art.

[0152] The reagents and raw materials used in the present invention are commercially available.

[0153] Unless otherwise specified, the terms used in this invention have the following meanings.

[0154] Those skilled in the art will recognize, according to the conventions used in the art, the groups used in the structural formulas of the groups described in this invention. [ka] means that the corresponding group is connected to another fragment or group in the compound via this site.

[0155] As used herein, substituents may be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond.

[0156] When a particular linking group is designated as "absent," the structures on either side of the linking group are directly connected via a single bond; for example, if B in -ABC- is absent, then -ABC- becomes -AC-.

[0157] The term "pharmaceutically acceptable" refers to salts, solvents, auxiliary agents, etc. that are generally non-toxic, safe, and suitable for use in patients. The "patient" is preferably a mammal, more preferably a human.

[0158] The term "pharmaceutically acceptable salt" refers to a salt prepared with a relatively non-toxic, pharmaceutically acceptable acid or base from a compound of the present invention. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base, either in solution or in a suitable inert solvent. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid, either in solution or in a suitable inert solvent. Such pharmaceutically acceptable acids include inorganic acids. Such pharmaceutically acceptable acids include organic acids. When a compound of the present invention contains both a relatively acidic and a relatively basic functional group, it can be converted into a base addition salt or an acid addition salt. Specifically, reference can be made to Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0159] The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in a solvate can be in an ordered or non-ordered arrangement. Such solvents include, but are not limited to, water, methanol, ethanol, etc.

[0160] The term "solvate of a pharmaceutically acceptable salt" refers to a substance formed by combining a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base, or a stoichiometric or non-stoichiometric amount of a solvent. The terms "pharmaceutically acceptable salt" and "solvate" are defined above and refer to a substance formed by combining a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base, or a stoichiometric or non-stoichiometric amount of a solvent. The term "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of a compound of the present invention.

[0161] When stereoisomers exist in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt," they may exist in the form of a single stereoisomer or a mixture thereof (e.g., a racemate). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis or chiral separation techniques (including, but not limited to, thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high performance liquid chromatography, etc.), or can be obtained by chiral resolution by bonding (e.g., chemical bonding) or salt formation (e.g., physical bonding) with other chiral compounds. The term "single stereoisomer" refers to a compound of the present invention in which the mass content of one stereoisomer relative to all stereoisomers of the compound is 95% or greater.

[0162] When tautomers exist in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt," they may exist in the form of a single tautomer or a mixture thereof, and preferably exist predominantly in the form of a more stable tautomer.

[0163] In the definition of a compound, any variable (e.g., R 1-1 When R occurs more than once, the definition of that variable at each occurrence is independent of its definition at any other occurrence, and the definitions are independent of and do not influence each other. Thus, when a particular group occurs at one, two, or three R 1-1 The term "substituted by a group" means that the group is substituted by up to three R 1-1and R at that position may be substituted by 1-1 The definition of R is the remaining position 1-1 Further, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0164] The term "alkyl" refers to a straight or branched chain alkyl containing the specified number of carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like alkyls.

[0165] The term "alkoxy" refers to an -OR X refers to the group, where R X is alkyl as defined above.

[0166] The term "alkenyl" refers to a straight or branched chain alkene having the specified number of carbon atoms and containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds, which may be internal or terminal; illustrative alkenes include vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl, 1,1-dimethyl-2propenyl, hexenyl, and the like.

[0167] The term "alkynyl" refers to a straight or branched chain hydrocarbon group having one or more triple bonds with a specified number of carbon atoms (e.g., C2-C6 alkynyl, also e.g., C2-C4 alkynyl). The one or more carbon-carbon triple bonds can be internal or terminal, for example, propynyl, which has an internal triple bond. [ka] or propynyl having a terminal triple bond [ka] And so on.

[0168] The term "cycloalkyl" refers to a saturated monocyclic, bridged, or spirocyclic group consisting solely of carbon atoms having a specified number of carbon atoms (e.g., C3-C6). Monocyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0169] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one, two, or three of N, O, and S), which may be monocyclic, bridged, or spirocyclic, and all rings are saturated. Heterocycloalkyls include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0170] The term "heteroaryl" refers to a cyclic aromatic group having a specified number of ring atoms (e.g., 3 to 15 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one, two, or three of N, O, and S), which can be monocyclic or polycyclic, and in the case of bicyclic rings, each ring is aromatic, such as, for example, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolinyl, and the like.

[0171] The term "carbocycle" refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic ring group having a specified number of ring atoms (e.g., 5 to 15 members) and consisting solely of carbon atoms. If bicyclic or tricyclic, the ring may be fused or spiro-bonded, e.g., [ka] And so on.

[0172] The term "heterocycle" refers to a saturated or unsaturated cyclic group having a specified number of ring atoms (e.g., 5-15 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one, two, or three of N, O, and S), which, when monocyclic, bicyclic, or tricyclic, may be fused or spiro-linked, e.g., [ka] And so on.

[0173] The term "pharmaceutically acceptable auxiliaries" refers to excipients and additives used in the manufacture and formulation of pharmaceuticals, including all substances contained in drug formulations except for active ingredients. For details, please refer to Part 4 of the Pharmacopoeia of the People's Republic of China (2015 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0174] The term "treatment" refers to therapeutic therapy. With respect to a particular disease, treatment refers to (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disease or (b) one or more biological manifestations of the disease, (3) ameliorating one or more symptoms, effects, or side effects associated with the disease or one or more symptoms, effects, or side effects associated with the disease or its treatment, or (4) reducing the disease or one or more biological manifestations of the disease.

[0175] The term "prevention" refers to reducing the risk of acquiring or developing a disease or disorder.

[0176] The term "therapeutically effective amount" refers to the amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age of the patient being treated, but can be adjusted as needed by one skilled in the art.

[0177] The term "patient" refers to any animal to which or which has been administered a compound or composition according to an embodiment of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal, including, but not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being most preferred.

[0178] The positive advancement effect of the present invention is that the compounds of the present invention can effectively inhibit the proliferation of tumor cells, have good inhibitory activity, and can treat related diseases. DETAILED DESCRIPTION OF THE INVENTION

[0179] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described can be selected according to conventional methods and conditions or product instructions.

[0180] Example 1 [ka] [ka]

[0181] Step 1: Sodium bicarbonate (36.1 g, 903 mmol, 60%) was dissolved in dimethyl sulfoxide (700 mL), heated to 70 °C, and reacted for 1 hour. The mixture was cooled to room temperature, diluted with THF (350 mL), and trimethyl iodide (298 g, 1.36 mol) was added in batches at 5 °C. The mixture was heated to room temperature and reacted for 30 minutes. Compound 1-1 (90.0 g, 451 mmol) was dissolved in tetrahydrofuran (350 mL) and added dropwise to the reaction solution. After the addition was complete, the mixture was allowed to react at room temperature overnight. After the reaction was completed, the mixture was cooled to 5°C, slowly poured into ice water (2 L) to quench the reaction, and extracted with ethyl acetate (1000 mL x 2). The combined organic phases were washed with saturated brine (1000 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1) to give compound 1-2 (32.1 g, Y: 33%). LC-MS m / z (ESI): 214.1 [M+H] + .

[0182] Step 2: Under nitrogen gas protection, 1-bromo-3,5-difluoro-2-iodobenzene (62.4 g, 196 mmol) was dissolved in tetrahydrofuran (624 mL) and cooled to -70 °C. A solution of isopropylmagnesium chloride in tetrahydrofuran (97.8 mL, 196 mmol, 2.0 mol / L) was added dropwise, and the mixture was heated to -40 °C and reacted for 1 hour. Cuprous iodide (8.60 g, 45.2 mmol) was added, and the reaction was continued for 10 minutes. The reaction mixture was cooled to -70 °C, and compound 1-2 (32.1 g, 150 mmol) was dissolved in tetrahydrofuran (300 mL) and added dropwise. The reaction mixture was reacted for 30 minutes, then warmed to room temperature and reacted for 12 hours. After detecting the completion of the reaction by TLC (PE:EA = 5:1), the reaction mixture was cooled to room temperature in an ice-water bath and quenched with saturated ammonium chloride (200 mL). The organic phase was separated, collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1) to give compound 1-3 (27.5 g, Y: 45%). LC-MS m / z (ESI): 428.1, 430.1 [M+Na] + .

[0183] Step 3: Under nitrogen gas protection, compound 1-3 (27.5 g, 67.7 mmol) was dissolved in dichloromethane (200 mL) and Dess-Martin oxidant (43.1 g, 101 mmol) was added in batches at room temperature. The reaction mixture was allowed to react for 2 hours. The reaction mixture was cooled in an ice-water bath and quenched by adding saturated sodium bicarbonate solution. The organic phase was separated, collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 8:1) to give compound 1-4 (21.9 g, Y: 80%). LC-MS m / z (ESI): 426.1, 428.1 [M+Na] + .

[0184] Step 4: Under nitrogen gas protection, compound 1-4 (21.9 g, 54.2 mmol) was dissolved in dichloromethane (220 mL) and n-heptane (220 mL). The reaction mixture was cooled to 0°C, and phenylmagnesium bromide (48.4 mL, 135 mmol, 2.8 mol / L) was added dropwise. The mixture was then warmed to room temperature and reacted for 12 hours. After completion of the reaction, the reaction mixture was cooled to 0°C and quenched by adding saturated ammonium chloride (20 mL). The organic phase was separated, collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1) to give compound 1-5 (17.5 g, Y: 67%). LC-MS m / z (ESI): 482.2, 484.2 [M+H] + .

[0185] Step 5: Under nitrogen gas protection, compound 1-5 (17.5 g, 36.3 mmol) was dissolved in tetrahydrofuran (200 mL). The reaction solution was cooled to -5 °C, and a solution of potassium tert-butoxide in tetrahydrofuran (54.4 mL, 54.4 mmol, 1.0 mol / L) was added dropwise. After the addition was complete, the mixture was maintained at -5 to 0 °C and reacted for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5:1) to give compound 1-6 (13.2 g, Y: 78%). LC-MS m / z (ESI): 406.1, 408.2 [M-tBu]+ .

[0186] Step 6: Compound 1-6 (13.2 g, 28.6 mmol) was dissolved in tetrahydrofuran (70 mL) and acetonitrile (140 mL), cooled to 0°C, and p-toluenesulfonic acid (6.39 g, 37.1 mmol) and N-chlorosuccinimide (4.96 g, 37.1 mmol) were added. The mixture was warmed to room temperature and reacted for 12 hours. After the reaction was completed, the mixture was quenched with saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1) to give the product (8.50 g, ee: 82%). Separation by chiral separation (CHIRALPAK IA, CO2:IPA = 70:30) gave compound 1-7 (7.0 g, ee > 98%, Y: 49%). LC-MS m / z (ESI): 518.1, 520.1 [M+Na] + .

[0187] Step 7: Compound 1-7 (7.00 g, 14.1 mmol) was dissolved in toluene (70 mL), and bis(neopentylglycolate)diboron (9.05 g, 35.4 mmol), potassium acetate (4.15 g, 42.4 mmol), and 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.46 g, 1.41 mmol) were added sequentially. The mixture was purged with nitrogen gas, heated to 110 °C, and reacted for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5:1) to obtain 9.80 g of crude product. This was then purified by reverse phase chromatography to obtain compound 1-8 (4.20 g, Y: 55%). LC-MS m / z (ESI): 566.3, 568.3 [M+Na] + .

[0188] Step 8: Compound 1-9 (5.0 g, 21.8 mmol) was dissolved in N-methylpyrrolidone (50 mL) and cooled to 0 °C under nitrogen gas protection. Sodium bicarbonate (5.24 g, 87.3 mmol) and 1,2-dibromoethane (140 mg, 1.98 mmol) were added sequentially. The temperature was gradually raised to 25 °C and the reaction was allowed to proceed for 12 h. TLC (PE: EtOAc = 5:1) showed complete reaction of the starting materials. The reaction solution was poured into 0.5 M glacial hydrochloric acid (200 mL) to quench the reaction. Ethyl acetate (100 mL × 3) was added and extracted. The combined organic phase was washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA: PE = 1:10) to give compound 1-10 (3.0 g, Y: 53%). 1 H NMR (400 MHz, DMSO-d6) δ 7.91-7.85 (m, 1H), 7.68 (s, 1H), 3.22 (s, 2H), 1.37-1.25 (m, 4H).

[0189] Step 9: Compound 1-10 (3.0 g, 11.7 mmol) was dissolved in methanol (30 mL) and cooled to 0 °C under nitrogen gas protection. Sodium borohydride (489 mg, 12.9 mmol) was added in batches and the mixture was allowed to react at 0 °C for 2 h. TLC (PE:EA = 5:1) showed the starting material had completely reacted. The reaction solution was poured into 15% sodium hydroxide solution (20 mL) at 0 °C to quench the reaction. Ethyl acetate (20 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-11 (3.0 g, crude product).

[0190] Step 10: Compound 1-11 (3.0 g, 11.7 mmol) was dissolved in triethoxysilane (9 mL) and cooled to 0 °C under nitrogen gas protection. Trifluoroacetic acid (6 mL) was added and the mixture was gradually heated to 25 °C for 12 h. TLC (PE:EA = 20:1) showed complete reaction of the starting materials. The reaction solution was poured into saturated sodium bicarbonate (50 mL) to quench the reaction. Ethyl acetate (50 mL x 3) was added for extraction. The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (EA:PE = 1:10) afforded compound 1-12 (1.1 g, Y: 38%). 1 H NMR (400 MHz, DMSO-d6) δ 7.31-7.25 (m, 2H), 2.90 (s, 2H), 2.83 (s, 2H), 0.65-0.60 (m, 4H).

[0191] Step 11: Compound 1-12 (1.1 g, 4.98 mmol) was dissolved in N,N-dimethylformamide (10 mL). Under nitrogen gas protection, zinc cyanide (584 mg, 4.98 mmol), tris(dibenzylideneacetone)dipalladium (227 mg, 248 μmol), and 1,1'-bis(diphenylphosphine)ferrocene (380 mg, 496 μmol) were added sequentially. The mixture was gradually heated to 100°C and reacted for 12 hours. TLC (PE:EA=20:1) showed that the starting materials had completely reacted. The reaction solution was cooled to 25°C, filtered through diatomaceous earth, water (30 mL) was added to the filtrate, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 1-13 (600 mg, Y: 64%). 1 H NMR (400 MHz, DMSO-d6) δ 7.66-7.60 (m, 1H), 7.57 (s, 1H), 2.95 (s, 4H), 0.65 (d, J = 4.2 Hz, 4H).

[0192] Step 12: Compound 1-13 (600 mg, 3.59 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to -70 °C under nitrogen gas protection. Lithium diisopropylamide (2 M, 1.8 mL) was added and stirred for 30 minutes. Iodine (1.03 g, 4.05 mmol) was then added and the mixture was heated to 25 °C and reacted for 1 hour. TLC (PE:EA = 20:1) showed complete reaction of the starting materials. The reaction solution was poured into saturated ammonium chloride (10 mL) to quench the reaction. Ethyl acetate (20 mL x 3) was added and extracted. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (EA:PE = 1:10) afforded compound 1-14 (600 mg, Y: 68%). 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 2.97 (s, 2H), 2.91 (s, 2H), 0.64 (d, J = 4.7 Hz, 4H).

[0193] Step 13: Compound 1-14 (200 mg, 638 μmol) and compound 1-8 (382 mg, 702 μmol) were dissolved in toluene (2 mL) and water (0.4 mL). Under the protection of nitrogen gas, tris(dibenzylideneacetone)dipalladium (58.4 mg, 63.8 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (73.8 mg, 127 μmol), and potassium phosphate (406 mg, 1.92 μmol) were added sequentially. The temperature was gradually raised to 110°C and the reaction was continued for 12 hours. LCMS showed that the raw materials had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated ammonium chloride (10 mL) to quench the reaction, extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 1-15 (180 mg, Y: 46%). LC-MS m / z (ESI): 625 [M+Na] + .

[0194] Step 14: Compound 1-15 (180 mg, 289 μmol) and sodium hydroxide (92.5 mg, 2.31 mmol) were dissolved in ethanol (2 mL) and water (1 mL). The mixture was heated to 110 °C and reacted for 24 hours. LCMS showed that the starting material had completely reacted. After cooling to 0 °C, the reaction solution was poured into 1 M hydrochloric acid (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-16 (110 mg, crude product). LC-MS m / z (ESI): 619 [M−H] - .

[0195] Step 15: Compound 1-16 (110 mg, 117 μmol) was dissolved in tetrahydrofuran (2 mL) and added in batches with sodium bicarbonate (9.85 mg, 164.19 μmol) and di-tert-butyl dicarbonate (35.8 mg, 164 μmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 hours. TLC (PE:EA = 2:1) showed complete reaction of the starting material. After cooling to 0 °C, the reaction solution was poured into 1 M hydrochloric acid (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-17 (110 mg, crude product).

[0196] Step 16: Compound 1-17 (110 mg, crude product) was dissolved in tetrahydrofuran (2 mL) and sequentially added with sodium bicarbonate (9.85 mg, 164 μmol) and methyl iodide (35.8 mg, 164 μmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. TLC (PE:EA = 2:1) showed complete reaction of the starting materials. After cooling to 0 °C, the reaction solution was poured into 1 M hydrochloric acid (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 10:1) to give compound 1-18 (100 mg, Y: 98%). LC-MS m / z (ESI): 735 [M+H] + .

[0197] Step 17: Compound 1-18 (110 mg, 117 μmol) was dissolved in 2 mL of 20% trifluoroacetic acid in dichloromethane and reacted at 25 °C for 0.5 h. TLC (DCM:MeOH = 10:1) showed that the starting material had completely reacted. The reaction mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL), and quenched. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by preparative high-performance liquid chromatography (column model: Xselect CSH Prep Fluoro-Phenyl, 150 x 19 mm, 5 μm; eluent: 0.05% FA / CH3CN; gradient: 41% to 61%; flow rate: 20 mL / min; run time: 11 min; peak time: 7.2 min) to give compound 1a (10.5 mg, Y: 14%). LC-MS m / z (ESI): 535.30 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.98 (br, 1H), 8.35-8.28 (m, 1H), 7.58-7.51 (m, 2H), 7.48-7.43 (m, 2H), 7.40-7.36 (m, 2H), 7.12 (d, J = 9.2 Hz, 1H), 4.30-4.20 (m, 1H), 3.60-3.50 (m, 1H), 3.22-3.02 (m, 2H), 3.00-2.88 (m, 4H), 2.63 (d, J = 4.4 Hz, 3H), 2.48-2.40 (m, 1H), 2.18-2.10 (m, 1H), 1.96-1.70 (m, 3H), 0.66 (s, 4H).

[0198] Example 2 [ka] [ka]

[0199] Step 1: Compound 2-1 (50 g, 226 mmol) was dissolved in dimethyl sulfoxide (250 mL) and cooled to 0 °C under nitrogen gas protection. Potassium hydroxide (25.3 g, 452 mmol) was added in batches. After the addition was complete, the mixture was heated to 60 °C and reacted for 4 hours. TLC (PE:EA = 5:1) showed complete reaction of the starting material. The reaction solution was cooled to room temperature and poured into 0.5 M glacial hydrochloric acid (500 mL) to quench the reaction. Ethyl acetate (500 mL x 3) was added and extracted. The combined organic phase was washed with saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-2 (35.0 g, crude product). LC-MS m / z (ESI): 219, 221 [M+H] + .

[0200] Step 2: Compound 2-2 (35.0 g, 159 mmol) was dissolved in acetonitrile (350 mL) and cooled to 0 °C under nitrogen gas protection. Potassium carbonate (22.0 g, 159 mmol), 1,2-dibromoethane (150 g, 799 mmol), and potassium iodide (2.65 g, 15.9 mmol) were added sequentially. The mixture was heated to 80 °C and reacted for 12 hours. TLC (PE:EA = 5:1) showed that the raw materials had completely reacted. The reaction solution was poured into 0.5 M glacial hydrochloric acid (500 mL) at 0°C to quench the reaction, and ethyl acetate (500 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 2-3 (26.0 g, Y: 49%). 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.40 (d, J = 1.2 Hz, 1H), 7.35-7.29 (m, 1H), 4.58-4.52 (m, 2H), 3.89-3.82 (m, 2H).

[0201] Step 3: Compound 2-3 (3.5 g, 10.7 mmol) was dissolved in a mixture of toluene (30.0 mL) and 50% sodium hydroxide (10 mL). The mixture was cooled to 0 °C under nitrogen gas protection. Tetrabutylammonium hydrogen sulfate (3.83 g, 11.2 mmol) was added and the mixture was heated to 10 °C and reacted for 1 h. TLC (PE:EA = 20:1) showed complete reaction of the starting materials. The reaction solution was poured into 0.5 M glacial hydrochloric acid (50 mL) at 0 °C to quench the reaction. Methyl tert-butyl ether (50 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-4 (2.63 g, crude product).

[0202] Step 4: Compound 2-4 (400 mg, 1.63 mmol) was dissolved in tetrahydrofuran (4 mL). Under nitrogen gas protection, p-toluenesulfonylhydrazide (455 mg, 2.45 mmol) was added and the mixture was reacted at 25 °C for 2 h. TLC (PE:EA = 20:1) showed that the starting material had reacted completely. The reaction solution was directly purified by reverse phase chromatography to give compound 2-5 (50 mg, Y: 7%). 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.95 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.38-7.33 (m, 1H), 7.19 (s, 1H), 6.93-6.86 (m, 1H), 4.83-4.77 (m, 1H), 4.67-4.61 (m, 1H), 2.36 (s, 3H). LC-MS m / z (ESI): 413, 415 [M+H] + .

[0203] Step 5: Compound 2-5 (500 mg, 1.21 mmol) was dissolved in toluene (5.0 mL). Under nitrogen gas protection, rhodium(II) acetate dimer (53.4 mg, 120 μmol) and sodium bicarbonate (79.8 mg, 1.33 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 3 h. TLC (PE:EA = 20:1) showed complete reaction of the starting materials. The reaction solution was poured into saturated ammonium chloride (20 mL) at 0 °C to quench the reaction. Ethyl acetate (20 mL × 3) was added and extracted. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (PE:EA = 10:1) to give compound 2-6 (100 mg, Y: 36%). 1 H NMR (400 MHz, CDCl3) δ 7.20-7.14 (m, 2H), 4.89-4.83 (m, 1H), 2.74-2.67 (m, 1H), 1.12-1.05 (m, 1H), 0.42-0.35 (m, 1H).

