Boric acid beta-lactamase inhibitors, processes for their preparation and use

Abstract

This invention relates to the pharmaceutical field, and provides a β-lactamase inhibitor or its application. The β-lactamase inhibitor is a compound of formula (I), or an optical isomer thereof, or a pharmacodynamically acceptable salt. The β-lactamase inhibitor of this invention has good water solubility, superior pharmacokinetic properties, and good drug-likeness. It has good inhibitory activity against β-lactamases of types A, B, C, and D, and can produce strong antibacterial activity when used in combination with antibiotics, especially against carbapenem-resistant Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and other bacteria, and is used to treat diseases related to bacterial infections.

Description

Boric acid β-lactamase inhibitors and their preparation method and application Technical Field

[0001] The present invention relates to a new class of boric acid compounds, in particular to a compound represented by formula (I), an optical isomer or a pharmaceutically acceptable salt thereof, and the use of the compound as a β-lactamase inhibitor or an antibacterial drug. Background Art

[0002] For the past half century, antibiotics have been an effective tool for treating infectious diseases. From the development of antibiotic therapy until the late 1980s, bacterial infections were almost completely controlled in developed countries. However, in response to the pressure to use antibiotics, multiple resistance mechanisms have become prevalent and threaten the clinical utility of antimicrobial therapy. The increase in antibiotic-resistant strains has been particularly prevalent in major hospitals and nursing homes. The consequences of this increase in resistant strains include higher morbidity and mortality, longer hospitalizations, and increased treatment costs. In 2016, the prevalence of carbapenem resistance among clinically isolated Klebsiella pneumoniae in my country was greater than 15%, while the prevalence of carbapenem resistance among Pseudomonas aeruginosa and Acinetobacter baumannii was nearly 30% and 70%, respectively, both higher than the resistance rates in 2015.

[0003] The challenge of bacterial resistance is compounded by a shortage of new antimicrobial drugs. Over the past half century, only five new antimicrobial drugs have been marketed: linezolid, daptomycin, bedaquiline, delamanid, and the topical drug retapalin. These drugs are only effective against Gram-positive bacteria and Mycobacterium tuberculosis. This makes infections caused by Gram-negative bacteria, especially those with drug-resistant Gram-negative bacteria, the most challenging challenge in the clinical treatment of infectious diseases. The search for drugs to combat drug-resistant Gram-negative bacteria is urgent.

[0004] Progress in screening and developing drugs targeting the physiological metabolism of pathogens has been slow. Consequently, another strategy for developing drugs against drug-resistant bacteria has gained increasing attention: targeting resistance mechanisms to identify and discover antimicrobial synergists, thereby dismantling bacterial resistance defenses and restoring bacterial susceptibility to currently available antimicrobial drugs. To date, the most successful antimicrobial synergist is the β-lactamase inhibitor. β-lactams, with their high efficacy and low toxicity, are the most widely used class of antimicrobial drugs worldwide, with a clinical usage rate of 62.1% in my country. However, with widespread use of β-lactams, bacteria have developed resistance to these drugs through the production of β-lactamases, altered cell wall or outer membrane permeability, mutations in target proteins, and the expression of efflux pumps. The primary mechanism is the hydrolytic inactivation of the drug by the production of β-lactamases. Therefore, screening for new β-lactamase inhibitors has the potential to yield a variety of new antimicrobial synergists, potentially restoring the susceptibility of resistant bacteria to this broad class of antimicrobials.

[0005] The main mechanism of resistance to β-lactam antibiotics is the production of β-lactamase by bacteria, which can covalently bind to the carbonyl group on the β-lactam ring of β-lactam antibiotics, hydrolyzing and inactivating them. There are currently more than 300 known β-lactamases. According to the Bush classification, β-lactamases are divided into four groups based on their preferred substrates and inhibitor spectra. Ambler divided them into four categories: A, B, C, and D based on their respective amino acid homology sequences. The active groups of categories A, C, and D are serine, and the active group of category B is Zn 2+ , a metalloenzyme. Currently used clinically, β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam effectively combat bacterial resistance by interacting with class A and B β-lactamases, blocking their destruction of the β-amide ring. However, there are currently no effective drugs targeting class B β-lactamases and Acinetobacter baumannii. The demand for extended-spectrum antibiotics that can inhibit class B β-lactamases and Acinetobacter baumannii is increasing.

[0006] In recent years, novel boronic acid-based β-lactamase inhibitors have become a hot topic in the antibiotic field, based on the design concept of competitive inhibitors. By improving the affinity of inhibitors for enzymes and the stability of complexes, novel boronic acid-based β-lactamase inhibitors have become a hot topic in research. Our new generation of boronic acid-based β-lactamase inhibitors represents a class of extended-spectrum β-lactamase inhibitors, demonstrating inhibitory activity against class A, B, C, and D enzymes, as well as against carbapenem-resistant bacteria such as Acinetobacter baumannii, Enterobacteriaceae, and Pseudomonas aeruginosa.

[0007] The present invention will meet the clinical demand for therapeutic drugs for diseases caused by bacterial infections and has great clinical value. Summary of the Invention

[0008] In view of the above technical status, the present invention discloses a boric acid β-lactamase inhibitor and its preparation method and application. Specifically, the β-lactamase inhibitor is a compound of formula (I), or an optical isomer or a pharmaceutically acceptable salt thereof:

[0009] Wherein, the E and G are each independently H, C, N elements or do not exist;

[0010] M is a single bond or C;

[0011] T is a single bond, or -(CH) m -, wherein m is selected from 0 or 1;

[0012] X is a single bond, -(CH2) t -, wherein t is selected from 0 or 1;

[0013] Y is B, O, or P;

[0014] Z is O, S, B, or N;

[0015] L1 is selected from a single bond, halogen, H, -O-, -S-, -CR a R b -、-NH-、-CH2-、-C(O)NR a R b or group or does not exist;

[0016] L2 is selected from a single bond, H, -C(O)-, -CR a R b -、-CO-、-NR a -、 or does not exist;

[0017] L3 is selected from H, single bond, halogen, -O-, -S-, -N-, -C-, -CR a R b - or does not exist;

[0018] L4 is selected from H, amino, halogen, cyano, hydroxy, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-S-、-CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S)-, -NHC(O)-, -NHC(O)NH-, -CH2NRaRb, Single bond or absent;

[0019] R1 is selected from H, -S(O)(O)NR a R b 、-S(O)(O)R a 、-S(O)(O)(CH2) n R a 、-S(O)NR a R b 、-(O)NR a R b 、-CHR a R b 、-C(O)R a 、-C(O)NR a R b 、-COR a 、-CONR a R b 、-NR a COR b 、 C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 3-8 Aromatic heterocycle, C 3-8 Alkyl bridge ring, C 3-8 Epoxyalkyl, C 1-8 Alkyl, aryl or heteroaryl or absent;

[0020] Preferably, R1 is selected from -H-, -C(O)-aryl, -C(O)NH-C 1-6 Oxoalkyl, -C(O)NH-(CH2) n -cycloalkyl, -C(O)NH-C 1-6 Alkyl, -C(O)N(C 1-6 alkyl)-cycloalkyl, -S(O)(O)-aryl, -S(O)(O)-C 1-6 Alkyl, -S(O)(O)-C 3-8 Cycloalkyl, -S(O)(O)-C 3-8 Heterocycloalkyl, -S(O)(O)-halogenated aromatic ring, -S(O)(O)-(CH2) n -cycloalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 3-8 Aromatic heterocycle, C 3-8 Alkyl bridge ring, C 3-8 Epoxyalkyl, C 1-8 Alkyl, aryl or heteroaryl or absent;

[0021] R2 is alkyl, -OR a 、-SR a 、-NR a R b 、 or does not exist;

[0022] R3 is H, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl, or absent;

[0023] Preferably, the C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl is substituted by 1, 2 or 3 F, Cl, Br, I, OH, alkyl or heteroalkyl;

[0024] More preferably, R3 is CH3 or absent.

[0025] R4 is selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -(CH2)n-cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthiol, C 1-6 Alkoxy, C 1-6 Alkylthiol, hydroxyl, carboxyl, -O-(CH2) n -aromatic heterocycle, -O-(CH2) n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a、 -S-(CH2) n -aromatic heterocycle, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n -Aryl, -C(O)R a 、-C(O)NR a R b 、-NHCOR a 、-NR a R b 、C 3-8 Cycloheteroalkyl, aryl, halogenated aryl and heteroaromatic ring, -(CH2) n -C 3-8 Cycloalkyl, -(CH2) n -Halogenated C 3-8 Cycloalkyl, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aryl, -(CH2) n -haloaryl, -(CH2) n -aromatic heteroyl, C1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH(C=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- and C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl- or absent, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8.

[0026] Among them, the C 1-6 Alkyl, C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NHC(=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- or C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl-optionally substituted by 1, 2 or 3 R a replace;

[0027] Wherein, the -O-(CH2) n -aromatic heterocycle, -O-(CH2)n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a、 -S-(CH2) n -aromatic heterocycle, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n -Aryl is optionally substituted with 1, 2 or 3 Ra

[0028] The halogen is -F, -Cl, -Br, -I, or -B;

[0029] R5 and R6 are each independently H or absent, or R5 and R6 together with the atoms to which they are attached form a C 3-8 Carbon ring, C 3-8 a carbon heterocyclic ring, an aromatic ring, a heteroaromatic ring, or a fused ring;

[0030] R7 is carboxyl, sulfonic acid, amide, sulfonamide, triazole, tetrazole or Or not present; preferably R7 is COOH, SO3H, CONH2, or does not exist;

[0031] R8 and R9 are each independently selected from H, hydroxyl or absent;

[0032] R a 、R b Each is independently a hydrogen atom or an alkyl group, a halogen group, a hydroxyl group, an amino group, a carbonyl group, a carboxyl group, a cyano group, a deuterated group, a C 1-6 Alkoxy, aryl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Oxoalkyl, C 1-6 Thioalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, halogenated C3-8 Cycloalkyl, halogenated C 3-8 Epoxyalkyl, C 3-8 Aromatic heterocycle or halogenated C 3-8 Aromatic heterocyclic group, -(CH2) n -C 3-8 Cycloalkyl, -(CH2) n -Halogenated C 3-8 Cycloalkyl, -(CH2) n -Halogenated aromatic ring, -(CH2) n -Halogenated aromatic heterocycle, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH(C 1-6 alkyl), -C(O)(C 1-6 Alkyl), -C(O)(halogenated C 1-6 Alkyl), -C(O)(halogenated C 3-8 Cycloalkyl), -C(O)(C 3-8 Cycloalkyl), -C(O)NH-C 1-6 Alkyl, -C(O)NH-halogenated C 1-6 Alkyl, -NHCO-haloalkyl, -NHC 3-8 The cycloalkyl group is or is not present, and n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0033] In the present invention, as one embodiment, in the compound of formula (I),

[0034] When m is 1,

[0035] L2 and R6 are both hydrogen atoms,

[0036] X is a single bond,

[0037] Y and Z are each independently selected from B or O atoms,

[0038] M, E, G are selected from C,

[0039] L3 is selected from H,

[0040] L4 is selected from H, amino, halogen, cyano, hydroxy, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S)-,

[0041] R4 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl, C3-8 Epoxyalkyl, halogenated C 3-8 alkylene oxide group, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a replace.

[0042] In the present invention, as one embodiment, in the compound of formula (I),

[0043] When t is 1, R5 and R6 are hydrogen atoms or the atoms they are connected to form C 3-8 Carbon ring, C 3-8 a carbon heterocyclic ring, an aromatic ring, a heteroaromatic ring, or a fused ring;

[0044] M, E, and G are each independently a C or N atom,

[0045] T is a single bond,

[0046] L2 is a hydrogen atom,

[0047] L1, L3, and L4 are each independently a single bond, -O-, -S-, or -CR a R b -,

[0048] R1, R3, and R4 are each independently -H-, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated, amino-substituted, cyano-substituted cycloalkyl or aryl or heteroaromatic group.

[0049] In the present invention, as one embodiment, in the compound of formula (I),

[0050] When t is 1, m is 1, Y is selected from B atoms, Z is selected from O atoms, and R5 and R6 are each independently selected from hydrogen atoms,

[0051] 1) L1 is H, -O-, -NH-, -CH2-, -C(O)NR a R b 、

[0052] R1 is -S(O)(O)NR a R b 、-S(O)(O)R a 、-S(O)(O)(CH2) n R a 、-S(O)NR a R b 、-C(O)NR a R b 、-CHRa R b 、-C(O)R a 、 C 3-8 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-8 Heterocyclyl, optionally substituted C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a Substitution, halogenated C 3-8 Cycloalkyl, halogenated C 3-8 Epoxyalkyl, C 3-8 Aromatic heterocycle or halogenated C 3-8 Aromatic heterocycle, C 1-8 Alkyl bridge ring or methyl substituted C 3-8 Cycloalkyl, cyano substituted C 3-8 Cycloalkyl, amino substituted C 3-8 cycloalkyl groups;

[0053] L2 and L3 are each independently H; M, E, and G are N, O, S, or (-CH2-) i , where i is 1;

[0054] L4 is a single bond, amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -, -NHC(O)-, -NHC(O)NH-, -O-, -CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S)-,

[0055] R4 is H, halogen, -CH2(aryl), -CH2(heteroaryl), -CH2(cycloalkyl), -CH2(C 3-8 Heterocyclyl), optionally substituted C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a Substituted or unsubstituted C 3-8 Cycloalkyl, unsubstituted C 3-8 Epoxyalkyl, halogenated C 3-8 Cycloalkyl, or halogenated C 3-8 an alkylene oxide group; or

[0056] 2) L1 and L3 are hydrogen atoms,

[0057] L2 is -C(O)-, -CR a R b -、-NRa-、

[0058] R2 is alkyl, -OR a 、-SR a , -NRaRb group; M, E, G are each independently a C or N atom;

[0059] L4 is a single bond, H, amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S-; optionally substituted C 3-8 Heterocyclyl, optionally substituted C 1-6 Alkyl, the C 1-6 Alkyl, C 3-8 The heterocyclic group is optionally substituted with 1, 2 or 3 R a Substituted or unsubstituted C 3-8 Cycloalkyl, unsubstituted C 3-8 Epoxyalkyl, halogenated C 3-8 Cycloalkyl, halogenated C 3-8 Epoxyalkyl group.

[0060] In the present invention, as one embodiment, the β-lactamase inhibitor compound of formula (I) is:

[0061] When t=1, m=1,

[0062] Y is a B atom;

[0063] Z is an O atom

[0064] When R5 and R6 are H or R5, R6 and the atoms to which they are attached together form a fused ring or ring system, the fused ring or ring system is preferably a 3-10 membered carbocyclic group or a 3-10 membered heterocyclic group, preferably a 3-7 membered carbocyclic group or a 3-7 membered heterocyclic group including but not limited to: a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0065] L3 is O, S, N, or C atom;

[0066] R3 is C 1-6 Alkyl, C 1-6 heteroalkyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, aryl or heteroaryl is optionally substituted with 1, 2 or 3 F, Cl, Br, I, OH, alkyl or heteroalkyl;

[0067] L4 is amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-CR a R b-, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, or -C(S)-,

[0068] R4 is selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -(CH2)n-cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthiol, C 1-6 Alkoxy, C 1-6 Alkylthiol, hydroxyl, carboxyl, -O-(CH2) n -aromatic heterocycle, -O-(CH2) n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a、 -S-(CH2) n -aromatic heterocycle, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n -Aryl, -C(O)R a 、-C(O)NR a R b 、-NHCOR a 、-NR a R b 、C 3-8 Cycloheteroalkyl, aryl, halogenated aryl and heteroaromatic ring, -(CH2) n -C 3-8 Cycloalkyl, -(CH2) n -Halogenated C 3-8 Cycloalkyl, -(CH2) n -C3-8 Cycloheteroalkyl, -(CH2) n -aryl, -(CH2) n -haloaryl, -(CH2) n -aromatic heteroyl, C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH(C=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- and C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl- or absent, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8.

[0069] Among them, the C 1-6 Alkyl, C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NHC(=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- or C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl-optionally substituted by 1, 2 or 3 Ra replace;

[0070] Wherein, the -O-(CH2) n -aromatic heterocycle, -O-(CH2) n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a、 -S-(CH2) n -aromatic heterocycle, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n -Aryl is optionally substituted with 1, 2 or 3 R a replace.

[0071] The halogen is -F, -Cl, -Br, -I, or -B.

[0072] In the present invention, as one embodiment, in the compound of formula (I), when M=1 and T is -CH-, T, E, G, and M form a six-membered ring, preferably a benzene ring.

[0073] In the present invention, as one embodiment, in the compound of formula (I), when T is a single bond, the ring containing E, G, and M is a five-membered ring;

[0074] In the present invention, as one embodiment, in the compound of formula (I), m is 0, and when T does not exist, E and G also do not exist, and the ring is open.

[0075] In the present invention, as one embodiment, in the compound of formula (I), L1 is selected from NH, F, H, O, CH3, Or does not exist.

[0076] In the present invention, as one embodiment, in the compound of formula (I), L2 is selected from H, N, CH2, CH3, -CO-, or NH.

[0077] In the present invention, as one of the embodiments, in the compound of formula (I), L3 is selected from H, a single bond, a halogen, -O-, -S-, -N-, -C-, -CH3- or does not exist; further preferably, the halogen is F, Cl, Br or I.

[0078] In the present invention, as one embodiment, in the compound of formula (I), L4 is selected from H, F, O, S, CH3, CH2, -NCH3, NH, -CH2NR a R b Or does not exist.

[0079] In the present invention, as one embodiment, in the compound of formula (I), the R1 is selected from -H-, -CH3, -CH2F, -CH2Cl, -CHCH3F, -CHF2, -CHOHOH, -CHCNCN, -CH2COCH3, Or does not exist.

[0080] In the present invention, as one embodiment, in the compound of formula (I), R2 is CH3, CH3O, CH3NH, Or does not exist.

[0081] In the present invention, as one embodiment, the R4 is selected from H, -CH3, CH3CH2-, -OCH3, (CH3)2CH2CH2-, -CH2CN, CNCH2CH2-, CH3CH2CH2O-, CH3O-, (CH3)2CHCH2O-, CH3CH2O-, (CH3CH2)2CH-, (CH3)2CH-, CH3(CH2)3-, CH3S-, CH3CH2S-, (CH3)3CO-, (CH3)2CHO-;

[0082] F2CH-, FCH2CH2-, CF3CH2-, FCH2CH2O-, FCH2CH2O-, F2CHCH2O-, CF3CH2O-;

[0083] -N(CH3)2, CH3CO-, F2CHCH2NHCO-, -NHCH2CH(CH3)2, CH3CH2NHCO-, NH2CH2CH2NHCO-, FCH2CH2NHCO-, CF3CH2NHCO-, CH3NH-, or not present.

[0084] In the present invention, as one embodiment, in the compound of formula (I), R5 and R6 are each independently H or absent, or R5, R6 and the carbon atoms to which they are connected together form cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0085] In the present invention, as one of the embodiments, the alkane group, as an exemplary illustration, may include but is not limited to methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl, hexyl, etc.

[0086] In the present invention, as one embodiment, the olefin group can be, for example, vinyl, propenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, etc.

[0087] In the present invention, as one of the embodiments, the C 2～6 Alkyne groups can be exemplified by ethynyl, propynyl, butynyl, isobutynyl, pentynyl, isopentenyl, hexynyl, and the like.

[0088] In the present invention, as one embodiment, the saturated cycloalkyl group is, for example, cyclopropane, cyclobutane, cyclopentane, and cyclohexane; the unsaturated cycloalkyl group is, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc., and optionally, one, two or more carbon atoms in the ring are independently substituted by N, O, B, or S.

[0089] In the present invention, as one embodiment, the fused ring or ring system includes an aryl group or a fused ring aryl group, which includes, but is not limited to, substituted or unsubstituted phenyl, naphthyl, indolyl, indazolyl, pyrazole, imidazole, thiazole, thiophene, pyrimidine, pyrrole, oxazole, isoxazole, triazolyl, tetrazolyl, furan, pyridine, pyrazine, piperidine, piperazine, morpholine, dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0090] In the present invention, as one embodiment, the aromatic hetero group refers to one, two or more carbon atoms in the above aromatic ring being independently substituted by N, O, B or S.

[0091] In the present invention, as one of the embodiments, the halogenated alkyl group, as an exemplary illustration, is a halogenated methyl group, a halogenated ethyl group, a halogenated propyl group, a halogenated butyl group, a halogenated pentyl group, a halogenated cyclopentyl group, a halogenated hexyl group, and the halogen group is fluorine, chlorine, bromine, iodine or boron.

[0092] In the present invention, as one embodiment, the alkoxy group can be, for example, a methoxy group, an ethoxy group, a propoxy group, a pentyloxy group, or a cyclohexyloxy group.

[0093] In the present invention, as one embodiment, the β-lactamase inhibitor is a compound represented by Formula I-1, or an optical isomer or a pharmaceutically acceptable salt thereof.

[0094] In the present invention, as one embodiment, the β-lactamase inhibitor is a compound represented by formula I-1, or an optical isomer or a pharmaceutically acceptable salt thereof.

[0095] Said R5 and R6 are defined above;

[0096] The L1 and L2 are defined above;

[0097] Said R1 and R2 are as defined above;

[0098] Said R7 is defined above;

[0099] The L4 is defined above;

[0100] Said R4 is defined above;

[0101] In the present invention, as one embodiment, the compound represented by formula I-1, or its optical isomers or pharmaceutically acceptable salts

[0102] in,

[0103] The R5, R6 and the atoms to which they are attached together form a cyclopropyl group;

[0104] The L1 and L2 are each independently a single bond;

[0105] Said R1 and R2 are each independently H;

[0106] R7 is selected from carboxyl, sulfonic acid, amide, sulfonamide, or tetrazole;

[0107] The L4 is -CR a R b -, -S-, halogen;

[0108] The R4 is H, alkyl, cycloalkyl, halogenated alkoxy, or alkoxy.

[0109] In the present invention, as one embodiment, the β-lactamase inhibitor is a compound represented by formula I-2, or an optical isomer or a pharmaceutically acceptable salt thereof:

[0110] The L4 is defined above;

[0111] Said R4 is defined above;

[0112] Said R7 is defined above;

[0113] The R a 、R b As defined above.

[0114] In the present invention, as one embodiment, the β-lactamase inhibitor is a compound represented by formula I-2, or an optical isomer or a pharmaceutically acceptable salt thereof.

[0115] in,

[0116] The L4 is -CR a R b -;

[0117] Said R4 is selected from -OCH2CH2F, -OCH3, or -OCH2CH3;

[0118] The R7 is a carboxyl group;

[0119] The R a 、R b For H.

[0120] In the present invention, as one embodiment, the compound represented by formula I-2 is selected from the following compounds, or optical isomers or pharmaceutically acceptable salts thereof:

[0121] In the present invention, as one embodiment, the β-lactamase inhibitor is selected from the following compounds, or optical isomers or pharmaceutically acceptable salts thereof:

[0122] In the present invention, as one embodiment, the pharmaceutically acceptable salt of the β-lactamase inhibitor is an organic salt, an inorganic salt or an amino acid salt.

[0123] In the present invention, as one of the embodiments, the β-lactamase inhibitor, the pharmaceutically acceptable salt is an inorganic salt selected from sodium salt.

[0124] In the present invention, as one of the embodiments, there is also provided a pharmaceutical composition comprising the compound of formula (I), its optical isomers or pharmaceutically acceptable salts and a β-lactamase antibacterial agent;

[0125] In the present invention, as one of the embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0126] In the present invention, as one of the embodiments, the β-lactamase antibacterial agent is meropenem, biapenem or imipenem; preferably meropenem.

[0127] In the present invention, as one of the embodiments, the present invention also provides a use of the compound, or its optical isomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a drug for treating bacterial infection diseases.

[0128] In the present invention, as one embodiment, the bacterial infection-related disease is caused by bacteria expressing β-lactamase.

[0129] In the present invention, as one embodiment, the bacterial infection-related disease is caused by Klebsiella pneumoniae.

[0130] The present invention discloses a boric acid β-lactamase inhibitor with good water solubility, excellent pharmacokinetic properties, and good drugability. The boric acid β-lactamase inhibitor has good inhibitory activity against A, B, C, and D β-lactamases and can produce strong antibacterial activity when used in combination with antibiotics, especially against carbapenem-resistant Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and other bacteria. The boric acid β-lactamase inhibitor is used to treat diseases related to bacterial infections.

[0131] Definition and Description

[0132] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0133] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0134] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0135] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0136] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0137] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0138] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0139] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0140] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0141] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0142] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.

[0143] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0144] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0145] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0146] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium (3H), iodine-125 (125I), or C-14 (14C). As another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and extended drug biological half-life. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0147] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0148] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0149] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0150] When a substituent is -(CH)O-, it means that the substituent is absent. When the substituent is listed without specifying the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom thereof. For example, tetrazole as a substituent can be bonded to the substituted group through any nitrogen atom of tetrazole.

[0151] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0152] Unless otherwise specified, "B" in the present invention represents boron.

[0153] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "5-7 membered ring" refers to a "ring" having 5, 6, or 7 atoms arranged around it.

[0154] Unless otherwise specified, a "3-8 membered ring" refers to a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl group consisting of 3, 4, 5, 6, 7, or 8 ring atoms. The ring includes a monocyclic ring and also includes bicyclic ring systems such as spirocyclic, fused rings and bridged rings. Unless otherwise specified, the ring optionally contains 1, 2 or more heteroatoms independently selected from N, O, B, and S. The 3-8 membered ring includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, and 8-membered rings. "3-8 membered rings" include, for example, phenyl, pyridyl, and piperidyl; on the other hand, the term "3-8 membered heterocycloalkyl" includes piperidyl and the like. The term "ring" also includes a ring system containing at least one ring, each of which independently meets the above definition.

[0155] Unless otherwise specified, the term “C 1-8 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 8 carbon atoms. 1-8 Alkyl groups include C 1-7 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-8 、C 2-6 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-8 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, octyl, and the like.

[0156] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0157] Unless otherwise specified, “C 3-8 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3, 4, 5, 6, 7, or 8 carbon atoms, which is a monocyclic or bicyclic ring system. 3-8 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0158] For example, C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0159] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0160] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art.

[0161] The solvents used in the present invention can be obtained commercially. The present invention uses the following abbreviations: eq stands for equivalent; aq stands for water; Cu(I)-NHC stands for monovalent copper-nitrogen heterocyclic carbene complex; Ti(OiPr)4 stands for tetraisopropyl titanate; HATU stands for O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; m-CPBA stands for 3-chloroperoxybenzoic acid; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butyloxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; RT stands for room temperature; THF stands for tetrahydrofuran ; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; TFAA represents trifluoroacetic anhydride; TES represents tris ethanesulfonic acid; DIPEA represents diisopropylethylamine; SOCl2 represents thionyl chloride; TsOH represents p-toluenesulfonic acid; NCS represents 1-chloropyrrolidine-2,5-dione; iPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamide; Pd(dppf)Cl2.CH2Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; EDCI represents carbodiimide; DIEA represents N,N-diisopropylethylamine; IPA represents isopropanol; HOBt represents 1-hydroxybenzotriazole; KOAc represents potassium acetate; K2CO3 represents potassium carbonate; K3PO4 represents potassium phosphate; XPhos Pd G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II); t-BuOH represents tert-butanol; Et3N represents triethylamine; Pd / C represents palladium on carbon; MeCN represents acetonitrile; PdCl2(MeCN)2 represents bis(acetonitrile)palladium chloride; PCy3 represents tricyclohexylphosphine; DPPF represents diphenylphosphinoferrocene; Cs2CO3 represents cesium carbonate; Me3O + BF4 -stands for trimethyltinium tetrafluoroboric acid; BH3DMS stands for borane dimethyl sulfide complex; DMAP stands for 4-dimethylaminopyridine; LDA stands for lithium diisopropylamide; DIEA stands for N,N-diisopropylethylamine; EOMCl stands for chloromethyl ethyl ether; SFC stands for supercritical fluid chromatography; MeOD stands for deuterated methanol; D2O stands for heavy water; PdCl2(MeCN)2 stands for dichlorobis(acetonitrile)palladium; NBS stands for N-bromosuccinimide; AIBN stands for azobisisobutyronitrile; BPO stands for dibenzoyl peroxide; CDCl3 stands for deuterated chloroform; BnBr stands for benzyl bromide; AcOH stands for acetic acid; DMAP stands for 4-dimethylaminopyridine; MOMBr stands for bromomethyl methyl ether; TBSCI stands for tert-butyldimethylchlorosilane; TBAF stands for tetra-n-butylammonium fluoride; t-Bu3P stands for tri-tert-butylphosphine; Et3N stands for triethylamine; P d(t-Bu3P)2 represents di(tri-tert-butylphosphine)palladium; iBuB(OH)2 represents isobutylboronic acid; BH3-SMe2 represents borane dimethyl sulfide; BnOH represents benzyl alcohol; Pd(PPh3)4 represents tetrakistriphenylphosphine palladium; KOAc represents potassium acetate; MeMgBr represents methylmagnesium bromide; DME represents ethylene glycol dimethyl ether; con represents concentrated solution; PhNTf2 represents phenylbis(trifluoromethanesulfonyl)imide; PPTS represents pyridine p-toluenesulfonate; STAB represents sodium triacetoxyborohydride; Pd2(dba)3 represents trisdibenzylideneacetone dipalladium; Cy2NMe represents N,N-dicyclohexylmethylamine; tBu3PBHF4 represents tributylphosphine tetrafluoroborate, Ir(ppy)3 represents tris(2-phenylpyridine)iridium; TEMPO represents 2,2,6,6-tetramethylpiperidinium oxide; and DCE represents dichloroethane.