[0204] Step 6: Compound 2-6 (0.6 g, 2.62 mmol) was dissolved in N,N-dimethylformamide (10 mL). Under nitrogen gas protection, zinc cyanide (307 mg, 2.62 mmol), tris(dibenzylideneacetone)dipalladium (119 mg, 130 μmol), and 1,1'-bis(diphenylphosphine)ferrocene (200 mg, 261 μmol) were added sequentially. The temperature was gradually raised to 100 °C and the reaction was continued for 12 hours. TLC (PE:EA = 20:1) showed that the starting materials had completely reacted. The reaction solution was cooled to 25°C, filtered through diatomaceous earth, water (30 mL) and ethyl acetate (50 mL) were added to the filtrate, the combined organic phase was washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (EA:PE = 1:10) to give compound 2-7 (350 mg, Y: 76%). 1 H NMR (400 MHz, CDCl3) δ 6.96-6.90 (m, 1H), 6.89 (s, 1H), 4.99-4.93 (m, 1H), 2.83-2.77 (m, 1H), 1.26-1.20 (m, 1H), 0.47-0.41 (m, 1H).

[0205] Step 7: Compound 2-7 (350 mg, 2.00 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to -70 °C under nitrogen gas protection. Lithium diisopropylamide (2 M, 1.8 mL) was added and stirred for 30 min. Iodine (557 mg, 2.20 mmol) was then added. The dry ice bath was removed, and the mixture was warmed to 25 °C and reacted for 1 h. TLC (PE:EA = 20:1) indicated complete reaction of the starting materials. At 0 °C, the reaction solution was poured into saturated ammonium chloride (10 mL) to quench the reaction. Ethyl acetate (20 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA = 10:1) afforded compound 2-8 (600 mg, Y: 64%). 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 5.02-4.95 (m, 1H), 2.86-2.80 (m, 1H), 1.28-1.23 (m, 1H), 0.48-0.43 (m, 1H).

[0206] Step 8: Compound 2-8 (250 mg, 664 μmol) and compound 1-8 (361 mg, 664 μmol) were dissolved in toluene (2 mL) and water (0.4 mL). Under the protection of nitrogen gas, tris(dibenzylideneacetone)dipalladium (60.7 mg, 66.4 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (776 mg, 132 μmol), and potassium phosphate (422 mg, 1.99 mmol) were added sequentially. The temperature was gradually raised to 110°C and the reaction was continued for 12 hours. LCMS showed that the raw materials had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated ammonium chloride (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 2-9 (260 mg, Y: 66%). LC-MS m / z (ESI): 613 [M+Na] + .

[0207] Step 9: Compound 2-9 (50.0 mg, 84.6 μmol) and sodium hydroxide (27.0 mg, 676 mmol) were dissolved in ethanol (2 mL) and water (1 mL). The mixture was heated to 110 °C and reacted for 24 hours. LCMS showed that the starting material had completely reacted. After cooling to 0 °C, the reaction solution was poured into 1 M HCl (10 mL) to quench the reaction. Ethyl acetate (20 mL × 3) was added and extracted. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-10 (50 mg, crude product). LC-MS m / z (ESI): 609 [M+H] +

[0208] Step 10: Compound 2-10 (50 mg, 82.0 μmol) was dissolved in tetrahydrofuran (2 mL) and sequentially added with sodium bicarbonate (9.85 mg, 164 μmol) and di-tert-butyl dicarbonate (35.8 mg, 164 μmol) at 0 °C. The mixture was stirred at room temperature for 2 h. TLC (PE:EA = 2:1) showed complete reaction of the starting materials. After cooling to 0 °C, the reaction solution was poured into 1 M hydrochloric acid (10 mL) to quench the reaction. Ethyl acetate (20 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-11 (50 mg, crude product).

[0209] Step 11: Compound 2-11 (50 mg, 82.0 μmol) was dissolved in tetrahydrofuran (2 mL). Sodium bicarbonate (9.85 mg, 164 μmol) and methyl iodide (35.8 mg, 164 μmol) were added sequentially at 0 °C. The mixture was stirred at room temperature for 2 hours. TLC (PE:EA = 2:1) showed complete reaction of the starting materials. After cooling to 0 °C, the reaction solution was poured into 1 M hydrochloric acid (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 2-12 (30 mg, Y: 50%). LC-MS m / z (ESI): 646 [M+Na] + .

[0210] Step 12: Compound 2-12 (150 mg, 240 μmol) was dissolved in 2 mL of 20% trifluoroacetic acid in dichloromethane and reacted at 25° C. for 0.5 h. TLC (DCM:MeOH=10:1) showed that the starting material had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (column model: Xselect CSH Prep Fluoro-Phenyl, 150 x 19 mm, 5 μm; eluent: 0.05% FA / CH3CN; gradient: 40% to 60%; flow rate: 20 mL / min; run time: 13 min; peak time: 8.9 min, 2a and 7.6 min, 2b) to obtain compound 2a (9.5 mg, Y: 7%) and compound 2b (11.0 mg, Y: 8%). 2a: 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.50-7.33 (m, 5H), 7.05 (d, J = 11.5 Hz, 1H), 6.98 (s, 1H), 5.18-5.13 (m, 1H), 3.52-3.46 (m, 1H), 2.95-2.78 (m, 4H), 2.68-2.50 (m, 3H), 1.87-1.21 (m, 6H), 0.38-0.33 (m, 1H). LC-MS m / z (ESI): 523.3 [M+H] + 2b: 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.16-8.10 (m, 1H), 7.49-7.43 (m, 2H), 7.33-7.22 (m, 3H), 6.97-6.90 (m, 2H), 5.19-5.14 (m, 1H), 3.53-3.47 (m, 1H), 3.19-3.13 (m, 2H), 2.94-2.88 (m, 1H), 2.80-2.70 (m, 1H), 2.61-2.50 (m, 1H), 2.24-2.17 (m, 3H), 1.52-1.23 (m, 6H), 0.42-0.37 (m, 1H). LC-MS m / z (ESI): 523.3 [M+H] + .

[0211] Example 3 [ka] [ka]

[0212] Step 1: Compound 3-1 (8.5 g, 48.0 mmol) was dissolved in dimethyl sulfoxide (85 mL). The starting materials, pyrrolidine-2-methanol (4.9 g, 48.0 mmol) and potassium hydroxide (8.1 g, 144.0 mmol), were added sequentially. The mixture was allowed to react at 25 °C for 2 h, then gradually heated to 80 °C and allowed to react for 2 h. LCMS analysis indicated complete reaction of the starting materials. After cooling to 25 °C, the reaction solution was poured into ice water (400 mL) to quench the reaction. Ethyl acetate (100 mL x 3) was added for extraction. The combined organic phase was washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:2) to give compound 3-2 (4.8 g, 41%). LC-MS m / z (ESI): 239.1 [M+H] + .

[0213] Step 2: Compound 3-2 (4.7 g, 19.7 mmol) was dissolved in ethanol (50 mL). Water (10 mL), iron powder (1.8 g, 98.5 mmol), and ammonium chloride (5.2 g, 98.5 mmol) were added sequentially. The mixture was gradually heated to 80 °C and reacted for 2 h. LCMS analysis indicated complete reaction of the starting materials. After cooling to 25 °C, the reaction mixture was filtered through diatomaceous earth. Water (100 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:1) to give compound 3-3 (3.1 g, Y: 65%). LC-MS m / z (ESI): 209.2 [M+H] + .

[0214] Step 3: Compound 3-3 (3.1 g, 14.9 mmol) was dissolved in acetonitrile (40 mL), cuprous iodide (8.5 g, 44.7 mmol) was added, and the mixture was cooled to 0 °C. tert-Butyl nitrite (1.9 g, 22.3 mmol) was added dropwise, and the mixture was gradually heated to 80 °C for 16 h. LCMS showed that the starting material had completely reacted. After cooling to 25 °C, the reaction solution was filtered through diatomaceous earth. Water (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 1:5) to give compound 3-4 (1.1 g, Y: 23%). 1 H NMR (400 MHz, CDCl3): δ 7.00-6.95 (m, 1H), 6.69-6.63 (m, 1H), 4.25-4.19 (m, 1H), 3.93-3.88 (m, 1H), 3.50-3.45 (m, 1H), 3.35-3.28 (m, 1H), 3.08-3.01 (m, 1H), 2.21-2.15 (m, 1H), 1.98-1.90(m, 2H), 1.53-1.45(m, 1H).

[0215] Step 4: Compound 3-4 (1.1 g, 3.45 mmol) was dissolved in N-methylpyrrolidone (11 mL), cuprous cyanide (1.2 g, 13.8 mmol) was added, and the mixture was gradually heated to 100 °C and reacted for 16 hours. LCMS analysis indicated complete reaction of the starting material. After cooling to 25 °C, the reaction solution was filtered through diatomaceous earth. Water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 1:5) to give compound 3-5 (0.6 g, Y: 45%). LC-MS m / z (ESI): 219.1 [M+H] + .

[0216] Step 5: Compound 3-5 was dissolved in tetrahydrofuran (5 mL) and cooled to -70 °C under nitrogen gas protection. Lithium diisopropylamide (2 M in THF, 1.38 mL, 2.77 mmol) was added dropwise and stirred at -70 °C for 0.5 h. Elemental iodine (704 mg, 2.77 mmol) was added batchwise and allowed to react at -70 °C for 1 h. The temperature was gradually raised to 25 °C and the reaction was allowed to react for 1 h. TLC (PE:EA = 10:1) showed complete reaction of the starting materials. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified under reduced pressure by silica gel column chromatography (EA:PE = 1:10) to give compound 3-6 (610 mg, Y: 70%). LC-MS m / z (ESI): 345.1[M+H] + .

[0217] Step 6: Compound 3-6 (610 mg, 1.77 mmol) was dissolved in ethanol (8 mL) and water (8 mL), sodium hydroxide (708 mg, 17.70 mmol) was added, and the mixture was gradually heated to 100 °C for 16 hours. TLC (PE:EA = 5:1) showed that the starting materials had completely reacted. The reaction solution was quenched with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated brine (40 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 3-7 (300 mg, Y: 46%). LC-MS m / z (ESI): 364.1 [M+H] + .

[0218] Step 7: Compound 3-7 (300 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (5 mL). 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (471 mg, 1.24 mmol), methylamine hydrochloride (110 mg, 1.65 mmol), and triethylamine (250 mg, 2.48 mmol) were added sequentially. The mixture was allowed to react at 25 °C for 2 h. LCMS analysis indicated complete reaction of the starting material. Water (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:1) to give compound 3-8 (201 mg, Y: 64%). LC-MS m / z (ESI): 376.9[M+H] + .

[0219] Step 8: Compound 3-7 (201 mg, 0.53 mmol) was dissolved in toluene (5 mL), followed by the addition of compounds 1-8 (290 mg, 0.53 mmol), potassium phosphate (226 mg, 1.06 mmol), water (1 mL), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (61 mg, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium (48 mg, 0.05 mmol). The mixture was then reacted at 80 °C for 16 hours under nitrogen gas protection. LCMS analysis indicated complete reaction of the starting materials. The reaction solution was cooled to 25 °C, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:2) to give compound 3-8 (110 mg, Y: 30%). LC-MS m / z (ESI): 666.1 [M+H] + .

[0220] Step 9: Compound 3-8 (110 mg, 0.16 mol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at 25° C. for 0.5 hours. LCMS showed that the starting material had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (20 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: Xselect CSH Prep Fluoro-Phenyl, 150 x 19 mm, 5 μm; eluent: 0.05% FA / CH3CN + MeOH = 1:1; gradient: 38% to 58%; flow rate: 20 mL / min; run time: 11 min; peak time: 8.9 min, 3a and 7.8 min, 3b) to give compound 3a (18.0 mg, Y: 11%) and compound 3b (38.0 mg, Y: 24%). 3a: 1H NMR (400 MHz, DMSO-d6): δ 8.18-8.09 (m, 1H), 7.55-7.32 (m, 5H), 7.06 (s, 1H), 7.04 (d, J=6.4 Hz, 1H), 4.49-4.40 (m, 1H), 4.08-3.95 (m, 1H), 3.73-3.62 (m, 1H), 3.51-3.28 (m, 3H), 3.27-2.87 (m, 4H), 2.61 (d, J=4.4 Hz, 3H), 1.97-1.45 (m, 8H). LC-MS m / z (ESI): 556.4 [M+H] + 3b: 1 H NMR (400 MHz, DMSO-d6): δ 8.14-7.90 (m, 1H), 7.49-7.31 (m, 5H), 7.06-6.92 (m, 2H), 4.48-4.32 (m, 1H), 4.00-3.76 (m, 2H), 3.50-3.40 (m, 4H), 3.09-2.90 (m, 3H), 2.37-2.26 (m, 3H), 2.18-1.45 (m, 8H). LC-MS m / z (ESI): 556.4 [M+H] + .

[0221] Example 4

change

change

[0222] Step 1: Compound 3-1 (40.0 g, 22.6 mmol) was dissolved in dimethyl sulfoxide (320 mL), and the raw material (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride (34.0 g, 22.6 mmol) was added. Under the protection of nitrogen gas, potassium hydroxide (50.6 g, 90.4 mmol) was added in batches. The mixture was reacted at 25°C for 2 hours, then heated to 60°C and reacted for 2 hours. LCMS showed that the raw material had completely reacted. The reaction solution was cooled to 25°C, filtered through diatomaceous earth, and the cake was rinsed with ethyl acetate (200 mL). The pH of the filtrate was adjusted to 5-6 with 1 M hydrochloric acid and extracted with ethyl acetate (600 mL x 3). The combined organic phase was washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (PE:EA = 1:2) to give compound 4-1 (13.0 g, Y: 22%). 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J =10.4 Hz, 1H), 7.52 (s, 1H), 5.19 (s, 1H), 4.65-4.59 (m, 1H), 4.39 (s, 1H), 3.84-3.70 (m, 3H), 3.48-3.42 (m, 1H), 2.04-1.95 (m, 1H), 1.62-1.52 (m, 1H).

[0223] Step 2: Compound 4-1 (15.2 g, 59.8 mmol) was dissolved in ethanol (150 mL), and a solution of ammonium chloride (16.4 g, 299 mmol) in water (150 mL) was added. The mixture was heated to 80 °C, and iron powder (16.7 g, 299 mmol) was added in batches. The mixture was then allowed to react at 80 °C for 1.5 h. LCMS analysis showed the starting materials had reacted completely. The reaction mixture was cooled to 25 °C, filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by column chromatography (PE:EA = 2:3) to give compound 4-2 (8.7 g, Y: 64%). 1H NMR (400 MHz, DMSO-d6) δ 6.05-5.95 (m, 1H), 5.91 (s, 1H), 4.92-4.75 (m, 3H), 4.27-4.22 (m, 1H), 4.07-4.01 (m, 1H), 3.50-3.42 (m, 1H), 3.30-3.20 (m, 1H), 2.90-2.80 (m, 1H), 1.98-1.90 (m, 1H), 1.74-1.64 (m, 1H). LC-MS m / z (ESI): 225 [M+H] + .

[0224] Step 3: Compound 4-2 (8.7 g, 38.8 mmol) was dissolved in acetonitrile (100 mL) and cooled to 0 °C under nitrogen gas protection. tert-Butyl nitrite (4.8 g, 45.6 mmol) was added dropwise and the mixture was allowed to react at 0 °C for 0.5 hours. Cuprous iodide (7.3 g, 38.8 mmol) and potassium iodide (19.3 g, 116.4 mmol) were then added sequentially. The mixture was heated to 60 °C and allowed to react for 12 hours. TLC (PE:EA = 2:1) showed that the starting materials had completely reacted. The reaction solution was cooled to 0°C, poured into saturated sodium bicarbonate (100 mL) to quench the reaction, extracted with ethyl acetate (100 mL × 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (PE:EA = 3:1) to give compound 4-3 (2.2 g, Y: 16%).

[0225] Step 4: Compound 4-3 (1.5 g, 4.5 mmol) was dissolved in dichloromethane (20 mL). Under nitrogen gas protection, imidazole (913 mg, 13.4 mmol) was added and stirred for 0.5 h. tert-Butyldimethylchlorosilane (1.0 g, 6.7 mmol) was added and the mixture was allowed to react at 25 °C for 2 h. LCMS showed that the starting material had reacted completely. The reaction solution was diluted with dichloromethane (20 mL) and washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 1:10) to give compound 4-4 (1.1 g, Y: 37%). 1 H NMR (400 MHz, DMSO-d6) δ 7.06 (d, J=13.2 Hz, 1H), 6.98 (s, 1H), 4.54-4.46 (m, 1H), 4.36-4.31 (m, 1H), 3.59-3.50 (m, 2H), 3.37-3.28 (m, 2H), 1.98-1.90 (m, 2H), 1.72-1.68 (m, 2H) 0.86 (s, 9H), 0.07 (s, 6H). LC-MS m / z (ESI): 450 [M+1] + .

[0226] Step 5: Compound 4-4 (1.1 g, 2.5 mmol) was dissolved in N-methylpyrrolidone (20 mL). Under nitrogen gas protection, copper(I) cyanide (1.8 g, 4.1 mmol) was added, and the mixture was heated to 110 °C and reacted for 16 hours. LCMS analysis showed that the starting material had completely reacted. The reaction solution was cooled to 80 °C, and ethyl acetate (100 mL) was slowly poured into it. The mixture was stirred for 0.5 hours, filtered through diatomaceous earth, and the filtrate was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (EA:PE = 5:1) to give compound 4-5 (500 mg, Y: 58%). LC-MS m / z (ESI): 349 [M+H] + .

[0227] Step 6: Compound 4-5 (500 mg, 1.4 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to -75 °C under nitrogen gas protection. Lithium diisopropylamide (0.86 mL, 1.72 mol, 2.0 M) was added dropwise. After the addition was complete, the mixture was stirred at -75 °C for 0.5 h. Iodine-tetrahydrofuran (435 mg, 1.72 mmol / 2 mL) was added dropwise. After the addition was complete, the reaction was continued at -75 °C for 0.5 h. LCMS showed that the starting material had completely reacted. The reaction solution was poured into saturated ammonium chloride (10 mL) at 0 °C to quench the reaction. Ethyl acetate (50 mL × 3) was added, and the combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (PE:THF = 1:3) to give compound 4-6 (410 mg, Y: 60%). 1 H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 4.58-4.52 (m, 2H), 3.78-3.64 (m, 3H), 3.45-3.40 (m, 1H), 1.99-1.92 (m, 1H), 1.69-1.59 (m, 1H), 0.87 (s, 9H), 0.09 (s, 6H). LC-MS m / z (ESI): 475 [M+H] + .

[0228] Step 7: Compound 4-6 (280 mg, 591 μmol) was dissolved in toluene (5 mL) and water (1 mL). Under the protection of nitrogen gas, compound 1-8 (336 mg, 621 μmol), tris(dibenzylideneacetone)dipalladium (108 mg, 118 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (137 mg, 236 μmol), and potassium phosphate (376 mg, 1.77 mmol) were added sequentially. The temperature was raised to 110° C. and the reaction was continued for 12 hours. LCMS showed that the raw materials had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated ammonium chloride (10 mL) to quench the reaction, extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 1:10) to give compound 4-7 (270 mg, Y: 39%). LC-MS m / z (ESI): 664 [M+Na] + .

[0229] Step 8: Compound 4-7 (270 mg, 354 μmol) was dissolved in ethanol (2 mL) and water (1 mL), sodium hydroxide (65 mg, 2.83 mmol) was added, and the mixture was heated to 120 °C and reacted for 16 hours. LCMS showed that the starting material had completely reacted. After cooling to 0 °C, the reaction solution was poured into 0.3 M hydrochloric acid (10 mL) to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 4-8 (190 mg, Y: 72%). LC-MS m / z (ESI): 668 [M+H] + .

[0230] Step 9: Compound 4-8 (190 mg, 284 μmol) was dissolved in dichloromethane (10 mL). Under nitrogen gas protection, imidazole (58 mg, 854 μmol) was added and the reaction was continued at 25°C for 0.5 hours. tert-Butyldimethylchlorosilane (85 mg, 569 μmol) was added and the reaction was continued at 25°C for 2 hours. LCMS showed that the starting material had completely reacted. The reaction solution was diluted with dichloromethane (10 mL), washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 4-9 (110 mg, Y: 49%) was obtained by column chromatography (PE:EA = 1:2). LC-MS m / z (ESI): 782 [M+H] + .

[0231] Step 10: Compound 4-9 (110 mg, 141 μmol) was dissolved in tetrahydrofuran (2 mL), and sodium bicarbonate (22 mg, 423 μmol) was added in batches at 0 °C. The reaction was allowed to proceed for 0.5 hours. Di-tert-butyl dicarbonate (87 mg, 400 μmol) was added, and the reaction was allowed to proceed for 2 hours at 25 °C. LCMS analysis showed that the starting material had completely reacted. After cooling to 0 °C, the reaction solution was poured into 0.5 M hydrochloric acid (10 mL) to quench the reaction. Ethyl acetate (20 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 4-10 (100 mg, crude product). LC-MS m / z (ESI): 882 [M+H] + .

[0232] Step 11: Compound 4-10 (100 mg, 113 μmol) was dissolved in tetrahydrofuran (2 mL), sodium bicarbonate (6 mg, 135 μmol) was added at 0 °C, and the mixture was allowed to react for 0.5 hours at 0 °C. Methyl iodide (20 mg, 135 μmol) was added dropwise, and the mixture was allowed to react for 0.5 hours at 25 °C. TLC (PE:EA = 2:1) showed that the starting materials had completely reacted. The mixture was cooled to 0 °C, and the reaction solution was poured into 0.1 M hydrochloric acid (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 1:10) to give compound 4-11 (54 mg, Y: 42%). LC-MS m / z (ESI): 796 [M+H] + .