[0162] Compounds are manually or Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0163] The following examples are used to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.

[0164] Example 1

[0165] Step 1: Preparation of compound 1-2

[0166] Compound 1-1 (5.00 g, 59.4 mmol, 1.00 eq) and N,N-diisopropylethylamine (7.69 g, 59.4 mmol, 10.3 mL, 1.00 eq) were dissolved in dichloromethane (30.0 mL), and benzyl bromide (15.2 g, 89.2 mmol, 10.6 mL, 1.50 eq) was added at 0°C. The mixture was warmed to 25°C and allowed to react for 3 h. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to afford compound 1-2 (7.90 g, 45.3 mmol, 76.2% yield) as a light yellow oil. LCMS: EC2514-5-P1B, RT = 0.485 min, m / z = 175.2 (M+H) + .

[0167] Step 2: Preparation of compound 1-3

[0168] Compound 1-2 (1.00 g, 5.74 mmol, 1.00 eq) and tetramethylethylenediamine (751 mg, 6.47 mmol, 976 uL, 1.13 eq) were dissolved in tetrahydrofuran (30.0 mL), and n-butyllithium (2.50 M, 2.53 mL, 1.10 eq) was added dropwise at -78 °C. The mixture was stirred at this temperature for 1 h. After 1 h, N,N-dimethylformamide (2.10 g, 28.7 mmol, 2.21 mL, 5.00 eq) was added. The mixture was stirred at 25 °C for 1 h. The mixture was analyzed by TLC (petroleum ether: ethyl acetate = 5:1, R1 (R f =0.6),P1(R f =0.7)) to detect completion of the reaction. Ammonium chloride solution (10.0 mL) was added at 25°C to quench the reaction, which was then diluted with purified water (20.0 mL) and extracted three times with ethyl acetate (20.0 mL). The combined organic phases were collected and washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, and filtered. The residue was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 50:1) to obtain compound 1-3 (800 mg, 3.96 mmol, 68.9% yield) as a colorless oil.

[0169] 1 HNMR: EC2523-10-P1A2 (CDCl3, 400MHz) δ 9.55-9.39 (m, 1H), 7.36-7.29 (m, 5H), 6.63 (d, J = 2.5Hz, 1H), 5.38 (s, 2H), 5.26 (s, 1H).

[0170] Step 3: Preparation of compound 1-4

[0171] Compound 1-3 (0.500 g, 2.47 mmol, 1.00 eq) was dissolved in tetrahydrofuran (2.00 mL), and compound 1-3a (1.00 M, 7.42 mL, 3.00 eq) was added. The mixture was stirred at 0°C for 1 h and the reaction was monitored by LCMS (EC2523-68-P1A1). After the reaction was completed, ammonium chloride solution (10.0 mL) was added at 0°C to quench the reaction and the mixture was extracted three times with ethyl acetate (20.0 mL). The organic phases were collected and washed with saturated sodium chloride aqueous solution (20.0 mL), dried over anhydrous sodium sulfate, and the organic layer was collected by filtration. The residue was collected by vacuum concentration and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1, petroleum ether: ethyl acetate = 10:1, P1 (R f =0.3)) to separate and purify to obtain compound 1-4 (400 mg, 1.64 mmol, yield 66.2%) as a yellow oil.

[0172] LCMS: EC2523-68-P1A1, RT=0.439min, m / z=245.1(M+H) + ; 1 HNMR: EC2523-68-P1A1 (CDCl3, 400MHz) δ7.43-7.36 (m, 3H), 7.35-7.30 (m, 2H), 7.30-7.26 (m, 1H), 6.08 (d, J = 2. 3Hz,1H),5.75-5.61(m,1H),5.37(d,J=4.6Hz,2H),5.13(s,1H),5.11-5.07(m,1H),4.52-4.45(m,1H),2.44(br d,J=7.5Hz,1H),2.35(br d,J=1.1Hz,1H).

[0173] Step 4: Preparation of compound 1-5

[0174] Compound 1-4 (1.00 g, 4.09 mmol, 1.00 eq) was dissolved in toluene (30.0 mL), and Grubbs' first-generation catalyst (336 mg, 409 umol, 0.100 eq) and compound 1-4a (1.88 g, 10.2 mmol, 2.50 eq) were added. The mixture was stirred at 70°C for 12 h. LCMS (EC2523-68-P1A1) revealed approximately 20.4% of the desired product and approximately 24.5% of the substrate. The residue was collected by vacuum concentration and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1). The TLC plate (petroleum ether:ethyl acetate = 3:1, P1(R f=0.25)). Compound 1-5 (940 mg, crude product) was obtained as a brown oil. LCMS: EC2523-109-P1A1, RT=0.912 min, m / z=271.2 (M+H) + .

[0175] Step 5: Preparation of compound 1-6

[0176] Compound 1-5 (350 mg, 1.30 mmol, 1.00 eq) and palladium acetate (14.5 mg, 64.8 umol, 0.050 eq) were dissolved in tetrahydrofuran (2.00 mL), and diazomethane (1.00 M, 13.0 mL, 10.0 eq) was slowly added. The mixture was stirred at -40°C for 2 h. The reaction system was slowly warmed to 25°C and stirred for 2 h. The desired product was detected by LCMS (EC2523-68-P1A1). The residue was concentrated in vacuo and collected to give compound 1-6 (350 mg, crude product) as a brown oil. LCMS: EC2523-112-P1A1, RT = 0.196 min, m / z = 285.2 (M+H) + .

[0177] Step 6: Preparation of compound 1

[0178] Compound 1-6 (350 mg, 1.23 mmol, 1.00 eq) and palladium on carbon (14.5 mg, 64.8 umol, 0.050 eq) were dissolved in methanol (3.00 mL) and stirred at 25°C under a stream of hydrogen (15 psi) for 1 h. The desired product was detected by LCMS (EC2523-68-P1A1). The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford Compound 1 as a white solid (31.1 mg, 152 umol, 12.3% yield, 94.6% purity).

[0179] 1 HNMR:EC2523-113-P1A1(MeOD,400MHz)δ7.12(d,J=2.3Hz,1H),6.20-6.16(m,1H),4.71-4.50(m,1H),2.19(br d,J=13.9Hz,1H),2.09-1.99(m,1H),1.53-1.44(m,1H),1.02(br d, J=2.0Hz, 1H), 0.86-0.76 (m, 1H), 0.04 (dt, J=5.7, 9.3Hz, 1H); LCMS: EC2523-113-P1B2, RT=0.290min, m / z=195.1(M+H)+ ; HPLC: EC2523-113-P1B1, RT=1.186min, purity: 94.6%.

[0180] Example 2

[0181] Compound 1-5 from Example 1 (70.0 mg, 259 μmol, 1.00 eq) and 10.0% palladium on carbon (50.0 mg, 259 μmol, 1.00 eq) were dissolved in methanol (2.00 mL) and stirred at 25°C under a stream of hydrogen (15 psi) for 1 h. The desired product was detected by LCMS (EC2523-68-P1A1). The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford Compound 2 as a gray solid (31.1 mg, 152 μmol, 6.79% yield, 94.6% purity).

[0182] 1 HNMR: EC2523-104-P1A1 (MeOD, 400MHz) δ7.14 (d, J = 2.1Hz, 1H), 6.15 (s, 1H), 2.10-1.98 (m, 1H) ,1.86-1.56(m,3H),1.00-0.77(m,2H);LCMS:EC2523-104-P1S2,RT=0.316min,m / z=183.0(M+H) + ; HPLC: EC2523-104-P1S1, RT=0.921min, purity: 94.5%.

[0183] Example 3

[0184] Step 1: Preparation of compound 3-2

[0185] Compound 3-1 (50.0 g, 261.7 mmol, 1 eq), triethylamine (52.9 g, 523.57 mmol, 72.8 mL, 2 eq), and 4-dimethylaminopyridine (1.60 g, 13.0 mmol, 0.05 eq) were dissolved in tetrahydrofuran (500 mL). Di-tert-butyl dicarbonate (57.1 g, 261.7 mmol, 60.1 mL, 1 eq) was added in several portions at 25°C. Stirring was continued for 16 h. The residue was collected by vacuum concentration and purified by flash silica gel chromatography to obtain compound 3-2 (71.0 g, crude product) as a yellow oil.

[0186] 1HNMR: ES20989-56-P1A (CDCl3, 400MHz) δ7.57 (dd, J = 5.8, 8.9 Hz, 1H), 7.02 (dd, J = 2.9, 8.7 Hz, 1H), 6.91 (ddd, J = 2.9, 7.8, 8.9 Hz, 1H), 1.67-1.50 (m, 9H).

[0187] Step 2: Preparation of compound 3-3

[0188] Compound 3-2 (71.0 g, 243.8 mmol, 1 eq) was dissolved in tetrahydrofuran (280 mL). This mixture was then added to lithium diisopropylamide (2 M, 146.3 mL, 1.2 eq) in tetrahydrofuran (450 mL) at -78°C. After 0.5 h, the reaction system was warmed to 25°C and stirred for 16 h. At 0°C, cooled saturated ammonium chloride solution (800 mL) was slowly added to the reaction system, followed by extraction twice with ethyl acetate (500 mL). The collected organic layer was washed twice with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 3-3 (63.0 g, 216.41 mmol, 88.73% yield) as a yellow oil. 1 HNMR: ES20989-57-P1A (CDCl3, 400MHz) δ 12.27 (s, 1H), 7.62 (dd, J = 5.4, 8.9Hz, 1H), 6.55 (dd, J = 8.9, 10.4Hz, 1H), 1.72-1.54 (m, 9H).

[0189] Step 3: Preparation of compound 3-4

[0190] Compound 3-3 (63.0 g, 216.41 mmol, 1 eq) was dissolved in dichloromethane (400 mL). Trifluoroacetic acid (100 mL) was added at 25°C and stirred for 10 h. The residue was collected by vacuum concentration, and petroleum ether (200 mL) was added at 25°C and triturated for 3 h. The crude product was concentrated and dried under vacuum to afford compound 3-4 (47.0 g, 199.9 mmol, 92.41% yield) as a yellow solid. 1 HNMR: ES20989-57-P1A (DMSO-d6, 400MHz) δ 7.80 (dd, J = 5.7, 8.9 Hz, 1H), 6.78 (dd, J = 9.0, 10.3 Hz, 1H).

[0191] Step 4: Preparation of compound 3-5

[0192] Compound 3-4 (50.0 g, 261.7 mmol, 1 eq), benzyl bromide (35.2 g, 205.5 mmol, 24.4 mL, 2.2 eq), and potassium carbonate (38.8 g, 280.8 mmol, 3 eq) were dissolved in acetonitrile (500 mL) and stirred at 80°C for 3 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 3-5 (65 g, 156.5 mmol, 78.14% yield) as a yellow oil.

[0193] 1 HNMR: ES20989-60-P1A (CDCl3, 400MHz) δ7.64 (dd, J=5.9, 8.9Hz, 1H), 7.49-7.31 (m, 10H), 6.89 (t, J=8.7Hz, 1H), 5.36 (s, 2H), 5.09 (s, 2H).

[0194] Step 5: Preparation of compound 3-6

[0195] Compound 3-5 (46.0 g, 110.78 mmol, 1 eq), potassium ethylene trifluoroborate (22.26 g, 166.16 mmol, 1.5 eq), triethylamine (22.42 g, 221.55 mmol, 30.84 mL, 2 eq), and DPPF palladium dichloride (4.05 g, 5.54 mmol, 0.05 eq) were dissolved in acetonitrile (800 mL) and heated to 95°C under nitrogen with continuous stirring for 16 h. The mixture was treated with ethyl acetate (1000 mL) and water (1000 mL), and the organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford compound 3-6 as a yellow solid (20.0 g, 55.19 mmol, 49.82% yield).

[0196] 1 HNMR: ES20989-68-P1A(CDCl3,400MHz)δ7.65-7.56(m,1H),7.51-7.23(m,10H),7.02-6.84(m,2H),5.75(br d,J=17.6Hz,1H),5.46-5.30(m,3H),5.04-4.90(m,2H)

[0197] Step 6: Preparation of compound 3-7

[0198] Bisacetonitrile palladium chloride (178.97 mg, 689.86 μmol, 0.05 eq) and p-benzoquinone (1.64 g, 15.18 mmol, 3.42 mL, 1.1 eq) were added to a mixture of purified water (248.63 mg, 13.80 mmol, 248.63 μL, 1 eq) and compound 3-6 (5.0 g, 13.80 mmol, 1 eq) at 85°C and stirred for 2 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash silica gel chromatography to afford compound 3-7 (1.6 g, 4.23 mmol, 30.65% yield) as a yellow oil.

[0199] 1 HNMR: ES20989-69-P1A (CDCl3, 400MHz) δ9.60 (t, J = 1.7Hz, 1H), 7.50-7.18 (m, 11H), 6.95 (t, J = 8.7Hz, 1H), 5.39 (s, 2H), 4.87 (s, 2H), 3.61 (d, J = 1.3Hz, 2H).

[0200] Step 7: Preparation of compound 3-8

[0201] Compound 3-7 (8.3 g, 21.93 mmol, 1 eq) and tert-butylsulfenamide (3.19 g, 26.32 mmol, 1.2 eq) were dissolved in tetrahydrofuran (160 mL), and tetraisopropyl titanate (12.47 g, 43.87 mmol, 12.95 mL, 2 eq) was added. Stirring was continued at 25 ° C for 16 h, quenched with saturated brine (30 mL), filtered through celite and extracted twice with ethyl acetate (100 mL). The organic phase was collected and concentrated in vacuo. The residue was separated and purified by flash silica gel chromatography to obtain yellow oily compound 3-8 (7.48 g, 15.53 mmol, yield 70.81%).

[0202] 1 HNMR: ES20989-72-P1A (CDCl3, 400MHz) δ8.03 (t, J=4.6Hz, 1H), 7.46-7.22 (m, 12H), 6.92 (t, J=8.6Hz, 1H), 5.38 (s, 2H), 4.91 (d, J= 2.0Hz, 2H), 3.76 (d, J= 4.5Hz, 2H), 1.23-1.07 (m, 9H).

[0203] Step 8: Preparation of compound 3-9

[0204] Compound 3-8 (2.0 g, 4.15 mmol, 1 eq), bis(1S,2S,3R,5S)(+)-pinanediol diboron ester (1.78 g, 4.98 mmol, 1.2 eq), and Cu(I)-NHC (153.25 mg, 415.30 umol, 0.1 eq) were dissolved in toluene (20 mL) and stirred at 25°C under nitrogen for 16 h. The mixture was filtered through celite, and the organic phase was collected and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 3-9 (1.15 g, 1.74 mmol, 41.85% yield) as a yellow oil. 1 HNMR: ES20989-77-P1A (CDCl3, 400MHz) δ7.52-7.31 (m, 11H), 6.89 (t, J = 8.7Hz, 1H), 6.96-6.83 (m, 1 H),5.34(s,2H),4.99-4.88(m,2H),4.03(dd,J=1.6,8.7Hz,1H),3.40(q,J=7.1Hz,1H),3.27(d,J=7 .5Hz,1H),3.19-3.06(m,1H),3.06-2.92(m,1H),2.27-2.14(m,1H),2.13-2.01(m,1H),2.00-1.80( m,3H),1.79-1.63(m,2H),1.23(d,J=9.5Hz,6H),1.17-1.08(m,9H),0.97-0.89(m,1H),0.76(s,3H).

[0205] Step 9: Preparation of compound 3-10

[0206] Compound 3-9 (400.0 mg, 604.57 μmol, 1 eq) was dissolved in 1,4-dioxane (6 mL). A 4M hydrogen chloride / 1,4-dioxane solution (453.4 μL, 3 eq) was added at 25°C and stirred for 4 h. Petroleum ether (5 mL) was added to the residue obtained by vacuum concentration. After 16 h, the solid was collected by filtration and dried under vacuum to obtain the crude product, which was used directly in the next reaction to obtain compound 3-10 (345.0 mg, crude product, HCl) as a yellow solid.

[0207] 1HNMR:ES20989-87-P1A(DMSO-d6,400MHz)δ7.89(br s,2H),7.49(dd,J=6.8,8.6Hz,1H),7.44-7.29(m,9H),7.14(t,J=8.9Hz,1H),5.45-5.28(m,2H),4.96-4.79(m,2H),4.21(br d,J=7.1Hz,1H),3.14-2.89(m,3H),2.28-2.12(m,1H),2.11-1.97(m,1H),1.94-1.84(m,1H), 1.82-1.51(m,3H),1.23(d,J=15.9Hz,6H),1.14-1.01(m,3H),0.97-0.86(m,1H),0.75(s,3H).

[0208] Step 10: Preparation of compound 3-11

[0209] Compound 3-10 (100.0 mg, 168.3 μmol, 1 eq, HCl) and triethylamine (34.0 mg, 336.7 μmol, 46.8 μL, 2 eq) were dissolved in dichloromethane (2 mL). Benzoyl chloride (28.4 mg, 202.0 μmol, 23.4 μL, 1.2 eq) was added at 25°C and stirred for 16 h. The resulting residue was concentrated in vacuo and purified by flash silica gel chromatography to afford compound 3-11 (50.0 mg, crude product) as a yellow oil.

[0210] 1 HNMR: ES20989-93-P1A (CDCl3, 400MHz) δ7.60-7.18 (m, 17H), 6.92 (t, J=8. 6Hz,1H),5.46-5.31(m,2H),5.05-4.89(m,2H),4.35-4.24(m,1H),3.10-2 .91(m,3H),2.49-2.33(m,1H),2.26-2.11(m,1H),2.04(t,J=5.4Hz,1H),1 .96-1.82(m,2H),1.55-1.43(m,5H),1.35-1.23(m,6H),0.97-0.83(m,6H).

[0211] Step 11: Preparation of compound 3-12

[0212] Compound 3-11 (50.0 mg, 75.58 μmol, 1 eq) and 10% palladium on carbon (40.0 mg, 75.58 μmol, 1 eq) were dissolved in methanol (5 mL) and stirred at 30°C under hydrogen (1.52 mg, 755.78 μmol, 10 eq) / (15 PSI) for 16 h. The organic phase was collected by filtration through celite and concentrated in vacuo to afford compound 3-12 (40.0 mg, crude product) as a yellow oil.

[0213] Step 12: Preparation of compound 3

[0214] Compound 3-12 (35.0 mg, 72.72 μmol, 1 eq) was dissolved in acetonitrile (0.3 mL) and water (0.3 mL). Triethylsilane (3.33 mg, 14.54 μmol, 0.2 eq), trifluoroacetic acid (1.66 mg, 14.54 μmol, 1.08 μL, 0.2 eq), and isobutylboronic acid (14.83 mg, 145.43 μmol, 2 eq) were added at 25°C and stirred for 16 h at 25°C. The pH was adjusted to 14 with 1N sodium hydroxide and extracted three times with dichloromethane (5 mL). The aqueous phase was adjusted to pH 3 with 1N hydrogen chloride and extracted twice with dichloromethane (10 mL). The mixture was dried over anhydrous sodium sulfate, collected by filtration, and concentrated in vacuo to afford compound 3 as a white solid (4.1 mg, 11.59 μmol, 15.93% yield, 93% purity). 1HNMR: ES20989-99-P1A (MeOH, 400MHz) δ7.94-7.85 (m, 2H), 7.73-7.65 (m, 1H), 7.57-7.48 (m, 2H), 7.12 (dd, J=6.5, 8.1Hz, 1H), 6.58 (dd, J=8.4, 9.8Hz, 1H), 3.37 (s, 1H), 2.98 (d, J=3.3Hz, 2H); HPLC: ES20989-99-P1A, RT=5.329min, purity: 93.9%. LCMS: ES20989-99-P1C, RT=0.577min,, m / z=329.09(M+H) + .

[0215] Example 4

[0216] Step 1: Preparation of compound 4-1

[0217] Compound 3-10 (100.0 mg, 168.3 μmol, 1 eq, HCl) from Example 3 and triethylamine (34.0 mg, 336.7 μmol, 46.8 μL, 2 eq) were dissolved in dichloromethane (1 mL). Isopropyl isocyanate (17.2 mg, 202.0 μmol, 19.8 μL, 1.2 eq) was added at 25°C and stirred for 3 h. The mixture was washed with 1N hydrogen chloride (2 mL) and saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product, which was used directly in the next step, to obtain compound 4-1 (110.0 mg, crude) as a yellow solid.

[0218] Step 2: Preparation of compound 4-2

[0219] Compound 4-1 (110.0 mg, 171.19 μmol, 1 eq) and 10% palladium on carbon (50.0 mg, 171.19 μmol, 1 eq) were dissolved in methanol (4 mL) and stirred at 30°C under a flow of hydrogen (345.08 μg, 171.19 μmol, 1 eq) / (15 PSI) for 16 h. The organic phase was collected by filtration through celite and concentrated in vacuo to afford compound 4-2 (85.0 mg, crude product) as a yellow oil.

[0220] Step 3: Preparation of compound 4

[0221] Compound 4-2 (85.0 mg, 183.86 μmol, 1 eq) was dissolved in acetonitrile (1 mL) and water (1 mL). Trifluoroacetic acid (4.19 mg, 36.77 μmol, 2.72 μL, 0.2 eq), isobutylboronic acid (37.48 mg, 367.71 μmol, 2 eq), and triethylsilane (8.43 mg, 36.77 μmol, 0.2 eq) were added at 25°C and stirred for 16 h. The pH was adjusted to 14 with 1N sodium hydroxide and extracted three times with dichloromethane (5 mL). The aqueous phase was adjusted to pH 3 with 1N hydrogen chloride and extracted twice with dichloromethane (10 mL). The aqueous phase was freeze-dried and the resulting residue was purified by preparative HPLC to afford compound 4 as a white solid (1.3 mg, 3.90 μmol, 2.12% yield, 93% purity).

[0222] 1HNMR: ES20989-125-P1A (MeOH, 400MHz) δ7.17 (br s, 1H), 6.64 (dd, J=8.4, 10.4Hz, 1H), 3.86-3.41 (m, 1H), 3.19-3.01 (m, 1H), 2.80 (br s, 2H), 1.21-0.89 (m, 6H); HPLC: ES20989-99-P1A, RT=6.065min, purity: 93.7%. LCMS: ES20989-99-P1C, RT=3.636min,, m / z=311.2(M+H) + .

[0223] Example 5

[0224] Step 1: Preparation of compound 5-2

[0225] Compound 5-1 (25 g, 115.2 mmol, 1 eq) was dissolved in N,N-dimethylformamide (250 mL). Potassium carbonate (63.6 g, 460.7 mmol, 4 eq) and benzyl bromide (43.3 g, 253.4 mmol, 30.1 mL, 2.2 eq) were added and stirred at 80°C for 4 h. Water (250 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (150 mL). The organic phase was collected and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 5-2 (41.5 g, 104.4 mmol, 90.6% yield) as a yellow oil. 1 HNMR: ES20978-163-P1 (DMSO, 400MHz) δ7.92 (dd, J=1.5, 8.0Hz, 1H), 7.79 (dd, J=1. 5,7.8Hz,1H),7.47-7.31(m,10H),7.23(t,J=7.9Hz,1H),5.33(s,2H),4.97(s,2H).

[0226] Step 2: Preparation of compound 5-3

[0227] Compound 5-2 (20.5 g, 51.7 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL) and water (20 mL). Potassium phosphate (32.9 g, 155.3 mmol, 3 eq), potassium ethylene trifluoroborate (10.4 g, 77.6 mmol, 1.5 eq), and XPhos Pd G3 (2.19 g, 2.59 mmol, 0.05 eq) were added under nitrogen. Stirring was continued at 80°C for 16 h. Water (300 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (200 mL). The organic phase was collected and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 5-3 (25 g, 72.5 mmol, 70.1% yield) as a yellow oil. 1 HNMR: ES20978-165-P1 (DMSO, 400MHz) δ7.86 (dd, J=1.5, 7.8Hz, 1H), 7.71 (dd, J=1.6, 7.7Hz, 1H), 7.48-7.31 (m, 10H), 7.27 ( t,J=7.8Hz,1H),6.96(dd,J=11.1,17.7Hz,1H),5.90(dd,J=1.0,17.7Hz,1H),5.44-5.37(m,1H),5.32(s,2H),4.85(s,2H).

[0228] Step 3: Preparation of compound 5-4

[0229] At 85°C, bis(acetonitrile)palladium dichloride (235.4 mg, 907.3 μmol, 0.05 eq) and 1,4-p-benzoquinone (2.16 g, 19.9 mmol, 4.50 mL, 1.1 eq) were added to tert-butanol (65 mL). Under nitrogen, pure water (326.9 mg, 18.1 mmol, 326.9 μL, 1 eq) and compound 5-3 (6.25 g, 18.1 mmol, 1 eq) were added. Stirring was continued at 85°C for 1 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 5-4 (12.3 g, 34.2 mmol, 47.1% yield) as a yellow oil. 1 HNMR: ES20978-167-P1(DMSO,400MHz)δ9.61(s,1H),7.75(dd,J=1.8,7.8Hz,1H),7.52(dd,J=1.7,7.6Hz,1H ),7.46-7.40(m,2H),7.39-7.30(m,9H),7.29-7.22(m,1H),5.33(s,2H),4.82(s,2H),3.79(d,J=0.8Hz,2H).

[0230] Step 4: Preparation of compound 5-5

[0231] Compound 5-4 (12.3 g, 34.2 mmol, 1 eq) was dissolved in tetrahydrofuran (120 mL), and tetraisopropyl titanate (19.4 g, 68.4 mmol, 20.2 mL, 2 eq) and tert-butylsulfenamide (4.98 g, 41.1 mmol, 1.2 eq) were added. Stirring was continued at 25°C for 16 h. Saturated brine (100 mL) was added, the mixture was filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 5-5 (9.4 g, 20.2 mmol, 59.2% yield) as a yellow oil. 1 HNMR: ES20978-171-P1 (DMSO, 400MHz) δ7.95 (t, J=4.3Hz, 1H), 7.73 (dd, J=1.8, 7.8Hz, 1H), 7.55 (dd, J=1.6, 7.6Hz, 1H), 7.46- 7.41(m,2H),7.39-7.31(m,8H),7.25(t,J=7.6Hz,1H),5.33(s,2H),4.87(d,J=1.6Hz,2H),3.89(d,J=4.3Hz,2H),0.99(s,9H).

[0232] Step 5: Preparation of compound 5-6

[0233] Compound 5-5 (1.00 g, 2.16 mmol, 1 eq) was dissolved in toluene (10 mL). Under nitrogen, Cu(I)-NHC (79.7 mg, 216.0 umol, 0.1 eq) and bis(1S,2S,3R,5S)(+)-pinanediol diboron ester (928.1 mg, 2.59 mmol, 1.2 eq) were added. Stirring was continued at 25°C for 16 h. The product was filtered through celite, and the organic phase was collected and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 5-6 (0.81 g, 1.26 mmol, 58.2% yield) as a yellow oil. 1HNMR: ES20978-181-P1 (DMSO, 400MHz) δ7.64 (dd, J=1.6, 7.8Hz, 1H), 7.51 (dd, J=1.6 ,7.6Hz,1H),7.42(td,J=2.2,4.8Hz,4H),7.39-7.29(m,6H),7.16(t,J=7.6Hz,1H), 5.76(s,1H),5.31(s,2H),4.94-4.85(m,3H),4.19-4.12(m,1H),3.27-3.15(m,1H), 3.08-2.90(m,2H),2.23-2.12(m,1H),1.98-1.81(m,2H),1.81-1.66(m,2H),1.58(br d,J=14.4Hz,1H),1.22-1.15(m,5H),1.03(s,7H),0.93(s,1H),0.83-0.68(m,4H).

[0234] Step 6: Preparation of Compound 5-7

[0235] Compound 5-6 (0.81 g, 1.26 mmol, 1 eq) was dissolved in 1,4-dioxane (10 mL). A hydrogen chloride / 1,4-dioxane solution (2 mL) was added at 25°C and stirred for 3 h. The reaction mixture was concentrated in vacuo, and petroleum ether was added to the crude product at 20°C. After 16 h, compound 5-7 (610.0 mg, 84.1% yield, HCl) was obtained as a yellow oil. 1 HNMR: ES20978-183-P1 (DMSO, 400MHz) δ7.71 (dd, J=1.5, 7.8Hz, 1H), 7.56-7.49 (m, 1H), 7. 47-7.29(m,10H),7.22(t,J=7.7Hz,1H),5.38-5.27(m,2H),4.96-4.78(m,2H),3.14-2.94 (m,2H),2.26-2.13(m,1H),2.07-1.96(m,1H),1.93-1.83(m,1H),1.81-1.54(m,3H),1.30 -1.18(m,6H),1.14-1.08(m,1H),1.04(s,1H),0.93(d,J=10.9Hz,1H),0.81-0.71(m,3H).