[0233] Step 12: Compound 4-11 (54 mg, 60 μmol) was dissolved in a solution of trifluoroacetic acid in dichloromethane (2 mL / 4 mL) and reacted for 0.5 hours at 25° C. LCMS showed that the starting material had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (5 mL) to quench the reaction, adjusted to pH 8-9, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH3.H2O / CH3CN; gradient: 64%-84%; flow rate: 20 mL / min; run time: 10 min; peak time: 8.0 min, 4a, and 6.8 min, 4b) to give compound 4a (3.6 mg, Y: 10%) and compound 4b (1.8 mg, Y: 5%). 4a: 1H NMR(400 MHz, DMSO-d6) δ 7.89 (br, 1H), 7.48-7.45 (m, 2H), 7.42-7.22 (m, 3H), 7.01 (s, 1H), 6.99-6.90 (m, 1H), 5.03 (br, 1H), 4.49-4.41 (m, 1H), 4.34-4.23 (m, 2H), 4.68-4.41 (m, 5H), 2.99-2.88 (m, 1H), 2.85-2.59 (m, 5H), 2.04-1.92 (m, 1H), 1.64-1.26 (m, 4H). LC-MS m / z (ESI): 582 [M+H] + 4b: 1 HNMR(400 MHz,DMSO-d6) δ 7.95 (br, 1H), 7.46-7.41 (m, 2H), 7.36-7.25 (m, 3H), 6.96 (s, 1H), 6.94-6.88 (m, 1H), 5.12-5.05 (m, 1H), 4.51-4.31 (m, 3H), 3.74-3.38 (m, 5H), 3.11-3.02 (m, 1H), 2.78-2.55 (m, 2H), 2.28 (d, J=4.4 Hz, 3H), 2.05-1.95 (m, 1H), 1.70-1.62 (m, 1H),1.52-1.40 (m, 3H). LC-MS m / z (ESI): 582 [M+H] + .

[0234] Example 5

change

change

[0235] Step 1: Compound 4-1 (4.2 g, 16.5 mmol) was dissolved in dichloromethane (40 mL) and diethylaminosulfur trifluoride (5.3 g, 33.1 mmol) was added dropwise at 25 °C. The reaction was allowed to proceed for 2 hours at 25 °C. The completion of the reaction was monitored by LCMS. The reaction solution was quenched by adding saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:THF = 4:1) to give compound 5-1 (2.1 g, Y: 50%). LC-MS m / z (ESI): 257 [M+H] + .

[0236] Step 2: Compound 5-1 (2.1 g, 8.2 mmol), ammonium chloride (2.2 g, 41.0 mmol), iron powder (2.3 g, 41.0 mmol), ethanol (20 mL), and water (20 mL) were mixed and reacted at 80 °C for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. It was then extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:THF = 3:2) to give compound 5-2 (1.2 g, Y: 66%). LC-MS m / z (ESI): 227 [M+H] + .

[0237] Step 3: Compound 5-2 (3.5 g, 14.16 mmol) was dissolved in acetonitrile (40 mL). tert-Butyl nitrite (4.4 g, 42.48 mmol) was added dropwise at 0 °C. Potassium iodide (7.0 g, 42.48 mmol) and cuprous iodide (2.7 g, 14.16 mmol) were added, and the mixture was allowed to react at 60 °C for 2 hours. The reaction was monitored for completion by LCMS. 20 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 19:1) to give compound 5-3 (2.0 g, Y: 38%). LC-MS m / z (ESI): 338 [M+H] + .

[0238] Step 4: Compound 5-3 (2.0 g, 5.93 mmol), N-methylpyrrolidone (20 mL), and copper(I) hydroxide (4.4 g, 47.46 mmol) were heated to 100 °C and reacted for 12 hours. Completion of the reaction was monitored by LCMS. The reaction solution was cooled to 40 °C and filtered. Water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 9:1) to give compound 5-4 (0.9 g, Y: 64%). LC-MS m / z (ESI): 237 [M+H] + .

[0239] Step 5: Compound 5-4 (450 mg, 1.91 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) at -70 °C and added dropwise to lithium diisopropylamide (244 mg, 2.29 mmol). The mixture was then incubated at -70 °C for 0.5 h. A solution of iodine (581 mg, 2.29 mmol) in tetrahydrofuran was then added dropwise. The mixture was then incubated at -70 °C for 0.5 h, then allowed to warm to room temperature and incubated at room temperature for 2 h. The reaction was monitored for completion by LCMS. The reaction mixture was cooled to 0 °C, quenched by adding 5 mL of saturated ammonium chloride solution, and 5 mL of saturated sodium sulfite solution. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography to give compound 5-5 (550 mg, Y: 79%). 1 H NMR (400 MHz, CDCl3): δ 7.00 (s, 1H), 5.36-5.21 (m, 1H), 4.34-4.28 (m, 1H), 4.08-3.81 (m, 2H), 3.65-3.58 (m, 2H), 2.57-2.35 (m, 1H), 2.20-2.11 (m, 1H). LC-MS m / z (ESI): 363 [M+H] + .

[0240] Step 6: Compound 5-5 (214 mg, 0.59 mmol), compound 1-8 (337 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium (54 mg, 0.06 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (34 mg, 0.06 mmol), and potassium phosphate (377 mg, 1.78 mmol) were dissolved in toluene (5 mL) and water (1 mL) and reacted at 100 °C for 24 h under nitrogen gas protection. Completion of the reaction was monitored by LCMS. 5 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 17:3) to give compound 5-6 (110 mg, Y: 28%). LC-MS m / z (ESI): 552 [M+H-Boc] +

[0241] Step 7: Compound 5-6 (110 mg, 0.17 mmol) and sodium hydroxide (121 mg, 3 mmol) were dissolved in ethanol (2 mL) and water (1 mL) and reacted at 120 °C for 24 hours. Completion of the reaction was monitored by LCMS. 5 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 5-7 (95 mg, crude product). LC-MS m / z (ESI): 670 [M+H] + .

[0242] Step 8: Compound 5-7 (95 mg, 0.14 mmol), sodium bicarbonate (17 mg, 0.71 mmol), and di-tert-butyl dicarbonate (124 mg, 0.57 mmol) were reacted at room temperature for 48 hours. Completion of the reaction was monitored by LCMS. The reaction solution was quenched by adding dropwise 5 mL of water, extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 5-8 (95 mg, crude product). LC-MS m / z (ESI): 770 [M+H] + .

[0243] Step 9: Compound 5-8 (95 mg, 0.14 mmol), sodium bicarbonate (17 mg, 0.71 mmol), and methyl iodide (80 mg, 0.57 mmol) were reacted at room temperature for 24 hours. Completion of the reaction was monitored by LCMS. The reaction solution was quenched by adding dropwise 5 mL of water, extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 4:1) to give compound 5-9 (50 mg, 45%). LC-MS m / z (ESI): 784 [M+H] + .

[0244] Step 10: Compound 5-9 (48 mg, 0.061 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and reacted at room temperature for 1 hour. The reaction was monitored for completion by LCMS. 5 mL of water was added to the reaction solution, the pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by preparative high-performance liquid chromatography (Xselect CSH Prep Fluoro-Phenyl column, 150 × 19 mm, 5 μm; eluent: 0.05% FA / CH3CN; gradient: 40%–60%; flow rate: 20 mL / min; run time: 12 min; peak time: 7.8 min) and lyophilized to give compound 5a (7.4 mg, 20%). 1 H NMR (400 MHz, DMSO-d6) δ 88.25 (s, 1H), 7.96-7.92 (m, 1H), 7.49-7.43 (m, 2H), 7.38-7.24 (m, 3H), 7.02 (s, 1H), 6.96 (d, J=9.6 Hz, 1H), 5.41-5.24 (m, 1H), 4.48-4.38 (m, 1H), 3.93-3.77 (m,1H), 3.62-3.38 (m, 5H), 3.02-2.96 (m, 1H), 2.77-2.58 (m, 5H), 2.45-2.39 (m, 1H), 2.15-2.03 (m, 1H),1.58-1.33 (m, 4H). LC-MS m / z (ESI): 584 [M+H] + .

[0245] Example 6 [ka] [ka]

[0246] Step 1: Compound 6-1 (12.5 g, 110.6 mmol) was dissolved in N,N-dimethylformamide (250 mL) and cooled to 0 °C under nitrogen gas protection. Sodium bicarbonate (5.2 g, 331.8 mmol) was added in batches and stirred for 20 min. Bromomethyl methyl ether (13.43 g, 452 mmol) was added dropwise and the mixture was allowed to react at 0 °C for 2 h. TLC (PE:EA = 5:1) showed complete reaction of the starting material. The reaction solution was poured into saturated aqueous ammonium chloride (20 mL) to quench the reaction. Ethyl acetate (400 mL × 3) was added and extracted. The combined organic phase was washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6-2 (14.0 g, crude product). 1 H NMR (400 MHz, DMSO-d6) δ 7.83-7.77 (m, 1H), 7.56-7.50 (m, 1H), 7.12-7.07 (m, 1H), 5.22 (s, 2H), 3.51 (s, 3H).

[0247] Step 2: Compound 6-2 (9.6 g, 61.1 mmol) was dissolved in tetrahydrofuran (90 mL) and cooled to -75°C under nitrogen gas protection. n-Butyllithium solution (26.9 mL, 67.2 mmol, 2.5 mol / L) was added dropwise. After the addition was completed, the mixture was stirred at -75°C for 40 minutes. Then, hexachloroethane (28.95 g, 122.2 mmol) was added dropwise and the mixture was reacted at -75°C for 3 hours. TLC (PE:EA=5:1) showed that the raw materials had completely reacted. The reaction mixture was quenched by dropwise addition of saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (300 mL × 3), and the combined organic phase was washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (EA:PE = 1:5) to give compound 6-3 (5.0 g, Y: 49%). 1 H NMR (400 MHz, DMSO-d6) δ 7.87-7.81 (m, 1H), 7.23 (d, J = 4.0 Hz, 1H), 5.22 (s, 2H), 3.62 (s, 3H).

[0248] Step 3: Compound 6-3 (9.0 g, 47.1 mmol) was dissolved in tetrahydrofuran (90.0 mL) and cooled to -75 °C under nitrogen gas protection. n-Butyllithium solution (26.9 mL, 51.8 mmol, 2.5 M) was added dropwise and stirred for 40 min. Carbon dioxide gas was then introduced. TLC (PE:EA = 7:1) showed complete reaction of the starting materials. Saturated aqueous ammonium chloride (20 mL) was added dropwise at -75 °C to quench the reaction. 1N hydrochloric acid was added to adjust the pH to 5-6, and ethyl acetate (200 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 6-4 (3.0 g, crude product) was obtained by silica gel column chromatography (EA:PE = 1:6).

[0249] Step 4: Compound 6-4 (2.4 g, 19.15 mmol) was dissolved in N,N-dimethylformamide (30 mL), diisopropylethylamine (7.4 g, 57.45 mmol) and methylamine hydrochloride (1.93 g, 28.72 mmol) were added, and 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.0 g, 21.06 mmol) was added in batches under ice bath. The reaction was continued for 2 hours, and TLC (MeOH:DCM = 1:10) showed that the starting materials had completely reacted. The reaction mixture was quenched with water, ethyl acetate (100 mL) was added, and water (80 mL × 2) was added and washed. The combined organic phase was washed with saturated brine (150 mL), filtered, and the filtrate was concentrated under reduced pressure. Compound 6-5 (2.4 g, Y: 51%) was obtained by silica gel column chromatography (EA:PE = 1:1). LC-MS m / z (ESI): 413, 415 [M+H] + .

[0250] Step 5: 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (1.55 g, 10.64 mmol) was dissolved in tetrahydrofuran (30.0 mL) and added in batches at 0 °C with sodium bicarbonate (425 mg, 10.64 mmol). The mixture was stirred for 20 minutes. Compound 6-5 (2.4 g, 9.67 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction mixture at 0 °C for 3 hours. TLC (PE:EA = 1:1) showed complete reaction of the starting materials. The reaction mixture was quenched by adding water (10 mL) dropwise at 0 °C. Ethyl acetate (60 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reverse-phase chromatography to give compound 6-6 (1.0 g, Y: 27%).

[0251] Step 6: Compound 1-8 (500 mg, 0.92 mmol) and compound 6-6 (344 mg, 0.92 mmol) were dissolved in toluene (8 mL) and water (0.8 mL). Under nitrogen gas protection, tris(dibenzylideneacetone)dipalladium (95.3 mg, 0.092 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (106 mg, 0.184 mmol), and potassium carbonate (318 mg, 2.3 mmol) were added sequentially. The mixture was heated to 110 °C and reacted for 16 h. LCMS showed complete reaction of the starting material. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by preparative silica gel plate (EA:PE = 1:1) to give compound 6-7a (40 mg, Y: 5%, Rf = 0.3) and compound 6-7b (50 mg, Y: 7%, Rf = 0.35). LC-MS m / z (ESI): 756.3 [M+H] + .

[0252] Step 7: Compound 6-7a (40 mg, 0.05 mmol) was dissolved in 20% trifluoroacetic acid / dichloromethane solution (2 mL) and reacted at 5° C. for 1 hour. TLC (DCM:MeOH=10:1) showed that the starting material had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN; gradient: 43% to 63%; flow rate: 20 mL / min; run time: 11 min; peak time: 7.9 min) to give compound 6a (12.1 mg, Y: 43%). 1 H NMR (400 MHz, DMSO-d6) δ7.80-7.50 (m, 1H), 7.46-7.18 (m, 6H), 6.88-6.76 (m, 1H), 4.48-4.12 (m, 3H), 3.85-3.60 (m, 2H), 3.51-3.43 (m, 1H), 3.33-3.25 (m, 1H), 3.10-2.88 (m, 1H), 2.75-2.55 (m, 3H), 2.48-2.40 (m, 2H), 1.99 (s, 1H), 1.77-1.63 (m, 1H), 1.43-1.37 (m, 2H), 1.25-1.15 (m, 1H). LC-MS m / z (ESI): 528.2 / 530.3 [M+H] + .

[0253] Step 8: Compound 6-7b (50 mg, 0.07 mmol) was dissolved in 20% trifluoroacetic acid / dichloromethane solution (2 mL) and reacted for 1 hour at 5° C. TLC (DCM:MeOH=10:1) showed that the starting material had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN; gradient: 43% to 63%; flow rate: 20 mL / min; run time: 10 min; peak time: 7.8 min) to give compound 6b (17.8 mg, Y: 51%). 1 H NMR (400 MHz, DMSO-d6) δ 8.04-7.98 (m, 1H), 7.59-7.23 (m, 6H), 6.86 (d, J = 10.4 Hz, 1H), 4.35-4.28 (m, 2H), 3.75 (s, 2H), 3.51-3.45 (m, 2H), 3.04-2.98 (m, 1H), 2.75-2.66 (m, 1H), 2.31 (d, J = 4.4 Hz, 3H), 2.05 (s, 1H), 1.52-1.14 (m, 4H). LC-MS m / z (ESI) : 528.2 / 530.3 [M+H] + .

[0254] Example 7 [ka] [ka]

[0255] Step 1: Compound 7-1 (25 g, 196.67 mmol) was dissolved in tetrahydrofuran (250 mL) and cooled to -75°C under nitrogen gas protection. n-Butyllithium (86.61 mL, 216.34 mmol, 2.5 M) was added dropwise. After the addition was completed, the reaction was continued for 0.5 hours. Then, hexachloroethane (69.90 g, 295.01 mmol) was added in batches at -75°C. The reaction was continued for 4 hours at -75°C. TLC (PE:EA=5:1) showed that the raw materials had completely reacted. The reaction mixture was poured into saturated ammonium chloride solution (50 mL) to quench the reaction, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:5) to give compound 7-2 (7.65 g, Y: 24%). LC-MS m / z (ESI): 162.10 [M+H] + .

[0256] Step 2: Compound 7-2 (7.65 g, 47.35 mmol) was dissolved in tetrahydrofuran (80 mL) and cooled to -75 °C under nitrogen gas protection. n-Butyllithium (21.71 mL, 52.09 mmol) was added dropwise and the mixture was allowed to react for 40 min. Carbon dioxide was passed through the mixture at -75 °C and the mixture was allowed to react for 2 h. TLC (PE:EA = 5:1) showed complete reaction of the starting materials. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture at 0 °C to quench the reaction. Ethyl acetate (50 mL × 3) was added and extracted. The combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:5) to give compound 7-3 (3.90 g, Y: 40%). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 3.95 (s, 3H). LC-MS m / z (ESI):206.1, 208.1 [M+H] + .

[0257] Step 3: Compound 7-3 (1.35 g, 6.57 mmol) was dissolved in N,N-dimethylformamide (15.0 mL) and cooled to 0-5 °C. 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.5 g, 6.57 mmol) and diisopropylethylamine (2.55 g, 19.70 mmol) were added and the mixture was incubated at 0-5 °C for 5 min. Methylamine hydrochloride (0.89 g, 13.13 mmol) was added and the mixture was incubated at room temperature for 1 h. TLC (PE:EA = 1:1) showed the starting material had completely reacted. The reaction solution was poured into water (10 mL) at 0°C to quench the reaction, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:1) to give compound 7-4 (1.00 g, Y: 69%).

[0258] Step 4: 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (1.55 g, 10.64 mmol) was dissolved in tetrahydrofuran (30.0 mL) and sodium bicarbonate (425 mg, 10.64 mmol) was added in batches at 0 °C. The mixture was stirred for 20 min. Compound 7-4 (2.4 g, 9.67 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction mixture at 0 °C. The mixture was then allowed to react at room temperature for 1 h. TLC (PE:EA = 1:1) showed complete reaction of the starting materials. The reaction mixture was quenched with ice water (10 mL) at 0 °C and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 7-5 (1.0 g, Y: 27%) was obtained by reverse-phase purification.

[0259] Step 5: Compound 1-8 (500 mg, 0.92 mmol) and compound 7-5 (317 mg, 0.92 mmol) were dissolved in toluene (8 mL) and water (0.8 mL). Under nitrogen gas protection, tris(dibenzylideneacetone)dipalladium (95.3 mg, 0.092 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (106 mg, 0.184 mmol), and potassium carbonate (318 mg, 2.3 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 16 h. LCMS showed the starting material had reacted completely. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by preparative silica gel plate (EA:PE = 1:1) to give compound 7-6a (23 mg, Y: 3%, Rf = 0.3) and compound 7-6b (32 mg, Y: 4%, Rf = 0.35). LC-MS m / z (ESI): 726.2[M+H] + .

[0260] Step 6: Compound 7-6a (23 mg, 0.032 mmol) was dissolved in 2 mL of 20% trifluoroacetic acid / dichloromethane solution and reacted at 5 °C for 1 h. TLC (DCM:MeOH = 10:1) showed complete reaction of the starting material. After cooling to 0 °C, the reaction solution was poured into saturated sodium carbonate (15 mL) to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 7a (9.4 mg, Y: 54%) as a yellow oil. The crude product was purified on a preparative silica gel plate (DCM:MeOH = 5:1) and then lyophilized to give compound 7a (9.4 mg, Y: 54%). 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(br, 1H), 8.15 (s, 1H), 7.49-7.42 (m, 2H), 7.38-7.25 (m, 3H), 7.02 (d, J = 9.6 Hz, 1H), 4.87 (t, J = 5.2 Hz, 1H), 4.43-4.33 (m, 2H), 3.78-3.73 (m, 2H), 3.68-3.61 (m, 1H), 3.45-3.35 (m, 4H), 3.29 (s, 1H), 2.90-2.73 (m, 2H), 2.63-2.52 (m, 3H), 1.70-1.42 (m, 4H). LC-MS m / z (ESI): 542.3 / 544.3 [M+H] + .

[0261] Step 7: Compound 7-6b (32 mg, 0.044 mmol) was dissolved in 2 mL of 20% trifluoroacetic acid / dichloromethane solution and reacted at 5 °C for 1 h. TLC (DCM:MeOH = 10:1) showed complete reaction of the starting material. After cooling to 0 °C, the reaction solution was poured into saturated sodium carbonate (15 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative silica gel plate (DCM:MeOH = 5:1) and then lyophilized to give compound 7b (12.3 mg, Y: 51%). 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(br, 1H), 8.10 (d, J = 3.6 Hz, 1H), 7.47-7.23 (m, 5H), 6.96 (d, J = 10.4 Hz, 1H), 4.90 (t, J = 3.2 Hz, 1H), 4.45-4.38 (m, 2H), 3.85-3.72 (m, 2H), 3.68 (s, 3H), 3.65-3.60 (m, 1H), 3.31-3.26 (m, 1H), 3.08 (d, J = 10.4 Hz, 1H), 2.80-2.60 (m, 3H), 2.33 (s, 3H), 1.60-1.30 (m, 4H). LC-MS m / z (ESI): 542.3 / 544.3[M+H] + .

[0262] Example 8 [ka] [ka]

[0263] Step 1: Compound 8-1 (10.0 g, 69.2 mmol), tert-butyl-(2-iodoethoxy)dimethylsilane (21.8 g, 76.1 mmol), and silver carbonate (21.0 g, 76.1 mmol) were dissolved in toluene (150 mL) and reacted under nitrogen gas protection at 100 °C for 12 hours. LCMS confirmed complete reaction of the starting materials. The reaction solution was cooled to 25 °C, filtered through diatomaceous earth, and the cake was rinsed with ethyl acetate (30 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (PE:EA = 19:1) to give compound 8-2 (11.0 g, Y: 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 6.0 Hz, 1H), 4.50 (t, J = 4.8 Hz, 2H), 3.88 (t, J = 4.8 Hz, 2H), 0.81 (s, 9H), -0.01 (s, 6H).

[0264] Step 2: Compound 8-2 (10.0 g, 30.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to -70 °C under nitrogen gas protection. Lithium diisopropylamide (2 M, 18 mL) was added dropwise at -70 °C. After the addition was complete, the mixture was allowed to react at -70 °C for 0.5 hours. Dry ice was then added and the mixture was allowed to react at -70 °C for 0.5 hours. The mixture was then allowed to warm to room temperature and react at room temperature for 2 hours. LCMS confirmed the complete reaction of the starting materials. The reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 8-3 (3.8 g, crude product). LC-MS m / z (ESI): 377 [M+H] + .

[0265] Step 3: Compound 8-3 (3.8 g, 10.1 mmol), ammonium chloride (2.7 g, 50.4 mmol), iron powder (2.8 g, 50.4 mmol), ethanol (20 mL), and water (20 mL) were mixed and reacted at 60 °C for 2 hours. LCMS confirmed the complete reaction of the starting materials. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. It was then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by reverse phase chromatography to give compound 8-4 (900 mg, Y: 25%). LC-MS m / z (ESI): 347 [M+H] + .