[0236] Step 7: Preparation of Compound 5-8

[0237] Dissolve benzoyl chloride (29.2 mg, 208.3 μmol, 24.2 μL, 1.2 eq) in dichloromethane (1 mL), add triethylamine (26.3 mg, 260.4 μmol, 36.2 μL, 1.5 eq) and compound 5-7 (100 mg, 173.6 μmol, 1 eq, HCl). Stir at 25°C for 1 h. Wash twice with saturated brine (5 mL), dry over anhydrous sodium sulfate, collect the organic phase by filtration, and concentrate in vacuo to obtain the crude product, which can be used directly in the next reaction to obtain compound 5-8 (73 mg, 113.4 μmol, 65.3% yield) as a yellow oil. 1 HNMR: ES20978-190-P1(CDCl3,400MHz)δ7.86-7.77(m,2H),7.59-7.32(m,15H),7 .24-7.13(m,3H),5.38(s,2H),5.10-4.99(m,1H),4.89(d,J=10.0Hz,1H),4.29(br d,J=8.1Hz,1H),3.13-2.98(m,3H),2.45-2.33(m,1H),2.16(br s,1H),2.03(br t,J=5.3Hz,1H),1.97-1.83(m,2H),1.62-1.50(m,4H),1.36-1.24(m,3H),0.98-0.86(m,3H).

[0238] Step 8: Preparation of compound 5-9

[0239] Compound 5-8 (73.0 mg, 113.43 μmol, 1 eq) was dissolved in methanol (5 mL). 10% palladium on carbon was added and hydrogen (228.6 μg, 113.4 μmol, 1 eq) was added. Stirring was continued at 25°C for 16 h. Concentration in vacuo afforded the crude product, which was used directly in the next reaction to afford compound 5-9 (40 mg, 86.3 μmol, 76.1% yield) as a yellow oil. 1 HNMR: ES20978-191-P1 (DMSO, 400MHz) δ7.91-7.78 (m, 4H), 7.67-7.27 (m, 10H), 3.17 (s, 2H), 1.40-0.74 (m, 17H).

[0240] Step 9: Preparation of compound 5

[0241] Compound 5-9 (40 mg, 86.3 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Isobutylboric acid (17.6 mg, 172.6 μmol, 2 eq), triethylsilane (3.96 mg, 17.2 μmol, 0.2 eq), and trifluoroacetic acid (1.97 mg, 17.2 μmol, 1.28 μL, 0.2 eq) were added at 25°C. Stirring was continued at 25°C for 16 h. The residue was collected by filtration and concentrated in vacuo. It was separated and purified by preparative HPLC to obtain compound 5 (3.3 mg, 10.6 μmol, 12.2% yield) as a white solid. 1 HNMR: ES20989-191-P1A (MeOD, 400MHz); LCMS: ES2089-191-P1A, RT=2.409min, m / z=312.1(M+Na) + .

[0242] Example 6

[0243] Step 1: Preparation of compound 6-2

[0244] Compound 6-1 (25.0 g, 115.2 mmol, 1 eq) was dissolved in trifluoroacetic acid (150 mL). Trifluoroacetic anhydride (100 mL) and acetone (75 mL) were added at 0°C and stirred at 110°C for 16 h. The residue was collected by vacuum concentration and purified by flash silica gel chromatography to obtain compound 6-2 (18 g, 70.0 mmol, 60.8% yield) as a yellow oil. 1 HNMR: ES20989-189-P1A (CDCl3, 400MHz) δ7.84 (dd, J=1.6, 7.8Hz, 1H), 7.69 (dd, J=1.6, 7.9Hz, 1H), 6.94 (t, J=7.8Hz, 1H), 1.72-1.69 (m, 1H), 1.70 (s, 5H).

[0245] Step 2: Preparation of compound 6-3

[0246] Compound 6-2 (5.00 g, 19.4 mmol, 1 eq), potassium ethylene trifluoroborate (3.91 g, 29.1 mmol, 1.5 eq), and potassium phosphate (12.3 g, 58.3 mmol, 3 eq) were dissolved in tetrahydrofuran (100 mL) and water (100 mL). Xphos-Pd-G3 (823.1 mg, 972.4 μmol, 0.05 eq) was added at 25°C under nitrogen. Stirring was continued at 80°C under nitrogen for 16 h. The residue was collected by vacuum concentration and purified by flash silica gel chromatography to obtain compound 6-3 (3.5 g, 17.1 mmol, 88.1% yield) as a yellow solid. 1 HNMR: ES20989-199-P1A (CDCl3, 400MHz) δ7.83 (d, J=1.5Hz, 1H), 7.65 (dd, J=1.6, 7.8Hz, 1H), 7.03 (t, J=7.8Hz ,1H),6.82(dd,J=11.3,17.8Hz,1H),5.76(dd,J=0.9,17.8Hz,1H),5.31(d,J=11.3Hz,1H),1.78-1.62(m,6H).

[0247] Step 3: Preparation of compound 6-4

[0248] To tert-butyl alcohol (40 mL) at 85°C was added bis(acetonitrile)palladium chloride (222.3 mg, 856.9 μmol, 0.05 eq) and 1,4-benzoquinone (2.04 g, 18.8 mmol, 4.25 mL, 1.1 eq). Water (308.8 mg, 17.1 mmol, 308.8 μL, 1 eq) and compound 6-3 (3.5 g, 17.1 mmol, 1 eq) were then added. Stirring was continued at 85°C for 30 minutes. The residue was collected by filtration and vacuum concentration and purified by flash silica gel chromatography to afford compound 6-4 (1.6 g, 7.27 mmol, 42.3% yield) as a yellow solid. 1 HNMR: ES20978-210-P1 (CDCl3, 400MHz) δ9.84-9.70 (m, 1H), 7.95 (dd, J=1.5, 7.8Hz, 1H) ,7.43(dd,J=1.2,7.4Hz,1H),7.14(t,J=7.6Hz,1H),3.75(d,J=1.0Hz,2H),1.74(s,6H).

[0249] Step 4: Preparation of compound 6-5

[0250] Compound 6-4 (1.6 g, 7.27 mmol, 1 eq) was dissolved in tert-butyl alcohol (10 mL) / purified water (10 mL) / tetrahydrofuran (20 mL), and sodium dihydrogen phosphate (8.72 g, 72.6 mmol, 10 eq) was added. The suspension was stirred for 10 minutes until completely dissolved, at which point the reaction system was cooled to 0°C. 2-Methyl-2-butene (5.10 g, 72.6 mmol, 7.70 mL, 10 eq) was then added, followed by a sodium chlorite solution (2.63 g, 29.0 mmol, 4 eq) in purified water (10 mL). Stirring was continued at 0°C for 3 hours. The reaction was quenched by the addition of solid sodium sulfite (500 mg) and purified water (30 mL), and stirring was continued at this temperature for 5 minutes. 1N hydrogen chloride was added to the reaction system, followed by extraction with ethyl acetate (30 mL) three times. The organic phases were collected and combined, washed with acidic brine (30 mL), and dried over anhydrous magnesium sulfate. The organic phases were collected by filtration and concentrated in vacuo to obtain a crude product, which was directly used in the next reaction. A yellow oily compound 6-5 (1.7 g, crude product) was obtained. 1 HNMR: ES20978-211-P1 (CDCl3, 400MHz) δ7.93 (dd, J=1.4, 7.8Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.11 (t, J=7.7Hz, 1H), 3.69 (s, 2H), 1.80-1.66 (m, 6H).

[0251] Step 5: Preparation of compound 6-6

[0252] Compound 6-5 (1.7 g, 7.20 mmol, 1 eq) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (3.98 g, 28.7 mmol, 4 eq) and benzyl bromide (1.48 g, 8.64 mmol, 1.03 mL, 1.2 eq) were added. Stirring was continued at 85°C for 3 h. Purified water (40 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 6-6 (1.7 g, 5.21 mmol, 72.38% yield) as a yellow oil. 1 HNMR: ES20978-214-P1 (CDCl3, 400MHz) δ7.79 (dd, J=1.3, 7.8Hz, 1H), 7.65 (d, J=7.5Hz, 1H ),7.41-7.30(m,5H),7.17(t,J=7.6Hz,1H),5.19-5.08(m,2H),3.77(s,2H),1.56(s,6H).

[0253] Step 6: Preparation of compound 6-7

[0254] Compound 6-6 (1.6 g, 4.90 mmol, 1 eq) was dissolved in 1,4-dioxane (15 mL), and potassium carbonate (813.1 mg, 5.88 mmol, 1.2 eq), formaldehyde (323.9 mg, 10.7 mmol, 297.1 uL, 2.2 eq), and tetrabutylammonium bromide (316.1 mg, 980.5 umol, 0.2 eq) were added. Stirring was continued at 100°C for 16 h. Purified water (30 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 6-7 (0.94 g, 2.78 mmol, 56.6% yield) as a yellow oil. 1 HNMR: ES20978-216-P1 (CDCl3, 400MHz) δ7.97 (dd, J=1.7, 7.8Hz, 1H), 7.50 (dd, J=1.7, 7.6Hz, 1H), 7.41-7 .32(m,5H),7.13(t,J=7.7Hz,1H),6.49(d,J=1.0Hz,1H),5.89(d,J=1.0Hz,1H),5.25(s,2H),1.59(s,6H).

[0255] Step 7: Preparation of Compound 6-8

[0256] At 25 ° C, under nitrogen protection, cuprous chloride (8.25 mg, 83.3 umol, 1.99 uL, 0.03 eq), tricyclohexylphosphine (46.7 mg, 166.6 umol, 54.0 uL, 0.06 eq), biboronic acid pinacol ester (1.06 g, 4.17 mmol, 1.5 eq) and sodium tert-butoxide (293.6 mg, 3.06 mmol, 1.1 eq) were dissolved in tetrahydrofuran (10 mL). After 3 minutes, methanol (89.0 mg, 2.78 mmol, 1 eq) containing compound 6-7 (0.94 g, 2.78 mmol, 1 eq) was added and stirring was continued at 25 ° C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to give compound 6-8 (0.62 g, 1.33 mmol, 47.8% yield) as a colorless oil. 1HNMR: ES20978-219-P1 (CDCl3, 400MHz) δ7.87 (dd, J=1.6, 7.9Hz, 1H), 7.50 (dd, J=1.5, 7.6Hz, 1H), 7.34-7.21 (m, 6H), 7.07 (t,J=7.7Hz,1H),5.18-5.01(m,2H),4.18-4.11(m,1H),1.62(d,J=12.4Hz,6H),1.31-1.23(m,2H),1.16(d,J=3.5Hz,12H).

[0257] Step 8: Preparation of Compound 6-9

[0258] Compound 6-8 (600.0 mg, 1.29 mmol, 1 eq) was dissolved in methanol (10 mL). 10% palladium hydroxide (72.00 mg, 51.27 umol, 3.98e-2 eq) was added at 25°C under nitrogen. Stirring was continued for 16 h at 25°C under a flow of hydrogen (25.94 mg, 12.87 mmol, 10 eq) / (15 psi). The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 6-9 (300.0 mg, 797.43 umol, 61.98% yield) as a white solid. 1 HNMR: ES20989-231-P1A (CDCl3, 400MHz) δ7.81 (dd, J=1.5, 7.9Hz, 1H), 7.44 (dd, J=1.3, 7.6Hz, 1H ), 7.01 (t, J = 7.7Hz, 1H), 4.10-3.98 (m, 1H), 1.67-1.60 (m, 6H), 1.56-1.44 (m, 2H), 1.09 (s, 12H).

[0259] Step 9: Preparation of compound 6-10

[0260] Compound 6-9 (100.0 mg, 265.81 umol, 1 eq) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (103.06 mg, 797.43 umol, 138.90 uL, 3 eq), methylamine (26.92 mg, 398.72 umol, 1.5 eq, HCl) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (111.18 mg, 292.39 umol, 1.1 eq) were added, and stirring was continued at 25 ° C for 2 h. Water (2 mL) was added to dilute the mixture, and the mixture was extracted three times with dichloromethane (2 mL). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to give compound 6-10 (70.0 mg, 179.83 umol, 67.65% yield) as a colorless oil. 1 HNMR: ES20989-234-P1A (CDCl3, 400MHz) δ7.89 (dd, J=1.5, 7.8Hz, 1H), 7.62 (dd, J=1.5, 7.8Hz, 1H), 7.13 (t, J=7.8Hz, 1H), 4.00 (t, J = 8.3Hz, 1H), 2.78 (d, J = 4.8Hz, 3H), 1.77 (d, J = 13.3Hz, 6H), 1.61-1.53 ​​(m, 2H), 1.19 (d, J = 4.0Hz, 12H).

[0261] Step 10: Preparation of compound 6

[0262] Compound 6-10 (70.0 mg, 179.83 μmol, 1 eq) was dissolved in acetonitrile (0.7 mL) and water (0.7 mL). Sodium hydroxide solution (3 M, 179.83 μL, 3 eq) was added. After 1 h, isobutylboronic acid (36.66 mg, 359.67 μmol, 2 eq) and hydrogen chloride solution (12 M, 749.31 μL, 50 eq) were added. Stirring was continued at 25°C for 16 h. The pH was adjusted to 10 with 1N sodium hydroxide, filtered, and the resulting residue was purified by preparative HPLC to obtain compound 6 (23.0 mg, 92.36 μmol, 51.36% yield) as a white solid. 1 HNMR: ES20989-238-P1B(D2O,400MHz)δ7.19-7.04(m,1H),6.94-6.79(m,1H),6.69-6.55(m,1H),3.60(br s,1H),2.67(s,3H),0.78-0.49(m,2H).

[0263] Example 7

[0264] Step 1: Preparation of compound 7-2

[0265] Compound 7-1 (5.00 g, 23.0 mmol, 1 eq) was dissolved in trifluoroacetic acid (30 mL). Trifluoroacetic anhydride (100 mL) and acetone (75 mL) were added at 0°C under nitrogen. Stirring was continued at 100°C for 16 h. The residue was collected by vacuum concentration and purified by flash silica gel chromatography to obtain compound 7-2 (4 g, 15.5 mmol, 67.5% yield) as a yellow solid. 1 HNMR: ES20978-45-P1 (DMSO, 400MHz) δ7.99 (dd, J = 1.5, 8.0 Hz, 1H), 7.88 (dd, J = 1.5, 7.8 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 1.77-1.69 (m, 6H).

[0266] Step 2: Preparation of compound 7-3

[0267] Compound 7-2 (1.85 g, 7.20 mmol, 1 eq) was dissolved in 1,4-dioxane (20 mL). DPPF palladium chloride (526.5 mg, 719.6 μmol, 0.1 eq), potassium acetate (1.41 g, 14.3 mmol, 2 eq), and biboronic acid pinacol ester (2.74 g, 10.7 mmol, 1.5 eq) were added under nitrogen. Stirring was continued at 100°C for 16 h. Water (30 mL) was added and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the residue. The residue was purified by flash silica gel chromatography to afford compound 7-3 (1.5 g, 4.93 mmol, 68.5% yield) as a pale yellow solid. 1 HNMR: ES20978-95-P1A (CDCl3, 400MHz) δ8.04 (dd, J = 1.9, 7.7Hz, 1H), 7.92 (dd, J = 1.8, 7.3Hz, 1H), 7.11 (t, J = 7.5Hz, 1H), 1.74 (s, 6H), 1.35 (s, 12H). Step 3: Preparation of compound 7-4

[0268] Compound 7-3 (1.50 g, 4.93 mmol, 1 eq) was dissolved in 1,4-dioxane (10 mL) and water (5 mL). 2-Bromoallyl alcohol (743.10 mg, 5.43 mmol, 1.1 eq), XPHOS-Pd-G3 (417.4 mg, 493.1 mmol, 0.1 eq), and cesium carbonate (3.21 g, 9.86 mmol, 2 eq) were added under nitrogen. Stirring was continued at 60°C for 16 h. Water (40 mL) was added and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the residue. The residue was purified by flash silica gel chromatography to obtain compound 7-4 (0.9 g, 3.84 mmol, 77.90% yield) as a yellow solid.

[0269] 1 HNMR: ES20978-102-P1A (CDCl3, 400MHz) δ7.94 (dd, J=1.8, 7.8Hz, 1H), 7.53 (dd, J=1.8 ,7.5Hz,1H),7.12(t,J=7.7Hz,1H),5.56-5.50(m,1H),5.34(d,J=1.0Hz,1H),4.47(br s,2H),1.78-1.73(m,7H).

[0270] Step 4: Preparation of compound 7-5

[0271] Compound 7-4 (1.10 g, 4.70 mmol, 1 eq) was dissolved in dichloromethane (10 mL). Cesium carbonate (4.59 g, 14.10 mmol, 3 eq) and trimethyltinium tetrafluoroborate (861.5 mg, 14.1 mmol, 3 eq) were added and stirred at 25°C for 16 h. Water (10 mL) was added and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 7-5 (0.45 g, 1.81 mmol, 38.5% yield) as a brown oil.

[0272] 1 HNMR: ES20978-107-P1 (CDCl3, 400MHz) δ7.93 (dd, J=1.7, 7.8Hz, 1H), 7.53 (dd, J=1.7, 7.6Hz, 1H), 7.11(t,J=7.6Hz,1H),5.48(d,J=1.3Hz,1H),5.38(s,1H),4.27(s,2H),3.34(s,3H),1.75(s,6H).

[0273] Step 5: Preparation of compound 7-6

[0274] Compound 7-5 (0.45 g, 1.81 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL). Borane dimethyl sulfide complex (10 M, 543.7 uL, 3 eq) was added at -15°C under nitrogen, and stirring was continued at 25°C for 5 h. Water (15 mL) was slowly added at 5-10°C, and the mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The organic phases were collected and concentrated in vacuo to obtain the crude product, which was dissolved in tetrahydrofuran (10 mL) and (+)-pinanediol (401.1 mg, 2.36 mmol, 1.3 eq) was added. Stirring was continued at 25°C for 5 h. Water (15 mL) was slowly added at 5-10°C, and the mixture was extracted three times with ethyl acetate (15 mL). The combined organic phases were collected and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the organic phases were collected and concentrated in vacuo. The resulting residue was purified by silica gel plate preparation (petroleum ether / ethyl acetate = 5 / 1) to give a colorless oily compound 7-6 (0.25 g, 583.6 umol, 32.2% yield).

[0275] 1 HNMR: ES20978-108-P1A (CDCl3, 400MHz) δ7.82 (dd, J=1.5, 7.8Hz, 1H), 7.50 (ddd ,J=1.5,3.4,7.7Hz,1H),7.09-7.03(m,1H),4.18(ddd,J=1.9,4.6,8.8Hz,1H),3 .72-3.65(m,1H),3.57-3.50(m,2H),3.43-3.38(m,1H),3.34-3.30(m,3H),2.34 -2.22(m,1H),2.11-2.00(m,1H),1.99-1.93(m,1H),1.87-1.80(m,1H),1.74(br d,J=2.8Hz,6H),1.41(t,J=2.8Hz,1H),1.31-1.23(m,7H),0.84(d,J=4.0Hz,1H),0.80(s,3H).

[0276] Step 6: Preparation of compound 7

[0277] Compound 7-6 (0.25 g, 603.4 μmol, 1 eq) was dissolved in water (3 mL) and acetonitrile (3 mL). Sodium hydroxide (3 M, 603.43 μL, 3 eq) was added. After 1 hour, isobutylboronic acid (123.0 mg, 1.21 mmol, 2 eq) was added. Stirring was continued at 25°C for 5 hours. The mixture was extracted three times with ethyl acetate (5 mL) and the pH was adjusted to 3 with hydrogen chloride. The mixture was then extracted three times with ethyl acetate (5 mL). The organic phase was collected and concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC to afford compound 7 as a white solid (8 mg, 30.50 μmol, 5.06% yield, 90% purity). 1 HNMR: ES20978-114-P1(MeOH,400MHz)δ7.81-7.65(m,1H),7.51-7.31(m,1H),6.99-6.77(m,1H),3.77-3.38(m,3H) ,3.37-3.10(m,4H),1.26-0.96(m,1H),1.32-0.86(m,1H),1.36-0.77(m,1H); HPLC: ES20978-114-P1, RT=5.407min.

[0278] Example 8

[0279] Step 1: Preparation of compound 8-2

[0280] At 25°C, compound 8-1 (100.0 g, 523 mmol, 1 eq) was dissolved in dichloromethane (100 mL), and di-tert-butyl dicarbonate (120.0 g, 549.0 mmol, 126 mL, 1.05 eq) was added, followed by 4-dimethylaminopyridine (3.20 g, 26.2 mmol, 0.05 eq). Stirring was continued at 25°C for 16 h. The reaction mixture was washed twice with aqueous citric acid (500 mL) and twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain compound 8-2 (154.0 g, crude product) as a colorless oil.

[0281] 1 HNMR: ES25406-34-P1A (CDCl3, 400MHz) δ 7.56 (dd, J = 5.8, 8.9 Hz, 1H), 7.02 (dd, J = 2.9, 8.7 Hz, 1H), 6.90 (ddd, J = 2.9, 7.8, 8.9 Hz, 1H), 1.58 (s, 9H).

[0282] Step 2: Preparation of compound 8-3

[0283] At 25°C under nitrogen, lithium diisopropylamide (2M, 272 mL, 1.2 eq) was dissolved in tetrahydrofuran (800 mL). Compound 8-2 (132.0 g, 454.0 mmol, 1 eq) in tetrahydrofuran (530 mL) was added dropwise at -70°C under nitrogen. Stirring was continued at -70°C under nitrogen for 0.5 h, followed by stirring at 0-5°C for 2 h. The reaction mixture was slowly poured into cooled saturated ammonium chloride (2000 mL) at 25°C and adjusted to pH 5-6 with acetic acid. The aqueous phase was extracted twice with ethyl acetate (1000 mL). The combined organic phases were washed twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 8-3 (130.0 g, crude product) as a brown oil. 1 HNMR: ES25406-37-P1A (CDCl3, 400MHz) δ 12.24 (s, 1H), 7.61 (dd, J = 5.4, 8.9Hz, 1H), 6.54 (dd, J = 8.9, 10.5Hz, 1H), 1.67 (br s, 9H).

[0284] Step 3: Preparation of compound 8-4

[0285] At 0°C, compound 8-3 (60 g, 206 mmol, 1 eq) was dissolved in dichloromethane (600 mL), and lithium diisopropylamide (53.3 g, 412 mmol, 71.8 mL, 2 eq) was added, followed by chloromethyl ether (23.4 g, 247 mmol, 22.9 mL, 1.2 eq). Stirring was continued at 25°C for 16 h. The reaction mixture was slowly poured into cooled saturated ammonium chloride (500 mL), and the aqueous phase was extracted twice with dichloromethane (1000 mL). The organic phases were combined and washed twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 8-4 (74 g, crude product) as a brown oil. 1 HNMR: ES25406-39-P1A (CDCl3, 400MHz) δ7.52 (dd, J=6.0, 8.9Hz, 1H), 6.79 (t, J=8 .6Hz, 1H), 5.21 (s, 2H), 3.87 (q, J = 7.1Hz, 2H), 1.58 (s, 9H), 1.25 (t, J = 7.1Hz, 3H).

[0286] Step 4: Preparation of compound 8-5

[0287] Compound 8-4 (5.0 g, 14.3 mmol, 1 eq) was dissolved in 1,4-dioxane (50 mL) at 25°C, followed by the addition of compound 8-4a (6.67 g, 18.6 mmol, 1.3 eq) and potassium acetate (4.22 g, 42.9 mmol, 3 eq). Palladium chloride (585.0 mg, 716.0 μmol, 0.05 eq) was then added under nitrogen at 25°C, and the mixture was stirred at 110°C for 16 h. The filtrate was collected by filtration through celite and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford the crude product. The crude product was triturated with petroleum ether (5 mL) at 25°C for 15 minutes to afford compound 8-5 (5.77 g, 12.8 mmol) as a yellow oil.

[0288] 1 HNMR: ES25406-43-P1C (CDCl3, 400MHz) δ7.77 (dd, J=7.3, 8.3Hz, 1H), 6.86 (t, J=8.6Hz, 1H), 5.27-5.20 (m, 2H), 4.45 (dd, J=1.3 ,8.6Hz,1H),3.79-3.74(m,2H),2.01-1.86(m,3H),1.59(s,9H),1.48(s,2H),1.32(s,2H),1.23(t,J=7.1Hz,4H),0.89(s,2H).

[0289] Step 5: Preparation of compound 8-6

[0290] Compound 8-5 (3.89 g, 8.68 mmol, 1 eq) was dissolved in 1,4-dioxane (60 mL) and water (12 mL) at 25°C. 2-Bromoallyl alcohol (1.78 g, 13.0 mmol, 1.5 eq) and cesium carbonate (5.66 g, 17.4 mmol, 2 eq) were added. Xphos Pd G3 (734.7 mg, 868.0 μmol, 0.1 eq) was added at 25°C under nitrogen, and stirring was continued at 60°C for 16 h. After filtration, water (50 mL) was slowly added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the residue. The residue was purified by flash silica gel chromatography to afford compound 8-6 (1.02 g, 3.13 mmol, 36.0% yield) as a yellow oil.

[0291] 1HNMR: ES25406-46-P1C (CDCl3, 400MHz) δ7.21 (dd, J=6.5, 8.6Hz, 1H), 6.86 (t, J=8.6Hz, 1H), 5.52- 5.18(m,2H),5.08(s,2H),4.41(s,2H),3.74(q,J=7.1Hz,2H),1.59(s,9H),1.21(t,J=7.1Hz,3H).

[0292] Step 6: Preparation of compound 8-7

[0293] Compound 8-6 (1.02 g, 3.14 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL) at 25°C. 60% sodium hydride (188.0 mg, 4.71 mmol, 1.5 eq) was added at 0°C under nitrogen. Stirring was continued at 0°C under nitrogen for 0.5 h. Iodomethane (535 mg, 3.77 mmol, 235 μL, 1.2 eq) was then added, and stirring was continued at 25°C under nitrogen for 16 h. The reaction was quenched by the addition of ammonium chloride solution (50 mL) and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue concentrated in vacuo. Purification by flash silica gel chromatography afforded compound 8-7 (570.0 mg, 1.67 mmol, 53.3% yield) as a colorless oil. 1 HNMR: ES25406-48-P1B (CDCl3, 400MHz) δ7.23 (dd, J=6.5, 8.6Hz, 1H), 6.86 (t, J=8.6Hz, 1H), 5.51-5.30 ( m,2H),5.10(s,2H),4.24(s,2H),3.74(q,J=7.1Hz,2H),3.39(s,3H),1.61(s,9H),1.22(t,J=7.0Hz,3H).

[0294] Step 7: Preparation of compound 8-8

[0295] Compound 8-7 (400.0 mg, 1.18 mmol, 1 eq) and pinacol borane (300.7 mg, 2.35 mmol, 341.0 μL, 2 eq) were dissolved in dichloromethane (5 mL). 1,5-cyclooctadiene iridium chloride dimer (47.3 mg, 70.5 μmol, 0.06 eq) and 1,2-bis(diphenylphosphine)ethane (56.1 mg, 141.0 μmol, 0.12 eq) were added at 25°C under nitrogen protection. Stirring was continued at 25°C for 16 h. The residue was separated and purified by flash silica gel chromatography to obtain yellow oily compound 8-8 (160.0 mg, 341.62 μmol, yield 29.07%). 1 HNMR: ES20989-794-P1A (CDCl3, 400MHz) δ7.28-7.23 (m, 1H), 6.84 (t, J=8. 7Hz,1H),5.20-5.13(m,2H),3.95-3.81(m,2H),3.75-3.65(m,1H),3.51(d d,J=5.9,9.0Hz,1H),3.36-3.28(m,4H),1.61(s,9H),1.29(t,J=7.0Hz,3H ), 1.26-1.20 (m, 1H), 1.17 (d, J = 6.6Hz, 12H), 1.04 (dd, J = 7.3, 15.3Hz, 1H).

[0296] Step 8: Preparation of compounds 8-8A and 8-8B

[0297] Compound 8-8 (160.0 mg) was separated by SFC to give compound 8-8A (80.0 mg) and compound 8-8B (80.0 mg).

[0298] Step 9: Preparation of Compound 8-9A

[0299] Compound 8-8A (70.0 mg, 149.46 μmol, 1 eq) and trifluoroacetic acid (170.41 mg, 1.49 mmol, 111.02 μL, 10 eq) were dissolved in dichloromethane (2 mL) and stirred at 25°C for 2 h. After concentration in vacuo, the residue was dissolved in acetonitrile (0.5 mL) and water (0.5 mL) and adjusted to pH 10 with 1N NaOH. The residue was isolated and purified by preparative HPLC to obtain compound 8-9A (18.0 mg, 70.86 μmol, 47.41% yield) as a white solid.

[0300] 1HNMR: ES20989-822-P1A (MeOD, 400MHz) δ 7.59-7.02 (m, 1H), 6.66-6.05 (m, 1H), 3.93-3.39 (m, 3H), 3.28-3.04 (m, 2H), 1.28-0.58 (m, 2H).

[0301] Step 10: Preparation of compound 8A

[0302] Compound 8-9A (18.0 mg, 70.86 μmol, 1 eq) was dissolved in water (5 mL) and sodium hydroxide (1 M, 141.72 μL, 2 eq). Stirring was continued at 25°C for 1 h, and the compound was freeze-dried to obtain a brown solid, Compound 8A (13.0 mg, 43.33 μmol, 61.15% yield, 2 Na).

[0303] 1 HNMR: ES20989-827-P1A (MeOD, 400MHz) δ7.00 (t, J = 7.8Hz, 1H), 6.29 (t, J = 8.7Hz, 1H), 3.61-3.53 (m, 2H), 3.36 (s, 3H), 2.89 (br s, 1H), 0.56 (dd, J=5.3, 13.0Hz, 1H), 0.35 (dd, J=8.8, 13.2Hz, 1H); LCMS: ES20989-827-P1A, RT=1.85min, m / z=255.1(M+H) + ;SFC:ES20989-827-P1A1.

[0304] Step 10: Preparation of compound 8-9B

[0305] Compound 8-8B (80.0 mg, 170.81 μmol, 1 eq) and trifluoroacetic acid (194.76 mg, 1.71 mmol, 126.88 μL, 10 eq) were dissolved in dichloromethane (2 mL) and stirred at 25°C for 2 h. After concentration in vacuo, the residue was dissolved in acetonitrile (0.5 mL) and water (0.5 mL) and adjusted to pH 10 with 1N NaOH. The residue was purified by preparative HPLC to afford compound 8-9B (18.0 mg, 70.86 μmol, 47.49% yield) as a white solid.

[0306] 1HNMR: ES20989-823-P1A (MeOD, 400MHz) δ 7.48-7.01 (m, 1H), 6.66-6.05 (m, 1H), 3.92-3.39 (m, 3H), 3.26-2.98 (m, 2H), 1.27-0.50 (m, 2H).

[0307] Step 11: Preparation of compound 8B

[0308] Compound 8-9B (18.0 mg, 70.86 μmol, 1 eq) was dissolved in water (5 mL) and sodium hydroxide (1 M, 141.72 μL, 2 eq). Stirring was continued at 25°C for 1 h, and the compound was freeze-dried to obtain a brown solid compound 8B (13.0 mg, 43.33 μmol, 61.15% yield, 2 Na). 1 HNMR: ES20989-828-P1A (MeOD, 400MHz) δ7.00 (t, J = 7.7Hz, 1H), 6.29 (t, J = 8.7Hz, 1H), 3.64-3.53 (m, 2H), 3.36 (s, 3H), 2.95-2 .82(m,1H),0.56(dd,J=5.3,13.2Hz,1H),0.35(dd,J=9.0,13.2Hz,1H); LCMS: ES20989-828-P1A, RT=1.85min, m / z=255.1(M+H) + ;SFC:ES20989-828-P1A1.

[0309] Example 9

[0310] Step 1: Preparation of compound 9-1

[0311] Compound 6-9 (100.0 mg, 265.81 umol, 1 eq) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (103.06 mg, 797.43 umol, 138.90 uL, 3 eq), morpholine (49.27 mg, 398.72 umol, 49.77 uL, 1.5 eq, HCl) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (111.18 mg, 292.39 umol, 1.1 eq) were added, and stirring was continued at 25 ° C for 2 h. Water (2 mL) was added to dilute the mixture, and the mixture was extracted three times with dichloromethane (2 mL). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to give compound 9-1 (80 mg, 179.65 umol, 67.59% yield) as a colorless oil. 1 HNMR: ES20989-235-P1A (CDCl3, 400MHz) δ7.79 (dd, J=1.4, 7.7Hz, 1H), 7.47 (dd, J=1.5, 7.6Hz, 1H), 7 .03(t,J=7.7Hz,1H),4.25(dd,J=6.4,9.6Hz,1H),3.57-3.23(m,8H),1.68(d,J=4.6Hz,6H),1.29(br dd,J=9.7,15.8Hz,2H), 1.14(d,J=10.8Hz,12H).

[0312] Step 2: Preparation of compound 9

[0313] Compound 9-1 (80.0 mg, 179.65 μmol, 1 eq) was dissolved in acetonitrile (0.8 mL) and water (0.8 mL). Sodium hydroxide solution (3 M, 179.65 μL, 3 eq) was added. After 1 h, isobutylboronic acid (36.63 mg, 359.30 μmol, 2 eq) and hydrogen chloride solution (12 M, 748.54 μL, 50 eq) were added. Stirring was continued at 25°C for 16 h. The pH was adjusted to 10 with 1N sodium hydroxide, filtered, and the resulting residue was purified by preparative HPLC to afford compound 9 (1.2 mg, 3.93 μmol, 2.19% yield) as a white solid. 1HNMR: ES20989-239-P1A(D2O,400MHz)δ7.64(d,J=6.5Hz,1H),7.14(d,J=6.8Hz,1H),6.82(t,J=7.8Hz,1H),4.34(t,J=7.9Hz,1H),3.64(br d,J=9.8Hz,3H),3.56-3.29(m,6H),3.18-3.05(m,1H),1.17-0.98(m,2H).

[0314] Example 10

[0315] Step 1: Preparation of compound 10-1

[0316] Compound 3-4 (35.0 g, 148.9 mmol, 1 eq), iodomethane (63.4 g, 446.8 mmol, 27.8 mL, 3 eq), and potassium carbonate (61.7 g, 446.8 mmol, 3 eq) were dissolved in N,N-dimethylformamide (350 mL) and stirred at 80°C for 16 h. The reaction mixture was poured into water (700 mL) and extracted twice with ethyl acetate (300 mL). The organic phases were combined and washed three times with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was used in the next reaction. This afforded compound 10-1 (28.0 g, 106.4 mmol, 71.47% yield) as a brown liquid. 1 HNMR: ES20989-431-P1A (CDCl3, 400MHz) δ7.60 (dd, J=6.0, 8.9Hz, 1H), 6.85 (t, J=8.7Hz, 1H), 3.96 (d, J=11.6Hz, 6H).

[0317] Step 2: Preparation of compound 10-2

[0318] Compound 10-1 (28.0 g, 106.4 mmol, 1 eq), potassium ethylene trifluoroborate (28.5 g, 212.8 mmol, 2 eq), and potassium phosphate (67.7 g, 319.3 mmol, 3 eq) were dissolved in tetrahydrofuran (420 mL) and water (80 mL). Xphos-Pd-G3 (4.50 g, 5.32 mmol, 0.05 eq) was added at 95°C under nitrogen, and stirring was continued at 80°C for 16 h. The mixture was treated with ethyl acetate (300 mL) and water (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL). The organic phases were combined, washed twice with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford compound 10-2 (14.0 g, 66.6 mmol, 62.57% yield) as a yellow oil. 1 HNMR: ES20989-440-P1A (CDCl3, 400MHz) δ7.56 (dd, J=6.4, 8.7Hz, 1H), 6.97-6.85 (m, 2H ), 5.73 (d, J = 17.7Hz, 1H), 5.36 (d, J = 11.1Hz, 1H), 4.01-3.94 (m, 3H), 3.87-3.82 (m, 3H).

[0319] Step 3: Preparation of compound 10-3

[0320] At 85°C, bis(acetonitrile)palladium chloride (833.0 mg, 3.21 mmol, 0.05 eq) and 1,4-benzoquinone (7.64 g, 70.6 mmol, 15.91 mL, 1.1 eq) were dissolved in tert-butanol (270 mL). Water (1.16 g, 64.2 mmol, 1.16 mL, 1 eq) and compound 10-2 (13.5 g, 64.22 mmol, 1 eq) were then added. Stirring was continued at 85°C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The residue was extracted with dichloromethane (50 mL). The organic phase was collected and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 10-3 (4.0 g, 17.6 mmol, 27.53% yield) as a yellow oil. 1 HNMR: ES20989-443-P1A (CDCl3, 400MHz) δ9.74 (t, J = 1.8 Hz, 1H), 7.24 (dd, J = 6.3, 8.5 Hz, 1H), 6.91 (t, J = 8.7Hz, 1H), 4.03-3.94 (m, 3H), 3.81 (s, 3H), 3.70 (d, J = 1.6Hz, 2H).

[0321] Step 4: Preparation of compound 10-4

[0322] Compound 10-3 (4.00 g, 17.68 mmol, 1 eq) was dissolved in water (10 mL) / tert-butyl alcohol (10 mL) / tetrahydrofuran (30 mL). Sodium dihydrogen phosphate (21.2 g, 176.8 mmol, 10 eq) was added and stirred for 10 minutes until the solid was completely dissolved. The reaction system was then cooled to 0°C. 2-Methyl-2-butene (12.4 g, 176.8 mmol, 18.7 mL, 10 eq) was added, followed by sodium hypochlorite (6.40 g, 70.7 mmol, 4 eq) in water (10 mL). Stirring was continued at 25°C for 16 hours. The reaction system was rapidly cooled with sodium sulfite (50 mL), and the two phases were mixed by vigorous stirring at 0°C for 5 minutes. The reaction mixture was poured into 1 M hydrogen chloride (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were collected and combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to obtain a crude product, which was used directly in the next reaction to obtain compound 10-4 (4.30 g, crude product) as a yellow oil.

[0323] Step 5: Preparation of compound 10-5

[0324] Compound 10-4 (4.30 g, 17.75 mmol, 1 eq) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (7.36 g, 53.2 mmol, 3 eq) and benzyl bromide (3.64 g, 21.3 mmol, 2.53 mL, 1.2 eq) were added. Stirring was continued at 85°C for 3 h. The reaction mixture was poured into water (100 mL) and extracted twice with ethyl acetate (50 mL). The organic phases were combined and washed twice with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 10-5 (4.2 g, 12.64 mmol, 71.19% yield) as a yellow oil. 1 HNMR: ES20989-455-P1A (CDCl3, 400MHz) δ7.44-7.26 (m, 6H), 6.87 (t, J = 8.7H z,1H),5.22-5.15(m,2H),4.01-3.96(m,3H),3.81-3.76(m,3H),3.69(s,2H).

[0325] Step 6: Preparation of compound 10-6

[0326] Compound 10-5 (4.20 g, 12.64 mmol, 1 eq) was dissolved in 1,4-dioxane (80 mL), and potassium carbonate (2.10 g, 15.1 mmol, 1.2 eq), formaldehyde (834.8 mg, 27.8 mmol, 765.9 μL, 2.2 eq), and tetrabutylammonium bromide (814.8 mg, 2.53 mmol, 0.2 eq) were added. Stirring was continued at 100°C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 10-6 (2.40 g, 6.97 mmol, 55.15% yield) as a colorless oil. 1 HNMR: ES20989-459-P1A (CDCl3, 400MHz) δ7.30-7.14 (m, 6H), 6.75 (t, J = 8.8Hz, 1 H),5.13-4.93(m,2H),4.20-4.11(m,1H),3.91-3.84(m,3H),3.78-3.72(m,3H).

[0327] Step 7: Preparation of compound 10-7

[0328] At 25 ° C, under nitrogen protection, cuprous chloride (20.7 mg, 209.1 μmol, 5.00 μL, 0.03 eq), tricyclohexylphosphine (117.2 mg, 418.2 μmol, 135.5 μL, 0.06 eq), biphenylboronic acid pinacol ester (2.65 g, 10.4 mmol, 1.5 eq) and sodium tert-butoxide (736.8 mg, 7.67 mmol, 1.1 eq) were dissolved in tetrahydrofuran (50 mL). After 3 minutes, methanol (223.3 mg, 6.97 mmol, 282.0 μL, 1 eq) containing compound 10-6 (2.40 g, 6.97 mmol, 1 eq) was added and stirring was continued at 25 ° C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was separated and purified by flash silica gel chromatography to obtain compound 10-7 (1.2 g, 2.54 mmol, 36.45% yield) as a yellow oil. 1 HNMR: ES20989-463-P1A (CDCl3, 400MHz) δ7.38-7.20 (m, 6H), 6.84 (t, J = 8.7Hz, 1H), 5.23-5.05 (m,2H),4.25(dd,J=7.6,8.9Hz,1H),4.02-3.95(m,3H),3.86-3.77(m,3H),1.19-1.13(m,12H).

[0329] Step 8: Preparation of compound 10-8

[0330] Compound 10-7 (1.00 g, 2.12 mmol, 1 eq) was dissolved in methanol (20.0 mL). Palladium hydroxide (297.3 mg, 2.12 mmol, 1 eq) was added at 25°C under nitrogen. Stirring was continued for 16 h at 25°C under hydrogen (42.68 mg, 21.17 mmol, 10 eq). The product was filtered through celite and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 10-8 (600.0 mg, 1.57 mmol, 74.15% yield) as a yellow oil. 1 HNMR: ES20989-465-P1A (CDCl3, 400MHz) δ7.40-7.31 (m, 1H), 6.93-6.84 (m, 1H), 4.22 (dd, J=7 .6,8.9Hz,1H),4.00-3.95(m,3H),3.92-3.87(m,3H),1.59-1.45(m,2H),1.20-1.15(m,12H).

[0331] Step 9: Preparation of compound 10-9

[0332] Compound 10-8 (360.0 mg, 941.9 μmol, 1 eq) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (365.2 mg, 2.83 mmol, 492.2 μL, 3 eq), morpholine (123.0 mg, 1.41 mmol, 124.3 μL, 1.5 eq), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (429.7 mg, 1.13 mmol, 1.2 eq) were added. Stirring was continued at 25°C for 16 h. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the organic phase was collected by filtration and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford compound 10-9 (200 mg, 443.1 μmol, 47.05% yield) as a yellow oil.

[0333] 1 HNMR: ES20989-475-P1A (CDCl3, 400MHz) δ7.42 (dd, J=6.5, 8.8Hz, 1H), 6.89 (t, J=8.7Hz, 1H), 4.37 (dd, J=6.0, 10 .0Hz,1H),3.97(s,3H),3.91(s,3H),3.70-3.25(m,8H),1.47(dd,J=10.1,15.6Hz,1H),1.23(d,J=11.6Hz,12H).

[0334] Step 10: Preparation of compound 10-10

[0335] Compound 10-9 (120.0 mg, 265.90 μmol, 1 eq) was dissolved in dichloromethane (6 mL). Boron tribromide (1 M, 797.71 μL, 3 eq) was added at -78°C and stirred at 0°C for 1 h. The reaction mixture was poured into methanol (10 mL) at 0°C and concentrated in vacuo to afford the crude product, which was used directly in the next reaction to afford compound 10-10 (89.0 mg, crude product) as a yellow oil.

[0336] Step 11: Preparation of compound 10

[0337] Compound 10-10 (89.0 mg, 264.0 μmol, 1 eq) was dissolved in methanol (4 mL) and sodium hydroxide (1 M, 1.58 mL, 6 eq) and stirred at 25°C for 16 h. The organic phase was concentrated in vacuo, and the resulting residue was purified by preparative HPLC to afford compound 10 as a white solid (53.0 mg, 149.28 μmol, 56.54% yield, 91% purity).

[0338] Example 11

[0339] Step 1: Preparation of compound 11-2

[0340] Compound 11-1 (2.00 g, 8.73 mmol, 1 eq) was dissolved in 1,4-dioxane (40 mL). Under nitrogen, pinacol diboron (2.66 g, 10.48 mmol, 1.2 eq), bistriphenylphosphine palladium dichloride (612.8 mg, 873.1 mmol, 0.1 eq), and potassium acetate (2.57 g, 26.19 mmol, 3 eq) were added. Stirring was continued at 90°C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 11-2 (1.3 g, 4.71 mmol, 53.92% yield) as a white solid. 1 HNMR: ES20978-386-P1B (CDCl3, 400MHz) δ7.78 (d, J = 7.3Hz, 1H), 7.35-7.27 (m, 2H), 3.91 (s, 3H), 2.45 (s, 3H), 1.46 (s, 12H).

[0341] Step 2: Preparation of compound 11-3

[0342] Compound 11-2 (1.3 g, 4.71 mmol, 1 eq) was dissolved in carbon tetrachloride (23 mL), and azobisisobutyronitrile (231.9 mg, 1.41 mmol, 0.3 eq) and N-bromosuccinimide (1.42 g, 8.00 mmol, 1.7 eq) were added. Stirring was continued at 80°C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 11-3 (0.82 g, 2.31 mmol, 49.1% yield) as a yellow oil. 1 HNMR: ES20978-388-P1A (CDCl3, 400MHz) δ7.89 (dd, J=0.9, 7.7Hz, 1H), 7.58 (dd ,J=0.8,7.6Hz,1H),7.43-7.38(m,1H),4.61(s,2H),3.92(s,3H),1.49(s,12H).

[0343] Step 3: Preparation of compound 11

[0344] Compound 11-3 (163.6 mg, 460.9 μmol, 1 eq) was dissolved in acetonitrile (2 mL) / trifluoroacetic acid (2 mL) / water (2 mL) and stirred at 70°C for 16 h. The pH was adjusted to 8 with sodium bicarbonate solution and extracted three times with ethyl acetate (5 mL). Hydrogen chloride was added to the organic phase to adjust the pH to 3, and ethyl acetate (5 mL) was added and extracted three times. The organic phase was collected, concentrated, and vacuum-concentrated. The resulting residue was separated and purified by preparative HPLC to obtain compound 11 (27.0 mg, 151.7 μmol, 32.9% yield) as a white solid. 1 HNMR:ES20978-395-P1B(DMSO,400MHz)δ13.96(br s,1H),8.86(br s,1H),8.00(br d, J=7.4Hz, 1H), 7.75-7.70 (m, 1H), 7.69-7.62 (m, 1H), 5.11 (s, 2H); LCMS: ES20978-395-P1B1, RT=2.193min, m / z=178.9(M+H) + .

[0345] Example 12

[0346] Step 1: Preparation of compound 12-2

[0347] Compound 12-1 (3.2 g, 13.7 mmol, 1 eq) was dissolved in N,N-dimethyldiamide (60 mL). Methyl iodide (3.90 g, 27.5 mmol, 1.71 mL, 2 eq) and potassium carbonate (4.74 g, 34.3 mmol, 2.5 eq) were added and stirred at 25°C for 16 h. The mixture was diluted with water (100 mL), and 1 M hydrogen chloride was added at 0°C. The mixture was then extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 12-2 (3.20 g, 12.9 mmol, 94.3% yield) as a yellow oil. 1 HNMR: ES20978-409-P1 (CDCl3, 400MHz) δ7.32-7.24 (m, 1H), 7.01 (t, J = 8.5Hz, 1H), 4.00-3.95 (m, 3H), 2.43-2.35 (m, 3H).

[0348] Step 2: Preparation of compound 12-3

[0349] Compound 12-2 (1.00 g, 4.05 mmol, 1 eq) was dissolved in carbon tetrachloride (20 mL), and dibenzoyl peroxide (294.1 mg, 1.21 mmol, 0.3 eq) and N-bromosuccinimide (648.4 mg, 3.64 mmol, 0.9 eq) were added. Stirring was continued at 80°C for 16 h. The mixture was diluted with water (100 mL), and 1 M hydrogen chloride was added at 0°C. The mixture was then extracted twice with ethyl acetate (100 mL). The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 12-3 (850 mg, 2.61 mmol, 64.4% yield) as a yellow oil. 1 HNMR: ES20978-417-P1 (CDCl3, 400MHz) δ7.55-7.50 (m, 1H), 7.11 (t, J = 8.4Hz, 1H), 4.60 (s, 2H), 4.00 (s, 3H).

[0350] Step 3: Preparation of compound 12-4

[0351] Compound 12-3 (850.0 mg, 2.61 mmol, 1 eq) was dissolved in N,N-dimethylformamide (15 mL) and potassium acetate (383.9 mg, 3.91 mmol, 1.5 eq) was added. Stirring was continued at 80°C for 2 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 12-4 (530.0 mg, 1.74 mmol, 66.6% yield) as a yellow oil. 1 HNMR: ES20978-419-P1 (CDCl3, 400MHz) δ7.49 (dd, J=5.7, 8.7Hz, 1H), 7.12 (t, J=8.5Hz, 1H), 5.18 (s, 2H), 3.99 (s, 3H), 2.14 (s, 3H).

[0352] Step 4: Preparation of compound 12-5

[0353] Compound 12-4 (530.0 mg, 1.74 mmol, 1 eq) was dissolved in 1,4-dioxane (10 mL). Under nitrogen, pinacol diboron (529.3 mg, 2.08 mmol, 1.2 eq), bistriphenylphosphine palladium dichloride (121.9 mg, 173.7 μmol, 0.1 eq), and potassium acetate (511.4 mg, 5.21 mmol, 3 eq) were added. Stirring was continued at 90°C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography and further purified by preparative HPLC to afford compound 12-5 (100 mg, 283.9 μmol, 16.3% yield) as a colorless oil.

[0354] 1 HNMR: ES20978-422-P1B (CDCl3, 400MHz) δ7.53 (dd, J=4.6, 8.5Hz, 1H), 7.11 (dd, J=8.6, 1 0.1Hz,1H),5.19-5.12(m,2H),3.99-3.91(m,3H),2.10-2.05(m,3H),1.45-1.39(m,12H).

[0355] Step 5: Preparation of compound 12

[0356] Compound 12-5 (60.0 mg, 170.4 μmol, 1 eq) was dissolved in methanol (2 mL), and potassium carbonate (70.6 mg, 511.1 μmol, 3 eq) was added. Stirring was continued at 25°C for 16 h, followed by the addition of sodium hydroxide solution (3 M, 170.38 μL, 3 eq), and continued stirring for 16 h. The pH was adjusted to 3 with hydrogen chloride solution, and the residue was concentrated in vacuo and washed with acetonitrile. The residue was purified by preparative HPLC to afford compound 12 (1.9 mg, 9.70 μmol, 5.69% yield) as a white solid. 1 HNMR: ES20978-443-P1 (MeOH, 400MHz) δ7.50 (dd, J=4.0, 8.1Hz, 1H), 6.93 (dd, J=8.3, 10.1Hz, 1H), 4.66 (s, 2H), 4.63-4.55 (m, 1H); HPLC: ES20978-443-P1B3, RT=0.824min.

[0357] Example 13

[0358] Step 1: Preparation of compound 13-2

[0359] Sodium methoxide (5.4M, 1.80 mL, 1.2 eq) was dissolved in methanol (1.8 mL) and N,N-dimethylformamide (18 mL). Potassium carbonate (1.22 g, 8.82 mmol, 1.09 eq) was added and stirred at 0°C for 15 minutes. Compound 13-1 (2 g, 8.10 mmol, 1 eq) was then added and stirred at 100°C for 16 hours. The mixture was diluted with water (30 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford Compound 13-2 (980.0 mg, 3.78 mmol, 46.7% yield) as a yellow oil. 1 HNMR: ES20978-428-P1 (CDCl3, 400MHz) δ7.22 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.99-3.92 (m, 3H), 3.81 (s, 3H), 2.35 (s, 3H).

[0360] Step 2: Preparation of compound 13-3

[0361] Compound 13-2 (450.0 mg, 1.74 mmol, 1 eq) was dissolved in carbon tetrachloride (20 mL), and dibenzoyl peroxide (126.2 mg, 521.0 umol, 0.3 eq) and N-bromosuccinimide (278.2 mg, 1.56 mmol, 0.9 eq) were added. Stirring was continued at 80°C for 16 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 13-3 (370.0 mg, 1.09 mmol, 63.03% yield) as a yellow oil. 1 HNMR: ES20978-414-P1 (CDCl3, 400MHz) δ7.46 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 4.60 (s, 2H), 4.00-3.93 (m, 3H), 3.85 (s, 3H).

[0362] Step 3: Preparation of compound 13-4

[0363] Compound 13-3 (70 mg, 1.09 mmol, 1 eq) was dissolved in N,N-dimethylformamide (4 mL) and potassium acetate (161.1 mg, 1.64 mmol, 1.5 eq) was added. Stirring was continued at 80°C for 2 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 13-4 (220.0 mg, 693.7 umol, 63.3% yield) as a yellow oil. 1 HNMR: ES20978-418-P1 (CDCl3, 400MHz) δ7.43 (d, J = 8.7Hz, 1H), 6.89 (d, J = 8.6Hz, 1H), 5.15 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 2.11 (s, 3H).

[0364] Step 4: Preparation of compound 13-5

[0365] Compound 13-4 (220.0 mg, 693.72 μmol, 1 eq) was dissolved in 1,4-dioxane (4 mL). Under nitrogen, pinacol diboronate (211.3 mg, 832.4 μmol, 1.2 eq), bistriphenylphosphine palladium dichloride (48.6 mg, 69.3 μmol, 0.1 eq), and potassium acetate (204.2 mg, 2.08 mmol, 3 eq) were added. Stirring was continued at 90°C for 22 h. The organic phase was collected by filtration and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 13-5 (60.0 mg, 164.75 μmol, 23.75% yield) as a yellow oil. 1 HNMR: ES20978-420-P1A (CDCl3, 400MHz) δ7.44 (d, J=8.6Hz, 1H), 6.95 (d, J=8.6H z,1H),5.19(s,2H),3.91(s,2H),3.85(s,3H),2.06-2.04(m,3H),1.37(s,11H).

[0366] Step 5: Preparation of compound 13

[0367] Compound 13-5 (60.0 mg, 164.7 μmol, 1 eq) was dissolved in methanol (2 mL), and potassium carbonate (68.3 mg, 494.2 μmol, 3 eq) was added. Stirring was continued at 25°C for 16 h, followed by the addition of sodium hydroxide solution (3 M, 164.7 μL, 3 eq) and continued stirring for 16 h. The pH was adjusted to 3 with hydrogen chloride solution, and the residue was concentrated in vacuo and washed with acetonitrile. The residue was purified by preparative HPLC to afford compound 13 (3 mg, 14.42 μmol, 8.76% yield) as a white solid. 1 HNMR: ES20978-425-P1B (MeOH, 400MHz) δ7.44 (br d, J=8.1Hz, 1H), 6.86 (br d, J=8.6Hz, 1H), 4.63 (br s,2H),3.86(s,3H); LCMS: ES20978-425-P1D5, RT=0.889min, m / z=208.9(M+H) + .

[0368] Example 14

[0369] Step 1: Preparation of compound 14-2

[0370] Compound 14-1 (1.0 g, 2.98 mmol, 1 eq) and triethylamine (603.7 mg, 5.9 mmol, 830.4 μL, 2 eq) were dissolved in dichloromethane (20 mL). Benzoyl chloride (629.0 mg, 4.47 mmol, 519.4 μL, 1.5 eq) was added at 25°C and stirred for 16 h. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The resulting residue was concentrated in vacuo and purified by flash silica gel chromatography to obtain compound 14-2 (1.14 g, 2.59 mmol, 87.6% yield) as a yellow solid. 1 HNMR: ES20978-595-P1 (CDCl3, 400MHz) δ10.55 (s, 1H), 8.33 (d, J = 8.6Hz, 1H), 7.99-7.93 (m, 2H), 7.60-7.48 (m, 3H),7.44(d,J=8.6Hz,1H),4.00(s,3H),3.81(s,3H),2.82-2.75(m,2H),1.25-1.23(m,12H),1.18-1.10(m,2H).

[0371] Step 2: Preparation of compound 14-3

[0372] Compound 14-2 (50 mg, 113.8 μmol, 1 eq) was dissolved in dichloromethane (1 mL). Boron tribromide (1 M, 1.14 mL, 10 eq) was added at -78°C and stirred for 1 h. The mixture was stirred at 0°C for 3 h. Methanol (3 mL) was added at 10°C to quench the reaction. The crude product was concentrated in vacuo to afford compound 14-3 (37 mg, crude product) as a yellow oil.

[0373] Step 3: Preparation of compound 14

[0374] Compound 14-3 (37 mg, 113.8 μmol, 1 eq) was dissolved in acetonitrile (0.2 mL) and water (0.2 mL). Sodium hydroxide solution (1 M, 113.8 μL, 1 eq) was added and stirred at 25°C for 16 h. The residue was filtered and concentrated in vacuo. It was purified by preparative HPLC to afford compound 14 (2.8 mg, 9.00 μmol, 7.91% yield) as a white solid. 1HNMR: ES20978-604-P1A (MeOD, 400MHz) δ8.12 (d, J = 8.4 Hz, 1H), 8.07-8.00 (m, 2H), 7.57-7.49 (m, 3H), 7.15 (d, J =8.5Hz, 1H), 2.67 (t, J = 7.7Hz, 2H), 1.01-0.89 (m, 2H); LCMS: ES20978-604-P1A, RT = 2.221min, m / z = 310.1 (M-1) - .