[0266] Step 4: Compound 8-4 (400 mg, 1.2 mmol), 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (876 mg, 2.3 mmol), diisopropylethylamine (1.2 g, 9.2 mmol), and dichloromethane (10 mL) were mixed, and methylamine hydrochloride (196 mg, 2.9 mmol) was added. The mixture was allowed to react at 25 °C for 1 h. LCMS confirmed complete reaction. The reaction mixture was added with purified water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 1:1) to give compound 8-5 (250 mg, 60%). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (br, 1H), 7.41 (s, 1H), 5.20 (br, 1H), 4.37 (t, J = 4.8 Hz, 2H), 3.94 (t, J = 4.8 Hz, 2H), 2.72 (d, J = 4.4 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 6H).

[0267] Step 5: Compound 8-5 (460 mg, 1.3 mmol), compound 1-8 (730 mg, 1.3 mmol), tris(dibenzylideneacetone)dipalladium (234 mg, 0.26 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (296 mg, 0.51 mmol), and potassium carbonate (529 mg, 3.8 mmol) were dissolved in toluene (5 mL) and water (1 mL) and reacted under nitrogen gas protection at 120 °C for 12 hours. Complete reaction of the starting materials was monitored by LCMS. The reaction mixture was added with purified water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 1:1) to give compound 8-6a (100 mg, Y: 10%, Rf = 0.4) and compound 8-6b (110 mg, Y: 11%, Rf = 0.5). LC-MS m / z (ESI): 741 [M+H] + .

[0268] Step 6: Compound 8-6a (100 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added dropwise at 0 °C. The mixture was allowed to react at 25 °C for 1 h. The complete reaction of the starting material was monitored by LCMS. Water (5 mL) was added to the reaction solution, the pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by preparative high-performance liquid chromatography (Xbridge Prep Phenyl OBD, 150 × 19 mm, 5 μm column; eluent: 0.05% FA / CH3CN; gradient: 39% to 59%; flow rate: 20 mL / min; run time: 11 min; peak time: 8.3 min) to give compound 8a (8.1 mg, Y: 6%). 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(br, 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.61 (s, 1H), 7.50-7.40 (m, 2H), 7.36-7.21 (m, 3H), 6.97 (d, J = 10.0 Hz, 1H), 4.72 (br, 2H), 4.33-4.21 (m, 2H), 3.71-3.66 (m, 2H), 3.55-3.45 (m, 2H), 2.95 (d, J = 16.0 Hz, 1H), 2.78-2.58 (m, 5H), 1.58-1.31 (m, 4H). LC-MS m / z (ESI): 527 [M+H] + .

[0269] Step 7: Compound 8-6b (110 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added dropwise at 0° C. The reaction was allowed to proceed for 1 hour at 25° C. The complete reaction of the raw material was monitored by LCMS. The reaction mixture was added with water (5 mL), adjusted to pH 8 with saturated sodium bicarbonate, and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by preparative high-performance liquid chromatography (column model: Xbridge Prep Phenyl OBD, 150 × 19 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN + MeOH = 1:1; gradient: 12% to 32%; flow rate: 20 mL / min; run time: 11 min; peak time: 7.9 min) to give compound 8b (18.0 mg, Y: 12%). 1H NMR (400 MHz, DMSO-d6) δ 8.11-8.01 (m, 1H), 7.57 (s, 1H), 7.48-7.42 (m, 2H), 7.38-7.23 (m, 3H), 6.93 (d, J = 10.0 Hz, 1H), 4.99 (t, J = 6.4 Hz, 1H), 4.87 (br, 2H), 4.35-4.25 (m, 2H), 3.82-3.73 (m, 2H), 3.60-3.49 (m, 1H), 3.08-3.02 (m, 1H), 2.78-2.63 (m, 3H), 2.36 (d, J = 4.4 Hz, 3H), 1.52-1.32 (m, 4H). LC-MS m / z (ESI): 527 [M+H] + .

[0270] Example 9 [ka] [ka]

[0271] Step 1: Compound 9-1 (50 g, 227.2 mmol) was dissolved in acetic acid (500 mL). Under nitrogen gas protection, sodium acetate (95 g, 1.135 mol) was added, and the mixture was gradually heated to 110 °C for 13 hours. TLC (PE:EA = 3:1) showed that the starting materials had completely reacted. The reaction solution was cooled to 35 °C and poured into ice water (1 L). The solid precipitated, filtered, and rinsed with water until the pH reached 6. The cake was collected and slurried in petroleum ether (200 mL) for 2 hours. The cake was filtered and dried to give compound 9-2 (27.1 g, 59%). LC-MS m / z (ESI): 202 [M+H] + .

[0272] Step 2: Compound 9-2 (26 g, 129.3 mmol) was dissolved in acetonitrile (300 mL). Under nitrogen gas protection, N-iodosuccinimide (43.4 g, 194.0 mmol) was added in batches. The mixture was heated to 80 °C and reacted for 16 h. LCMS showed that the starting material had completely reacted. The reaction solution was cooled to 25 °C, filtered, and rinsed with water (300 mL) and then with ethyl acetate (30 mL). The cake was collected and dried to give compound 9-3 (27.2 g, Y: 64%). 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 4.26-4.17 (m, 2H), 1.27 (t, J =7.2 Hz, 3H). LC-MS m / z (ESI): 328 [M+H] + .

[0273] Step 3: Compound 9-3 (27 g, 82.5 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (12 g, 82.5 mmol) were dissolved in dichloromethane (270 mL). Under nitrogen gas protection, triphenylphosphine (25.9 g, 99.1 mmol) was added, and diethyl azodicarboxylate (20 g, 99.1 mmol) was added dropwise. The mixture was allowed to react at 35 °C for 1.5 h. LCMS showed that the starting material had completely reacted. The reaction solution was washed with water (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 10:1) to give compound 9-4 (6.4 g, Y: 17%). 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 4.72 (s, 1H), 4.54-4.48 (m, 2H), 4.34-4.28 (m, 2H), 3.97-3.91 (m, 1H), 3.84-3.73 (m, 2H), 3.46-3.40 (m, 1H), 1.71-1.61(m, 2H), 1.52-1.43 (m, 4H), 1.34-1.27 (m, 3H). LC-MS m / z (ESI): 478[M+Na] + .

[0274] Step 4: Compound 9-4 (1 g, 2.2 mol) was dissolved in tetrahydrofuran (10 mL) and, under nitrogen gas protection, triisopropylsilylacetylene (1.2 g, 6.6 mmol), triethylamine (665 mg, 6.6 mmol), cuprous iodide (41.6 mg, 220 μmol), and triphenylphosphinepalladium dichloride (259 mg, 440 μmol) were added sequentially. The temperature was gradually raised to 70 °C and the reaction was allowed to proceed for 2 h. TLC (PE:EA = 8:1) showed complete reaction of the starting materials. The reaction solution was cooled to 35 °C, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 9-5 (680 mg, Y: 61%) was obtained by silica gel column chromatography (PE:EA = 10:1). 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 4.62 (s, 1H), 4.56-4.54 (m, 2H), 4.35-4.28 (m, 2H), 3.96-3.91 (m, 1H), 3.73-3.67 (m, 2H), 3.43-3.38 (m, 1H), 1.68-1.55 (m, 2H), 1.49-1.41 (m, 4H), 1.34-1.28 (m, 3H), 1.18-1.08 (m, 21H).

[0275] Step 5: Compound 9-5 (500 mg, 980 μmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Under nitrogen gas protection, sodium hydroxide (235 mg, 5.88 mmol) was added and the mixture was gradually heated to 50 °C for 3 h. TLC (PE:EA = 5:1) showed that the starting materials had completely reacted. The reaction solution was poured into 2 M glacial hydrochloric acid (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 9-6 (500 mg, crude product).

[0276] Step 6: Compound 9-6 (500 mg, 1.03 mmol) was dissolved in N,N-dimethylformamide (16 mL). Under the protection of nitrogen gas, 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (770 mg, 2.07 mmol), diisopropylethylamine (400 mg, 3.1 mmol), and methylamine hydrochloride (139 mg, 2.07 mmol) were added sequentially. The mixture was reacted at 50 °C for 2 hours. LCMS showed that the starting material had completely reacted. The reaction mixture was cooled to 0°C, poured into 1 M hydrochloric acid (30 mL) to quench the reaction, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 5:1) to give compound 9-7 (380 mg, Y: 91%).

[0277] Step 7: Compound 9-7 (250 mg, 504 μmol) and compound 1-8 (329 mg, 605 μmol) were dissolved in toluene (2 mL) and water (0.4 mL). Under nitrogen gas protection, tris(dibenzylideneacetone)dipalladium (46.2 mg, 50.4 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (58.3 mg, 100 μmol), and potassium phosphate (209 mg, 1.51 mmol) were added sequentially. The temperature was gradually raised to 110 °C and the reaction was continued for 12 hours. TLC (PE:EA = 1:1) showed that the starting materials had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated ammonium chloride (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 1:1) to give compound 9-8 (100 mg, Y: 22%). LC-MS m / z (ESI): 876.1 [M+H] + .

[0278] Step 8: Compound 9-8 (100 mg, 114 μmol) was dissolved in tetrahydrofuran (1 mL) and, under nitrogen gas protection, a solution of tetrabutylammonium fluoride in tetrahydrofuran (208 mg, 798 μmol / 2 mL) was added dropwise. The mixture was allowed to react at 25 °C for 1 hour. TLC (PE:EA = 1:1) showed complete reaction of the starting material. The reaction solution was poured into saturated ammonium chloride (10 mL) to quench the reaction, and ethyl acetate (20 mL x 3) was added for extraction. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 1:1) to give compound 9-9 (80 mg, Y: 97%). LC-MS m / z (ESI): 692.10 [M+H] + .

[0279] Step 9: Compound 9-9 (80 mg, 111 μmol) was dissolved in 2 mL of 20% trifluoroacetic acid in dichloromethane and reacted at 25° C. for 1 hour. TLC (DCM:MeOH=10:1) showed that the starting material had completely reacted. The reaction mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN + MeOH = 1:1; gradient: 53% to 73%; flow rate: 20 mL / min; run time: 11 min; peak time: 9.1 min, 9a and 7.9 min, 9b), and then freeze-dried to give compound 9a (3.3 mg, Y: 5%) and compound 9b (3.6 mg, Y: 6%). 9a: 11H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.20 (m, 1H), 7.48 - 7.24 (m, 6H), 7.09 - 6.96 (m, 1H), 4.91 - 4.85 (m, 1H), 4.48 - 4.35 (m, 2H), 3.97 - 3.85 (m, 1H), 3.78 - 3.72 (m, 2H), 3.52 - 3.46 (m, 1H), 2.95 - 2.90 (m, 1H), 2.75 - 2.56 (m, 4H), 2.06 (s, 1H), 1.55 - 1.20 (m, 4H). LC-MS m / z (ESI): 536 [M+H] + 。 9b: 1 1H NMR (400 MHz, DMSO-d6) δ 8.38 - 8.25 (m, 1H), 7.46 - 7.40 (m, 2H), 7.33 - 7.24 (m, 4H), 7.03 - 6.96 (m, 1H), 4.94 - 4.88 (m, 1H), 4.55 - 4.31 (m, 3H), 4.37 - 4.32 (m, 1H), 3.80 - 3.75 (m, 2H), 3.52 - 3.48 (m, 1H), 3.05 - 2.99 (m, 1H), 2.35 - 2.29 (m, 3H), 2.05 - 1.99 (m, 1H), 1.58 - 1.23 (m, 4H). LC-MS m / z (ESI): 536 [M+H] + 。

[0280] Example 10

Chem.

Chem.

[0281] Step 1: Compound 10-1 (50.0 g, 434 mmol) and ethylene glycol (135 g, 2.17 mol) were dissolved in tetrahydrofuran (500 mL). Potassium tert-butoxide (53.63 g, 478 mmol) was then added in batches. The resulting mixture was stirred at room temperature for 2 h. Water (300 mL) was added for dilution and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 10-2 (48.4 g, crude product). LC-MS m / z (ESI): 158 [M+H] + .

[0282] Step 2: Compound 10-2 (5.00 g, 31.8 mmol) and p-toluenesulfonic acid (6.03 g, 35.0 mmol) were dissolved in tetrahydrofuran (100 mL), and 3,4-dihydro-2H-pyran (5.35 g, 63.6 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 10-3 (9.30 g, crude product). LC-MS m / z (ESI): 242 [M+H] + .

[0283] Step 3: Under nitrogen gas protection, compound 10-3 (7.56 g, 31.3 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL). n-Butyllithium (2.61 g, 40.7 mmol, 2.5 M) was added dropwise at -78 °C and the mixture was allowed to react at 78 °C for 2 h. A solution of hexachloroethane (9.64 g, 40.7 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred at room temperature for 2 h. The mixture was cooled to 0 °C and quenched by the dropwise addition of water (40 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 20:1) to give compound 10-4 (8.05 g, Y: 93%).

[0284] Step 4: Diisopropylamine (2.39 g, 23.6 mmol) was dissolved in anhydrous tetrahydrofuran (45 mL) and n-butyllithium (9.4 mL, 23.6 mmol, 2.5 M) was added dropwise at -75 °C. After completion of the addition, the mixture was allowed to react at -78 °C. A solution of compound 10-4 (5.00 g, 18.1 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise at -78 °C. The mixture was allowed to react for 30 minutes at -78 °C, followed by carbon dioxide gas and the mixture was allowed to react for 1 hour. After completion of the reaction, the reaction was quenched with 1N aqueous hydrochloric acid at 0 °C, the pH was adjusted to 2-3, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 10-5 (4.30 g, Y: 74%).

[0285] Step 5: Compound 10-5 (7.00 g, 21.9 mmol) and diisopropylethylamine (14.2 g, 109 mmol) were dissolved in N,N-dimethylformamide (70 mL), and methylamine hydrochloride (2.96 g, 43.8 mmol) and 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.6 g, 43.8 mmol) were added and the mixture was allowed to react at room temperature for 20 minutes. After the reaction was completed, the mixture was diluted with water (200 mL), the pH was adjusted to 10 with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with 1N hydrochloric acid (100 mL × 3) and saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give compound 10-6 (5.56 g, Y: 76%).

[0286] Step 6: Under nitrogen gas protection, compound 10-7 (15.0 g, 62.2 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0 °C. A solution of borane-dimethyl sulfide in tetrahydrofuran (10 M, 12.5 mL, 124.4 mmol) was added dropwise and the mixture was allowed to react at 25 °C for 16 hours. LCMS showed that the starting material had completely reacted. After cooling to 0 °C, the reaction mixture was quenched by adding methanol (30 mL) dropwise and concentrated under reduced pressure to give a yellow oil. The mixture was diluted with ethyl acetate (150 mL) and washed with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 10-8 (12.4 g, Y: 87%). LC-MS m / z (ESI): 228.3 [M+H] + .

[0287] Step 7: Under nitrogen gas protection, compound 10-8 (12.4 g, 54.5 mmol) was dissolved in dichloromethane (120 mL). Dimethyl sulfoxide (42.5 g, 545 mmol), N,N-diisopropylethylamine (42.2 g, 327 mmol), and sulfur trioxide pyridine complex (34.6 g, 218 mmol) were added in batches. The mixture was allowed to react at 25 °C for 4 h. LCMS analysis showed the starting material had reacted completely. The reaction solution was diluted with dichloromethane (240 mL) and washed with saturated sodium bicarbonate (120 mL), water (120 mL), and saturated brine (120 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 10-9 (10.1 g, Y: 82%). 1 H NMR (400 MHz, DMSO-d6): δ 9.52-9.48 (m, 1H), 4.23-4.17 (m, 1H), 3.33-3.27 (m, 1H), 3.24-3.18 (m, 1H), 2.09-2.06 (m, 1H), 1.86-1.80 (m, 1H), 1.45-1.30 (s, 9H), 0.62-0.42 (m, 4H). LC-MS m / z (ESI): 170.2 [M-tBu+H] + .

[0288] Step 8: Trimethylsulfoxide iodide (11.8 g, 53.7 mmol) was dissolved in dimethylsulfoxide (50 mL) and tetrahydrofuran (50 mL). Sodium hydride (2.1 g, 53.7 mmol, 60%) was added batchwise at room temperature. The mixture was allowed to react at 25 °C for 2 h, cooled to 0 °C, and a solution of compound 10-9 (10.1 g, 44.8 mmol) in tetrahydrofuran (50 mL) was added dropwise. The mixture was gradually heated to 25 °C and allowed to react for 16 h. LCMS analysis showed the starting material had completely reacted. The reaction mixture was quenched with ice water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 10-10 (4.2 g, Y: 39%). LC-MS m / z (ESI): 184.2 [M-tBu+H] + .

[0289] Step 9: 2,4-Difluoro-6-bromoiodobenzene (6.7 g, 21.0 mmol) was dissolved in tetrahydrofuran (42 mL) and cooled to -40 ° C under nitrogen gas protection. Isopropylmagnesium chloride (2 M, 10.5 mL, 21.0 mmol) was added dropwise and reacted at -40 ° C for 1 hour. Cuprous iodide (0.7 g, 3.5 mmol) was added and the temperature was raised to -10 ° C. A solution of compound 10-10 (4.2 g, 17.5 mmol) in tetrahydrofuran (10 mL) was added dropwise. The temperature was raised to 25 ° C. and the reaction was continued for 16 hours. LCMS showed that the raw materials had completely reacted. The reaction was quenched by the addition of saturated ammonium chloride (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:9) to give compound 10-11 (3.5 g, Y: 45%). LC-MS m / z (ESI): 454.1 [M+Na] + .

[0290] Step 10: Compound 10-11 (3.5 g, 8.0 mmol) was dissolved in dichloromethane (35 mL), and Dess-Martin reagent (6.8 g, 16.0 mmol) was added in batches. The mixture was allowed to react at 25 °C for 2 h. TLC (EA:PE = 1:8) indicated complete reaction of the starting materials. The reaction solution was diluted with dichloromethane (70 mL) and washed with saturated sodium bicarbonate (50 mL), water (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 10-12 (2.8 g, Y: 80%).

[0291] Step 11: Compound 10-12 (3.1 g, 7.1 mmol) was dissolved in dichloromethane (28 mL) and n-heptane (28 mL). The mixture was cooled to -40 °C under nitrogen gas protection, and phenylmagnesium bromide (1 M, 14.2 mL, 14.2 mmol) was added dropwise. After the addition was complete, the mixture was gradually heated to 25 °C and reacted for 2 h. LCMS analysis showed that the starting material had completely reacted. The reaction was quenched by adding saturated ammonium chloride (50 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 10-13 (1.4 g, Y: 38%). LC-MS m / z (ESI): 508.2 [M+H] + .

[0292] Step 12: Compound 10-13 (1.4 g, 2.7 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to 0 °C under nitrogen gas protection. Potassium tert-butoxide (0.6 g, 5.4 mmol) was added and the mixture was allowed to react at 0 °C for 1 h. TLC (EA:PE = 1:8) showed the starting materials had reacted completely. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:10) to give compound 10-14 (1.1 g, Y: 81%).

[0293] Step 13: Compound 10-14 (1.1 g, 2.2 mmol) was dissolved in tetrahydrofuran (5 mL) and acetonitrile (10 mL). p-Toluenesulfonic acid (416 mg, 2.4 mmol) and N-chlorosuccinimide (320 mg, 2.4 mmol) were added and the mixture was allowed to react at 25 °C for 1 hour. LCMS analysis showed the starting material had reacted completely. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 1:8) to give compound 10-15 (0.7 g, Y: 59%). 1 H NMR (400 MHz, CDCl3): δ 7.50-7.44 (m, 2H), 7.36-7.26 (m, 3H), 6.68-6.62 (m, 1H), 4.66-4.61 (m, 1H), 4.10-4.05 (m, 1H), 3.45-3.35 (m, 2H), 2.89-2.83 (m, 1H), 2.19-2.13 (m, 1H), 1.74-1.69 (m, 1H), 1.40 (s, 9H), 0.48-0.35 (m, 2H), 0.16-0.06 (m, 2H). LC-MS m / z (ESI): 468.1[M-tBu+H] + .

[0294] Step 14: Compound 10-15 (350 mg, 0.66 mmol) was dissolved in toluene (5 mL), and bis(pinacolato)diboron (184 mg, 0.72 mmol), potassium acetate (129 mg, 1.32 mmol), and 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (51 mg, 0.07 mmol) were added sequentially. The mixture was heated to 100 °C under nitrogen gas protection and reacted for 16 hours. LCMS analysis indicated that the starting materials had reacted completely. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE = 1:7) to give compound 10-16 (290 mg, Y: 75%). LC-MS m / z (ESI): 592.4 [M+Na] + .

[0295] Step 15: Compound 10-16 (260 mg, 0.45 mmol) and compound 10-6 (164 mg, 0.49 mmol) were dissolved in toluene (4 mL), water (0.8 mL), potassium phosphate (191 mg, 0.90 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (52 mg, 0.09 mmol), and tris(dibenzylideneacetone)dipalladium (33 mg, 0.045 mmol) were added, and the mixture was reacted at 100 °C for 16 hours under nitrogen gas protection. LCMS analysis indicated complete reaction of the starting material. After cooling to 25 °C, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE = 1:2) to give compound 10-17 (91 mg, Y: 26%). LC-MS m / z (ESI): 740.4 [M+H] + .

[0296] Step 16: Compound 10-17 (100 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted for 1 hour at 25° C. LCMS showed that the starting material had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (20 mL), and quenched. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC Triart Prep C18-S, 250 x 50 mm, 10 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN + MeOH = 1:1; gradient: 41% to 61%; flow rate: 120 mL / min; run time: 12 min; peak time: 6.8 min, 10a, and 5.7 min, 10b), followed by freeze-drying to give compound 10a (7.5 mg, Y: 9%) and compound 10b (14.4 mg, Y: 19%). 10a: 1 H NMR (400 MHz, DMSO-d6): δ 8.42-8.38 (m, 1H), 8.28 (s, 1H), 7.48-7.42 (m, 2H), 7.37-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.07 (d, J= 10.0 Hz, 1H), 4.96 (t, J =5.6 Hz, 1H), 4.50-4.38 (m, 2H), 3.79-3.68 (m, 3H), 3.51 (d, J =15.2 Hz, 1H), 2.98 (d, J =16.0 Hz, 1H), 2.70-2.60 (m, 6H), 1.59-1.53 (m, 1H), 1.36-1.23 (m, 1H), 0.40-0.25 (m, 4H). LC-MS m / z (ESI): 556.30 [M+H] + 10b: 1H NMR (400 MHz, DMSO-d6): δ 8.44 -8.40 (m, 1H), 8.23 ​​(s, 1H), 7.48-7.41 (m, 2H), 7.35-7.25 (m, 3H), 7.04 (d, J =10.0 Hz, 1H), 4.98 (t, 2.35 (d, J =4.0 Hz, 3H), 1.54-1.47 (m, 1H), 1.32-1.22 (m, 1H), 0.38-0.24 (m, 4H). LC-MS m / z (ESI): 556.30 [M+H] + .