[0375] Example 15

[0376] Step 1: Preparation of compound 15-2

[0377] Compound 15-1 (200.0 mg, 596.6 μmol, 1 eq) was dissolved in N,N-dimethylformamide (5 mL). Triethylamine (120.7 mg, 1.19 mmol, 166.1 μL, 2 eq) and N-cyclopropyl-4-nitrobenzenesulfonamide (265.1 mg, 1.19 mmol, 2 eq) were added and stirred at 70°C for 16 h. The mixture was diluted with water (15 mL) and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated brine (15 mL), filtered, and concentrated in vacuo to obtain the residue, which was purified by flash silica gel chromatography to afford compound 15-2 (104 mg, 248.6 μmol, 41.6% yield) as a yellow oil. 1 HNMR: ES20978-619-P1(CDCl3,400MHz)δ7.95(d,J=8.6Hz,1H),7.34(d,v8.6Hz,1H),6.71(d,J=8.3Hz,1H),3.96(s,3H),3.77( s,3H),2.80-2.69(m,4H),2.58(tt,J=3.4,6.7Hz,1H),1.24(s,15H),1.14-1.06(m,4H),0.94-0.87(m,2H),0.69-0.62(m,2H).

[0378] Step 2: Preparation of compound 15-3

[0379] Compound 15-2 (110.0 mg, 262.9 μmol, 1 eq) was dissolved in dichloromethane (6 mL). Boron tribromide (1 M, 2.63 mL, 10 eq) was added at -78°C and stirred for 1 h. The mixture was stirred at 0°C for 3 h. Methanol (5 mL) was added to the reaction mixture at 0°C and concentrated in vacuo to obtain a crude product which was used directly in the next reaction to afford compound 15-3 (80.0 mg, crude product) as a brown oil.

[0380] Step 3: Preparation of compound 15

[0381] Compound 15-3 (80.0 mg, 263.0 μmol, 1 eq) and sodium hydroxide (1 M, 263.0 μL, 1 eq) were dissolved in acetonitrile (1 mL) and water (1 mL) and stirred at 25°C for 16 h. The pH was adjusted to 7 with 1N hydrogen chloride. The residue was concentrated in vacuo and purified by preparative HPLC to afford compound 15 (8.0 mg, 27.5 μmol, 10.0% yield) as a white solid. 1 HNMR: ES20978-655-P1 (MeOD, 400MHz) δ7.34 (br s, 1H), 6.64-6.28 (m, 1H), 2.66 (br t, J = 7.7Hz, 2H), 2.74-2.61 (m, 1H), 1.12 (br s,3H),1.25-0.72(m,1H),0.85(br s,2H); LCMS: ES20978-655-P1A, RT=2.317min, m / z=273.2(M-OH) + .

[0382] Example 16

[0383] Step 1: Preparation of compound 16-2

[0384] Compound 16-1 (90 mg, 268.4 μmol, 1 eq) was dissolved in toluene (2 mL). Pyridine (42.4 mg, 536.9 μmol, 43.3 μL, 2 eq) and N-difluoroethyl-4-nitrobenzenesulfonamide (132.19 mg, 536.99 μmol, 2 eq) were added and stirred at 100°C for 16 h. The mixture was diluted with water (15 mL) and extracted three times with ethyl acetate (5 mL). The residue was concentrated in vacuo and purified by flash silica gel chromatography to afford compound 16-2 (54 mg, 122.1 μmol, 45.4% yield) as a yellow solid. 1HNMR: ES20978-644-P1A (CDCl3, 400MHz) δ7.72 (d, J = 8.6Hz, 1H), 7.34 (d, J = 8.7Hz ,1H),6.06-5.68(m,2H),4.13(q,J=7.1Hz,1H),3.96(s,3H),3.77(s,3H),3.60(br dd,J=4.0,14.7Hz,2H),2.77-2.69(m,2H),1.24-1.22(m,12H),1.14-1.08(m,2H).

[0385] Step 2: Preparation of compound 16-3

[0386] Compound 16-2 (54.0 mg, 122.1 μmol, 1 eq) was dissolved in dichloromethane (1 mL). Boron tribromide (1 M, 1.22 mL, 10 eq) was added under nitrogen and stirred at -78°C for 1 h. Methanol (5 mL) was added at 10°C to quench the reaction. The crude product was concentrated in vacuo to afford compound 16-3 (40.0 mg, crude product) as a brown oil.

[0387] Step 3: Preparation of compound 16

[0388] Compound 16-3 (40 mg, 121.9 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Sodium hydroxide (1 M, 1.22 mL, 10 eq) was added to adjust the pH to 12, and stirring was continued at 25°C for 16 h. The reaction was quenched with 1N hydrogen chloride to a pH of 6-7. The residue was concentrated in vacuo and purified by preparative HPLC to afford compound 16 (7.0 mg, 22.1 μmol, 18.2% yield) as a white solid. 1 HNMR: ES20989-629-P1A(DMSO-d6,400MHz)δ11.61-11.37(m,1H),7.42-7.21(m,2H),6.47-6.39(m,1H),6.31-5.91(m, 1H),4.25-4.06(m,2H),2.48-2.42(m,2H),0.90-0.64(m,2H); LCMS: ES20978-629-P1A, RT=2.840min, m / z=297.1(M-OH) + .

[0389] Example 17

[0390] Step 1: Preparation of compound 17-2

[0391] Compound 17-1 (0.5 g, 1.49 mmol, 1 eq) was dissolved in dichloromethane (10 mL). (7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (680.6 mg, 1.79 mmol, 1.2 eq), 3,3-difluorocyclobutanecarboxylic acid (243.6 mg, 1.79 mmol, 1.2 eq), and N,N-diisopropylethylamine (578.3 mg, 4.47 mmol, 779.4 μL, 3 eq) were added and stirred at 25°C for 16 h. Water (15 mL) was added and the mixture was extracted three times with dichloromethane (10 mL). The combined organic phases were collected and washed with saturated brine (15 mL). The resulting residue was filtered and concentrated in vacuo. Purification by flash silica gel chromatography afforded Compound 17-2 (0.42 g, 926.5 μmol, 62.1% yield) as a yellow solid. 1 HNMR:ES20978-614-P1(CDCl3,400MHz)δ9.69(br s,1H),8.12(d,J=8.6Hz,1H),7.39(d,J=8.7Hz,1H),3.98(s,3H),3.77(s,3H),3.00- 2.91(m,3H),2.77-2.71(m,2H),2.70-2.63(m,1H),1.23(s,13H),1.15-1.07(m,3H).

[0392] Step 2: Preparation of compound 17-3

[0393] Compound 17-2 (50.0 mg, 110.3 μmol, 1 eq) was dissolved in dichloromethane (1 mL). Boron tribromide (1 M, 1.10 mL, 10 eq) was added dropwise at -78°C and stirred for 1 h. The reaction mixture was quenched by adding methanol (5 mL) at 0°C and concentrated in vacuo to afford the crude product, compound 17-3 (35.0 mg, crude product) as a brown oil.

[0394] Step 3: Preparation of compound 17

[0395] Compound 17-3 (35 mg, 103.2 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Sodium hydroxide (1 M, 516.0 μL, 5 eq) was added to adjust the pH to 13, and the mixture was stirred at 25°C for 16 h. The residue was filtered and concentrated in vacuo. It was purified by preparative HPLC to afford compound 17 (2.8 mg, 8.61 μmol, 8.35% yield) as a white solid. 1HNMR: ES20978-618-P1 (MeOD, 400MHz) δ7.93-7.84 (m, 1H), 7.09 (br d, J=8.4Hz, 1H), 3.10-3.02 (m, 2H), 2.82 (br d, V3.3Hz, 3H), 2.63 (br t, J=7.6Hz, 2H), 2.60-2.57 (m, 1H), 0.93 (br t, J=7.6Hz, 2H); LCMS: ES20978-618-P1B, RT=2.709min, m / z=326.1(M+H) + .

[0396] Example 18

[0397] Step 1: Preparation of compound 18-2

[0398] Compound 18-1 (0.5 g, 1.49 mmol, 1 eq) was dissolved in dichloromethane (10 mL). (7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (680.6 mg, 1.79 mmol, 1.2 eq), 1-fluorocyclopropanecarboxylic acid (186.3 mg, 1.79 mmol, 1.2 eq), and N,N-diisopropylethylamine (578.3 mg, 4.47 mmol, 779.4 μL, 3 eq) were added and stirred at 25°C for 16 h. Water (15 mL) was added and the mixture was extracted three times with dichloromethane (10 mL). The combined organic phases were collected and washed with saturated brine (15 mL). The resulting residue was filtered and concentrated in vacuo. Purification by flash silica gel chromatography afforded compound 18-2 (0.42 g, 996.9 μmol, 66.8% yield) as a yellow solid. 1 HNMR:ES20978-613-P1(CDCl3,400MHz)δ10.25(br d,J=5.1Hz,1H),8.09(d,J=8.6Hz,1H),7.38(d,J=8.6Hz,1H),4.04-3.95(m,3H),3.83-3.76(m, 3H),2.80-2.72(m,2H),1.49-1.43(m,2H),1.42-1.34(m,2H),1.23(s,12H),1.16-1.09(m,2H).

[0399] Step 2: Preparation of compound 18-3

[0400] Compound 18-2 (50.0 mg, 118.6 μmol, 1 eq) was dissolved in dichloromethane (1 mL). Boron tribromide (1 M, 1.19 mL, 10 eq) was added dropwise at -78°C and stirred for 1 h. The reaction mixture was quenched by adding methanol (5 mL) at 10°C. The crude product was concentrated in vacuo to afford compound 18-3 (35.0 mg, crude) as a brown solid.

[0401] Step 3: Preparation of compound 18

[0402] Compound 18-3 (35 mg, 113.9 μmol, 1 eq) was dissolved in acetonitrile (0.2 mL) and water (0.2 mL). Sodium hydroxide (1 M, 569.8 μL, 5 eq) was added to adjust the pH to 13, and the mixture was stirred at 25°C for 16 h. The residue was filtered and concentrated in vacuo. It was purified by preparative HPLC to afford compound 18 (6.5 mg, 22.1 μmol, 19.4% yield) as a white solid. 1 HNMR: ES20978-617-P1B(MeOD,400MHz)δ7.98-7.83(m,1H),7.17-7.05(m,1H),7.26-7.05(m,1H),2.68-2.61(m, 2H),1.34(s,2H),1.37-1.30(m,1H),0.94-0.74(m,2H); LCMS: ES20978-617-P1C, RT=2.455min, m / z=294.1(M+H) + .

[0403] Example 19

[0404] Step 1: Preparation of compound 19-2

[0405] Compound 19-1 (5.00 g, 29.9 mmol, 1 eq) and triethylamine (4.54 g, 44.8 mmol, 6.24 mL, 1.5 eq) were dissolved in acetonitrile (50 mL). Di-tert-butyl dicarbonate (7.83 g, 35.8 mmol, 8.25 mL, 1.2 eq) was added at 0°C and stirred at 25°C for 16 h. The residue was collected by vacuum concentration and purified by flash silica gel chromatography to obtain compound 19-2 (1.10 g, 4.12 mmol, 13.76% yield) as a yellow solid. 1HNMR: ES20989-510-P1A(CDCl3,400MHz)δ11.62(br s,1H),11.16(br s,1H),8.29(dd,J=0.9,8.7Hz,1H),7.48(t,J=8.6Hz,1H),6.72-6.63(m,1H),4.10(s,3H),1.54(s,9H).

[0406] Step 2: Preparation of compound 19-3

[0407] Compound 19-2 (3.0 g, 11.22 mmol, 1 eq) was dissolved in N,N-dimethylformamide (60 mL). Methyl iodide (2.39 g, 16.84 mmol, 1.05 mL, 1.5 eq) and potassium carbonate (3.88 g, 28.06 mmol, 2.5 eq) were added and stirred at 25°C for 1 h. The reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (100 mL). The combined organic layers were collected and washed twice with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 19-3 (2.6 g, 9.24 mmol, 82.35% yield) as a yellow solid. 1 HNMR:ES20989-525-P1A(CDCl3,400MHz)δ8.46(br s,1H),7.75(d,J=8.4Hz,1H),7.27(t,J=8.4Hz,1H),6.54(d,J=8.4Hz,1H),3.89-3.83(m,3H),3.79-3.71(m,3H),1.47-1.40(m,9H).

[0408] Step 3: Preparation of compound 19-4

[0409] Compound 19-3 (2.6 g, 9.24 mmol, 1 eq) was dissolved in dichloromethane (60 mL) at 25°C, and N-bromosuccinimide (1.81 g, 10.17 mmol, 1.1 eq) was added. Stirring was continued at 25°C for 16 h. The reaction mixture was washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 19-4 (2.4 g, 6.66 mmol, 72.09% yield) as a yellow solid. 1HNMR: ES20989-526-P1A (CDCl3, 400MHz) δ 8.45 (br s, 1H), 7.85 (d, J = 9.1Hz, 1H), 7.51 (d, J = 9.0Hz, 1H), 3.91 (s, 3H), 3.83-3.77 (m, 3H), 1.44 (s, 9H).

[0410] Step 4: Preparation of compound 19-5

[0411] Compound 19-4 (15 g, 41.64 mmol, 1 eq) and potassium ethylene trifluoroborate (8.37 g, 62.47 mmol, 1.5 eq) were dissolved in 1,4-dioxane (300 mL) and water (75 mL). Triethylamine (8.43 g, 83.29 mmol, 11.59 mL, 2 eq) and DPPF palladium dichloride (1.52 g, 2.08 mmol, 0.05 eq) were added under nitrogen. Stirring was continued at 105°C for 16 h. The organic phase was collected and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 19-5 (7.5 g, 24.40 mmol, 58.60% yield) as a yellow oil. 1 HNMR:ES20989-556-P1A(CDCl3,400MHz)δ8.57(br s,1H),8.00(d,J=8.8Hz,1H),7.61(d,J=8.9Hz,1H),6.95(dd,J=11.1,17.8Hz,1H),5.72(dd,J =1.0,17.7Hz,1H),5.31(dd,J=1.0,11.1Hz,1H),4.01(s,3H),3.83-3.76(m,3H),1.54(s,9H).

[0412] Step 5: Preparation of compound 19-6

[0413] Compound 19-5 (4.00 g, 13.0 mmol, 1 eq) was dissolved in dichloromethane (80 mL), and pinacol borane (3.33 g, 26.0 mmol, 3.78 mL, 2 eq), 1,5-cyclooctadiene iridium chloride dimer (262.2 mg, 390.4 μmol, 0.03 eq), and 1,2-bis(diphenylphosphino)ethane (311.1 mg, 780.8 μmol, 0.06 eq) were added. The mixture was stirred at 25°C under nitrogen for 20 h. The organic phase was collected and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford Compound 19-6 (3.50 g, 8.04 mmol, 61.78% yield) as a yellow solid. 1HNMR:ES20989-559-P1B(CDCl3,400MHz)δ8.34(br s,1H),7.78(d,J=8.6Hz,1H),7.24(d,J=8.6Hz,1H),3.92-3.87(m,3H),3.6 9(s,3H),2.68-2.58(m,2H),1.43(s,9H),1.15(s,12H),1.06-0.99(m,2H).

[0414] Step 6: Preparation of compound 19-7

[0415] Compound 19-6 (2.00 g, 4.59 mmol, 1 eq) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) and stirred at 25°C for 1 h. Dichloromethane (100 mL) was added, and the mixture was washed twice with saturated sodium carbonate solution (50 mL). The mixture was extracted with dichloromethane (50 mL). The organic phases were collected and dried over anhydrous sodium sulfate. The organic phases were collected by filtration and concentrated in vacuo. The crude product was used in the next reaction to obtain compound 19-7 (1.4 g, crude product) as a yellow solid. 1 HNMR: ES20989-566-P1A (CDCl3, 400MHz) δ7.15 (d, J = 8.4Hz, 1H), 6.50 (d, J = 8.4Hz, 1H), 3 .98-3.93(m,3H),3.81-3.73(m,3H),2.72-2.63(m,2H),1.24(s,12H),1.14-1.04(m,2H).

[0416] Step 7: Preparation of compound 19-8

[0417] Compound 19-7 (400.0 mg, 1.19 mmol, 1 eq) and acetic acid (71.66 mg, 1.19 mmol, 68.31 μL, 1 eq) were dissolved in methanol (8 mL). 5-Fluoropyridine-2-carboxaldehyde (223.93 mg, 1.79 mmol, 1.5 eq) was added, followed by sodium cyanoborodeuteride (149.98 mg, 2.39 mmol, 2 eq). Stirring was continued at 25°C for 16 h. The reaction mixture was poured into saturated brine (20 mL) and extracted twice with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 19-8 (300.0 mg, 675.22 μmol, 56.58% yield) as a yellow solid. 1HNMR: ES20989-569-P1A(CDCl3,400MHz)δ8.50(d,J=2.6Hz,1H),7.55-7.43(m,2H),7.16(d,J=8.5Hz,1H),6.31(d,J =8.6Hz,1H),4.63(s,2H),3.98(s,3H),3.80-3.74(m,3H),2.73-2.60(m,2H),1.26-1.19(m,12H),1.12-1.03(m,2H).

[0418] Step 8: Preparation of compound 19-9

[0419] Compound 19-8 (50.0 mg, 112.54 μmol, 1 eq) was dissolved in dichloromethane (2 mL). Boron tribromide (1 M, 1.13 mL, 10 eq) was added dropwise at -78°C under nitrogen and stirred for 1 h. The temperature was raised to 0°C and stirred for 1 h. Methanol (5 mL) was then added to the reaction mixture, and the mixture was concentrated in vacuo to afford the crude product, compound 19-9 (37.0 mg, crude product) as a brown solid.

[0420] Step 9: Preparation of compound 19

[0421] Compound 19-9 (37.0 mg, 112.08 μmol, 1 eq) was dissolved in acetonitrile (1 mL) and water (1 mL). Sodium hydroxide (1 M, 224.16 μL, 2 eq) was added and stirred at 25°C for 4 h. The reaction mixture was adjusted to pH 7-8 and concentrated in vacuo to obtain a residue, which was dissolved in acetonitrile (1 mL) and water (1 mL) and purified by preparative HPLC to afford Compound 19 (2.50 mg, 7.91 μmol, 7.06% yield) as a white solid. 1 HNMR: ES20989-595-P1B (MeOH, 400MHz) δ8.42 (d, J = 2.8Hz, 1H), 7.69-7.35 (m, 2H), 7.12- 6.79(m,1H),6.09-5.69(m,1H),4.58-4.40(m,2H),2.83-2.28(m,2H),1.38-0.48(m,2H).

[0422] Example 20

[0423] Step 1: Preparation of compound 20-1

[0424] Compound 19-6 (400.0 mg, 918.8 μmol, 1 eq) was dissolved in tetrahydrofuran (8 mL) at 0°C under nitrogen. 60% sodium hydride (55.1 mg, 1.38 mmol, 1.5 eq) was added and stirred at 0°C for 0.5 h. Bromomethylcyclopropane (186.0 mg, 1.38 mmol, 131.5 μL, 1.5 eq) was added and stirred at 25°C for 16 h. The reaction mixture was slowly poured into water (10 mL) at 0°C and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 20-1 (110.0 mg, 224.76 μmol, 24.46% yield) as a yellow oil. 1 HNMR: ES20989-588-P1A(CDCl3,400MHz)δ7.19-7.15(m,1H),6.86(br d,J=14.1Hz,1H),3.74(s,3H),3.69(s,3H),2.72-2.55(m,2H),1.52-1. 30(m,5H),1.27-1.16(m,6H),1.11(s,12H),1.06-0.80(m,4H),0.30(br d,J=7.3Hz,2H),0.08--0.09(m,2H).

[0425] Step 2: Preparation of compound 20

[0426] Compound 20-1 (60.0 mg, 122.60 μmol, 1 eq) was dissolved in dichloromethane (4 mL). Boron tribromide (1 M, 1.23 mL, 10 eq) was added at -78°C under nitrogen and stirred for 1 h. The temperature was raised to 0°C and stirred for 1 h. Methanol (5 mL) was then added to the reaction mixture and concentrated in vacuo to afford the crude product, which was used directly in the next step. Compound 20 (30.0 mg, crude product) was obtained as a black oil. The residue was dissolved in acetonitrile (1 mL) and water (1 mL) and purified by preparative HPLC to afford Compound 20 (2.5 mg, 9.58 μmol, 5.27% yield) as a white solid.

[0427] Example 21

[0428] Step 1: Preparation of compound 21-2

[0429] Compound 21-1 (400.00 mg, 1.19 mmol, 1 eq) and acetic acid (71.6 mg, 1.19 mmol, 68.3 μL, 1 eq) were dissolved in methanol (8 mL). Tetrahydropyran-4-carbaldehyde (340.5 mg, 2.98 mmol, 2.5 eq) and sodium cyanoborohydride (149.98 mg, 2.39 mmol, 2 eq) were added and stirred at 25°C for 16 h. The reaction mixture was poured into saturated brine (20 mL) and extracted twice with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 21-2 (280.0 mg, 646.1 μmol, 54.15% yield) as a yellow oil. 1 HNMR: ES20989-607-P1A (CDCl3, 400MHz) δ7.22 (d, J=8.6Hz, 1H), 6.97-6.61 (m, 1H), 6.43 (d, J=8.7Hz, 1H), 4.01 (br dd,J=3.6,11.1Hz,2H),3.93(s,3H),3.75(s,3H),3.42(dt,J=2.0,11.8Hz,2H),3. 04(d,J=6.7Hz,2H),2.70-2.63(m,2H),1.90(dtt,J=3.7,7.3,11.2Hz,1H),1.74(br dd,J=1.8,13.0Hz,2H),1.47-1.33(m,2H),1.29-1.22(m,12H),1.13-1.04(m,2H).

[0430] Step 2: Preparation of compound 21-3

[0431] Compound 21-2 (150.0 mg, 346.1 μmol, 1 eq) was dissolved in dichloromethane (6 mL). Boron tribromide (1 M, 3.346 mL, 10 eq) was added dropwise at -78°C under nitrogen and stirred for 1 h. The mixture was warmed to 0°C and stirred for 1 h. Methanol (5 mL) was then added to the reaction mixture and concentrated in vacuo to afford the crude product, which was used directly in the next reaction to afford compound 21-3 (110.0 mg, crude product) as a black oil.

[0432] Step 3: Preparation of compound 21

[0433] Compound 21-3 (110.0 mg, 344.66 μmol, 1 eq) was dissolved in acetonitrile (2 mL) and water (2 mL). Sodium hydroxide (1 M, 1.03 mL, 3 eq) was added and stirred at 25°C for 16 h. The reaction mixture was adjusted to pH 7 and concentrated in vacuo to obtain a residue which was purified by preparative HPLC to afford Compound 21 (7.0 mg, 22.94 μmol, 6.66% yield) as a yellow solid.

[0434] Example 22

[0435] Step 1: Preparation of compound 22-2

[0436] Compound 22-1 (400.00 mg, 1.19 mmol, 1 eq) was dissolved in methanol (8 mL). Acetic acid (71.6 mg, 1.19 mmol, 68.3 μL, 1 eq), tetrahydropyran-4-carbaldehyde (340.5 mg, 2.98 mmol, 2.5 eq), and sodium cyanoborohydride (149.98 mg, 2.39 mmol, 2 eq) were added under nitrogen. Stirring was continued at 25°C for 16 h. The reaction mixture was poured into saturated brine (10 mL) and extracted twice with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 22-2 (290.0 mg, 669.2 μmol, 56.0% yield) as a colorless oil. 1 HNMR: ES20978-667-P1 (CDCl3, 400MHz) δ7.20 (d, J=8.6Hz, 1H), 6.39 (d, J=8.8H z,1H),4.04-3.96(m,3H),3.92(s,3H),3.74(s,3H),3.43-3.35(m,2H),3.03(br d,J=5.5Hz,2H),2.70-2.60(m,2H),1.93-1.83(m,2H),1.77-1.67(m,2H),1.24(s,12H),1.12-1.02(m,2H).

[0437] Step 2: Preparation of compound 22-3

[0438] Compound 22-2 (100 mg, 230.7 μmol, 1 eq) was dissolved in acetonitrile (2 mL). Acetic acid (27.7 mg, 461.5 μmol, 26.4 μL, 2 eq), formaldehyde (69.2 mg, 2.31 mmol, 63.5 μL, 10 eq), and sodium cyanoborohydride (21.7 mg, 346.1 μmol, 1.5 eq) were added under nitrogen. Stirring was continued at 40°C for 16 h. The reaction mixture was poured into saturated brine (5 mL) and extracted twice with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 22-3 (46.0 mg, 102.8 μmol, 44.5% yield) as a yellow oil. 1 HNMR: ES20978-671-P1 (CDCl3, 400MHz) δ7.21 (d, J = 8.4Hz, 1H), 6.83 (d, J = 8.3Hz, 1H), 3.95 (br dd,J=3.4,11.1Hz,2H),3.89(s,3H),3.79(s,3H),3.39-3.28(m,2H),2.80(d,J=7.1 Hz,2H),2.75-2.69(m,2H),2.68(s,3H),1.74(ddd,J=3.7,7.3,11.0Hz,1H),1.65(br d,J=13.3Hz,2H),1.29-1.24(m,2H),1.23(s,12H),1.16-1.09(m,2H).

[0439] Step 3: Preparation of compound 22-4

[0440] Compound 22-3 (46 mg, 102.8 μmol, 1 eq) was dissolved in dichloromethane (2 mL). Boron tribromide (1 M, 1.03 mL, 10 eq) was added dropwise under nitrogen and stirred at -78°C for 5 h. Methanol (3 mL) was added at 0°C to quench the reaction. The crude product was obtained after vacuum concentration, yielding compound 22-4 (40 mg, crude) as a brown oil.

[0441] Step 4: Preparation of compound 22

[0442] Compound 22-4 (40.0 mg, 120.0 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Sodium hydroxide (1 M, 600.2 μL, 3 eq) was added to adjust the pH to 12, and the mixture was stirred at 25°C for 16 h. The residue was concentrated in vacuo and purified by preparative HPLC to afford compound 22 (18 mg, 56.4 μmol, 46.9% yield) as a white solid. 1 HNMR: ES20978-702-P1(MeOD,400MHz)δ7.46-7.36(m,1H),7.13-7.00(m,1H),3.90(br dd,J=3.3,11.4Hz,2H),3.78(t,J=6.8Hz,1H),3.40-3.35(m,2H),3.33(br d,J=1.7Hz,1H),3.11-3.05(m,3H),2.93-2.84(m,1H),2.74-2.67(m,1H),1.85(dtd,J=3.5,7.5,14.8Hz,1H),1.69(br d, J=12.2Hz, 2H), 1.43-1.27(m, 2H), 1.18-1.04(m, 1H); LCMS: ES20978-702-P1A1, RT=0.746min, m / z=320.3(M+H) + .

[0443] Example 23

[0444] Step 1: Preparation of compound 23-2

[0445] Compound 23-1 (1.15 g, 3.43 mmol, 1 eq) was dissolved in methanol (20 mL). Acetic acid (206.0 mg, 3.43 mmol, 196.4 μL, 1 eq), 5-fluoropyridine-2-carboxaldehyde (643.7 mg, 5.15 mmol, 1.5 eq), and sodium cyanoborohydride (431.1 mg, 6.86 mmol, 2 eq) were added under nitrogen. Stirring was continued at 25°C for 16 h. The reaction mixture was poured into saturated brine (20 mL) and extracted twice with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 23-2 (1.00 g, 2.25 mmol, 65.6% yield) as a colorless oil. 1HNMR: ES20978-703-P1 (CDCl3, 400MHz) δ 8.52-8.43 (m, 1H), 7.59-7.53 (m, 1H), 7.39-7.32 (m, 2H), 7.14 (d, J = 8.8Hz, 1H), 6. 28(d,J=8.6Hz,1H),4.50(s,2H),3.98-3.92(m,3H),3.78-3.73(m,3H),2.64(t,J=8.1Hz,2H),1.24-1.20(m,12H),1.06(br t,J=8.1Hz,2H).

[0446] Step 2: Preparation of compound 23-3

[0447] Compound 23-2 (1.00 g, 2.25 mmol, 1 eq) was dissolved in acetonitrile (15 mL). Acetic acid (270.3 mg, 4.50 mmol, 257.6 μL, 2 eq), formaldehyde (675.8 mg, 22.51 mmol, 620.0 μL, 10 eq), and sodium cyanoborohydride (212.1 mg, 3.38 mmol, 1.5 eq) were added and stirred at 40°C for 16 h. The reaction mixture was poured into saturated brine (20 mL) and extracted twice with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 23-3 (330 mg, 720.0 μmol, 31.9% yield) as a yellow oil. 1 HNMR: ES20978-708-P1 (CDCl3, 400MHz) δ8.38 (d, J=2.9Hz, 1H), 7.54 (dd, J=4.5, 8.5Hz, 1H), 7.41 (dt, J=2.6, 8.4Hz, 1H), 7.21 (d, J=8.4 Hz,1H),6.86(d,J=8.4Hz,1H),4.31(s,2H),3.86(s,3H),3.83-3.74(m,3H),2.77-2.66(m,5H),1.26-1.18(m,12H),1.16-1.07(m,2H).

[0448] Step 3: Preparation of compound 23-4

[0449] Compound 23-3 was dissolved in dichloromethane (2 mL), and boron tribromide (1 M, 3.71 mL, 10 eq) was added dropwise under nitrogen. Stirring was continued at -78°C for 1 h. Methanol (5 mL) was added at 0°C to quench the reaction. The mixture was concentrated in vacuo to afford the crude product, compound 23-4 (120 mg, crude product), which was a brown solid.