[0297] Example 11 [ka] [ka]

[0298] Step 1: Compound 11-1 (300 g, 1.55 mol) was dissolved in tetrahydrofuran (5000 mL) and cooled to -78 ° C under nitrogen gas protection. Lithium diisopropylamide (855 mL, 2 M) was added dropwise. After the addition was complete, the mixture was reacted at -78 ° C for 2 hours. Trimethylsilyl chloride (203.3 g, 1.86 mol) was added dropwise at -78 ° C. The mixture was reacted for 1 hour while maintaining the temperature at -78 ° C. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure, and n-hexane (500 mL) was added. The mixture was then filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 11-2 (370.0 g, Y: 90%). LC-MS m / z (ESI): 282 [M+H] + .

[0299] Step 2: Compound 11-2 (370 g, 1.40 mol) was dissolved in tetrahydrofuran (5000 mL) and cooled to −78° C. under nitrogen gas protection. Lithium diisopropylamide (840 mL, 2 M) was added dropwise. After the addition was completed, the reaction was continued at −78° C. for 1 hour. Next, N,N-dimethylformamide (204.4 g, 2.80 mol) was dissolved in tetrahydrofuran (500 mL) and added dropwise to the reaction system. The reaction was continued at −78° C. for 1 hour. TLC (PE:EA=12:1) showed After the raw materials were completely reacted, the mixture was cooled to room temperature, and a solution of acetic acid (300 mL) / water (1400 mL) was added dropwise. The mixture was then stirred at room temperature for 1 hour and extracted with an organic solution (EA / PE = 1 / 10, 1000 mL x 2). The combined organic phases were washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 1:20) to obtain compound 11-3 (287.0 g, Y: 70%). 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.65-7.55 (m, 1H), 0.46-0.26 (m, 1H).

[0300] Step 3: Compound 11-3 (287.0 g, 0.98 mol) was dissolved in benzyl alcohol (480 mL), and sodium benzyl alcohol solution (1.07 mol, dissolved in 1000 mL of benzyl alcohol) was added dropwise. After the addition was complete, the mixture was heated to 40 °C and stirred for 15 minutes. After the reaction was complete, saturated ammonium chloride solution (1000 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (1000 mL × 2). The combined organic phase was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 11-4 (65.5 g, Y: 21%) was obtained by reverse-phase purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.54-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.39-7.30 (m, 3H), 5.29 (s, 1H).

[0301] Step 4: Compound 11-4 (65.5 g, 212.7 mmol) was dissolved in acetonitrile (500 mL). Under nitrogen gas protection, N-chlorosuccinimide (33.9 g, 255.2 mmol) and p-toluenesulfonic acid (54.9 g, 319.1 mmol) were added and the mixture was reacted at 25 °C for 16 hours. After the reaction, the mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (500 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 1:20) to give compound 11-5 (51.5 g, Y: 71%). 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.47-7.36 (m, 2H), 6.89-6.75 (m, 1H), 5.16(s, 2H).

[0302] Step 5: Compound 11-5 (51.0 g, 149.1 mmol) was dissolved in dichloromethane (800 mL) and cooled to -78 °C under nitrogen gas protection. A solution of boron tribromide (41.2 g, 164.1 mmol) in dichloromethane (200 mL) was added dropwise and reacted at -78 °C for 2 hours. After the reaction was completed, methanol (150 mL) was added dropwise to quench the reaction. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE = 1:10) to give compound 11-6 (22.3 g, Y: 59%).

[0303] Step 6: Compound 11-6 (20.0 g, 78.9 mmol) was dissolved in acetonitrile (400 mL). Under nitrogen gas protection, diisopropylethylamine (20.4 g, 157.8 mmol) and methyl bromophenylacetate (21.7 g, 94.7 mmol) were added sequentially. The temperature was gradually raised to 85 °C and the reaction was continued for 16 hours. TLC (PE:EA = 20:1) showed that the starting materials had completely reacted. The mixture was then directly concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE = 1:16) to give compound 11-7 (27.0 g, Y: 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.68-7.62 (m, 1H), 7.55-7.50 (m, 1H), 7.46-7.37 (m, 4H), 6.92 (d, J = 7.2 Hz, 0.5H), 6.11 (d, J = 8.8 Hz, 0.5H), 5.58 (d, J = 8.8 Hz, 0.5H), 5.41 (d, J = 7.6 Hz, 0.5H), 3.75-3.64 (m, 3H).

[0304] Step 7: Compound 11-7 (27.0 g, 67.5 mmol) was dissolved in dichloromethane (300 mL) and cooled to 0 °C under nitrogen gas protection. Triethylsilane (39.2 g, 337.5 mmol) and boron trifluoride diethyl etherate (32.1 g, 135.0 mmol) were added dropwise to the reaction mixture, which was then heated to 25 °C and reacted for 16 hours. After completion of the reaction, the mixture was poured into saturated sodium bicarbonate solution and extracted with dichloromethane (200 mL × 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow solid (20.8 g) was purified by silica gel column chromatography (EA:PE = 1:20). Chiral separation (chiral column model: Chiralpak AD-3100 × 3.0 mm, 3.0 μm, solvent: isopropanol, flow rate: 2.0 ml / min, t1 = 1.01 min, t2 = 0.87 min) gave compound 11-8 (10.1 g, t1 = 1.01 min, Y: 38%). 1 H NMR (400 MHz, DMSO-d6) δ 7.57-7.51 (m, 2H), 7.43-7.35 (m, 3H), 6.83 (d, J = 8.8 Hz, 1H), 4.22-4.15 (m, 1H), 3.77 (s, 3H), 3.58-3.51 (m, 1H).

[0305] Step 8: Compound 11-8 (1.9 g, 4.9 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium hydroxide (0.24 g, 9.8 mmol) dissolved in water (15 mL) was added dropwise to the reaction mixture. The mixture was then reacted under nitrogen gas protection at 25 °C for 16 h. LCMS analysis indicated complete reaction of the starting material. The pH was adjusted to 5-6 by adding aqueous hydrochloric acid (30 mL, 1 M) dropwise in an ice bath, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 11-9 (1.5 g, Y: 83%). LC-MS m / z (ESI): 369 [MH] + .

[0306] Step 9: Compound 11-9 (1.5 g, 4.1 mmol), diisopropylethylamine (2.6 g, 20.1 mmol), and methoxymethylamine hydrochloride (0.79 g, 8.2 mmol) were dissolved in N,N-dimethylformamide (30 mL). 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.1 g, 5.3 mmol) was added and the mixture was allowed to react at room temperature for 3 hours. LCMS analysis indicated complete reaction of the starting material. Extraction with ethyl acetate (20 mL x 3) was performed. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:8) to give compound 11-10 (1.5 g, Y: 93%). LC-MS m / z (ESI): 414 [M+H] + .

[0307] Step 10: Compound 11-10 (1.3 g, 3.14 mmol) was dissolved in tetrahydrofuran (40 mL) and methylmagnesium bromide (6.3 mL, 1 M) was added dropwise at 0 °C. The mixture was stirred for 2 hours at 0 °C. TLC (PE:EA = 8:1) showed complete reaction of the starting material. The reaction solution was poured into saturated ammonium chloride solution (100 mL) to quench the reaction. Ethyl acetate (20 mL x 3) was added and extracted. The combined organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:12) to give compound 11-11 (0.9 g, Y: 77%). LC-MS m / z (ESI): 371 [M+H] + .

[0308] Step 11: Compound 11-11 (800 mg, 2.16 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (30 mL) and stirred at 80 °C for 16 hours under nitrogen gas protection. After the reaction was completed, the mixture was cooled to 20 °C, poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 11-12 (820 mg, crude product). LC-MS m / z (ESI): 424 [M+H] + .

[0309] Step 12: Compound 11-12 (820 mg, 1.93 mmol) was dissolved in hydrazine hydrate (40 mL) and stirred at 60 °C for 4 hours. LCMS showed the starting material had completely reacted. The reaction solution was poured into HO (100 mL) to quench the reaction, and ethyl acetate (50 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:8) to give compound 11-13 (420 mg, Y: 52%). LC-MS m / z (ESI): 394 [M+H] + .

[0310] Step 13: Compound 11-13 (520 mg, 1.32 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0 °C. Sodium bicarbonate (110 mg, 60%, 2.65 mmol) was added and stirred for 30 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (300 mg, 1.76 mmol) was dissolved in tetrahydrofuran (3 mL) and added dropwise to the reaction system for 2 hours. After the reaction was complete, the reaction solution was poured into water (50 mL) to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:15) to give compound 11-14 (410 mg, Y: 59%). LC-MS m / z (ESI): 523 [M+H] + .

[0311] Step 14: Compound 11-14 (390 mg, 744 μmol) was dissolved in toluene (10 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (62.6 mg, 74.5 μmol), bis(pinacolato)diboron (567 mg, 2.3 mmol), and potassium acetate (146 mg, 1.5 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 16 hours. LCMS showed that the starting materials had completely reacted. The mixture was cooled to 25 °C, directly concentrated under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:20) to give compound 11-15 (350 mg, Y: 82%). LC-MS m / z (ESI): 572 [M+H] + .

[0312] Step 15: Compound 11-15 (300 mg, 525 μmol) and compound 10-6 (175 mg, 525 μmol) were dissolved in toluene (2 mL) and water (0.4 mL). Under the protection of nitrogen gas, tris(dibenzylideneacetone)dipalladium (96.2 mg, 105 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (116 mg, 210 μmol), and potassium carbonate (218 mg, 1.58 mmol) were added sequentially. The temperature was raised to 120°C and the reaction was continued for 16 hours. LCMS showed that the raw materials had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated ammonium chloride (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:8) to give compound 11-16 (105 mg, Y: 26%). LC-MS m / z (ESI): 763.2 [M+Na] + .

[0313] Step 16: Compounds 11-16 (105 mg, 240 μmol) were dissolved in 2 mL of 20% trifluoroacetic acid in dichloromethane and reacted at 25° C. for 0.5 h. TLC (DCM:MeOH=10:1) showed that the starting materials had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH3.H2O / CH3CN; gradient: 37% to 57%; flow rate: 20 mL / min; run time: 12 min; peak time: 8.2 min, 11a and 6.7 min, 11b) to give compound 11a (8.2 mg, Y: 11%) and compound 11b (6.0 mg, Y: 8%). 11a: 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.4 Hz, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.33-7.15 (m, 6H), 6.11 (s, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4.46-4.39 (m, 2H), 4.15 (d, J = 16.0 Hz, 1H), 3.81-3.73 (m, 2H), 3.20-3.14 (m, 1H), 2.66-2.62 (m, 3H). LC-MS m / z (ESI): 527.1 [M+H] + 11b: 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 4.8 Hz, 1H), 8.22 (s, 1H), 7.69 (s, 1H), 7.35-7.14 (m, 6H), 6.08 (s, 1H), 4.99 (t, J = 5.2 Hz, 1H), 4.49-4.43 (m, 2H), 4.08 (d, J = 16.0 Hz, 1H), 3.83-3.76 (m, 2H), 3.31-3.24 (m, 1H), 2.40-2.31 (m, 3H). LC-MS m / z (ESI): 527.1 [M+H] + .

[0314] Example 12

change

change

[0315] Step 1: Compound 1-6 (12.0 g, 26 mmol) was dissolved in acetonitrile / tetrahydrofuran (100 mL / 50 mL), p-toluenesulfonic acid (4.5 g, 26 mmol) was added, and N-iodosuccinimide (7.6 g, 33.8 mmol) was added in batches. The reaction was allowed to proceed at room temperature for 12 hours. TLC (PE:EA = 15:1) showed the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 6-7. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 15:1) to obtain compound 12-1 (9.7 g, crude product).

[0316] Step 2: Compound 12-1 (9.7 g, 16.5 mmol) was dissolved in dimethyl sulfoxide (100 mL), cuprous cyanide (2.9 g, 33 mmol) was added, and the mixture was heated to 90 °C and reacted for 12 h. TLC (PE:EA = 5:1) showed the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (200 mL) to precipitate a solid. The solid was collected and purified by silica gel column chromatography (EA:PE = 1:5) to give compound 12-2 (7.7 g, crude product). LC-MS m / z (ESI): 486 [M+H] + .

[0317] Step 3: Compound 12-2 (500 mg, 1.0 mmol) was dissolved in tetrahydrofuran (15 mL). Under nitrogen gas protection, the reaction mixture was cooled to -78 °C, n-butyllithium (2.5 mol / L, 0.62 mL, 1.5 mmol) was added dropwise, and the mixture was allowed to react at -78 °C for 30 min. Isopropoxyboronic acid pinacol ester (287 mg, 1.5 mmol) was added, and the mixture was gradually warmed to room temperature and reacted for 2 h. The mixture was quenched by the dropwise addition of saturated aqueous ammonium chloride (50 mL). The organic phase was collected, concentrated under reduced pressure, and purified by reverse phase chromatography to give compound 12-3 (240 mg, Y: 48%).

[0318] Step 4: Compound 12-3 (240 mg, 0.45 mmol) was dissolved in toluene (3 mL) and water (0.6 mL). Compound 10-6 (164 mg, 0.49 mmol), cesium fluoride (203.6 mg, 1.35 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (52 mg, 0.09 mmol), and tris(dibenzylideneacetone)dipalladium (41 mg, 0.045 mmol) were added sequentially. The mixture was then reacted at 100 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by preparative silica gel plate (EA:PE = 1:1) to give compound 12-4a (20 mg, Y: 8%, Rf = 0.3) and compound 12-4b (30 mg, Y: 12%, Rf = 0.35). LC-MS m / z (ESI): 705.3 [M+H] + .

[0319] Step 5: Compound 12-4a (20 mg, 0.028 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added at 5 °C. The mixture was allowed to react for 1 h. TLC (PE:EA = 1:1) showed the starting material had completely reacted. After concentration under reduced pressure, the mixture was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 × 20 mm, 5 μm; eluent: 10 mmol / L NH4HCO3 / CH3CN; gradient: 62% to 82%; flow rate: 20 mL / min; run time: 10 min; peak time: 7.5 min) to give compound 12a (6.7 mg, Y: 45%). 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 4.0 Hz, 1H), 8.35 (s, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.33-7.26 (m, 5H), 4.96 (t, J = 5.2 Hz, 1H), 4.51-4.45 (m, 2H), 3.80-3.70 (m, 3H), 3.42-3.33 (m, 2H), 2.77-2.66 (m, 5H), 1.52-1.23 (m, 4H). LC-MS m / z (ESI): 521.3 [M+H] + .

[0320] Step 6: Compound 12-4b (30 mg, 0.043 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added at 5 °C. The mixture was allowed to react for 1 h. TLC (PE:EA = 1:1) showed the starting material had reacted completely. After concentration under reduced pressure, the mixture was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 × 20 mm, 5 μm; eluent: 10 mmol / L NH4HCO3 / CH3CN; gradient: 62% to 82%; flow rate: 20 mL / min; run time: 11 min; peak time: 7.9 min) to give compound 12b (10.5 mg, Y: 47%). 1 H NMR (400 MHz, DMSO-d6) δ 8.62-8.56 (m, 1H), 8.34 (s, 1H), 7.73 (d, J = 6.4 Hz, 1H), 7.37-7.26 (m, 5H), 4.95 (t, J = 5.2 Hz, 1H), 4.51-4.46 (m, 2H), 3.83-3.76 (m, 2H), 3.71 (d, J = 16.0 Hz, 1H), 3.46-3.38 (m, 2H), 2.73-2.58 (m, 2H), 2.46 (d, J = 4.4 Hz), 1.42-1.33 (m, 4H). LC-MS m / z (ESI): 521.3 [M+H] + .

[0321] Example 13 [ka] [ka]

[0322] Step 1: Compound 11-8 (1 g, 2.81 mmol) was dissolved in methanol (10 mL) and cooled to 0 °C under nitrogen gas protection. Sodium borohydride (531 mg, 14.0 mmol) was added in batches and the mixture was allowed to react at 0 °C for 2 h. TLC (PE:EA = 10:1) showed that the starting materials had reacted completely. The reaction solution was poured into saturated ammonium chloride (20 mL) at 0 °C to quench the reaction. Ethyl acetate (30 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 13-1 (800 mg, crude product).

[0323] Step 2: Compound 13-1 (800 mg, 2.2 mmol) was dissolved in toluene (10 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (160 mg, 223 μmol), bis(pinacolato)diboron (1.14 g, 4.5 mmol), and potassium acetate (660 mg, 6.7 mmol) were added sequentially. The mixture was heated to 90 °C and reacted for 16 h. LCMS showed that the starting materials had completely reacted. The mixture was cooled to 25 °C and directly concentrated under reduced pressure. After purification by silica gel column chromatography (EA:PE = 1:20), compound 13-2 (400 mg, Y: 44%) was obtained. LC-MS m / z (ESI): 405 [M+H] + .

[0324] Step 3: Compound 2-7 (1.3 g, 7.42 mmol) was dissolved in tetrahydrofuran (13 mL) and cooled to -70 °C under nitrogen gas protection. Lithium diisopropylamide (2 M, 4.5 mL) was added dropwise and stirred at -70 °C for 30 minutes. 1,2-Dibromotetrachloroethane (3.2 g, 8.9 mmol) was then added. The dry ice bath was removed, and the temperature was allowed to return to 25 °C. The reaction was allowed to proceed for 1 hour. TLC (PE:EA = 20:1) indicated complete reaction of the starting materials. The reaction solution was poured into saturated ammonium chloride (20 mL) at 0 °C to quench the reaction. Ethyl acetate (30 mL x 3) was added for extraction. The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (EA:PE = 1:10) afforded compound 13-3 (1.5 g, Y: 79%). 1 H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 5.03-4.96 (m, 1H), 2.87-2.80 (m, 1H), 1.32-1.25 (m, 1H), 0.51-0.45 (m, 1H).

[0325] Step 4: Compound 13-3 (1.5 g, 5.9 mmol) was dissolved in a mixture of ethanol (10 mL) and water (10 mL). Under nitrogen gas protection, sodium hydroxide (1.4 g, 35.4 mmol) was added and the mixture was gradually heated to 110 °C for 40 h. LCMS showed that the starting material had completely reacted. After cooling to 0 °C, the reaction solution was poured into 1 M hydrochloric acid (30 mL) to quench the reaction. Ethyl acetate (50 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 13-4 (1.6 g, crude product). LC-MS m / z (ESI): 271 [MH] + .

[0326] Step 5: Compound 13-4 (1.6 g, 5.86 mmol) was dissolved in N,N-dimethylformamide (16 mL). Under the protection of nitrogen gas, 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.4 g, 11.7 mmol), diisopropylethylamine (2.2 g, 17.5 mmol), and methylamine hydrochloride (791 mg, 11.7 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 hours. LCMS showed that the starting material had completely reacted. The reaction mixture was cooled to 0°C, poured into 1M hydrochloric acid (30 mL) to quench the reaction, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:5) to give compound 13-5 (1.3 g, Y: 77%). LC-MS m / z (ESI): 285.9 [M+H] + .

[0327] Step 6: Compound 13-5 (200 mg, 699 μmol) and compound 13-2 (339 mg, 838 μmol) were dissolved in toluene (2 mL) and water (0.4 mL). Under nitrogen gas protection, tris(dibenzylideneacetone)dipalladium (63.9 mg, 69.9 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (80.8 mg, 139 μmol), and potassium phosphate (444 mg, 2.1 mmol) were added sequentially. The temperature was gradually raised to 110 °C and the reaction was continued for 12 h. TLC (PE:EA = 1:1) showed that the starting materials had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated ammonium chloride (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 2:1) to give compound 13-6 (200 mg, Y: 59%). LC-MS m / z (ESI): 484 [M+H] + .

[0328] Step 7: Oxalyl chloride (43.5 mg, 321 μmol) was dissolved in dichloromethane (1 mL) and cooled to −70° C. under nitrogen gas protection and stirred for 30 min. Dimethyl sulfoxide (53 mg, 650 μmol) was added and stirred at −70° C. for 30 min. Compound 13-6 (110 mg, 228 μmol) and triethylamine (135 mg, 1.20 mmol) were added sequentially and stirred for 30 min. The temperature was gradually raised to 25° C. The reaction solution was poured into saturated ammonium chloride (10 mL) to quench the reaction. Ethyl acetate (20 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 13-7 (100 mg, crude product).

[0329] Step 8: Compound 13-7 (100 mg, 206 μmol) was dissolved in dichloroethane (1 mL). Under nitrogen gas protection, trans-4-aminocyclohexanol (47.8 mg, 414 μmol) and acetic acid (1.2 mg, 20.6 μmol) were added sequentially and stirred at 85°C for 30 minutes. Sodium triacetoxyborohydride (7.84 mg, 207 μmol) was then added and stirred for 30 minutes. The mixture was gradually cooled to 25°C, and the reaction solution was poured into saturated sodium bicarbonate (5 mL) to quench the reaction. Ethyl acetate (5 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was then purified by preparative high-performance liquid chromatography (column model: Xselect CSH Prep). Fluoro-Phenyl, 150 × 19 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN + MeOH = 1:1; gradient: 17% to 37%; flow rate: 20 mL / min; run time: 11 min; peak times: 7.5 min, 13b and 6.1 min, 13a) to give compound 13a (10 mg, Y: 8%) and compound 13b (4 mg, Y: 3%). 13a: 1H NMR (400 MHz, DMSO-d6) δ 8.28-8.18 (m, 1H), 7.45-7.20 (m, 5H), 7.10-6.90 (m, 2H), 5.16-5.10 (m, 1H), 4.42 (s, 1H), 3.50-3.46 (m, 2H), 2.96-2.72 (m, 4H), 2.60 (d, J = 4.5 Hz, 3H), 2.25-2.17 (m, 1H), 1.78-1.62 (m, 4H), 1.30-0.85 (m, 5H), 0.40-0.30 (m, 1H). LC-MS m / z (ESI): 581.2 [M+H] + 13b: 1 H NMR (400 MHz, DMSO-d6) δ 8.15-8.03 (m, 1H), 7.50-7.28 (m, 5H), 7.12-6.85 (m, 2H), 5.20-5.14 (m, 1H), 3.50-3.36 (m, 2H), 3.05-2.82 (m, 4H), 2.12-1.98 (m, 4H), 1.82-1.68 (m, 3H), 1.40-0.80 (m, 5H), 0.42-0.25 (m, 1H). LC-MS m / z (ESI): 581.2 [M+H] + .