[0450] Step 4: Preparation of compound 23

[0451] Compound 23-4 (130.0 mg, 377.7 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Sodium hydroxide (1 M, 3.78 mL, 10 eq) was added and stirred at 25°C for 16 h. The residue was concentrated in vacuo and purified by reverse phase preparative HPLC to afford compound 23 (40.0 mg, 121.1 μmol, 32.0% yield) as a white solid. 1 HNMR: ES20978-720-P1(MeOD,400MHz)δ8.40(br s,1H),7.73-7.53(m,2H),7.25-7.03(m,1H),6.85(br s,1H),4.50(br s,2H),2.88(br s, 3H), 2.65 (t, J = 7.6Hz, 2H), 0.89 (br s, 2H).

[0452] Step 5: Preparation of compound 23a

[0453] Compound 23 (25 mg, 75.7 μmol, 1 eq) was dissolved in sodium hydroxide (1 M, 151.4 μL, 2 eq) and stirred at 25°C for 2 h. The mixture was diluted with water (50 mL), washed twice with ethyl acetate (3 mL), and freeze-dried to obtain the residue as a yellow solid, Compound 23a (27 mg, 81.7 μmol, 2 Na). 1 HNMR: ES20978-732-P1B (MeOD, 400MHz) δ8.27 (d, J=2.8Hz, 1H), 7.98 (dd, J=4.8, 8.8Hz, 1H), 7.56 (dt, J=2.9, 8.6Hz, 1H), 6.71 (d, J=8.1Hz, 1H), 6.36 (d, J = 7.9Hz, 1H), 4.24 (s, 2H), 2.62-2.55 (m, 5H), 0.44 (t, J = 6.9Hz, 2H); LCMS: ES20978-732-P1A1, RT = 0.691min, m / z = 331.2 (M+H) + .

[0454] Example 24

[0455] Step 1: Preparation of compound 24-2

[0456] Compound 24-1 (400.0 mg, 918.8 μmol, 1 eq) was dissolved in tetrahydrofuran (8 mL). 60% sodium hydroxide (55.1 mg, 1.38 mmol, 1.5 eq) was added at 0°C under nitrogen. Stirring was continued at 0°C for 0.5 h. Ethyl iodide (214.9 mg, 1.38 mmol, 110.2 μL, 1.5 eq) was then added, and stirring was continued at 25°C for 16 h. The reaction mixture was poured into water (5 mL) at 0°C and extracted twice with ethyl acetate (5 mL). The organic phases were combined and washed twice with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography to afford compound 24-2 (250.0 mg, 539.53 μmol, 58.72% yield) as a yellow oil. 1 HNMR: ES20989-587-P1A(CDCl3,400MHz)δ7.26-7.20(m,1H),6.95-6.68(m,1H),3.79(s,3H),3.74(s,3H),2.76-2.64(m,2H),1.43(s,3H),1.25(br s, 6H), 1.15 (s, 15H), 1.06 (br d, J = 6.3Hz, 5H).

[0457] Step 2: Preparation of compound 24-3

[0458] Compound 24-2 (120.0 mg, 258.97 μmol, 1 eq) was dissolved in 1,4-dioxane (1 mL) and hydrogen chloride / 1,4-dioxane (1 mL), and stirred at 25 ° C for 16 h. After vacuum concentration, the crude product was used for the next reaction to obtain yellow oily compound 24-3 (90.0 mg, crude product, HCl). 1 HNMR: ES20989-647-P1A (MeOD, 400MHz) δ7.60-7.52 (m, 1H), 7.11 (d, J = 8.1Hz, 1H), 4.05-4.00 (m, 3H), 3. 86-3.81(m,3H),3.50-3.39(m,2H),2.79(t,J=7.9Hz,2H),1.36(t,J=7.3Hz,3H),1.23(s,12H),1.11(br t,J=8.0Hz,2H).

[0459] Step 3: Preparation of compound 24-4

[0460] Compound 24-3 (80.0 mg, 200.14 μmol, 1 eq, HCl) and formaldehyde (60.09 mg, 2.00 mmol, 55.13 μL, 10 eq) were dissolved in acetonitrile (3 mL). Acetic acid (24.0 mg, 400.2 μmol, 22.9 μL, 2 eq) was added and stirred at 25°C for 0.5 h. The reaction system was cooled to 0°C and sodium cyanoborohydride (25.1 mg, 400.2 μmol, 2 eq) was added in two portions over 0.5 h. Stirring was continued at 25°C for 16 h. The mixture was filtered and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 24-4 (50.0 mg, 132.53 μmol, 66.22% yield) as a yellow oil. 1 HNMR: ES20989-650-P1A(CDCl3,400MHz)δ7.20(d,J=8.3Hz,1H),6.80(d,J=8.4Hz,1H),3.92(s,3H),3.80(s,3H),3 .01(q,J=7.1Hz,2H),2.75-2.68(m,5H),1.65-1.44(m,2H),1.24(s,12H),1.16-1.10(m,2H),1.06(t,J=7.1Hz,3H).

[0461] Step 4: Preparation of compound 24-5

[0462] Compound 24-4 (50.0 mg, 132.53 μmol, 1 eq) was dissolved in dichloromethane (3 mL). Boron tribromide (1 M, 1.33 mL, 10 eq) was added dropwise at -78°C under nitrogen. Stirring was continued at -78°C for 1 h. The temperature was raised to 0°C and stirring was continued for 1 h. Methanol (5 mL) was added to the reaction mixture at 0°C and concentrated in vacuo to obtain a crude product, which was used directly in the next reaction to afford compound 24-5 (34.87 mg, crude) as a black solid.

[0463] Step 5: Preparation of compound 24

[0464] Compound 24-5 (34.8 mg, 132.5 μmol, 1 eq) and sodium hydroxide (1 M, 1.33 mL, 10 eq) were dissolved in acetonitrile (0.5 mL) and water (0.5 mL) and stirred at 25°C for 16 h. The pH was adjusted to 7 and the mixture was concentrated in vacuo to obtain a residue, which was purified by preparative HPLC to afford compound 24 (4.0 mg, 16.06 μmol, 12.12% yield) as a white solid. 1 HNMR: ES20989-655-P1A (MeOD, 400MHz) δ7.41 (d, J = 8.1Hz, 1H), 7.06 (d, J = 8.1Hz, 1H), 3.54 (q, J = 7.0Hz, 2H) ,3.13(s,3H),2.78-2.68(m,2H),1.27-1.06(m,6H);LCMS:ES20989-655-P1B,RT=0.778min,m / z=250.1(M+H) + .

[0465] Example 25

[0466] Step 1: Preparation of compound 25-2

[0467] Compound 25-1 (165 mg, 379.0 μmol, 1 eq) was dissolved in tetrahydrofuran (4 mL). 60% sodium hydride (30.3 mg, 758.0 μmol, 2 eq) was added at 0°C and stirred for 0.5 h. 1-Fluoro-2-iodoethane (79.1 mg, 454.8 μmol, 1.2 eq) was added and stirred at 25°C for 16 h. The reaction was quenched by the addition of ammonium chloride solution. Saturated brine (5 mL) was added and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 25-2 (91.0 mg, 189.0 μmol, 49.8% yield) as a yellow oil. 1 HNMR:ES20978-661-P1(CDCl3,400MHz)δ7.30(br d,J=7.9Hz,1H),7.05-6.92(m,1H),4.79-4.36(m,2H),3.88(s,3H),3.82(s,3H),3.69-3.45(m,1H),2.78(br s,2H),1.35-1.25(m,9H),1.23(s,12H),1.15(br t,J=7.6Hz,2H).

[0468] Step 2: Preparation of compound 25-3

[0469] Compound 25-2 (80 mg, 166.2 μmol, 1 eq) was dissolved in trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) and stirred at 25° C. for 2 h. The crude product was obtained after vacuum concentration, giving compound 25-3 (65.0 mg, crude product) as a yellow oil.

[0470] Step 3: Preparation of compound 25-4

[0471] Compound 25-3 (50.0 mg, 131.1 μmol, 1 eq) was dissolved in acetonitrile (1 mL). Under nitrogen, acetic acid (15.7 mg, 262.30 μmol, 15.0 μL, 2 eq), formaldehyde (39.3 mg, 1.31 mmol, 36.1 μL, 10 eq), and sodium cyanoborohydride (12.3 mg, 196.7 μmol, 1.5 eq) were added. Stirring was continued at 25°C for 16 h. The reaction mixture was poured into saturated brine (3 mL) and extracted twice with ethyl acetate (2 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 25-4 (26.0 mg, 65.7 μmol, 50.1% yield) as a yellow oil. 1 HNMR: ES20978-670-P1 (CDCl3, 400MHz) δ7.22 (d, J = 8.4Hz, 1H), 6.87 (d, J = 8.4Hz, 1H), 4.59-4.42 (m, 2H), 3.95-3. 88(m,3H),3.82-3.76(m,3H),3.35-3.21(m,2H),2.80(s,3H),2.75-2.68(m,2H),1.23(s,12H),1.15-1.07(m,2H).

[0472] Step 4: Preparation of compound 25-5

[0473] Compound 25-4 (26.0 mg, 65.7 μmol, 1 eq) was dissolved in dichloromethane (1 mL). Boron tribromide (1 M, 657.7 μL, 10 eq) was added dropwise under nitrogen. Stirring was continued at -78°C for 1 h. The reaction was quenched by the addition of methanol (3 mL) at 0°C. The crude product was obtained after concentration in vacuo, yielding compound 25-5 (20 mg, crude) as a brown oil.

[0474] Step 5: Preparation of compound 25

[0475] Compound 25-5 (20 mg, 71.1 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Sodium hydroxide (1 M, 213.4 μL, 3 eq) was added, and the pH was adjusted to 12. Stirring was continued at 25°C for 16 h. The residue was concentrated in vacuo and purified by preparative HPLC to afford compound 25 (5 mg, 18.7 μmol, 26.3% yield) as a white solid. 1 HNMR: ES20978-679-P1B (MeOD, 400MHz) δ 6.80-6.71 (m, 1H), 6.47-6.33 (m, 1H), 6.35 (s, 1H), 4.66-4.58 (m, 1H), 4.51 (t, J = 5.3Hz, 1H), 3.39-3. 34(m,1H),3.31-3.26(m,1H),2.86-2.72(m,3H),2.63-2.53(m,2H),0.50-0.41(m,2H); LCMS: ES20978-679-P1C, RT=3.698min, m / z=268.1(M+H) + .

[0476] Example 26

[0477] Step 1: Preparation of compound 26-2

[0478] Compound 26-1 (0.3 g, 894.9 μmol, 1 eq) was dissolved in methanol (4 mL). Under nitrogen, acetic acid (53.7 mg, 894.9 μmol, 51.2 μL, 1 eq), isobutyraldehyde (193.6 mg, 2.68 mmol, 245.0 μL, 3 eq), and sodium cyanoborohydride (112.4 mg, 1.79 mmol, 2 eq) were added. Stirring was continued at 25°C for 16 h. The reaction mixture was poured into saturated brine (10 mL) and extracted twice with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 26-2 (250 mg, 638.8 μmol, 71.3% yield) as a yellow oil. 1HNMR: ES20978-669-P1(CDCl3,400MHz)δ7.18(d,J=8.6Hz,1H),6.38(d,J=8.8Hz,1H),3.95-3.89(m,3H),3.76-3.71(m,3H),2.93(br d,J=6.6Hz,2H),2.68-2.61(m,2H),1.26-1.21(m,13H),1.14-1.04(m,4H),1.00(d,J=6.6Hz,6H).

[0479] Step 2: Preparation of compound 26-3

[0480] Compound 26-2 (100 mg, 255.5 μmol, 1 eq) was dissolved in acetonitrile (2 mL). Acetic acid (30.6 mg, 511.1 μmol, 29.2 μL, 2 eq), formaldehyde (76.7 mg, 2.56 mmol, 70.4 μL, 10 eq), and sodium cyanoborohydride (24.0 mg, 383.3 μmol, 1.5 eq) were added and stirred at 40°C for 16 h. The reaction mixture was poured into saturated brine (5 mL) and extracted twice with ethyl acetate (3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 26-3 (62 mg, 152.9 μmol, 59.8% yield) as a yellow oil. 1 HNMR: ES20978-672-P1 (CDCl3, 400MHz) δ7.19 (d, J = 8.4Hz, 1H), 6.82 (d, J = 8.4Hz, 1H), 3.92-3.87 (m, 3H), 3.81-3.77 (m, 3H), 2.73-2.68(m,4H),2.67(s,3H),1.79(td,J=6.8,13.6Hz,1H),1.25-1.21(m,12H),1.14-1.09(m,2H),0.87(d,J=6.6Hz,6H).

[0481] Step 3: Preparation of compound 26-4

[0482] Compound 26-3 (62 mg, 152.9 μmol, 1 eq) was dissolved in dichloromethane (2 mL). Boron tribromide (1 M, 1.53 mL, 10 eq) was added dropwise under nitrogen and stirred at -78°C for 5 h. Methanol (5 mL) was added at 0°C to quench the reaction. The crude product was obtained after vacuum concentration, yielding compound 26-4 (50 mg, crude) as a brown oil.

[0483] Step 4: Preparation of compound 26

[0484] Compound 26-4 (50.0 mg, 171.7 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Sodium hydroxide (1 M, 515.2 μL, 3 eq) was added, and the pH was adjusted to 12. Stirring was continued at 25°C for 16 h. The residue was concentrated in vacuo and purified by preparative HPLC to afford compound 26 (12 mg, 43.3 μmol, 25.2% yield) as a white solid. 1 HNMR: ES20978-678-P1(MeOD,400MHz)δ7.51-7.34(m,1H),7.12-6.97(m,1H),3.44(br d,J=6.4Hz,1H),3.28-3.25(m,1H),3.26-3.14(m,1H),3.12-3.01(m,2H),2.75-2.44(m,2H),1.88(qui nd, J=6.8, 13.5Hz, 1H), 1.01 (d, J=6.8Hz, 7H); LCMS: ES20978-678-P1B, RT=3.429min, m / z=278.1(M+H) + .

[0485] Example 27

[0486] Step 1: Preparation of compound 27-2

[0487] Compound 27-1 (500.0 mg, 1.15 mmol, 1 eq) was dissolved in acetonitrile (10 mL). 60% sodium hydride (68.9 mg, 1.72 mmol, 1.5 eq) was added at 0°C under nitrogen. Stirring was continued at 0°C for 0.5 h. Bromomethylcyclopropane (232.5 mg, 1.72 mmol, 164.49 μL, 1.5 eq) was then added, and stirring was continued at 25°C for 16 h. The reaction mixture was slowly poured into water (10 mL) at 0°C and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 27-2 (300.0 mg, 612.9 μmol, 53.37% yield) as a yellow oil. 1HNMR: ES20989-671-P1A(CDCl3,400MHz)δ7.30(s,1H),7.10-6.92(m,1H),3.87(s,3H),3.83(s,3H),2.79(br s,2H),1.67-1.42(m,3H),1.41-1.29(m,7H),1.24(s,12H),1.20-1.03(m,3H),0.44(br d,J=6.8Hz,2H),0.14(br s,2H).

[0488] Step 2: Preparation of compound 27-3

[0489] Compound 27-2 (300.0 mg, 612.99 μmol, 1 eq) was dissolved in 1,4-dioxane (4 mL) and hydrogen chloride / 1,4-dioxane (4 mL) and stirred at 25°C for 16 h. The crude product was concentrated in vacuo and used directly in the next step. This afforded compound 27-3 (250.0 mg, 587.19 μmol, HCl) as a yellow solid.

[0490] Step 3: Preparation of compound 27-4

[0491] Compound 27-3 (250.0 mg, 587.1 μmol, 1 eq, HCl) and formaldehyde (176.3 mg, 5.87 mmol, 161.7 μL, 10 eq) were dissolved in acetonitrile (5 mL). Acetic acid (70.52 mg, 1.17 mmol, 67.23 μL, 2 eq) was added and stirred at 25°C for 0.5 h. The reaction mixture was cooled to 0°C and sodium borocyanide (73.80 mg, 1.17 mmol, 2 eq) was added in two portions over 0.5 h. Stirring was continued at 25°C for 16 h, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 27-4 (130.0 mg, 322.33 μmol, 54.89% yield) as a yellow oil. 1 HNMR: ES20989-673-P1A (CDCl3, 400MHz) δ7.09 (br d, J=8.4Hz, 1H), 6.71 (br d,J=8.3Hz,1H),3.81(s,3H),3.71-3.65(m,3H),2.73-2.66(m,5H),2.64-2.55(m,2H), 1.18-1.09(m,14H),1.05-0.97(m,2H),0.86-0.70(m,1H),0.41-0.31(m,2H),-0.01(br d,J=4.8Hz,2H).

[0492] Step 4: Preparation of compound 27-5

[0493] Compound 27-4 (130.0 mg, 322.33 μmol, 1 eq) was dissolved in dichloromethane (6 mL). Boron tribromide (1 M, 3.22 mL, 10 eq) was added dropwise at -78°C under nitrogen. Stirring was continued at -78°C for 1 hour. The mixture was warmed to 0°C and stirred for 1 hour. Methanol (5 mL) was added at 0°C to quench the reaction. The mixture was concentrated in vacuo to obtain the crude product, which was used directly in the next step without purification, yielding compound 27-5 (93.2 mg, crude) as a black solid.

[0494] Step 5: Preparation of compound 27

[0495] Compound 27-5 (93.2 mg, 322.34 μmol, 1 eq) and sodium hydroxide (1 M, 3.22 mL, 10 eq) were dissolved in acetonitrile (0.5 mL) and water (0.5 mL) and stirred at 25°C for 16 h. The residue was concentrated in vacuo and purified by preparative HPLC to afford compound 27 (13.0 mg, 47.25 μmol, 14.66% yield) as a white solid. 1 HNMR: ES20989-676-P1A (MeOD, 400MHz) δ7.40 (d, J = 8.2Hz, 1H), 7.07 (d, J = 8.2Hz, 1H), 3.37 (d ,J=7.5Hz,2H),3.15(s,3H),2.78-2.68(m,2H),1.16-1.08(m,2H),1.01-0.88(m,1H),0.61(br d, J=7.2Hz, 2H), 0.37 (br d, J=5.0Hz, 2H); LCMS: ES20989-676-P1B, RT=0.783min, m / z=276.3(M+H) + .

[0496] Example 28

[0497] Step 1: Preparation of compound 28-2

[0498] To a solution of 2-bromo-5-hydroxymethylphenol (10.0 g, 49.2 mmol) in dichloromethane (100 mL) was slowly added dropwise a solution of phosphorus tribromide (6.67 g, 24.6 mmol) in dichloromethane (30 mL) at 0°C (the addition process lasted for more than 0.5 hours). The mixture was allowed to react at room temperature for 4 hours. The reaction solution was poured into 200 mL of water and the pH was adjusted to 8 with saturated aqueous sodium carbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the desired product 28-2 (9.1 g, 69.4% yield) as a yellow solid. 1 HNMR: ES20978-809-P1 (CDCl3, 400MHz) δ7.44 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 2.1, 8.3 Hz, 1H), 4.43-4.38 (m, 2H).

[0499] Step 2: Preparation of compound 28-3

[0500] Under nitrogen at 0°C, sodium hydroxide (676.8 mg, 16.9 mmol) was slowly added to a solution of 2-fluoroethanol (867.1 mg, 13.5 mmol) in N,N-dimethylformamide (60 mL). The reaction solution was stirred at 0°C for 0.5 hours, and then a solution of 2-bromo-5-bromomethylphenol (3 g, 11.2 mmol) in N,N-dimethylformamide (15 mL) was slowly added. The mixture was allowed to react at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target product 28-3 (2.91 g, crude product) as a light yellow oil. 1 HNMR: ES25406-76-P1A (CDCl3, 400MHz) δ7.43 (d, J = 8.2Hz, 1H), 7.02 (d, J = 1.8Hz, 1H), 6.81 (dd, J = 2.0, 8.1Hz, 1H), 4.66-4.51 (m, 4H), 3.79-3.65 (m, 2H).

[0501] Step 3: Preparation of compound 28-4

[0502] To a solution of 2-bromo-5-((2-fluoroethoxy)methyl)phenol (2.91 g, 11.6 mmol) and di-tert-butyl dicarbonate (2.68 g, 12.2 mmol) in dichloromethane (30 mL) was added 4-dimethylaminopyridine (71.4 mg, 0.585 mmol) and allowed to react at room temperature for 16 hours. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 28-4 (2.4 g, 58.7% yield) as a light yellow oil. 1 HNMR: ES25406-80-P1A (CDCl3, 400MHz) δ7.56 (d, J = 8.2Hz, 1H), 7.20 (d, J = 1.7Hz, 1H), 7.10 (dd, J = 2.0, 8.2Hz, 1H), 4.67-4.48 (m, 4H), 3.78-3.64 (m, 2H).

[0503] Step 4: Preparation of compound 28-5

[0504] To a solution of lithium diisopropylamide (2M, 4.30 mL, 1.5 eq) in tetrahydrofuran (40 mL) was slowly added a solution of tert-butyl 2-bromo-5-((2-fluoroethoxy)methyl)phenyl carbonate (2 g, 5.73 mmol, 1 eq) in tetrahydrofuran (10 mL) at -78°C under nitrogen, and the mixture was allowed to react for 2 hours at -78°C. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 28-5 (0.53 g, 26.5% yield) as a light yellow oil. 1 HNMR: ES20978-813-P1 (CDCl3, 400MHz) δ12.00 (s, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.08 (d,J=8.4Hz,1H),4.82(s,2H),4.72-4.54(m,2H),3.85-3.70(m,2H),1.65(s,9H).

[0505] Step 5: Preparation of compound 28-6

[0506] To a solution of tert-butyl 3-bromo-6-((2-fluoroethoxy)methyl)-2-hydroxybenzoate (530 mg, 1.52 mmol) in tetrahydrofuran (10 mL) was slowly added sodium hydroxide (121.4 mg, 3.04 mmol) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 0.5 hours, followed by the slow addition of bromomethyl methyl ether (3 g, 11.2 mmol) and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 28-6 (0.5 g, 83.7% yield) as a light yellow oil. 1 HNMR: ES20978-817-P1(CDCl3,400MHz)δ7.58(d,J=8.1Hz,1H),7.12(d,J=8.1Hz,1H),5.16(s,2H),4 .65-4.62(m,1H),4.60(s,2H),4.53-4.49(m,1H),3.75-3.70(m,1H),3.67-3.63(m,4H),1.61(s,9H).

[0507] Step 6: Preparation of compound 28-7

[0508] To a solution of tert-butyl 3-bromo-6-((2-fluoroethoxy)methyl)-2-(methoxymethoxy)benzoate (250 mg, 0.64 mmol) in dioxane (5 mL) and water (1 mL) was added triethylamine (128.6 mg, 1.27 mmol), potassium vinyl trifluoroborate (127.7 mg, 0.95 mmol), and catalyst Pd(dppf)Cl2.CH2Cl2 (25.9 mg, 0.03 mmol) in sequence under nitrogen. The mixture was reacted at 110°C for 16 hours. Two parallel batches were added and combined. Water (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 28-7 (230 mg, 53.1% yield) as a light yellow oil. 1HNMR: ES20978-820-P1 (CDCl3, 400MHz) δ7.55 (d, J = 8.0Hz, 1H), 7.20 (d, J = 8.1Hz, 1H), 7.05 (dd, J = 11.1, 17.7Hz, 1H), 5.75 (dd, J = 1.0, 17.6Hz, 1H),5.35(dd,J=1.0,11.0Hz,1H),5.06-4.99(m,2H),4.66-4.59(m,3H) ,4.54-4.49(m,1H),3.74-3.62(m,2H),3.58(s,3H),1.64-1.58(m,9H).

[0509] Step 7: Preparation of compound 28-8

[0510] To a solution of tert-butyl 6-((2-fluoroethoxy)methyl)-2-(methoxymethoxy)-3-vinylbenzoate (230 mg, 0.68 mmol) in dichloromethane (5 mL) was added 2-diphenylphosphino(diphenyl)phosphine (16.1 mg, 0.04 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172.9 mg, 1.35 mmol), and cycloocta-1,5-dieneiridium chloride (25.9 mg, 0.03 mmol) in sequence under nitrogen. The mixture was allowed to react at room temperature for 16 hours. Water (5 mL) was added to the reaction solution, which was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 28-8 (250 mg, 79.0% yield) as a yellow oil. 1 HNMR: ES20978-823-P1 (CDCl3, 400MHz) δ7.25 (s, 1H), 7.12 (d, J = 7.9Hz, 1H), 5.03 (s, 2H), 4.6 0(s,3H),3.71-3.58(m,6H),2.85-2.77(m,2H),1.60(s,9H),1.23(s,12H),1.16-1.10(m,2H).

[0511] Step 8: Preparation of compound 28

[0512] To a solution of tert-butyl 6-((2-fluoroethoxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (250 mg, 0.53 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (608 mg, 5.34 mmol, 0.4 mL) and allowed to react at room temperature for 2 hours. The reaction solution was concentrated, and acetonitrile (1 mL) and water (1 mL) were added to the resulting crude product. The pH was adjusted to 9 with 1 M aqueous sodium hydroxide solution, and the product was purified by reverse-phase HPLC to afford the desired product 28 (90 mg, 62.9% yield) as a yellow solid. 1 HNMR: ES20978-826-P1 (MeOH, 400MHz) δ7.23 (br dd, J=7.8, 12.4Hz, 1H), 7.04 (br dd,J=7.8,17.4Hz,1H),5.03-4.91(m,2H),4.66-4.49(m,2H),3.84-3.69(m,3H),2.87-2.63(m,2H),1.20(s,1H),0.76-0.61(m,1H).

[0513] Step 9: Preparation of compound 28a

[0514] To 7-((2-fluoroethoxy)methyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (90 mg, 336 μmol) was added 1 M sodium hydroxide in deionized water (672 μL) and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, which was extracted with methyl tert-butyl ether. The aqueous phase was collected and lyophilized to afford the desired product 28a (75 mg, 71.1% yield) as a white solid. 1 HNMR: ES20978-834-P1A(MeOH,400MHz)δ6.79(d,J=7.6Hz,1H),6.60(d,J=7.6Hz,1H),4.63-4.41(m,4H),3.75-3.62(m,2H),2.61(br t, J=6.9Hz, 2H), 0.45 (br t, J=6.9Hz, 2H); LCMS: ES20978-834-P1A1, RT=0.476min, m / z=269.3(M+H) + .

[0515] Example 29

[0516] Step 1: Preparation of compound 29-2

[0517] Imidazole (10.5 g, 154.4 mmol) was added to a solution of 2-bromo-5-(hydroxymethyl)phenol (28.5 g, 140.3 mmol) in tetrahydrofuran (300 mL). The mixture was cooled to 0°C in an ice bath. A solution of tert-butyldimethylsilyl chloride (23.2 g, 154.4 mmol) in tetrahydrofuran (90 mL) was then added dropwise. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield the desired product 29-2 (37.5 g, 84.2% yield) as a yellow oil. 1 HNMR: ES20978-733 (CDCl3, 400MHz) δ7.40 (d, J = 8.2Hz, 1H), 7.02-7.00 (m, 1H), 6.78 (dd, J = 2.0, 8.2Hz, 1H), 4.67 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H).

[0518] Step 2: Preparation of compound 29-3

[0519] To a solution of 2-bromo-5-((tert-butyldimethylsilyl)oxymethyl)phenol (31.2 g, 98.3 mmol) in tetrahydrofuran (320 mL) was added sodium hydride (7.87 g, 196.6 mmol, 60% purity) at 0°C under nitrogen. The mixture was stirred for half an hour, followed by the addition of bromomethyl methyl ether (18.4 g, 147.5 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (500 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product 29-3 (35 g, crude) as a yellow oil. 1 HNMR: ES20978-741 (CDCl3, 400MHz) δ7.50 (d, J = 8.1Hz, 1H), 7.18 (s, 1H), 6.87 (d ,J=8.3Hz,1H),5.31-5.24(m,2H),4.77-4.63(m,2H),3.54(s,3H),0.12(s,6H).

[0520] Step 3: Preparation of compound 29-4

[0521] To a solution of 4-bromo-(3-((methoxymethoxy)phenyl)oxy)3-tert-butyldimethylsilane (35.0 g, 96.86 mmol) in tetrahydrofuran (400 mL) was added 1 M tetrabutylammonium fluoride solution (106.5 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. Flash silica gel chromatography afforded the desired product 29-4 (23.0 g, 93.0 mmol, 96.1% yield) as a yellow oil. 1 HNMR: ES20978-742 (CDCl3, 400MHz) δ7.50 (d, J = 8.1Hz, 1H), 7.18 (s, 1H), 6.87 (d ,J=8.3Hz,1H),5.31-5.24(m,2H),4.77-4.63(m,2H),3.54(s,3H),0.12(s,6H).

[0522] Step 4: Preparation of compound 29-5

[0523] To a solution of 4-bromo-(3-(methoxymethoxy)phenyl)methanol (7.00 g, 28.3 mmol) in N,N-dimethylformamide (70 mL) at 0°C under nitrogen was added sodium hydride (1.70 g, 42.5 mmol, 60% purity). The mixture was stirred for half an hour, followed by the addition of bromomethylcyclopropane (4.59 g, 34.00 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to flash silica gel chromatography to afford the desired product 29-5 (8.5 g, crude) as a yellow oil. 1 HNMR: ES20978-743-P1(CDCl3,400MHz)δ7.50(d,J=8.1Hz,1H),7.15(d,J=1.7Hz,1H),6.89(dd,J=1.8,8.1Hz,1H),5. 26(s,2H),4.48(s,2H),3.53(s,3H),3.31(d,J=6.8Hz,2H),1.16-1.05(m,1H),0.60-0.50(m,2H),0.25-0.18(m,2H).

[0524] Step 5: Preparation of compound 29-6

[0525] To a solution of 1-bromo-(4-(cyclopropylmethoxy)methyl)-2-(methoxymethoxy)benzene (8.50 g, 28.2 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (40 mL), and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the crude product was adjusted to pH 8 with saturated sodium carbonate solution. The product was extracted with dichloromethane, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product 29-6 (7.2 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification. 1 HNMR: ES20978-745-P1(DMSO,400MHz)δ10.19(s,1H),7.41(d,8.1Hz,1H),6.93(s,1H),6. 67(d,J=7.9Hz,1H),4.37(s,2H),1.07-1.00(m,1H),0.51-0.43(m,2H),0.21-0.13(m,2H).

[0526] Step 6: Preparation of compound 29-7

[0527] To a solution of 2-bromo-(5-(cyclopropylmethoxy)methyl)phenol (7.20 g, 28.0 mmol) in dichloromethane (70 mL) were added 4-dimethylaminopyridine (171.0 mg, 1.40 mmol) and BOC anhydride (6.72 g, 30.80 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was then purified by flash silica gel chromatography to afford the desired product 29-7 (7.80 g, 77.9% yield) as a yellow oil. 1 HNMR: ES20978-746-P1(CDCl3,400MHz)δ7.56(d,J=8.1Hz,1H),7.22(d,J=1.8Hz,1H),7.11(dd,J=1.9,8.2Hz,1 H), 4.51 (s, 2H), 3.31 (d, J = 6.9Hz, 2H), 1.58 (s, 10H), 1.15-1.04 (m, 1H), 0.59-0.52 (m, 2H), 0.24-0.19 (m, 2H).

[0528] Step 7: Preparation of compound 29-8

[0529] To a 2M solution of lithium diisopropylamide (13.1 mL) in tetrahydrofuran (80 mL) was added a solution of tert-butyl 2-bromo-(5-(cyclopropylmethoxy)methyl)phenyl carbonate (7.8 g, 21.8 mmol) in tetrahydrofuran (40 mL) at -78°C under nitrogen. The reaction mixture was stirred at -78°C for 2 hours. The mixture was quenched by slowly adding saturated ammonium chloride (120 mL) at 5-10°C and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was subjected to flash silica gel chromatography to afford the desired product 29-8 (1.30 g, 16.6% yield) as a yellow oil. 1 HNMR: ES20978-747-P1 (CDCl3, 400MHz) δ12.01-11.94 (m, 1H), 7.65 (d, J = 8.3Hz, 1H), 7.10 (d, J = 8.4Hz, 1H) ,4.74(s,2H),3.35(d,J=6.9Hz,2H),1.65(s,9H),1.16-1.07(m,1H),0.60-0.54(m,2H),0.26-0.21(m,2H).

[0530] Step 8: Preparation of compound 29-9

[0531] To a solution of tert-butyl 3-bromo-(6-(cyclopropylmethoxy)methyl)-2-hydroxybenzoate (1.2 g, 3.36 mmol) in tetrahydrofuran (20 mL) at 0°C under nitrogen was added sodium hydride (268.7 mg, 6.72 mmol, 60% purity). The mixture was stirred for half an hour, followed by the addition of bromomethyl methyl ether (629.6 mg, 5.0 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. Flash silica gel chromatography afforded the desired product 29-9 (1.27 g, 94.2% yield) as a yellow oil. 1 HNMR: ES20978-752-P1(CDCl3,400MHz)δ7.56(d,J=8.2Hz,1H),7.13(d,J=8.3Hz,1H),5.15(s,2H),4.53(s,2 H), 3.65 (s, 3H), 3.29 (d, J = 7.0Hz, 2H), 1.61 (s, 9H), 1.13-1.01 (m, 1H), 0.57-0.49 (m, 2H), 0.24-0.16 (m, 2H).

[0532] Step 9: Preparation of compound 29-10

[0533] To a solution of tert-butyl 3-bromo-6-((cyclopropylmethoxy)methyl)-2-(methoxymethyl)benzoate (1.27 g, 3.16 mmol) in dioxane (15 mL) and water (3 mL) was added triethylamine (640.4 mg, 6.33 mmol), potassium vinyl trifluoroborate (635.8 mg, 4.75 mmol), and the catalyst, Pd(dppf)Cl₂.CH₂Cl₂ (115.7 mg, 158.2 μmol), under nitrogen. The mixture was allowed to react at 110°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 29-10 (862.0 mg, 78.1% yield) as a light yellow oil. 1 HNMR: ES20978-753 (CDCl3, 400MHz) δ7.54 (d, J=8.0Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.05 (dd, J=11.1,17.7Hz,1H),5.74(dd,J=1.1,17.7Hz,1H),5.33(dd,J=1.1,11.0Hz,1H),5.05-5.01( m,2H),4.57(s,2H),3.58(s,3H),3.28(d,J=6.9Hz,2H),1.61(s,9H),1.14-1.01(m,1H),0.5 7-0.49(m,2H),0.24-0.17(m,2H); LCMS: ES20978-753-P1A1, RT=0.840min, m / z=371.1(M+Na) + .

[0534] Step 10: Preparation of compound 29-11

[0535] To a solution of tert-butyl 6-((cyclopropylmethoxy)methyl)-2-(methoxymethyl)-3-vinylbenzoate (462.0 mg, 1.33 mmol) in dichloromethane (6 mL) was added 2-diphenylphosphino(diphenyl)phosphine (31.7 mg, 79.5 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (339.3 mg, 2.65 mmol), and cycloocta-1,5-dieneiridium chloride (26.7 mg, 39.7 μmol) in sequence under nitrogen. The mixture was allowed to react at 25°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 29-11 (570.0 mg, 90.2% yield) as a yellow oil.1 HNMR:ES20978-772(CDCl3,400MHz)

[0536] δ7.25(d,J=7.9Hz,1H),7.13(d,J=7.9Hz,1H),5.03(s,2H),4.54(s,2H),3 .59(s,3H),3.26(d,J=7.0Hz,2H),2.86-2.77(m,2H),1.60(s,9H),1.26-1 .21(m,13H),1.16-1.10(m,2H),1.09-1.02(m,1H),0.54-0.47(m,2H),0.2 3-0.15(m,2H); LCMS: ES20978-772-P1A1, RT=0.895min, m / z=499.3(M+Na) + .

[0537] Step 11: Preparation of compound 29-12

[0538] To a solution of tert-butyl 6-((cyclopropylmethoxy)methyl)-2-(methoxymethyl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (200.0 mg, 419.8 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (957.35 mg, 8.40 mmol, 623.68 μL) and reacted at 25°C for 16 hours. The reaction solution was concentrated, and acetonitrile (1 mL) and water (1 mL) were added to the resulting crude product. The pH was adjusted to 9 with 1 M aqueous sodium hydroxide solution, and the product was purified by reverse-phase HPLC to afford the desired product 29-12 (100.0 mg, 86.2% yield) as a white solid. 1HNMR: ES20978-776-P1 (MeOD, 400MHz) δ7.02 (br d, J=7.5Hz, 1H), 6.86 (br d, J=7.5Hz, 2H), 4.77 (s, 2H), 3.35 (d, J=6.8Hz, 2H), 2.66 (br t, J=7.0Hz, 2H), 1.10 (br d, J=7.7Hz, 2H), 0.52 (br d, J=7.9Hz, 3H), 0.23 (br d, J=3.3Hz, 4H); LCMS: ES20978-776-P1A1, RT=0.2min.

[0539] Step 12: Preparation of compound 29

[0540] To 7-((cyclopropylmethoxy)methyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (100.0 mg, 362.2 μmol) was added 1 M sodium hydroxide in deionized water (725 μL) and deionized water (1 mL), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The aqueous phase was collected and lyophilized to afford the desired product 29 (35 mg, 30.0% yield) as a yellow solid. 1 HNMR: ES20978-788-P1A(MeOD,400MHz)δ6.79(d,J=7.6Hz,1H),6.61(d,J=7.6Hz,1H),4.57(s,2H),3.31-3.29(m,2H),2.61(br t,J=6.9Hz,2H),1.14-0.99(m,1H),0.53-0.42(m,4H),0.23-0.16(m,2H); LCMS:ES20978-788-P1A2,RT=0.667min,m / z=277.2(M+H) + .

[0541] Example 30

[0542] Step 1: Preparation of compound 30-2

[0543] To a solution of (5-fluoro-2-pyridine)methanol (1.72 g, 13.5 mmol) in N,N-dimethylformamide (30 mL) at 0°C under nitrogen was added sodium hydride (676.8 mg, 16.9 mmol, 60% purity). The mixture was stirred for half an hour, followed by the addition of 2-bromo-5-(bromomethyl)phenol (3 g, 11.2 mmol) in N,N-dimethylformamide (15 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution (60 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product 30-2 (4.5 g, crude product) as a yellow oil. 1 HNMR: ES25406-75-P1A (CDCl3, 400MHz) δ7.52-7.38 (m, 4H), 7.03 (d, J = 1.8Hz, 1H), 6.81 (dd, J = 1.8, 8.2Hz, 1H), 6.33-5.93 (m, 1H), 4.64 (s, 2H), 4.55 (s, 2H).

[0544] Step 2: Preparation of compound 30-3

[0545] To a solution of 2-bromo-5-(((5-fluoro-2-pyridyl)methoxy)methyl)phenol (4.33 g, 13.8 mmol) in dichloromethane (45 mL) were added 4-dimethylaminopyridine (84.7 mg, 693.8 μmol) and BOC anhydride (3.18 g, 14.5 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by flash silica gel chromatography to afford the desired product 30-3 (3.1 g, 54.1% yield) as a yellow oil. 1 HNMR: ES25406-79-P1A (CDCl3, 400MHz) δ8.41 (d, J = 2.6Hz, 1H), 7.57 (d, J = 8.2Hz, 1H), 7.48-7.37 (m, 2H) ,7.26(s,1H),7.24(d,J=1.7Hz,1H),7.13(dd,J=1.7,8.2Hz,1H),4.65(s,2H),4.60(s,2H),1.56(s,9H).

[0546] Step 3: Preparation of compound 30-4

[0547] To a solution of tert-butyl 2-bromo-5-(((5-fluoro-2-pyridyl)methoxy)methyl)phenyl carbonate (2.90 g, 7.03 mmol) in tetrahydrofuran (40 mL) was added a 2M solution of lithium diisopropylamide (5.27 mL) at -78°C under nitrogen. The reaction mixture was stirred at -78°C for 2 hours. The mixture was then reacted at 20°C for half an hour. The reaction mixture was slowly added to a saturated ammonium chloride solution (50 mL) at 5-10°C to quench the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was subjected to flash silica gel chromatography to afford the desired product 30-4 (410 mg, 14.1% yield) as a yellow oil. 1 HNMR: ES20978-844-P1 (CDCl3, 400MHz) δ12.03 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 8. 3Hz, 1H), 7.52-7.40 (m, 2H), 7.13 (d, J = 8.4Hz, 1H), 4.86 (s, 2H), 4.71 (s, 2H), 1.61 (s, 9H).

[0548] Step 4: Preparation of compound 30-5

[0549] To a solution of tert-butyl 3-bromo-6-(((5-fluoro-2-pyridyl)methoxy)methyl)-2-hydroxybenzoate (410 mg, 994.5 μmol) in tetrahydrofuran (7 mL) at 0°C under nitrogen was added sodium hydride (79.5 mg, 1.99 mmol, 60% purity). The mixture was stirred for half an hour, followed by the addition of bromomethyl methyl ether (186.4 mg, 1.49 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. Flash silica gel chromatography afforded the desired product 30-5 (360 mg, 79.3% yield) as a yellow oil. 1 HNMR: ES20978-845-P1 (CDCl3, 400MHz) δ8.41 (d, J = 2.6Hz, 1H), 7.58 (d, J = 8.1Hz, 1H), 7.49-7. 39(m,2H),7.13(d,J=8.1Hz,1H),5.16(s,2H),4.63(d,J=4.6Hz,4H),3.65(s,3H),1.56(s,9H).

[0550] Step 5: Preparation of compound 30-6

[0551] To a solution of tert-butyl 3-bromo-6-(((5-fluoro-2-pyridyl)methoxy)methyl)-2-(methoxymethoxy)benzoate (360 mg, 788.9 μmol) in dioxane (6 mL) and water (1 mL) was added triethylamine (159.6 mg, 1.58 mmol), potassium vinyl trifluoroborate (158.5 mg, 1.18 mmol), and the catalyst Pd(dppf)Cl2.CH2Cl2 (28.8 mg, 39.4 μmol) in sequence under nitrogen. The mixture was allowed to react at 110°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 30-6 (220 mg, 69.1% yield) as a light yellow oil. 1HNMR: ES20978-846-P1(CDCl3,400MHz)δ8.40(d,J=2.7Hz,1H),7.55(d,J=8.1Hz,1H),7.51-7.46(m,1H),7.45-7.37(m,1H),7.22(d,J=7.9Hz,1H ), 7.06 (dd, J = 10.9, 17.7Hz, 1H), 5.75 (d, J = 17.7Hz, 1H), 5.35 (d, J = 11.1Hz, 1H), 5.04 (s, 2H), 4.65 (d, J = 19.6Hz, 4H), 3.59 (s, 3H), 1.56 (s, 9H).

[0552] Step 6: Preparation of compound 30-7

[0553] To a solution of tert-butyl 6-(((5-fluoro-2-pyridyl)methoxy)methyl)-2-(methoxymethoxy)-3-vinylbenzoate (220 mg, 545.3 μmol) in dichloromethane (4 mL) was added 2-diphenylphosphino(diphenyl)phosphine (13.0 mg, 32.7 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (139.5 mg, 1.09 mmol), and cycloocta-1,5-dieneiridium chloride (10.9 mg, 16.3 μmol) in sequence under nitrogen. The mixture was allowed to react at 25°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 30-7 (210 mg, 72.4% yield) as a yellow oil. 1 HNMR: ES20978-848-P1 (CDCl3, 400MHz) δ8.39 (d, J = 2.7Hz, 1H), 7.52-7.46 (m, 1H), 7.43-7.36 (m, 1H), 7.26 (s, 1H), 7.13 (d, J = 7.9 Hz,1H),5.07-5.02(m,2H),4.63(d,J=15.3Hz,4H),3.60(s,3H),2.87-2.78(m,2H),1.55(s,9H),1.23(s,12H),1.17-1.10(m,2H).

[0554] Step 7: Preparation of compound 30

[0555] To a solution of tert-butyl 6-(((5-fluoro-2-pyridyl)methoxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (210 mg, 395.1 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (450.5 mg, 3.95 mmol, 293.5 μL) and reacted at 25°C for 2 hours. The reaction solution was concentrated, and acetonitrile (1 mL) and water (1 mL) were added to the resulting crude product. The pH was adjusted to 9 with 1 M aqueous sodium hydroxide solution, and the product was purified by reverse-phase HPLC to afford the desired product 30 (64 mg, 48.9% yield) as a white solid. 1 HNMR: ES20978-849-P1(MeOD,400MHz)δ8.38(s,1H),7.71-7.57(m,2H),7.28-6.95(m,2H),4.98(br s,2H),4.73-4.64(m,2H),2.90-2.47(m,2H),1.10-0.60(m,2H).

[0556] Step 8: Preparation of compound 30a

[0557] To 7-((((5-fluoro-2-pyridyl)methoxy)methyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (64 mg, 193.2 μmol) was added 1 M sodium hydroxide solution in deionized water (387 μL) and stirred at 25°C for 1 hour. The reaction mixture was lyophilized to afford the desired product 30a (71 mg, 97.4% yield) as a white solid. 1 HNMR: ES20978-850-P1(MeOD,400MHz)δ8.35(s,1H),7.70-7.55(m,2H),6.80(d,J =7.6Hz,1H),6.63(d,J=7.6Hz,1H),4.71-4.56(m,4H),2.67-2.57(m,2H),0.46(br s, 2H); LCMS: ES20978-850-P1A, RT=1.217min, m / z=332.2(M+H) + .

[0558] Example 31

[0559] Step 1: Preparation of compound 31-2

[0560] To a solution of 2-bromo-5-(hydroxymethyl)phenol (5.0 g, 24.63 mmol) in phosphoric acid (50 mL) was added 2-methyl-1-propanol (50 mL), and the reaction was stirred at 90°C for 48 hours. The reaction was diluted with water (100 mL) and ethyl acetate (100 mL), and the mixture was adjusted to pH 8 with saturated sodium carbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 31-2 (2.75 g, 43.09% yield) as a yellow oil. 1 HNMR: ES20989-776-P1A (CDCl3, 400MHz) δ7.43 (d, J = 8.4Hz, 1H), 7.04 (d, J = 2.0Hz, 1H), 6.81 (dd, J = 1.9, 8.3Hz,1H),5.66-5.44(m,1H),4.45(s,2H),3.25(d,J=6.8Hz,2H),2.01-1.86(m,1H),1.00-0.87(m,5H).

[0561] Step 2: Preparation of compound 31-3

[0562] To a solution of 2-bromo-5-(isobutoxymethyl)phenol (2.70 g, 10.4 mmol) in dichloromethane (40 mL) were added 4-dimethylaminopyridine (63.6 mg, 520.96 μmol) and BOC anhydride (2.50 g, 11.4 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was then purified by flash silica gel chromatography to afford the desired product 31-3 (3.5 g, 93.51% yield) as a yellow oil. 1 HNMR: ES20989-786-P1A(CDCl3,400MHz)δ7.48(d,J=8.1Hz,1H),7.12(d,J=1.9Hz,1H),7.03(dd,J=1.9,8.2Hz,1H),4 .39(s,2H),3.16(d,J=6.6Hz,2H),1.89-1.76(m,1H),1.52-1.48(m,9H),1.40(d,J=3.9Hz,1H),0.85(d,J=6.6Hz,6H).

[0563] Step 3: Preparation of compound 31-4

[0564] To a 2M solution of lithium diisopropylamide (8.98 mL) in tetrahydrofuran (50 mL) at -78°C under nitrogen was added hexamethylphosphoric triamide (1.29 g, 7.18 mmol, 1.26 mL), followed by a solution of tert-butyl 2-bromo-5-(isobutoxymethyl)phenyl carbonate (4.3 g, 11.97 mmol) in tetrahydrofuran (12 mL). The reaction mixture was stirred at -78°C for 1 hour. The mixture was quenched by slowly adding saturated ammonium chloride (50 mL) at 5-10°C and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. Flash silica gel chromatography afforded the desired product 31-4 (1.33 g, 30.93% yield) as a yellow solid. 1 HNMR: ES20989-791-P1A (CDCl3, 400MHz) δ12.03 (s, 1H), 7.66 (d, J = 8.3Hz, 1H), 7.11 (d, J = 8.3Hz, 1H), 4. 72(s,2H),3.29(d,J=6.6Hz,2H),1.96(quind,J=6.7,13.4Hz,1H),1.69-1.63(m,9H),1.01-0.95(m,6H).

[0565] Step 4: Preparation of compound 31-5

[0566] To a solution of tert-butyl 3-bromo-6-(isobutoxymethyl)-2-hydroxybenzoate (1.33 g, 3.70 mmol) in tetrahydrofuran (40 mL) at 0°C under nitrogen was added sodium hydride (296.1 mg, 7.40 mmol, 60% purity). The mixture was stirred for half an hour, followed by the addition of bromomethyl methyl ether (555.1 mg, 4.44 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. Flash silica gel chromatography afforded the desired product 31-5 (1.0 g, 66.98% yield) as a colorless oil. 1 HNMR: ES20989-793-P1A (CDCl3, 400MHz) δ7.58 (d, J = 8.1Hz, 1H), 7.15 (d, J = 8.4Hz, 1H), 5.16 (s, 2H), 4.50 (s ,2H),3.70-3.62(m,3H),3.21(d,J=6.6Hz,2H),1.97-1.85(m,1H),1.64-1.59(m,9H),0.93(d,J=6.6Hz,6H).

[0567] Step 5: Preparation of compound 31-6

[0568] To a solution of tert-butyl 3-bromo-6-(isobutoxymethyl)-2-(methoxymethoxy)benzoate (500.0 mg, 1.24 mmol) in dioxane (10 mL) and water (2 mL) was added triethylamine (250.9 mg, 2.48 mmol), potassium vinyl trifluoroborate (249.1 mg, 1.86 mmol, 1.5 eq), and the catalyst Pd(dppf)Cl2.CH2Cl2 (45.3 mg, 61.9 μmol) sequentially under nitrogen. The mixture was allowed to react at 110°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 31-6 (250.0 mg, 57.54% yield) as a yellow oil. 1 HNMR: ES20989-796-P1A (CDCl3, 400MHz) δ7.46 (d, J = 8.0Hz, 1H), 7.14 (d, J = 8.0Hz, 1H), 6.97 (dd, J = 11.0, 17.8Hz, 1H), 5.70-5.62 (m, 1H) ,5.28-5.22(m,1H),4.95(s,2H),4.44(s,2H),3.50(s,3H),3.12(d,J=6.8Hz,2H),1.89-1.77(m,1H),1.53(s,9H),0.84(d,J=6.8Hz,6H).

[0569] Step 6: Preparation of compound 31-7

[0570] To a solution of tert-butyl 6-(isobutoxymethyl)-2-(methoxymethoxy)-3-vinylbenzoate (250.0 mg, 713.3 μmol) in dichloromethane (5 mL) was added 2-diphenylphosphino(diphenyl)phosphine (34.1 mg, 85.6 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (182.5 mg, 1.43 mmol), and cycloocta-1,5-dieneiridium chloride (28.7 mg, 42.8 μmol) in sequence under nitrogen. The mixture was allowed to react at 25°C for 16 hours. The reaction mixture was concentrated, and the crude product was purified by flash silica gel chromatography to afford the desired product 31-7 (260.0 mg, 76.18% yield) as a yellow oil. 1HNMR: ES20989-797-P1A (CDCl3, 400MHz) δ7.27 (d, J=7.9Hz, 1H), 7.16 (d, J=7.9Hz, 1H), 5.09-5.02 (m, 2H), 4.51 (s, 2H), 3.61 (s, 3H), 3.19 ( d,J=6.6Hz,2H),2.91-2.78(m,2H),1.90(quind,J=6.6,13.3Hz,1H),1.61(s,9H),1.24(s,12H),1.19-1.10(m,2H),0.92(d,J=6.7Hz,6H).

[0571] Step 7: Preparation of compound 31-8

[0572] To a solution of tert-butyl 6-(isobutoxymethyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (260.0 mg, 543.4 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (619.6 mg, 5.43 mmol, 403.6 μL) and reacted at 25°C for 2 hours. The reaction solution was concentrated, and acetonitrile (1 mL) and water (1 mL) were added to the resulting crude product. The pH was adjusted to 9 with 1 M aqueous sodium hydroxide solution, and the product was purified by reverse-phase HPLC to afford the desired product 31-8 (70.0 mg, 46.32% yield) as a white solid. 1 HNMR: ES20989-800-P1A(MeOD,400MHz)δ7.29-7.19(m,1H),7.13-6.96(m,1H),2.85(br t,J=6.9Hz,1H),2.77-2.65(m,1H),2.57-2.43(m,1H),2.04-1.85(m,1H),1.03-0.93(m,8H),0.79-0.59(m,2H).

[0573] Step 8: Preparation of compound 31

[0574] To 7-(isobutoxymethyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (70.0 mg, 251.70 μmol) was added 1 M sodium hydroxide in deionized water (503 μL) and deionized water (1 mL), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was lyophilized to afford the desired product 31 (80.0 mg, 98.07% yield) as a yellow solid. 1HNMR: ES20989-814-P1A (MeOD, 400MHz) δ6.80 (d, J = 7.6Hz, 1H), 6.64 (d, J = 7.6Hz, 1H), 4.56 (s, 2H), 3.26 (d, J = 6.8Hz, 2H), 2.63 (br t,J=6.9Hz,2H),1.97-1.79(m,1H),0.93(d,J=6.6Hz,6H),0.47(br t,J=7.0Hz,2H); LCMS: ES20989-814-P1A, RT=3.655min, m / z=279.1(M+H) + .

[0575] Example 32

[0576] Step 1: Preparation of compound 32-2

[0577] To a solution of tert-butyl 6-(hydroxymethyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (300.0 mg, 710.3 μmol) and 4-fluorophenol (103.5 mg, 923.4 μmol) in tetrahydrofuran at 25°C under nitrogen was added diethyl azodicarboxylate (185.5 mg, 1.07 mmol) and tri-tert-butylphosphine (215.5 mg, 1.07 mmol), respectively. The mixture was allowed to react at 25°C for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 32-2 (110 mg, 29.99% yield) as a light yellow oil. 1 HNMR: ES20989-718-P1A (CDCl3, 400MHz) δ7.33-7.27 (m, 1H), 7.17 (d, J = 7.9Hz, 1H), 7.01-6.94 (m, 2H), 6.93-6.85 (m, 2H ),5.07(s,2H),5.03(s,2H),3.66-3.58(m,3H),2.89-2.81(m,2H),1.58-1.52(m,9H),1.24(s,12H),1.19-1.13(m,2H).

[0578] Step 2: Preparation of compound 32-3

[0579] To a solution of tert-butyl 6-((4-fluorophenoxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (110.0 mg, 213.0 μmol) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was added triethylsilane (24.7 mg, 213.0 μmol) and reacted at 25°C for 2 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC to afford the desired product 32-3 (20.0 mg, 29.7% yield) as a white solid. 1 HNMR: ES20989-721-P1A (MeOD, 400MHz) δ 7.43-6.88 (m, 5H), 5.53-5.52 (m, 1H), 5.63-5.35 (m, 1H), 2.98-2.47 (m, 2H), 1.33-0.60 (m, 2H).

[0580] Step 3: Preparation of compound 32

[0581] To 7-((4-fluorophenoxy)methyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (20.0 mg, 63.27 μmol) was added 1 M sodium hydroxide in deionized water (127 μL) and deionized water (1 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was lyophilized to afford the desired product 32 (21.0 mg, 91.67% yield) as a brown solid. 1 HNMR: ES20989-735-P1A (MeOD, 400MHz) δ7.02-6.90 (m, 4H), 6.81 (d, J = 7.7Hz, 1H), 6.65 (d, J = 7.7Hz, 1H), 5. 09(s,2H),2.69-2.58(m,2H),0.48(t,J=7.0Hz,2H); LCMS: ES20989-735-P1A, RT=2.717min, m / z=317.1(M+H) + .

[0582] Example 33

[0583] Step 1: Preparation of compound 33-2

[0584] To a solution of 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)phenol (32.0 g, 100.85 mmol) in dichloromethane (300 mL) were added 4-dimethylaminopyridine (616.0 mg, 5.04 mmol) and BOC anhydride (24.21 g, 110.94 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane. The organic layer was washed with 0.5 M hydrochloric acid (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product 33-2 (31 g, crude) as a yellow oil. 1 HNMR: ES20978-705-P1A (CDCl3, 400MHz) δ7.54 (d, J = 8.2Hz, 1H), 7.18 (d, J = 1.7Hz, 1H ), 7.09 (dd, J = 1.8, 8.2Hz, 1H), 4.70 (s, 2H), 1.58 (s, 10H), 0.94 (s, 9H), 0.10 (s, 6H).

[0585] Step 2: Preparation of compound 33-3

[0586] To a 2M solution of lithium diisopropylamide (55.70 mL) in tetrahydrofuran (330 mL) was added a solution of tert-butyl 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)benzoate (31.0 g, 74.27 mmol) in tetrahydrofuran (100 mL) at -78°C under nitrogen. The reaction mixture was stirred at -78°C for 2 hours. The mixture was slowly added to a saturated ammonium chloride solution (500 mL) at 5-10°C to quench the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was subjected to flash silica gel chromatography to afford the desired product 33-3 (24.1 g, 77.74% yield) as a yellow oil. 1 HNMR: ES20978-706-P1A (CDCl3, 400MHz) δ7.68 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 4.92 (s, 2H), 1.64 (s, 9H), 0.97 (s, 9H), 0.12 (s, 6H).

[0587] Step 3: Preparation of compound 33-4

[0588] To a solution of tert-butyl 3-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-hydroxybenzoate (24.1 g, 57.74 mmol) in dichloromethane (250 mL) at 0°C were added triethylamine (12.8 g, 127.0 mmol) and bromomethyl methyl ether (14.43 g, 115.47 mmol), respectively. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 33-4 (20.2 g, 75.82% yield) as a yellow oil. 1 HNMR: ES20978-707-P1A (CDCl3, 400MHz) δ7.58 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5. 14(s,2H),4.71(s,2H),3.64(s,3H),1.60(s,9H),0.95-0.93(m,10H),0.10-0.08(m,6H).