[0330] Example 14

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[0331] Step 1: Compound 13-7 (70 mg, 145 μmol) was dissolved in dichloroethane (1 mL). Under nitrogen gas protection, trans-4-amino-1-methylcyclohexanol (129 mg, 290 μmol) and acetic acid (0.8 mg, 14.5 μmol) were added sequentially and stirred at 85°C for 30 minutes. Sodium triacetoxyborohydride (10.9 mg, 290 μmol) was then added and stirred for 30 minutes. The mixture was gradually cooled to 25°C. The reaction solution was poured into saturated sodium bicarbonate (5 mL) to quench the reaction. Ethyl acetate (5 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was then purified by preparative high-performance liquid chromatography (column model: Xselect CSH Prep). Purification by Fluoro-Phenyl, 150 × 19 mm, 5 μm; eluent: 0.05% FA / CHCN; gradient: 39% to 59%; flow rate: 20 mL / min; run time: 10 min; peak time: 8.0 min) gave compound 14a (7 mg, Y: 8%). 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.13 (s, 1H), 7.48-7.26 (m, 6H), 7.10-7.00 (m, 1H), 6.95 (s, 1H), 5.17-5.11 (m, 1H), 4.10 (s, 1H), 3.53-3.45 (m, 2H), 3.03-2.93 (m, 2H), 2.88-2.80 (m, 3H), 2.58 (d, J = 4.6 Hz, 3H), 1.70-1.60 (m, 2H), 1.45-1.35 (m, 2H), 1.30-1.10 (m, 5H), 1.08-0.90 (m, 3H), 0.38-0.32 (m, 1H). LC-MS m / z (ESI): 595.2 [M+H] + .

[0332] Step 2: Compound 14a (24 mg, 40.3 μmol) was subjected to chiral separation (chiral column model: Cellulose-SB; eluent: carbon dioxide / (methanol + 20 mM NH3); gradient: 10%; flow rate: 3.0 mL / min; run time: 4 min) to give compound 14a1 (7.0 mg, Y: 29%, RT = 1.89 min) and compound 14a2 (5.0 mg, Y: 20%, RT = 2.12 min). 14a1: LC-MS m / z (ESI): 595.3 [M+H] + . 14a2:LC-MS m / z (ESI): 595.3[M+H] + .

[0333] Example 15 [ka] [ka]

[0334] Step 1: Compound 3-5 (500 mg, 2.29 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to -70 °C under nitrogen gas protection. Lithium diisopropylamide (1 M, 2.75 mL, 2.75 mmol) was added dropwise. After the addition was complete, the reaction was continued at -70 °C for 0.5 hours. A solution of 1,2-dibromotetrachloroethane (903 mg, 3.44 mmol) in tetrahydrofuran (2 mL) was added dropwise and the reaction was continued at -70 °C for 0.5 hours. The temperature was gradually raised to 25 °C and the reaction was continued for 2 hours. The complete reaction of the raw materials was monitored by LCMS. The reaction mixture was cooled to 0°C, quenched by the addition of saturated ammonium chloride (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (PE:EA = 4:1) to give compound 15-1 (550 mg, Y: 73%). LC-MS m / z (ESI): 297 [M+H] + .

[0335] Step 2: Compound 15-1 (500 mg, 1.68 mmol) was dissolved in ethanol (5 mL) and water (5 mL), and sodium hydroxide (673 mg, 16.8 mmol) was added. The mixture was then reacted at 100°C for 16 hours. LCMS confirmed the complete reaction of the starting material. The reaction solution was cooled to 25°C, water (10 mL) was added, and the pH was adjusted to 5 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 15-2 (450 mg, crude product). LC-MS m / z (ESI): 316 [M+H] + .

[0336] Step 3: Compound 15-2 (430 mg, 1.3 mmol) was dissolved in dichloromethane (10 mL). Methylamine hydrochloride (185 mg, 2.7 mmol), diisopropylethylamine (1.2 g, 9.5 mmol), and 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (734 mg, 1.9 mmol) were added sequentially and the mixture was allowed to react at 25 °C for 1 h. The reaction mixture was monitored by LCMS for complete reaction. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 2:1) to give compound 15-3 (400 mg, Y: 89%). 1 H NMR (400 MHz, DMSO-d6) δ 8.17-8.12 (m, 1H), 6.78-6.73 (m, 1H), 4.42-4.36 (m, 1H), 3.85-3.77 (m, 1H), 3.20-3.12 (m, 1H), 2.75-2.65 (m, 5H), 2.18-2.04 (m, 1H), 1.95-1.79 (m, 2H), 1.60-1.45 (m, 1H).

[0337] Step 4: Compound 15-3 (192 mg, 0.58 mmol) and compound 10-16 (350 mg, 0.61 mmol) were dissolved in toluene (5 mL) and water (1 mL). Tris(dibenzylideneacetone)dipalladium (107 mg, 0.12 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (135 mg, 0.23 mmol), and potassium phosphate (372 mg, 1.75 mmol) were added under nitrogen gas protection. The reaction was carried out at 100 °C for 24 hours under nitrogen gas protection. LCMS showed that the starting materials had completely reacted. The reaction mixture was cooled to 25°C, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (PE:EA = 3:1) to give compound 15-4 (120 mg, 29%). LC-MS m / z (ESI): 692 [M+H] + .

[0338] Step 5: Compound 15-4 (138 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at 25° C. for 1 hour. LCMS was used to monitor the complete reaction of the raw materials. Water (5 mL) was added to the reaction solution, the pH was adjusted to 8 with saturated sodium bicarbonate, and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was then purified by preparative high-performance liquid chromatography (column model: Xbridge Prep Phenyl OBD, 150 × 19 mm, 5 μm; eluent: 0.05% NH 3 .H 2 O + 10 mmol / L NH 4 HCO 3 / CH 3 CN + MeOH = 1:1; gradient: 12% to 32%; flow rate: 20 mL / min; run time: 11 min; peak time: 7.9 min, 15a and 6.7 min, 15b). 15a: 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.49-7.22 (m, 5H), 7.04-6.91 (m, 2H), 4.50-4.38 (m, 1H), 3.76-3.68 (m, 2H), 3.54-3.36 (m, 3H), 3.22-3.06 (m, 1H), 3.00-2.81 (m, 1H), 2.70-2.62 (m, 2H), 2.62-2.57 (m, 3H), 2.20-1.75 (m, 3H), 1.68-1.25 (m, 4H), 0.45-0.20 (m, 4H). LC-MS m / z (ESI): 592 [M+H] + 15b: 1 H NMR (400 MHz, DMSO-d6) δ 8.02-7.90 (m, 1H), 7.50-7.40 (m, 2H), 7.38-7.20 (m, 3H), 7.05-6.85 (m, 2H), 4.50-4.32 (m, 1H), 3.90-3.65 (m,2H), 3.51-3.36 (m, 3H), 3.27-3.00 (m, 2H), 2.77-2.57 (m, 2H), 2.35-2.20 (m, 3H), 2.20-2.06 (m, 1H), 2.09-1.82 (m, 2H), 1.65-1.20 (m, 4H), 0.47-0.20 (m, 4H). LC-MS m / z (ESI): 592 [M+H] + .

[0339] Example 16

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[0340] Step 1: Compound 13-5 (100 mg, 0.35 mmol), compound 10-16 (338 mg, 0.59 mmol), tris(dibenzylideneacetone)dipalladium (64 mg, 0.07 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (81 mg, 0.14 mmol), and potassium carbonate (145 mg, 1.05 mmol) were dissolved in toluene (5 mL) and water (1 mL) and reacted at 120 °C for 12 h under nitrogen gas protection. Completion of the reaction was monitored by LCMS. 5 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 7:3) to give compound 16-1 (50 mg, Y: 22%). LC-MS m / z (ESI): 649 [M+H] + .

[0341] Step 2: Compound 16-1 (95 mg, 0.15 mmol), dichloromethane (5 mL), and trifluoroacetic acid (1 mL) were reacted at room temperature for 1 hour. Completion of the reaction was monitored by LCMS. 5 mL of water was added to the reaction solution, the pH was adjusted to 8 with saturated sodium bicarbonate, and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL). Anhydrous sodium sulfate was added to the organic phase for drying, and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (column model: Xselect CSH Prep Fluoro-Phenyl, 150 × 19 mm, 5 μm; eluent: 0.05% FA / CH3CN; gradient: 48% to 68%; flow rate: 20 mL / min; run time: 12 min; peak time: 7.9 min, 16a and 6.9 min, 16b). 16a: 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.08 (m, 1H), 7.48-7.40 (m, 2H), 7.38-7.22 (m, 3H), 7.06-6.96 (m, 2H), 5.20-5.13 (m, 1H), 3.79-3.72 (m,1H), 3.53-3.45 (m, 1H), 2.95-2.85 (m, 2H), 2.70-2.60 (m, 2H), 2.60-2.54 (m, 3H), 1.61-1.52 (m, 1H), 1.43-1.20 (m, 2H), 0.40-0.28 (m, 5H). LC-MS m / z (ESI): 549 [M+H] + 16b: 1 H NMR (400 MHz, DMSO-d6) δ 8.16-8.08 (m, 1H), 7.50-7.28 (m, 5H), 7.10-6.90 (m, 2H), 5.18-5.16 (m, 1H), 3.50-3.32 (m,3H), 3.17-3.06 (m, 1H), 2.95-2.61 (m, 4H), 2.29-2.15 (m, 3H), 1.80-1.07 (m, 3H), 0.58-0.30 (m, 5H). LC-MS m / z (ESI): 549 [M+H] + .

[0342] Example 17

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[0343] Step 1: Compound 17-1 (200 g, 913.21 mmol) was dissolved in acetonitrile (3 L) and potassium carbonate (252.40 g, 1.83 mol) was added in batches at room temperature. After the addition was complete, 1,2-dibromoethane (856 g, 4.56 mol) was slowly added dropwise and the mixture was reacted at 80 °C for 12 h. TLC (PE:EA = 10:1) showed that the starting materials had reacted completely. The reaction solution was cooled to room temperature, filtered with suction, and the cake was washed with acetonitrile (300 mL × 3). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:10) to give compound 17-2 (201.4 g, Y: 67%). LC-MS m / z (ESI): 325.0, 327.0 [M+1] + .

[0344] Step 2: Compound 17-2 (110 g, 337.47 mmol) was dissolved in tetrahydrofuran (1.5 L) and cooled to -30 °C. A solution of potassium tert-butoxide (676.90 mL, 674.94 mmol) in tetrahydrofuran was slowly added dropwise and reacted at -30 °C for 2 hours. TLC (PE:EA = 10:1) showed complete reaction of the starting material. The reaction was quenched at -30 °C with saturated aqueous ammonium chloride (400 mL). 3 portions of ethyl acetate (500 mL each) were added for extraction. The combined organic phase was washed with saturated brine (100 mL each). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 17-3 (95.2 g, crude product). LC-MS m / z (ESI): 246.1 [M+H] + .

[0345] Step 3: Compound 17-3 (95.2 g, 388.5 mmol) was dissolved in tetrahydrofuran (1 L) and p-toluenesulfonylhydrazide (72.3 g, 388.50 mmol) was added in batches. The reaction was allowed to proceed at 70 °C for 12 hours. TLC (PE:EA = 1:1) showed complete reaction of the starting materials. The reaction solution was cooled to room temperature, and saturated ammonium chloride (400 mL) was added dropwise to quench the reaction. Ethyl acetate (400 mL x 3) was added for extraction. The combined organic phase was washed with saturated brine (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:1) to give compound 17-4 (59.0 g, Y: 36%). LC-MS m / z (ESI): 415.1 [M+H] + .

[0346] Step 4: Compound 17-4 (47.5 g, 114.9 mmol) was dissolved in toluene (500 mL), sodium bicarbonate (5.07 g, 211.25 mmol) was added in a batchwise manner, and the mixture was stirred for 5 min. Rhodium(II) acetate dimer (1.53 g, 3.45 mmol) was added and the mixture was reacted at 100 °C for 12 h. TLC (PE:EA = 20:1) showed complete reaction of the starting materials. The reaction mixture was cooled to room temperature, quenched by the dropwise addition of water (200 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with saturated brine (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:20) to give compound 17-5 (18.50 g, Y: 70%).

[0347] Step 5: Compound 17-5 (18.50 g, 80.77 mmol) and zinc cyanide (5.69 g, 48.46 mmol) were dissolved in N,N-dimethylacetamide (200 mL). Under nitrogen gas protection, tris(dibenzylideneacetone)dipalladium (1.67 g, 1.62 mmol), 1,1'-bis(diphenylphosphine)ferrocene (1.80 g, 3.23 mmol), and zinc powder (0.53 g, 8.08 mmol) were added sequentially. The temperature was gradually raised to 120 °C. After reacting for 1 hour, TLC (PE:EA=10:1) showed that the starting materials had completely reacted. The mixture was cooled to room temperature, water (200 mL) was added to quench the reaction, and ethyl acetate (300 mL x 3) was added for extraction. The combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE=1:10) to obtain compound 17-6 (11.00 g, Y: 77%). 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 1.6 Hz, 1H), 7.22-7.19 (m, 1H), 5.05-5.02 (m, 1H), 2.72-2.67 (m, 1H), 1.23-1.18 (m, 1H), 0.46-0.42 (m, 1H).

[0348] Step 6: Compound 17-6 (11.00 g, 62.80 mmol) was dissolved in tetrahydrofuran (110 mL) and cooled to -70 °C. Lithium diisopropylamide (34.57 mL, 69.08 mmol) was slowly added dropwise. After stirring at -70 °C for 0.5 hours, 1,2-dibromotetrachloroethane (19.80 g, 75.36 mmol) was added in batches. After the addition was complete, the reaction was continued from -70 °C to room temperature for 2 hours. TLC (PE:EA = 5:1) showed that the raw materials had completely reacted. The reaction mixture was quenched by adding saturated ammonium chloride (100 mL), extracted with ethyl acetate (200 mL × 3), and the combined organic phase was washed with saturated brine (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (EA:PE = 1:5) to give compound 17-7 (9.30 g, Y: 48%). 1 H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 5.06-5.00 (m, 1H), 2.73-2.66 (m, 1H), 1.24-1.17 (m, 1H), 0.47-0.41 (m, 1H).

[0349] Step 7: Compound 17-7 (6.15 g, 24.21 mmol) was dissolved in ethanol (70 mL), and sodium hydroxide (4.84 g, 121.04 mmol) was added in batches. The mixture was then heated at 100 °C for 6 h. TLC (PE:EA = 5:1) showed the starting materials were completely reacted. The reaction mixture was cooled to room temperature, adjusted to pH 3 with 2 M hydrochloric acid, and extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 5:1, with 2% glacial acetic acid) to give compound 17-8 (3.90 g, Y: 58%).

[0350] Step 8: Compound 17-8 (3.86 g, 14.14 mmol) was dissolved in N,N-dimethylformamide (40 mL) and cooled to 0 °C. Diisopropylethylamine (6.38 g, 49.48 mmol) and 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.91 g, 15.55 mmol) were added sequentially. The mixture was allowed to react at 0 °C for 0.5 hours. Methylamine hydrochloride (1.91 g, 28.27 mmol) was then added. After the addition was complete, the mixture was allowed to react at 0 °C for 2 hours. TLC (PE:EA = 1:1) showed that the raw materials had completely reacted. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:1) to give compound 17-9 (1.99 g, Y: 49%). LC-MS m / z (ESI): 286.1 [M+H] + .

[0351] Step 9: Compound 1-8 (385 mg, 708 μmol) and compound 17-9 (203 mg, 708 μmol) were dissolved in toluene (3 mL) and water (0.3 mL). Under the protection of nitrogen gas, tris(dibenzylideneacetone)dipalladium (58 mg, 70.88 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (65 mg, 141.76 μmol), and potassium carbonate (232 mg, 141.76 μmol) were added sequentially. The temperature was gradually raised to 100°C and the reaction was continued for 12 hours. LCMS showed that the raw materials had completely reacted. After cooling to room temperature and concentrating under reduced pressure, the mixture was purified by preparative silica gel plate (EA:PE=1:1) to give compound 17-10a (70.4 mg, Y: 19%, Rf=0.3) and compound 17-10b (105.6 mg, Y: 29%, Rf=0.35). LC-MS m / z (ESI): 623.2 [M+H] + .

[0352] Step 10: Compound 17-10a (70.4 mg, 0.11 mmol) was dissolved in 20% trifluoroacetic acid / dichloromethane solution (5 mL) and reacted at 5 °C for 1 h. TLC (DCM:MeOH = 10:1) showed that the starting material had completely reacted. The mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN; gradient: 61% to 81%; flow rate: 20 mL / min; run time: 14 min; peak time: 8.0 min) to give compound 17a (33.0 mg, Y: 55%). 1 H NMR (400 MHz, DMSO-d6) δ 8.11-8.07 (m, 1H), 7.51 (s, 1H), 7.48-7.39 (m, 2 H), 7.38-7.22 (m, 3H), 6.98 (d, J = 9.6 Hz, 1H), 5.24-5.17 (m, 1H), 3.52-3.32 (m, 2H), 3.30-3.28 (m, 1H), 2.91-2.86 (m, 2H), 2.75-2.69 (m, 1H), 2.67-2.55 (m, 4H), 1.58-1.22 (m, 6H), 0.50-0.40 (m, 1H). LC-MS m / z (ESI): 523.3 / 525.3 [M+H] + .

[0353] Step 11: Compound 17-10b (105.6 mg, 0.17 mmol) was dissolved in 20% trifluoroacetic acid / dichloromethane solution (5 mL) and reacted at 5 °C for 1 h. TLC (DCM:MeOH = 10:1) showed that the starting material had reacted completely. The mixture was cooled to 0°C, poured into saturated sodium carbonate (10 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN; gradient: 59% to 79%; flow rate: 20 mL / min; run time: 13 min; peak time: 8.3 min) to give compound 17b (35.0 mg, Y: 39%). 1 H NMR (400 MHz, DMSO-d6) δ 8.15-8.10 (m, 1H), 7.47-7.41 (m, 3H), 7.35-7.27 (m, 3H), 6.95 (d, J = 9.6 Hz, 1H), 5.28-5.20 (m, 1H), 3.50-3.38 (m, 1H), 3.29-3.21 (m, 1H), 3.11-3.03 (m, 1H), 2.90-2.82 (m, 1H), 2.73-2.55 (m, 2H), 2.31-2.21 (m, 3H), 1.48-1.23 (m, 6H), 0.50-0.42 (m, 1H). LC-MS m / z (ESI): 523.3 / 525.3 [M+H] + .

[0354] Example 18 [ka] [ka]

[0355] Step 1: Compound 17-9 (350 mg, 0.61 mmol) and compound 10-16 (192.5 mg, 0.68 mmol) were dissolved in toluene (3 mL) and water (0.6 mL), and tris(dibenzylideneacetone)dipalladium (56.2 mg, 0.06 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (70.9 mg, 0.12 mmol), and potassium carbonate (212 mg, 1.53 mmol) were added. After the addition was complete, the mixture was heated to 100 °C under nitrogen gas protection and reacted for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified using a preparative silica gel plate (EA:PE = 1:1) to give compound 18-1a (50 mg, Y: 22%, Rf = 0.3) and compound 18-1b (70 mg, Y: 31%, Rf = 0.35). LC-MS m / z (ESI): 649.2 [M+H] + .

[0356] Step 2: Compound 18-1a (50 mg, 0.077 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added at 5 °C. The reaction was continued for 2 h at 5 °C. TLC (PE:EA = 1:1) showed the starting material had reacted completely. The mixture was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 × 20 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN; gradient: 62% to 82%; flow rate: 20 mL / min; run time: 12 min; peak time: 7.9 min) to give compound 18a (15 mg, Y: 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 4.0 Hz, 1H), 7.58-7.50 (m, 1H), 7.48-7.40 (m, 2H), 7.38-7.24 (m, 3H), 7.02 (d, J = 9.6 Hz, 1H), 5.23-5.17 (m, 1H), 3.82-3.74 (m, 1H), 3.52-3.42 (m, 1H), 2.90-2.82 (m, 2H), 2.68 (s, 2H), 2.65-2.55 (m, 3H), 1.64-1.54 (m, 1H), 1.46-1.38 (m, 1H), 1.29-1.21 (m, 3H), 0.49-0.26 (m, 5H). LC-MS m / z (ESI): 549.3 / 551.3 [M+H] + .

[0357] Step 3: Compound 18-1b (70 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added at 5 °C. The reaction was continued for 2 h at 5 °C. TLC (PE:EA = 1:1) showed the starting material had reacted completely. The mixture was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 × 20 mm, 5 μm; eluent: 0.05% NH3.H2O + 10 mmol / L NH4HCO3 / CH3CN; gradient: 57% to 77%; flow rate: 20 mL / min; run time: 13 min; peak time: 7.7 min) to give compound 18b (13 mg, Y: 22%). 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.11 (m, 1H), 7.48-7.41 (m, 3H), 7.35-7.27 (m, 3H), 6.95 (d, J = 9.6 Hz, 1H), 5.25-5.18 (m, 1H), 3.73-3.66 (m, 1H), 3.38-3.31 (m, 1H), 3.10-3.00 (m, 1H), 2.90-2.80 (m, 1H), 2.68-2.57 (m, 2H), 2.33-2.25 (m, 3H), 1.50-1.43 (m, 1H), 1.33-1.23 (m, 3H), 0.48-0.23 (m, 5H). LC-MS m / z (ESI): 549.3 / 551.3 [M+H] + .

[0358] Example 19 [ka] [ka]

[0359] Step 1: Compound 1-7 (5.0 g, 10.0 mmol) was dissolved in ethyl acetate (50 mL) and cooled to 0 °C. Sodium periodate (10.8 g, 50.5 mmol) was dissolved in water (50 mL) and slowly added dropwise to the reaction solution at 0 °C. Ruthenium trichloride (620 mg, 3.0 mmol) was then added to the reaction solution and the mixture was allowed to react at 25 °C for 3 h. LCMS analysis showed that the starting materials had completely reacted. The reaction solution was quenched by adding dropwise to an aqueous solution of sodium sulfite (100 mL). Ethyl acetate (30 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (EA:PE = 1:4) to give compound 19-1 (2.0 g, Y: 38%). LC-MS m / z (ESI): 532.0 [M+Na] + .

[0360] Step 2: Compound 19-1 (1.5 g, 2.9 mmol) was dissolved in anhydrous methanol (20 mL), cooled to 0 °C, and sodium methoxide (0.7 mL, 3.5 mmol, 5 mol / L) was slowly added dropwise to the reaction solution at 0 °C. The mixture was then allowed to react for 15 minutes. LCMS analysis showed that the starting material had completely reacted. Water (10 mL) was added to the reaction solution, the pH was adjusted to 7 with 1 M hydrochloric acid, and ethyl acetate (15 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 1:4) to give compound 19-2 (1.2 g, Y: 76%). LC-MS m / z (ESI): 564.0 [M+Na] + .

[0361] Step 3: Compound 19-2 (1.4 g, 2.6 mmol) was dissolved in toluene (15 mL). Bis(pinacolato)diboron (1.3 g, 5.16 mmol), anhydrous potassium acetate (0.5 g, 5.16 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.22 g, 0.26 mmol) were added to the reaction solution. The mixture was then reacted overnight at 100 °C under nitrogen gas protection. LCMS analysis indicated complete reaction of the starting material. After cooling to 25 °C, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE = 1:9) to give 1.5 g of crude product. This was further purified by low-pressure reverse-phase liquid chromatography (C18 column, water / CH3CN, 85% CH3CN to 90% CH3CN) to give compound 19-3 (0.7 g, Y: 46%). LC-MS m / z (ESI): 612.0 [M+Na] + .

[0362] Step 4: Compound 19-3 (227 mg, 0.38 mmol) and compound 10-6 (100 mg, 0.3 mmol) were dissolved in toluene (3 mL) and water (0.5 mL). Tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (70 mg, 0.12 mmol), and anhydrous potassium carbonate (124 mg, 0.9 mmol) were added sequentially. The mixture was then heated under nitrogen gas at 120 °C overnight. LCMS analysis showed that the starting materials had reacted completely. The mixture was cooled to 25 °C, concentrated under reduced pressure, and purified by silica gel column chromatography (THF:PE = 1:3) to give compound 19-4 (74 mg, Y: 32%). LC-MS m / z (ESI): 760.0 [M+H] + .

[0363] Step 5: Compound 19-4 (200 mg, 0.26 mol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. LCMS showed that the starting material had completely reacted. After cooling to 0 °C, the reaction solution was poured into saturated aqueous sodium carbonate (10 mL) to quench the reaction, followed by extraction with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 19-5 (120 mg, crude product). LC-MS m / z (ESI): 576.0 [M+H] + .

[0364] Step 6: Compound 19-5 (140 mg, 0.24 mol) was dissolved in anhydrous methanol (5 mL), triethylamine (1 mL) was added, and the mixture was allowed to react at room temperature overnight. LCMS showed that the starting material had completely reacted. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with water (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid. This was then purified by preparative high-performance liquid chromatography (column model: Xselect CSH Prep). Fluoro-Phenyl, 150 × 19 mm, 5 μm; eluent: 0.1% TFA / CH3CN; gradient: 21% to 41%; flow rate: 20 mL / min; run time: 12 min; peak time KG0126A: 8.5 min; KG026: 9.1 min). Each fraction was collected, adjusted to pH 8 with saturated sodium carbonate solution, extracted with ethyl acetate (10 mL × 3), the combined organic phase was washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and freeze-dried to give compound 19a (55.0 mg, Y: 42%) and compound 19b (60.3 mg, Y: 46%). 19a: 1 H NMR (400 MHz, DMSO-d6): δ 8.48-8.42 (m, 1H), 8.31 (s, 1H), 7.76 (s, 1H), 7.45-7.28 (m, 5H), 7.17 (d, J = 9.6 Hz, 1H), 4.51-4.39 (m, 2H), 4.05-3.95 (m, 1H), 3.85-3.70 (m, 2H), 3.50-3.40 (m, 2H), 3.05-2.95 (m, 1H), 2.72-2.63 (m, 3H), 2.10-1.79 (m, 3H), 1.68-1.52 (m, 1H). LC-MS m / z (ESI): 544.2 [M+H] + 19b: 1H NMR (400 MHz, DMSO-d6): δ 8.45-8.8.37 (m, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.48-7.31 (m, 5H), 7.12 (d, J = 9.6 Hz, 1H), 5.03-4.95 (m, 1H), 4.55-4.38 (m, 2H), 4.05-3.95 (m, 1H), 3.90-3.75 (m, 2H), 3.40-3.25 (m, 1H), 3.20-3.05 (m, 1H), 2.42-2.30 (m, 3H), 1.97-1.65 (m, 3H), 1.57-1.40 (m, 1H). LC-MS m / z (ESI): 544.2 [M+H] + .

[0365] Example 20 [ka] [ka]

[0366] Step 1: Compound 13-5 (100 mg, 0.35 mmol) was dissolved in toluene (3 mL) and water (0.5 mL). Compound 1-8 (240 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium (64 mg, 0.07 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (81 mg, 0.14 mmol), and anhydrous potassium carbonate (145 mg, 1.05 mmol) were added sequentially. The mixture was evacuated and purged with nitrogen gas three times, and the reaction was carried out at 120 °C overnight. LCMS showed that the starting material had completely reacted. The reaction mixture was cooled to 25°C, water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 7:3) to give compound 20-1 (74 mg, Y: 33%). LC-MS m / z (ESI): 623.3 [M+H] + .

[0367] Step 2: Compound 20-1 (210 mg, 0.34 mmol) was dissolved in ethyl acetate (5 mL) and cooled to 0 °C. Under nitrogen gas protection, sodium periodate (361 mg, 1.68 mmol) in aqueous solution (5 mL) was added dropwise, ruthenium trichloride (14 mg, 0.07 mmol) was added, and the mixture was heated to 25 °C and reacted at 25 °C for 3 hours. Completion of the reaction was monitored by LCMS. The mixture was cooled to 0°C, saturated sodium sulfite solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 1:1) to give compound 20-2a (50.1 mg, Y: 23%, Rf = 0.4) and compound 20-2b (48.5 mg, Y: 22%, Rf = 0.6).

[0368] Step 3: Compound 20-2a (62 mg, 0.097 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL) was added dropwise at 0 °C. The mixture was allowed to react at room temperature for 2 hours. LCMS showed that the starting material had completely reacted. The reaction solution was diluted with water (5 mL), the pH was adjusted to 8 with saturated sodium carbonate, and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified by preparative high-performance liquid chromatography (column model: Xbridge Prep Phenyl OBD, 150 × 19 mm, 5 μm; eluent: 0.05% NH 3. Purification by H2O / CH3CN; gradient: 25% to 45%; flow rate: 20 mL / min; run time 12 min; peak time: 8.9 min) gave compound 20a (10.5 mg, Y: 20%). 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.10 (m, 1H), 7.78-7.67 (m, 1H), 7.45-7.30 (m, 5H), 7.11-7.08 (m, 1H), 6.99 (s, 1H), 5.20-5.11 (m, 1H), 4.02-3.91 (m, 1H), 3.48-3.40 (m, 1H), 3.00-2.81 (m, 2H), 2.62-2.58 (m, 3H), 2.06-1.80 (m, 3H), 1.65-1.50 (m, 1H), 1.30-1.20 (m, 1H), 0.41-0.30(m, 1H). LC-MS m / z (ESI): 537.2 [M+H] + .

[0369] Step 4: Compound 20-2b (60 mg, 0.094 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL) was added dropwise at 0 °C. The mixture was allowed to react at room temperature for 2 hours. LCMS showed that the starting material had completely reacted. The reaction solution was diluted with water (5 mL), the pH was adjusted to 8 with saturated sodium carbonate, and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified by preparative high-performance liquid chromatography (column model: Xbridge Prep Phenyl OBD, 150 × 19 mm, 5 μm; eluent: 0.05% NH 3. Purification by HCl / CHCN; gradient: 54% to 74%; flow rate: 20 mL / min; run time: 12 min; peak time: 10.2 min) gave compound 20b (15.4 mg, Y: 30%). 1H NMR (400 MHz, DMSO-d6) δ 8.19-8.07 (m, 1H), 7.98-7.90 (m, 1H), 7.49-7.30 (m, 5H), 7.10-7.03 (m, 1H), 6.95-6.90 (m, 1H), 5.22-5.12 (m, 1H), 4.05-3.95 (m,1H), 3.16-3.12 (m, 1H), 2.98-2.87 (m, 1H), 2.70-2.61 (m, 1H), 2.31-2.23 (m, 3H), 2.05-1.65 (m, 3H), 1.58-1.40 (m, 1H), 1.34-1.20 (m, 1H), 0.48-0.33(m, 1H). LC-MS m / z (ESI): 537.2 [M+H] + .

[0370] Example 21 [ka] [ka]

[0371] Step 1: Compound 17-9 (500 mg, 1.8 mmol) and compound 1-8 (1.2 g, 2.25 mmol) were dissolved in toluene (10 mL) and water (2 mL). Tris(dibenzylideneacetone)dipalladium (329 mg, 0.36 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (415 mg, 0.74 mmol), and anhydrous potassium carbonate (729 mg, 5.4 mmol) were added sequentially. The mixture was incubated at 120 °C overnight under nitrogen gas protection. LCMS analysis showed complete reaction of the starting materials. The mixture was cooled to 25 °C, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:5) to give compound 21-1a (140 mg, Y: 12%, Rf = 0.5) and compound 21-1b (180 mg, Y: 16%, Rf = 0.4). LC-MS m / z (ESI): 645.2[M+Na] + .

[0372] Step 2: Compound 21-1a (140 mg, 0.22 mmol) was dissolved in ethyl acetate (4 mL), and the reaction mixture was cooled to 0 °C. Sodium periodate (305 mg, 1.1 mmol) was dissolved in water (4 mL) and slowly added dropwise to the reaction mixture at 0 °C. Ruthenium trichloride (9 mg, 0.04 mmol) was then added to the reaction mixture and the mixture was allowed to react at 25 °C for 3 hours. The reaction mixture was quenched by adding 200 mL of aqueous sodium sulfite solution to the reaction mixture. Ethyl acetate (100 mL × 3) was added and the resulting mixture was extracted. The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EA:PE = 1:1) to give compound 21-2a (60 mg, Y: 42%) as a yellow solid. LC-MS m / z (ESI): 537.2 [M+H-Boc] + .

[0373] Step 3: Compound 21-2a (60 mg, 0.09 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.1 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. LCMS showed that the starting material had completely reacted. The mixture was cooled to 0 °C, and the reaction solution was poured into saturated aqueous sodium carbonate (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by preparative high-performance liquid chromatography (column model: Xbridge Prep Phenyl OBD, 150 × 19 mm, 5 μm; eluent: 0.05% NH 3. Purification by HCl / CHCN; gradient: 60% to 70%; flow rate: 20 mL / min; run time: 15 min; peak time: 11.2 min) gave compound 21a (13.7 mg, Y: 28.5%). 1H NMR (400 MHz, DMSO-d6): δ 8.18-8.14(m, 1H), 7.72-7.68 (m, 1H), 7.52 (s, 1H), 7.38-7.28 (m, 5H), 7.10-7.07 (m, 1H), 5.22-5.19 (m, 1H), 3.97-3.93 (m, 1H), 3.38-3.35 (m, 1H), 2.96-2.81 (m, 2H), 2.63-2.58 (m, 3H), 2.02-1.78 (m, 3H), 1.57-1.51 (m, 1H), 1.28-1.23 (m, 1H), 0.44-0.41 (m, 1H). LC-MS m / z (ESI): 537.2 [M+H] + .

[0374] Step 4: Compound 21-1b (180 mg, 0.29 mmol) was dissolved in ethyl acetate (4 mL) and the reaction mixture was cooled to 0 °C. Sodium periodate (313 mg, 1.45 mmol) was dissolved in water (4 mL) and slowly added dropwise to the reaction mixture at 0 °C. Ruthenium trichloride (12 mg, 0.06 mmol) was then added to the reaction mixture and the mixture was allowed to react at 25 °C for 3 hours. The reaction mixture was quenched by adding an aqueous solution of sodium sulfite (200 mL) dropwise. Ethyl acetate (100 mL × 3) was added for extraction. The combined organic phase was washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE = 1:1) to give compound 21-2b (65 mg, Y: 35%). LC-MS m / z (ESI): 537.2 [M+H-Boc] + .

[0375] Step 5: Compound 21-2b (65 mg, 0.1 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.1 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. LCMS showed that the starting material had completely reacted. The mixture was cooled to 0 °C, and the reaction solution was poured into saturated aqueous sodium carbonate (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid. This was purified by preparative high-performance liquid chromatography (column model: Xbridge Prep Phenyl OBD, 150 × 19 mm, 5 μm; eluent: 0.05% NH 3. Purification by H2O / CH3CN; gradient: 40% to 65%; flow rate: 20 mL / min; run time: 12 min; peak time: 10.5 min) gave compound 21b (18.7 mg, Y: 34%). 1 H NMR (400 MHz, DMSO-d6): δ 8.15-8.10(m, 1H), 7.92 (s, 1H), 7.48-7.32 (m, 6H), 7.05 (d, J=9.6 Hz, 1H), 5.26-5.23 (m, 1H), 3.99-3.96 (m, 1H), 3.28-3.23 (m, 1H), 3.11-3.05 (m, 1H), 2.86-2.82 (m, 1H), 2.31-2.27 (m, 3H), 1.95-1.65 (m, 3H), 1.47-1.41 (m, 1H), 1.32-1.28 (m, 1H), 0.45-0.41 (m, 1H). LC-MS m / z (ESI): 537.2 [M+H] + .

[0376] Example 22 [ka] [ka]

[0377] Step 1: Compound 17-9 (50 mg, 0.17 mmol) was dissolved in toluene (1 mL) and water (0.2 mL). Under nitrogen gas protection, compound 13-2 (106 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (47.9 mg, 0.052 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (60.6 mg, 0.10 mmol), and anhydrous potassium phosphate (111 mg, 0.52 mmol) were added sequentially. The mixture was reacted at 110 °C for 16 h. TLC (PE:EA = 1:1) showed that the starting materials had completely reacted. Eight batches were treated together according to the same procedure as above, cooled to 25°C, poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, followed by purification by silica gel column chromatography (PE:EA = 1:1, Rf = 0.3 is the product, Rf = 0.36 is the isomer) to obtain compound 22-1 (60.0 mg, Y: 9%). 1 H NMR (400 MHz, DMSO-d6) δ 8.14-8.06(m, 1H), 7.53-7.24(m, 6H), 7.02 (d,J=5.0 Hz, 1H), 5.24-5.18(m, 2H), 3.64-3.59(m, 2H), 2.89-2.81 (m, 1H), 2.78-2.70 (m, 1H), 2.61(d,J=2.4 Hz, 3H), 0.88-0.80(m, 1H), 0.48-0.39 (m, 1H). LC-MS m / z (ESI): 484.2 [M+H] + .

[0378] Step 2: Oxalyl chloride (47.2 mg, 0.371 mmol) was dissolved in dichloromethane (3 mL) and cooled to -70 °C under nitrogen gas protection. The mixture was stirred for 30 minutes. Dimethyl sulfoxide (58.1 mg, 0.744 mmol) was added and stirred at -70 °C for 30 minutes. After that, starting material 22-1 (60 mg, 0.124 mmol) was dissolved in dichloromethane (3 mL) and added to the reaction solution at -70 °C. The mixture was stirred for 30 minutes. Triethylamine (113 mg, 1.12 mmol) was added and stirred for 30 minutes. The mixture was then warmed to 25 °C and stirred for 1 hour. The reaction mixture was poured into saturated ammonium chloride (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 22-2 (60 mg, crude product).

[0379] Step 3: Compound 22-2 (60 mg, 0.125 mmol) was dissolved in 1,2-dichloroethane (4 mL). Under the protection of nitrogen gas, trans-4-amino-1-methylcyclohexanol (32.2 mg, 0.25 mmol) and acetic acid (0.74 mg, 0.012 mmol) were added sequentially. The mixture was heated to 85 °C and stirred for 30 minutes. Sodium triacetoxyborohydride (52.8 mg, 0.25 mmol) was then added and stirred at 85 °C for 2 hours. LCMS showed that the raw materials had completely reacted. The mixture was cooled to 25 °C, and the reaction solution was poured into saturated sodium bicarbonate (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was then purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart C18, 150 x 20 mm, 5 μm; eluent: 0.05% NH 3. Purification by HO / CHCN; gradient: 55.6% to 75.6%; flow rate: 20 mL / min; run time: 12 min; peak time: 8.9 min) gave compound 22a (18.4 mg, Y: 24%). 1H NMR (400 MHz, DMSO-d6) δ 8.25-8.15 (m, 1H), 7.52-7.18 (m, 6H), 7.03 (d, J=4.8 Hz, 1H), 5.25-5.17 (m, 1H), 4.15-4.05 (m, 1H), 3.48-3.38 (m, 2H), 3.02-2.71 (m, 4H), 2.63 (d, J=2.2 Hz, 3H), 1.72-1.58 (m, 2H), 1.48-1.38 (m, 2H), 1.35-1.15(m, 4H), 1.12-1.04(m, 2H), 1.01(s, 3H), 0.45-0.38 (m, 1H). LC-MS m / z (ESI): 595.2 [M+H] + .

[0380] Example 23

change

change

[0381] Step 1: Compound 13-3 (60 mg, 0.23 mmol) was dissolved in toluene (1 mL) and water (0.2 mL). Under nitrogen gas protection, compound 13-2 (114 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (43.3 mg, 0.047 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (54.6 mg, 0.094 mmol), and anhydrous potassium phosphate (150 mg, 0.71 mmol) were added sequentially. The mixture was reacted at 100 °C for 16 h. TLC (PE:EA = 1:1) showed that the starting materials had completely reacted. The same procedure as above was repeated six times, and seven batches were combined and treated. The mixture was cooled to 25°C, poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 23-1a (340 mg, Y: 45%, R f =0.35) and 23-1b (100 mg, Y: 15%, R f =0.30). 23-1a: LC-MS (1.5 ml-5 min-5-100-FA) Rt=2.93, m / z (ESI): 474.1 [M+Na] + . 23-1b: LC-MS (1.5ml-5min-5-100-FA) Rt=2.90, m / z (ESI): 474.1 [M+Na] + .

[0382] Step 2: Oxalyl chloride (286 mg, 2.26 mmol) was dissolved in dichloromethane (3 mL) and cooled to -78 °C under nitrogen gas protection. The mixture was stirred for 30 minutes. Dimethyl sulfoxide (352 mg, 4.51 mmol) was added and stirred at -78 °C for 30 minutes. After that, starting material 23-1a (340 mg, 0.752 mmol) was dissolved in dichloromethane (3 mL) and added to the reaction solution at -78 °C. The mixture was stirred for 30 minutes. Triethylamine (685 mg, 6.77 mmol) was added and stirred for 30 minutes. The mixture was then warmed to 25 °C and stirred for 1 hour. The reaction solution was poured into saturated ammonium chloride (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 23-2 (340 mg, crude product).

[0383] Step 3: Compound 23-2 (340 mg, 0.75 mmol) was dissolved in 1,2-dichloroethane (4 mL). Under nitrogen gas protection, trans-4-amino-1-methylcyclohexanol (117 mg, 0.91 mmol) and acetic acid (4.54 mg, 0.075 mmol) were added sequentially. The mixture was heated to 85°C and stirred for 30 minutes. Sodium triacetoxyborohydride (57.1 mg, 1.51 mmol) was then added and stirred at 85°C for 2 hours. LCMS showed that the starting material had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated sodium bicarbonate (20 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 1:1) to give compound 23-3 (280 mg, Y: 65%). LC-MS m / z (ESI): 563.3 [M+H] + .

[0384] Step 4: Compound 23-3 (280 mg, 0.48 mmol) was dissolved in dimethyl sulfoxide (2 mL). Under the protection of nitrogen gas, anhydrous potassium carbonate (103 mg, 0.95 mmol) and 30% hydrogen peroxide (5.49 mg, 0.048 mmol) were added sequentially. The mixture was stirred at 25 °C for 3 hours. LCMS showed that the starting materials had completely reacted. The reaction solution was poured into saturated ammonium chloride (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. This was then purified by preparative high-performance liquid chromatography (column model: YMC-Actus Triart) Purification by C18, 150 × 20 mm, 5 μm; eluent: 0.05% NH3H2O-10 mmol / L NH4HCO3-CAN; gradient: 55.9% to 75.9%; flow rate: 20 mL / min; run time: 10 min, peak time: 7.2 min) gave compound 23a (48.4 mg, Y: 16%). 1 H NMR (400 MHz, DMSO-d6) δ 7.67-7.58 (m, 1H), 7.44-7.23 (m, 6H), 7.05-6.92 (m,2H), 5.16-5.11 (m, 1H), 4.04 (s, 1H), 3.50-3.43 (m, 1H), 3.02-2.78 (m, 4H), 1.69-1.54(m, 2H), 1.42-1.30(m, 2H), 1.24-1.13(m, 4H), 1.09-0.97(m, 5H), 0.41-0.32(m, 1H). LC-MS m / z (ESI): 581.3 [M+H] + .

[0385] Example 24 [ka] [ka]

[0386] Step 1: Compound 17-7 (60 mg, 0.23 mmol) was dissolved in toluene (1 mL) and water (0.2 mL). Under nitrogen gas protection, compound 13-2 (114 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (43.3 mg, 0.047 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (54.6 mg, 0.094 mmol), and anhydrous potassium phosphate (150 mg, 0.71 mmol) were added sequentially. The mixture was reacted at 120 °C for 16 h. TLC (PE:EA = 3:1) showed that the starting materials had reacted completely. The same procedure as above was repeated nine times, and the mixture was cooled to 25 ° C. The reaction solution was poured into saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 3:1) to give compound 24-1b (240 mg, Y: 24%, Rf = 0.4) and 24-1a (150 mg, Y: 15%, Rf = 0.3). 24-1a: LC-MS (1.5 ml - 2.0 min - 5 - 90% B): Rt = 1.49, m / z (ESI): 515.1 [M + CH3CN + Na] + . 24-1b: LC-MS (1.5ml-2.0min-5-90%B): Rt=1.45, m / z (ESI): 515.1 [M+CH3CN+Na] + .

[0387] Step 2: Oxalyl chloride (83 mg, 1.32 mmol) was dissolved in dichloromethane (2 mL) and cooled to -78 °C under nitrogen gas protection. The mixture was stirred for 30 minutes. Dimethyl sulfoxide (52 mg, 4.51 mmol) was added and stirred at -78 °C for 30 minutes. After that, starting material 24-1a (150 mg, 0.33 mmol) was dissolved in dichloromethane (2 mL) and added to the reaction solution at -78 °C. The mixture was stirred for 30 minutes. Triethylamine (168 mg, 1.65 mmol) was added and stirred for 30 minutes. The mixture was then warmed to 25 °C and stirred for 1 hour. The reaction solution was poured into saturated ammonium chloride (10 mL) to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 24-2 (140 mg, crude product).

[0388] Step 3: Compound 24-2 (140 mg, 0.31 mmol) was dissolved in 1,2-dichloroethane (3 mL). Under nitrogen gas protection, trans-4-amino-1-methylcyclohexanol (80 mg, 0.62 mmol) and acetic acid (1.8 mg, 0.031 mmol) were added sequentially. The mixture was heated to 85°C and stirred for 30 minutes. Sodium triacetoxyborohydride (130 mg, 0.62 mmol) was added and stirred at 85°C for 2 hours. LC MS showed that the raw materials had completely reacted. The reaction mixture was cooled to 25°C, poured into saturated sodium bicarbonate (20 mL) to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The combined org...

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however, Y is CH or N; W is O or CH—R Ｗ and R Ｗ is H, OH, C １ ~C ６ Alkoxy, -C １ ~C ６ Alkyl-OR Ｗ－１ or C １ ~C ６ alkyl, and R Ｗ－１ is H or C １ ~C ６ is alkyl, Z is CH ２ , O, S or NH; R ２ is H or a halogen, R ６ is H, CN, -CONHR ６－１ , -NHR ６－２ or one, two or three NH ２ or C substituted by OH １ ~C ６ is an alkoxy, R ６－１ is H, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one, two, or three C １ ~C ６ "a 5- to 6-membered monocyclic heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three," substituted with alkyl; R ６－２ is one, two or three NH ２ or C substituted by OH １ ~C ６ is alkyl, A partial structure in the formula (I) linked to X, 【Chemistry 2】 is a double bond, X is C-R Ｘ１ and R Ｘ１ , R １ together with the atoms to which they are attached form ring B, i.e. The partial structure in the formula (I) is 【Transformation 3】 teeth, Based on the formula below 【Chemistry 4】 and Ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R １－１ a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted by one, two, or three R １－２ wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three, and is substituted by R １－１ and R １－２ are independently oxo (=O), OH, NH ２ , halogen, —S(O) ２ -C １ ~C ６ Alkyl, C-N, C １ ~C ６ alkyl, one, two or three R １－１－１ C substituted by １ ~C ６ alkyl, one, two or three R １－１－２ C substituted by １ ~C ６ Alkoxy, -(CH ２ ) ｎ１ -O-(CH ２ ) ｎ２ -O-C ３ ~C ６ cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R １－１－１ and R １－１－２ are each independently OH, NH ２ or a halogen, R ４ is a halogen, NH ２ , C.N., O.H., C. １ ~C ６ Alkoxy, C substituted by one hydroxy １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C substituted by 1, 2 or 3 halogens １ ~C ６ Alkyl or C ２ ~C ６ is alkynyl, R ３ is halogen, CN, C ２ ~C ６ Alkynyl, NH ２ , OH or C １ ~C ６ is an alkoxy, A is C ６ ~C １０ monocyclic or bicyclic aryl, one, two or three R Ａ－１ C substituted by ６ ~C １０ monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R Ａ－２ wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R Ａ－１ and R Ａ－２ are independently halogen, C １ ~C ６ Alkoxy, NH ２ , C.N., C. ３ ~C ６ Cycloalkyl, C substituted by one hydroxy １ ~C ６ alkyl or oxo (=O), Q is -CR ７ R ８ -NR ９ -R １０ or R １１ and R ７ , R ８ and R ９ are independently H or C １ ~C ６ is alkyl, R １０ is H, C １ ~C ６ Alkyl or -(CH ２ ) ０－２ -R １０－１ and R １０－１ is a C substituted by one, two or three OH １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or R １０－２ and R １０－２ and R １１ are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," one, two, or three R Ｑ－１ "a 3- to 15-membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C ３ ~C ６ cycloalkyl or one, two or three R Ｑ－１ C substituted by ３ ~C ６ is cycloalkyl, R Ｑ－１ are independently OH, halogen, NR Ｑ－１－１ R Ｑ－１－２ , C １ ~C ６ alkyl, one, two or three R Ｑ－１－３ C substituted by １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one, two or three R Ｑ－１－４ C substituted by １ ~C ６ Alkoxy, oxo (=O), methylene (=CH ２ ) or C ２ ~C ６ is alkenyl, R Ｑ－１－１ and R Ｑ－１－２ are independently H or C １ ~C ６ is alkyl, R Ｑ－１－３ and R Ｑ－１－４ are independently halogen, OH or NH ２ It is.)

2. Y is CH or N; W is O or CH—R Ｗ and R Ｗ is H, OH, C １ ~C ６ Alkoxy, -C １ ~C ６ Alkyl-OR Ｗ－１ or C １ ~C ６ alkyl, and R Ｗ－１ is H or C １ ~C ６ is alkyl, Z is CH ２ , O, S or NH; R ２ is H or a halogen, R ６ is H, CN, -CONHR ６－１ , -NHR ６－２ or one, two or three NH ２ or C substituted by OH １ ~C ６ is an alkoxy, R ６－１ is H, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, "5-6 membered monocyclic heteroaryl in which the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," or one, two or three C １ ~C ６ "5-6 membered monocyclic heteroaryl, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted with alkyl; R ６－２ is one, two or three NH ２ or C substituted by OH １ ~C ６ is alkyl, A partial structure in the formula (I) linked to X, 【Transformation 5】 is a double bond, X is C-R Ｘ１ and R Ｘ１ , R １ together with the atoms to which they are attached form ring B, i.e. The partial structure in the formula (I) is 【Transformation 6】 teeth, Based on the formula below 【Transformation 7】 and Ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R １－１ a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted by one, two, or three R １－２ wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three, and is substituted by R １－１ and R １－２ are independently oxo (=O), OH, NH ２ , halogen, —S(O) ２ -C １ ~C ６ Alkyl, C-N, C １ ~C ６ alkyl, one, two or three R １－１－１ C substituted by １ ~C ６ Alkyl, -(CH ２ ) ｎ１ -O-(CH ２ ) ｎ２ -O-C ３ ~C ６ cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R １－１－１ are independently OH, NH ２ or a halogen, R ４ is a halogen, NH ２ , C.N., O.H., C. １ ~C ６ Alkoxy, C substituted by one hydroxy １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C substituted by 1, 2 or 3 halogens １ ~C ６ Alkyl or C ２ ~C ６ is alkynyl, R ３ is halogen, CN, C ２ ~C ６ Alkynyl, NH ２ , OH or C １ ~C ６ is an alkoxy, A is C ６ ~C １０ monocyclic or bicyclic aryl, one, two or three R Ａ－１ C substituted by ６ ~C １０ monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R Ａ－２ wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R Ａ－１ and R Ａ－２ are independently halogen, C １ ~C ６ Alkoxy, NH ２ , C.N., C. ３ ~C ６ Cycloalkyl, C substituted by one hydroxy １ ~C ６ alkyl or oxo (=O), Q is -CR ７ R ８ -NR ９ -R １０ or R １１ and R ７ , R ８ and R ９ are independently H or C １ ~C ６ is alkyl, R １０ is H, C １ ~C ６ Alkyl or -(CH ２ ) ０－２ -R １０－１ and R １０－１ is a C substituted by one, two or three OH １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or R １０－２ and R １０－２ and R １１ are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," one, two, or three R Ｑ－１ "a 3- to 15-membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted by C ３ ~C ６ cycloalkyl or one, two or three R Ｑ－１ C substituted by ３ ~C ６ is cycloalkyl, R Ｑ－１ are independently OH, halogen, NR Ｑ－１－１ R Ｑ－１－２ , C １ ~C ６ alkyl, one, two or three R Ｑ－１－３ C substituted by １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one, two or three R Ｑ－１－４ C substituted by １ ~C ６ Alkoxy, oxo (=O), methylene (=CH ２ ) or C ２ ~C ６ is alkenyl, R Ｑ－１－１ and R Ｑ－１－２ are independently H or C １ ~C ６ is alkyl, R Ｑ－１－３ and R Ｑ－１－４ are independently halogen, OH or NH ２ 2. The compound represented by formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein:

3. Y is CH or N; W is O or CH—R Ｗ and R Ｗ is H, OH, C １ ~C ６ Alkoxy, -C １ ~C ６ Alkyl-OR Ｗ－１ or C １ ~C ６ alkyl, and R Ｗ－１ is H or C １ ~C ６ is alkyl, Z is CH ２ , O, S or NH; R ２ is H or a halogen, R ６ is H, CN, -CONHR ６－１ , -NHR ６－２ or one, two or three NH ２ or C substituted by OH １ ~C ６ is an alkoxy, R ６－１ is H, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, "5-6 membered monocyclic heteroaryl in which the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," or one, two or three C １ ~C ６ "5-6 membered monocyclic heteroaryl, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," substituted with alkyl; R ６－２ is one, two or three NH ２ or C substituted by OH １ ~C ６ is alkyl, A partial structure in the formula (I) linked to X, 【Transformation 8】 is a double bond, X is C-R Ｘ１ and R Ｘ１ , R １ together with the atoms to which they are attached form ring B, i.e. The partial structure in the formula (I) is 【Chemistry 9】 teeth, Based on the formula below 【Chemistry 10】 and Ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R １－１ a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted by one, two, or three R １－２ wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three, and is substituted by R １－１ and R １－２ are independently oxo (=O), OH, NH ２ , halogen, —S(O) ２ -C １ ~C ６ Alkyl, C-N, C １ ~C ６ alkyl, one, two or three R １－１－１ C substituted by １ ~C ６ Alkyl, -(CH ２ ) ｎ１ -O-(CH ２ ) ｎ２ -O-C ３ ~C ６ cycloalkyl, n1 is 0, 1 or 2, n2 is 1 or 2, and R １－１－１ are independently OH, NH ２ or a halogen, R ４ is a halogen, NH ２ , C.N., O.H., C. １ ~C ６ Alkoxy, C substituted by one hydroxy １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C substituted by 1, 2 or 3 halogens １ ~C ６ Alkyl or C ２ ~C ６ is alkynyl, R ３ is halogen, CN, C ２ ~C ６ Alkynyl, NH ２ , OH or C １ ~C ６ is an alkoxy, A is C ６ ~C １０ monocyclic or bicyclic aryl, one, two or three R Ａ－１ C substituted by ６ ~C １０ monocyclic or bicyclic aryl, "8-12 membered bicyclic heteroaryl in which the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three," or one, two or three R Ａ－２ wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, substituted by R Ａ－１ and R Ａ－２ are independently halogen, C １ ~C ６ Alkoxy, NH ２ , C.N., C. ３ ~C ６ Cycloalkyl, C substituted by one hydroxy １ ~C ６ alkyl or oxo (=O), Q is -CR ７ R ８ -NR ９ -R １０ or R １１ and R ７ , R ８ and R ９ are independently H or C １ ~C ６ is alkyl, R １０ is H, C １ ~C ６ Alkyl or -(CH ２ ) ０－２ -R １０－１ and R １０－１ is a C substituted by one, two or three OH １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or R １０－２ and R １０－２ and R １１ are independently "a 3- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or one, two, or three R Ｑ－１ wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three, and is substituted by R Ｑ－１ are independently OH, halogen, NR Ｑ－１－１ R Ｑ－１－２ , C １ ~C ６ alkyl, one, two or three R Ｑ－１－３ C substituted by １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one, two or three R Ｑ－１－４ C substituted by １ ~C ６ Alkoxy, oxo (=O), methylene (=CH ２ ) or C ２ ~C ６ is alkenyl, R Ｑ－１－１ and R Ｑ－１－２ are independently H or C １ ~C ６ is alkyl, R Ｑ－１－３ and R Ｑ－１－４ are independently halogen, OH or NH ２ 2. The compound represented by formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein:

4. The compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate of the pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) Each C １ ~C ６ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (2) Each C １ ~C ６ alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (3) each halogen is independently F, Cl, Br, or I; (4) Each C ３ ~C ６ cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (5) each "5- to 6-membered monocyclic heteroaryl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "5- or 6-membered monocyclic heteroaryl in which the heteroatoms are selected from one or two of N and O, and the number of heteroatoms is one, two, or three"; (6) each "3- to 6-membered heterocycloalkyl in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "5- or 6-membered heterocycloalkyl in which the heteroatoms are selected from one or two of N and O, and the number of heteroatoms is one, two, or three"; (7) Each C ２ ~C ６ Alkynyl is independently a group of the formula: 【Chemistry 11】 and (8) Each C ２ ~C ６ Alkenyl is independently a group of the formula: 【Chemistry 12】 and (9) Each “C” ６ ~C １０ "monocyclic or bicyclic aryl" is independently phenyl or naphthyl; (10) each "8- to 12-membered bicyclic heteroaryl, wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "9- or 10-membered bicyclic heteroaryl, wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three"; (11) each "3- to 15-membered monocyclic or bicyclic heteroaryl, in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "5- to 10-membered monocyclic or bicyclic heteroaryl, in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three"; (12) each 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocycle is independently a 5- to 6-membered monocyclic, a 6- to 10-membered bicyclic, or an 8- to 15-membered tricyclic saturated or unsaturated carbocycle; (13) Each "5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three" is independently "5- to 6-membered monocyclic, 6- to 10-membered bicyclic, or 8- to 15-membered tricyclic saturated or unsaturated heterocycle in which the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three"; (14) each 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocycle is independently a 3- to 6-membered monocyclic or 6- to 10-membered bicyclic saturated or unsaturated carbocycle; (15) Each "3- to 15-membered monocyclic or bicyclic saturated or unsaturated heterocycle in which the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" is independently "a 3- to 6-membered monocyclic saturated heterocycle or a 6- to 10-membered bicyclic saturated or unsaturated heterocycle in which the heteroatoms are selected from one or two of N and O, and the number of heteroatoms is one or two."

5. The compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate of the pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) Each C １ ~C ６ alkyl is independently methyl or ethyl; (2) Each C １ ~C ６ alkoxy is independently methoxy or ethoxy; (3) each halogen is independently F or Cl; (4) Each C ３ ~C ６ cycloalkyl is independently cyclopropyl; (5) Each "5-6 membered monocyclic heteroaryl, wherein the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" independently represents a group of the following formula: 【Chemistry 13】 and (6) Each "3- to 6-membered heterocycloalkyl, wherein the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three" independently represents a group of the following formula: 【Chemistry 14】 and (7) Each C ２ ~C ６ Alkynyl is independently a group of the formula: 【Chemistry 15】 and (8) Each C ２ ~C ６ Alkenyl is independently a group of the formula: 【Chemistry 16】 and (9) Each “C” ６ ~C １０ "monocyclic or bicyclic aryl" is independently phenyl; (10) Each "8-12 membered bicyclic heteroaryl, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three" independently represents a group of the following formula: 【Chemistry 17】 and (11) Each "3- to 15-membered monocyclic or bicyclic heteroaryl, wherein the heteroatoms are one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three" independently represents a group of the following formula: [Chemistry 18] and (12) each 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring is independently a 5- to 6-membered monocyclic, a 6- to 10-membered bicyclic, or an 8- to 15-membered tricyclic saturated carbocyclic ring; (13) Each 3- to 15-membered monocyclic or bicyclic saturated or unsaturated carbocycle is independently a 3- to 6-membered monocyclic saturated carbocycle or a 6- to 10-membered bicyclic saturated or unsaturated carbocycle.

6. The compound represented by formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) W is CH-R Ｗ and (2) R Ｗ is H, OH or C １ ~C ６ is alkyl, (3) R ６ is -CONHR ６－１ and (4) R ６－１ is H or C １ ~C ６ is alkyl, (5) R １－１ is oxo (=O), OH, NH ２ , CN, halogen, -S(O) ２ -C １ ~C ６ Alkyl, C １ ~C ６ alkyl or one, two or three R １－１－２ C substituted by １ ~C ６ is an alkoxy, (6) R １－１－２ is OH, (7) R １－２ is OH or a halogen.

7. The compound represented by formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) W is CH-R Ｗ and R Ｗ is H, OH or C １ ~C ６ is alkyl, (2) R ６ is the basis of the following formula 【Chemistry 19】 and (3) R １－１ is oxo (=O), OH, NH ２ , CN, halogen, -S(O) ２ -C １ ~C ６ Alkyl, C １ ~C ６ alkyl or one, two or three R １－１－２ C substituted by １ ~C ６ is alkoxy, and R １－１－２ is OH.) 8. The compound represented by formula (I) according to claim 7, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein W is CH 2 , CH—OH, or CH—CH 3 .

9. The compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate of the pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: ((1) R ２ is a halogen, (2) R １－６ is C ３ ~C ６ It is cycloalkyl.

10. The compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate of the pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: (1) Y is CH; (2) W is CH ２ and (3) Z is O; (4) R ２ is F, (5) R ６ is the basis of the following formula 【Chemistry 20】 It is.)

11. The compound represented by formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: (1) A partial structure in the formula (I) of the following formula: 【Chemistry 21】 teeth, Based on the formula below 【Chemistry 22】 and Ring B is a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring, one, two, or three R １－１ a 5- to 15-membered monocyclic, bicyclic, or tricyclic saturated or unsaturated carbocyclic ring substituted by one, two, or three R １－２ wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three, and is substituted by R １－１ is oxo (=O), OH, NH ２ , CN, halogen, -S(O) ２ -C １ ~C ６ Alkyl, C １ ~C ６ alkyl or one, two or three R １－１－２ C substituted by １ ~C ６ is an alkoxy, R １－２ is OH or a halogen, R １－１－２ is OH, (2) R ４ are independently halogen, OH, NH ２ , C １ ~C ６ Alkoxy or C ２ ~C ６ It is alkynyl.

12. R ４ is the basis of the following formula 【Chemistry 23】 12. The compound represented by formula (I) according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein:

13. The compound represented by formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound represented by formula (I) satisfies one or more of the following conditions: (1) A partial structure in the formula (I) of the following formula: 【Chemistry 24】 teeth, Based on the formula below 【Chemistry 25-1】 【Chemistry 25-2】 【Chemistry 25-3】 【Chemistry 25-4】 【Chemistry 25-5】 and (2) R ４ are independently a group of the formula: 【Chemistry 26】 and (3) R ３ are independently the groups of the formula 【Chemistry 27】 and; (4) A is independently a group of the following formula: 【Chemistry 28】 and (5) Q is a group of the following formula: 【Chemistry 29】 It is.)

14. A compound represented by formula (I) according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. (The partial structure of the formula (I) below) 【Transformation 30】 teeth, Based on the formula below 【Chemistry 31-1】 【Chemistry 31-2】 It is.)

15. A compound represented by formula (I) according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. (The partial structure of the formula (I) below) 【Chemistry 32】 teeth, Based on the formula below 【Chemistry 33-1】 【Chemistry 33-2】 It is.)

16. A compound represented by formula (I) according to claim 3, a pharmaceutically acceptable salt thereof or a solvate of the pharmaceutically acceptable salt thereof. (The partial structure of the formula (I) below) 【Transformation 34】 teeth, Based on the formula below 【Chemistry 35-1】 【Chemistry 35-2】 It is.)

17. The compound represented by formula (I) according to any one of claims 1 to 3, wherein the compound represented by formula (I) is a compound represented by formula (IA): 【Transformation 36】 (However, R １ , R ２ , R ３ , R ４ , R ６ , X, Y, W, Z, A and Q are defined as in any one of claims 1 to 3.

18. The compound represented by formula (I) according to any one of claims 1 to 3, wherein the compound represented by formula (I) is a compound represented by formula (IB), a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. 【Chemistry 37】 (However, ring B, R ２ , R ３ , R ４ , R ６ , Y, W, Z, A and Q are defined as in any one of claims 1 to 3.

19. The compound represented by formula (I) according to any one of claims 1 to 3, wherein the compound represented by formula (I) is a compound represented by formula (IC), a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. 【Transformation 38】 (However, ring B, R ２ , R ３ , R ４ , R ６ , Y, W, Z, A and Q are defined as in any one of claims 1 to 3.

20. The compound represented by formula (I) according to claim 1 or 2, wherein the compound represented by formula (I) is a compound represented by formula (ID) or a compound represented by formula (IE), a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. 【Chemistry 39】 (where n1 is 0, 1, 2 or 3, and R １－１ , R ６－１ and R ｗ The definitions are as set forth in claim 1 or 2.

21. The compound represented by formula (I) is a compound of the following formula: 【Chemistry 40-1】 【Chemistry 40-2】 【Chemistry 40-3】 【Chemistry 40-4】 【Chemistry 40-5】 【Chemistry 40-6】 【Chemistry 40-7】 【Chemistry 40-8】 【Chemistry 40-9】 [Transformation 40-10] 【Chemistry 40-11】 【Chemistry 40-12】 【Chemistry 40-13】 【Chemistry 40-14】 [Chemistry 40-15] [Chemistry 40-16] 【Chemistry 40-17】 [Chemistry 40-18] [Chemistry 40-19] [Transformation 40-20] 【Chemistry 40-21】 【Chemistry 40-22】 【Chemistry 40-23】 [Chemistry 40-24] [Chemistry 40-25] [Chemistry 40-26] The compound represented by formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it is any one compound selected from the following:

22. 1. A pharmaceutical composition comprising: (1) A compound represented by formula (I) according to any one of claims 1 to 3, 6 to 8, 11 to 16 and 21, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; and (2) A pharmaceutical composition comprising a pharmaceutically acceptable auxiliary agent.

23. Use of a compound of formula (I) according to any one of claims 1 to 3, 6 to 8, 11 to 16 and 21, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament used in the prevention and / or treatment of cancer.

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