[0589] Step 4: Preparation of compound 33-5

[0590] To a solution of tert-butyl 3-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(methoxymethoxy)benzoate (10.0 g, 21.67 mmol) in dioxane (200 mL) and water (40 mL) were added triethylamine (4.39 g, 43.3 mmol), potassium vinyl trifluoroborate (4.35 g, 32.51 mmol), and the catalyst Pd(dppf)Cl₂.CH₂Cl₂ (792.8 mg, 1.08 mmol) in sequence under nitrogen. The mixture was allowed to react at 105°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 33-5 (4.4 g, 49.69% yield) as a yellow oil. 1 HNMR: ES20989-717-P1A(CDCl3,400MHz)δ7.58(d,J=8.1Hz,1H),7.41-7.30(m,1H),7.06(dd,J=11.0,17.8Hz,1H),5.75(d,J=17.8Hz ,1H),5.33(d,J=10.8Hz,1H),5.04(s,2H),4.80-4.75(m,2H),3.62-3.56(m,3H),1.63-1.60(m,9H),0.98-0.93(m,12H),0.10(s,6H).

[0591] Step 5: Preparation of compound 33-6

[0592] To a solution of tert-butyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(methoxymethoxy)-3-vinylbenzoate (4.4 g, 10.7 mmol) in dichloromethane (60 mL) was added 2-diphenylphosphino(diphenyl)phosphine (257.4 mg, 646.1 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.76 g, 21.5 mmol), and cycloocta-1,5-dieneiridium chloride (217.0 mg, 323.0 μmol) in sequence under nitrogen. The mixture was allowed to react at 25°C for 16 hours. The reaction mixture was concentrated, and the crude product was purified by flash silica gel chromatography to afford the desired product 33-6 (4.2 g, 72.69% yield) as a yellow oil. 1 HNMR: ES20989-722-P1A(CDCl3,400MHz)δ7.21-7.16(m,2H),4.95(s,2H),4.68-4.63(m,2H),3.55-3.47(m,3H),2. 79-2.67(m,2H),1.54-1.51(m,9H),1.18-1.10(m,12H),1.10-1.01(m,2H),0.87-0.83(m,9H),0.03--0.03(m,6H).

[0593] Step 6: Preparation of compound 33-7

[0594] Acetic acid (134.30 mg, 2.24 mmol, 128.03 μL) and 1 M tetrabutylammonium fluoride solution (2.35 mL) were added to a solution of tert-butyl 6-((((tert-butyldimethylsilyl)oxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (1.2 g, 2.24 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 33-7 (270.0 mg, 28.59% yield) as a yellow oil.

[0595] Step 7: Preparation of compound 33-8

[0596] To a solution of tert-butyl 6-(hydroxymethyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (420.0 mg, 994.5 μmol) and 6-fluoropyridine-3-hydroxy (123.7 mg, 1.09 mmol) in tetrahydrofuran (8 mL) was added diethyl azodicarboxylate (225.1 mg, 1.29 mmol) and tri-tert-butylphosphine (261.5 mg, 1.29 mmol) under nitrogen at 25°C. The reaction mixture was stirred at 25°C for 16 hours. Brine (10 mL) and ethyl acetate (10 mL) were added to the reaction mixture, the aqueous phase was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the target product 33-8 (110.0 mg, 21.38% yield) was obtained by flash silica gel chromatography as a yellow oil.

[0597] Step 8: Preparation of compound 33-9

[0598] To a solution of tert-butyl 6-(((6-fluoro-3-pyridyl)oxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (110.0 mg, 212.60 μmol) in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added triethylsilane (48.74 mg, 212.60 μmol) and reacted at 25°C for 16 hours. The reaction solution was concentrated, and water (3 mL) was added to the crude product. The pH was adjusted to 10 with 1 M aqueous sodium hydroxide solution, and the product was purified by reverse-phase HPLC to afford the desired product 33-9 (20.0 mg, 29.67% yield) as a white solid. 1 HNMR: ES20989-738-P1A(MeOD,400MHz)δ7.96-7.75(m,1H),7.60-7.48(m,1H),7.28(d,J =7.6Hz,1H),7.12-6.88(m,2H),5.70-5.25(m,2H),2.96-2.44(m,2H),1.42-0.52(m,2H).

[0599] Step 9: Preparation of compound 33

[0600] To 7-(((6-fluoro-3-pyridyl)oxy)methyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (20.0 mg, 63.08 μmol) was added 2M sodium hydroxide in deionized water (63.08 μL) and deionized water (2 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was lyophilized to afford the desired product 33 (21.0 mg, 57.84% yield) as a white-brown solid. 1 HNMR:ES20989-751-P1A(MeOD,400MHz)δ7.87(br s,1H),7.61(ddd,J=3.1,6.3,9.1Hz,1H),6.94(dd,J=3.0,8.9Hz,1H),6.82(d,J=7.8Hz,1H),6.63(d,J=7.6Hz,1H),5.19(s,2H),2.64(br t, J=6.9Hz, 2H), 0.48 (br t, J=6.9Hz, 2H); LCMS: ES20989-751-P1A, RT=4.20min, m / z=318.1(M+H) + .

[0601] Example 34

[0602] Step 1: Preparation of compound 34-2

[0603] To a solution of 4-bromo-(3-(methoxymethoxy)phenyl)methanol (7.00 g, 28.3 mmol, 1 eq) in tetrahydrofuran (70 mL) was added sodium hydride (1.70 g, 42.5 mmol, 60% purity) under nitrogen at 0°C. The reaction was allowed to proceed for half an hour, followed by the addition of iodomethane (4.83 g, 34.0 mmol). The reaction was stirred at 25°C for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 34-2 (6.6 g, 89.2% yield) as a yellow oil. 1 HNMR: ES20978-759-P1 (CDCl3, 400MHz) δ7.51 (d, J = 8.0Hz, 1H), 7.14 (d, J = 1.8Hz, 1H ), 6.87 (dd, J = 1.8, 8.1Hz, 1H), 5.27 (s, 2H), 4.41 (s, 2H), 3.54 (s, 3H), 3.40 (s, 3H).

[0604] Step 2: Preparation of compound 34-3

[0605] Dissolve 1-bromo-2-(methoxymethoxy)-4-(methoxymethyl)benzene (6.70 g, 25.7 mmol) in dichloromethane (35 mL) and trifluoroacetic acid (35 mL). Stir the mixture at 25°C for 16 hours. The reaction mixture is concentrated, and the crude product is adjusted to pH 8 with saturated sodium carbonate solution, then extracted with dichloromethane. The organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired product 34-3 (3.5 g, crude) as a yellow oil. The crude product is used directly in the next step without purification. 1HNMR: ES20978-760-P1 (CDCl3, 400MHz) δ7.43 (d, J = 8.3Hz, 1H), 7.01 (d, J = 2.0Hz, 1H), 6.80 (dd, J = 2.0, 8.1Hz, 1H), 4.41-4.39 (m, 2H), 3.39 (s, 3H).

[0606] Step 3: Preparation of compound 34-4

[0607] To a solution of 2-bromo-5-(methoxymethyl)phenol (5.50 g, 25.3 mmol) in dichloromethane (60 mL) were added 4-dimethylaminopyridine (154.8 mg, 1.27 mmol) and BOC anhydride (6.08 g, 27.8 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was then purified by flash silica gel chromatography to afford the desired product 34-4 (6.8 g, 84.6% yield) as a yellow solid. 1 HNMR: ES20978-761-P1 (CDCl3, 400MHz) δ7.57 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 1. 7Hz, 1H), 7.10 (dd, J = 1.8, 8.2Hz, 1H), 4.43 (s, 2H), 3.39 (s, 3H), 1.58 (s, 9H).

[0608] Step 4: Preparation of compound 34-5

[0609] To a 2M solution of lithium diisopropylamide (12.67 mL) in tetrahydrofuran (70 mL) was added a solution of tert-butyl 2-bromo-5-(methoxymethyl)benzoate (6.7 g, 21.12 mmol) in tetrahydrofuran (35 mL) at -78°C under nitrogen. The reaction mixture was stirred at -78°C for 2 hours. The mixture was slowly quenched by adding saturated ammonium chloride (100 mL) at 5-10°C and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was subjected to flash silica gel chromatography to afford the desired product 34-5 (1.87 g, 27.9% yield) as a yellow oil.1 HNMR: ES20978-767-P1 (CDCl3, 400MHz) δ 12.00 (s, 1H), 7.66 (d, J = 8.3Hz, 1H), 7.04 (d, J = 8.4Hz, 1H), 4.67 (s, 2H), 3.44 (s, 3H), 1.65 (s, 9H).

[0610] Step 5: Preparation of compound 34-6

[0611] To a solution of tert-butyl 3-bromo-(6-(methoxymethyl))-2-hydroxybenzoate (1.87 g, 5.90 mmol) in tetrahydrofuran (20 mL) at 0°C under nitrogen was added sodium hydride (471.6 mg, 11.7 mmol, 60% purity). The mixture was stirred for half an hour, followed by the addition of bromomethyl methyl ether (1.11 g, 8.84 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. Flash silica gel chromatography afforded the desired product 34-6 (1.92 g, 90.2% yield) as a yellow oil. 1 HNMR: ES20978-770-P1 (CDCl3, 400MHz) δ7.56 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8 .3Hz,1H),5.16(s,2H),4.45(s,2H),3.65(s,3H),3.36(s,3H),1.61(s,9H).

[0612] Step 6: Preparation of compound 34-7

[0613] To a solution of tert-butyl 3-bromo-(6-(methoxymethyl)-2-(methoxymethoxy)benzoate (1.00 g, 2.77 mmol) in dioxane (15 mL) and water (3 mL) was added triethylamine (560.2 mg, 5.54 mmol), potassium vinyl trifluoroborate (556.2 mg, 4.15 mmol), and the catalyst Pd(dppf)Cl2.CH2Cl2 (101.28 mg, 138.42 μmol) in sequence under nitrogen. The mixture was allowed to react at 110°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 34-7 (570.0 mg, 66.7% yield) as a light yellow oil. 1HNMR: ES20978-771-P1(CDCl3,400MHz)δ7.53(d,J=8.1Hz,1H),7.16(d,J=8.1Hz,1H),7.06(dd,J=11.0,17.7Hz,1H),5.7 5(dd,J=1.0,17.7Hz,1H),5.34(dd,J=1.0,11.1Hz,1H),5.04(s,2H),4.49(s,2H),3.58(s,3H),3.36(s,3H),1.61(s,9H).

[0614] Step 7: Preparation of compound 34-8

[0615] To a solution of tert-butyl 6-(methoxymethyl)-2-(methoxymethoxy)-3-vinylbenzoate (200 mg, 648.57 μmol) in dichloromethane (4 mL) was added 2-diphenylphosphino(diphenyl)phosphine (15.50 mg, 38.91 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (166.00 mg, 1.30 mmol), and cycloocta-1,5-dieneiridium chloride (13.07 mg, 19.46 μmol) in sequence under nitrogen. The mixture was allowed to react at 25°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to afford the desired product 34-8 (210.0 mg, 90.2% yield) as a yellow oil. 1 HNMR: ES20978-775-P1 (CDCl3, 400MHz) δ7.25 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 5.04 (s, 2H), 4. 46(s,2H),3.60(s,3H),3.34(s,3H),2.85-2.79(m,2H),1.60(s,9H),1.23(s,12H),1.16-1.09(m,2H).

[0616] Step 8: Preparation of compound 34-9

[0617] To a solution of tert-butyl 6-(methoxymethyl)-2-(methoxymethyl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (190.0 mg, 435.4 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (992.9 mg, 8.71 mmol, 646.9 μL) and reacted at 25°C for 16 hours. The reaction solution was concentrated, and acetonitrile (1 mL) and water (1 mL) were added to the resulting crude product. The pH was adjusted to 9 with 1 M aqueous sodium hydroxide solution, and the product was purified by reverse-phase HPLC to afford the desired product 34-9 (58 mg, 56.4% yield) as a yellow solid. 1 HNMR: ES20978-779-P1(MeOD,400MHz)δ7.17-6.96(m,1H),6.86-6.66(m,1H),4.78-4.71(m,2H),3.28(br s,1H),3.20(br s,1H),2.78-2.29(m,2H),0.63-0.24(m,2H).

[0618] Step 9: Preparation of compound 34

[0619] To 7-(methoxymethyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (58 mg, 245.73 μmol) was added 1 M sodium hydroxide in deionized water (492 μL) and stirred at 25°C for 2 hours. The reaction mixture was lyophilized to afford the desired product 34 (57.0 mg, 82.3% yield) as a yellow solid. 1 HNMR: ES20978-786-P1 (MeOD, 400MHz) δ6.80 (d, J = 7.7Hz, 1H), 6.58 (d, J = 7.6Hz, 1H), 5.17-4.90 (m, 1H), 4.51 (s, 2H), 3.35 (s, 3H), 2.63 (br t, J=6.9Hz, 2H), 0.47 (br t, J=7.0Hz, 2H); LCMS: ES20978-786-P1A1, RT=0.520min, m / z=237.1(M+H) + .

[0620] Example 35

[0621] Step 1: Preparation of compound 35-2

[0622] 4-Bromo-3-methoxymethoxybenzyl alcohol (7.02 g, 28.4 mmol) was dissolved in tetrahydrofuran (84 mL) at 25°C. Sodium hydride (1.70 g, 42.6 mmol, 60% purity) was added at 0°C under nitrogen. The reaction was stirred at 0°C under nitrogen for 0.5 hours, then the temperature was raised to 25°C and stirred for 16 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (150 mL) and then extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the desired product 35-2 (7.20 g, crude) as a brown oil. 1 HNMR: ES25406-50-P1A (CDCl3, 400MHz) δ7.49 (d, J = 8.1Hz, 1H), 7.13 (d, J = 1.3Hz, 1H), 6.87 (dd,J=1.5,8.1Hz,1H),5.25(s,2H),4.43(s,2H),3.57-3.49(m,5H),1.25(d,J=7.0Hz,3H).

[0623] Step 2: Preparation of compound 35-3

[0624] Dissolve trifluoroacetic acid (52.4 g, 459 mmol) in dichloromethane (35.0 mL). Add 1-bromo-4-(ethoxyethyl)-2-(methoxymethoxy)benzene (7.02 g, 25.5 mmol) at 25°C under nitrogen. Stir the reaction mixture for 0.5 h. Concentrate the reaction mixture to remove the trifluoroacetic acid. Add the crude product to water (50 mL), and adjust the pH of the aqueous phase to 8-9 with saturated sodium carbonate solution. Extract the aqueous phase with dichloromethane (100 mL x 3). Wash the organic layer with saturated sodium chloride solution (200 mL x 2), dry over anhydrous sodium sulfate, and filter and concentrate to obtain the desired product 35-3 (5.59 g, crude) as a yellow oil. 1 HNMR: ES25406-50-P1A (CDCl3, 400MHz) δ7.41 (d, J = 8.2Hz, 1H), 7.01 (d, J = 2.0Hz, 1H), 6.79(dd,J=2.0,8.2Hz,1H),5.73(s,1H),4.43(s,2H),3.59-3.49(m,2H),1.25(s,3H).

[0625] Step 3: Preparation of compound 35-4

[0626] At 25°C, 2-bromo-5-(ethoxyethyl)-phenol (5.59 g, 24.19 mmol) was dissolved in dichloromethane (60 mL). Di-tert-butyl dicarbonate (5.54 g, 25.4 mmol) and 4-dimethylaminopyridine (147 mg, 1.21 mmol) were added. The reaction was stirred at 25°C for 1 hour. The organic layer was washed with saturated sodium chloride solution (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 35-4 (6.39 g, 79.7% yield) as a yellow oil. 1 HNMR: ES25406-52-P1A (CDCl3, 400MHz) δ7.57 (d, J = 8.2Hz, 1H), 7.22 (d, J = 1.7Hz, 1H), 7.11 (d d,J=1.6,8.2Hz,1H),4.48(s,2H),3.55(q,J=6.9Hz,2H),1.58(s,9H),1.25(t,J=7.0Hz,3H).

[0627] Step 4: Preparation of compound 35-5

[0628] Lithium diisopropylamide (2M, 10.6 mL) was dissolved in tetrahydrofuran (60 mL) at 25°C under nitrogen. 2-Bromo-5-(ethoxyethyl)-phenylcarbonate (5.85 g, 17.7 mmol) dissolved in tetrahydrofuran (24 mL) was added dropwise to the reaction mixture at -70°C under nitrogen. The reaction was stirred at -70°C under nitrogen for 0.5 hour. The reaction was stirred at 0-5°C for 0.5 hour. The reaction mixture was slowly poured into cooled saturated ammonium chloride solution (200 mL) at 25°C. The aqueous layer was extracted with ethyl acetate (25 mL x 2), and the organic layer was washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 35-5 (1.16 g, 19.8% yield) as a yellow solid. 1 HNMR: ES25406-55-P1A (CDCl3, 400MHz) δ11.96 (s, 1H), 7.64 (d, J = 8.3Hz, 1H), 7.05 (d, J=7.8Hz,1H),4.70(s,2H),3.56(q,J=7.0Hz,2H),1.63(s,9H),1.27(t,J=6.8Hz,3H).

[0629] Step 5: Preparation of compound 35-6

[0630] Dissolve tert-butyl 3-bromo-6-(ethoxyethyl)-2-hydroxybenzoate (1.15 g, 3.46 mmol) in tetrahydrofuran (24 mL) at 0°C. Add sodium hydride (276.0 mg, 6.92 mmol, 60.0% purity) at 0°C. Stir the reaction at 0°C for 0.5 hours. Add bromomethyl methyl ether (648.0 mg, 5.19 mmol) at 0°C. Stir the reaction at 25°C for 1 hour. Pour the reaction mixture slowly into cooled saturated ammonium chloride solution (50 mL) at 25°C. The aqueous phase is extracted with ethyl acetate (20 mL x 2). The organic layer is washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by flash silica gel chromatography to yield the desired product 35-6 (910 mg, 70.0% yield) as a colorless oil. 1 HNMR: ES25406-61-P1A (CDCl3, 400MHz) δ7.54 (d, J = 8.3Hz, 1H), 7.09 (d, J = 8.3Hz, 1H), 5.14 ( s, 2H), 4.48 (s, 2H), 3.63 (s, 3H), 3.49 (q, J = 7.0Hz, 2H), 1.59 (s, 9H), 1.21 (t, J = 7.0Hz, 3H).

[0631] Step 6: Preparation of compound 35-7

[0632] Tert-butyl 3-bromo-6-(ethoxyethyl)-2-(methoxymethoxy)benzoate (909 mg, 2.42 mmol) was dissolved in dioxane (19 mL) and water (4.6 mL) at 25°C. Trifluoroacetic acid (490.0 mg, 4.84 mmol) was added at 25°C. Potassium vinyl trifluoroborate (486.7 mg, 3.63 mmol) was also added at 25°C. The catalyst, Pd(dppf)Cl₂.CH₂Cl₂ (297.0 mg, 363.0 μmol), was added to the mixture under nitrogen at 25°C. The reaction was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was poured into 25°C water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by flash silica gel chromatography to give the target product 35-7 (550.0 mg, 70.4% yield). 1HNMR: ES25406-62-P1A (CDCl3, 400MHz) δ7.52 (d, J = 8.1Hz, 1H), 7.18 (d, J = 8.1Hz, 1H), 7.04 (dd, J = 11.0, 17.7Hz, 1H), 5.73 (dd, J = 1.0, 17. 7Hz,1H),5.32(dd,J=1.0,11.1Hz,1H),5.02(s,2H),4.52(s,2H),3.57(s,3H),3.49(q,J=7.0Hz,2H),1.60(s,9H),1.22(t,J=7.0Hz,3H).

[0633] Step 7: Preparation of compound 35-8

[0634] Tert-butyl 6-(ethoxyethyl)-2-(methoxymethoxy)-3-vinylbenzoate (300 mg, 930 μmol) was dissolved in dichloromethane (12 mL) at 25°C. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (238.0 mg, 1.86 mmol), cycloocta-1,5-dieneiridium chloride (18.7 mg, 27.9 μmol), and 2-diphenylphosphino(diphenyl)phosphine (22.2 mg, 55.8 μmol) were added at 25°C. The reaction was stirred at 25°C for 16 hours. The mixture was filtered and concentrated to obtain a crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 35-8 (257.0 mg, 34.03% yield) as a colorless oil. 1 HNMR: ES25406-63-P1A (CDCl3, 400MHz) δ7.20-7.15 (m, 1H), 7.03 (d, J = 7.8Hz, 1H), 4.97-4.94 (m, 2H), 4.42 (s, 2 H), 3.52 (s, 3H), 3.40 (q, J = 7.0Hz, 2H), 2.77-2.71 (m, 2H), 1.52 (s, 9H), 1.16-1.12 (m, 14H), 1.12-1.01 (m, 3H).

[0635] Step 8: Preparation of compound 35-9

[0636] Tert-butyl 6-(ethoxyethyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-vinylbenzoate (235 mg, 521 μmol) was dissolved in dichloromethane (2.5 mL) at 25°C. Trifluoroacetic acid (595 mg, 5.22 mmol) was added at 25°C. The mixture was stirred at 25°C under nitrogen for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase HPLC to obtain the desired product 35-9 (80.0 mg, 60.46% yield) as a white solid. 1 HNMR: ES25406-66-P1A(CDCl3,400MHz)δ7.29-7.19(m,1H),7.06-6.94(m,1H),4.86(s,34H),3 .66-3.52(m,2H),3.31(td,J=1.6,3.3Hz,10H),2.89-2.43(m,2H),1.29-1.15(m,8H),1.10(br d, J=3.5Hz, 3H); LCMS: ES25406-66-P1B, RT=0.19min, m / z=251.3(M+1) + .

[0637] Step 9: Preparation of compound 35

[0638] 7-(Ethoxyethyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (79.2 mg, 316 μmol) was dissolved in water (4.75 mL) at 25°C. Sodium hydroxide (1 M, 633 μL) was added at 25°C. The reaction was stirred at 25°C for 1 hour. The mixture was lyophilized. After lyophilization, the crude sodium salt was dissolved in water (20.0 mL), extracted with isopropyl ether (20.0 mL x 3), and the aqueous phase was lyophilized. The desired product 35 (70 mg, 70.60% yield, 2Na) was obtained as a yellow solid. 1 HNMR: ES25406-74-P1F (MeOD, 400MHz) δ6.78 (d, J = 7.6Hz, 1H), 6.59 (d, J = 7.7Hz, 1H), 4.54 (s, 2H), 3.53 (q, J = 7.1Hz, 2H), 2.61 (br t, J=7.0Hz, 2H), 1.22-1.16 (m, 4H), 0.45 (br t, J=7.0Hz, 2H); LCMS: ES25406-74-P1E, RT=0.519min.

[0639] Example 36

[0640] Step 1: Preparation of compound 36-2

[0641] 2-Bromo-5-bromomethylphenol (3.00 g, 11.2 mmol), morpholine (1.18 g, 13.5 mmol), and N,N-diisopropylethylamine (2.19 g, 16.9 mmol) were added to N,N-dimethylformamide (60 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into saturated sodium chloride solution (60 mL) and extracted with ethyl acetate (50 mL x 2). The organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 36-2 (2.4 g, 78.18% yield) as a yellow oil. 1 HNMR: ES20989-753-P1A (CDCl3, 400MHz) δ7.41 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 1. 7Hz,1H),6.81(dd,J=1.8,8.2Hz,1H),3.78-3.69(m,4H),3.45(s,2H),2.47(br d,J=4.0Hz,4H).

[0642] Step 2: Preparation of compound 36-3

[0643] To a solution of 2-bromo-5-(morpholinylmethyl)phenol (2.4 g, 8.82 mmol) in dichloromethane (40 mL) were added 4-dimethylaminopyridine (53.87 mg, 420.9 μmol) and di-tert-butyl dicarbonate (2.12 g, 9.70 mmol). The reaction was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 36-3 (2.70 g, 82.24% yield) as a yellow oil. 1 HNMR: ES20989-756-P1A (CDCl3, 400MHz) δ7.55 (d, J = 8.2Hz, 1H), 7.24 (d, J = 1.5Hz, 1H), 7.13 (br d, J = 7.9Hz, 1H), 3.73 (br t,J=4.2Hz,4H),3.48(s,2H),2.46(br s,4H),1.59(s,9H).

[0644] Step 3: Preparation of compound 36-4

[0645] To a solution of lithium diisopropylamide (2M, 5.44 mL) in tetrahydrofuran (40 mL) was added a solution of tert-butyl 2-bromo-5-(morpholinomethyl)phenyl carbonate (2.7 g, 7.25 mmol) in tetrahydrofuran (10 mL) at -78°C under nitrogen. The reaction was stirred at -78°C for 1 hour. Saturated ammonium chloride (15 mL) was slowly added to the reaction mixture at 5-10°C, followed by stirring. The mixture was then extracted with ethyl acetate (20 mL x 2) and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 36-4 (650.0 mg, 24.07% yield) as a yellow oil. 1 HNMR: ES20989-762-P1A (CDCl3, 400MHz) δ11.00 (s, 1H), 7.58 (d, J = 8.2Hz, 1H ), 6.96 (d, J = 8.2Hz, 1H), 3.74-3.68 (m, 6H), 2.45-2.37 (m, 4H), 1.65 (s, 9H).

[0646] Step 4: Preparation of compound 36-5

[0647] To a solution of tert-butyl 3-bromo-6-(morpholinomethyl)-2-hydroxybenzoate (650.0 mg, 1.75 mmol) in tetrahydrofuran (10 mL) at 0°C under nitrogen was added sodium hydride (139.6 mg, 3.49 mmol, 60% purity). The mixture was stirred at 0°C under nitrogen for 0.5 hours, followed by the addition of bromomethyl methyl ether (327.30 mg, 2.62 μmol). The reaction was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (20 mL) at 25°C and then extracted with ethyl acetate (20 mL x 2). The organic layer was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash silica gel chromatography to yield the desired product 36-5 (600.0 mg, 82.54% yield) as a yellow oil. 1 HNMR: ES20989-763-P1A (CDCl3, 400MHz) δ7.44 (d, J=8.3Hz, 1H), 7.00 (d, J=8.3Hz, 1H), 5.07 (s,2H),3.62-3.58(m,4H),3.57(s,3H),3.39(s,2H),2.37-2.26(m,4H),1.58-1.51(m,9H).

[0648] Step 5: Preparation of compound 36-6

[0649] Tert-butyl 3-bromo-6-(morpholinylmethyl)-2-(methoxymethoxy)benzoate (600.0 mg, 1.44 mmol) and potassium vinyl trifluoroborate (289.5 mg, 2.16 mmol) were added to water (2.4 mL) and dioxane (12 mL). Under nitrogen, triethylamine (291.6 mg, 2.88 mmol) and catalyst Pd(dppf)Cl2 (52.7 mg, 72.0 μmol) were added. The reaction was stirred at 105°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 36-6 (300.0 mg, 57.27% yield) as a yellow oil. 1 HNMR: ES20989-764-P1A(CDCl3,400MHz)δ7.51(d,J=7.9Hz,1H),7.17(d,J=7.9Hz,1H),7.06(dd,J=11.0,17.7Hz,1H),5.74(dd,J =1.0,17.7Hz,1H),5.38-5.30(m,1H),5.04(s,2H),3.74-3.66(m,4H),3.59(s,3H),3.51(s,2H),2.48-2.37(m,4H),1.63(s,9H).

[0650] Step 6: Preparation of compound 36-7

[0651] To a solution of tert-butyl 6-(morpholinylmethyl)-2-(methoxymethoxy)-3-vinylbenzoate (300.0 mg, 825.4 μmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (211.2 mg, 1.65 mmol) in dichloromethane (7 mL) was added cycloocta-1,5-dieneiridium chloride (16.6 mg, 24.7 μmol) and 2-diphenylphosphino(diphenyl)phosphine (19.7 mg, 49.5 μmol). The reaction was stirred at 25°C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure to yield the crude product. The crude product was purified by flash silica gel chromatography to yield the desired product 36-7 (450.0 mg, crude) as a yellow oil.

[0652] Step 7: Preparation of compound 36-8

[0653] A solution of tert-butyl 6-(morpholinylmethyl)-2-(methoxymethyl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)vinylbenzoate (450.0 mg, 915.71 μmol) in dichloromethane (5 mL) and trifluoroacetic acid (1.04 g, 9.16 mmol) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was dissolved in water (2 mL) and adjusted to pH 10 with 1 M sodium hydroxide. The crude product was purified by reverse-phase HPLC to afford the desired product 36-8 (85.0 mg, 31.89% yield) as a white solid.

[0654] Step 8: Preparation of compound 36

[0655] 7-(Morpholinylmethyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (85.0 mg, 291.9 μmol) was added to a solution of water (5 mL) and sodium hydroxide (1 M, 583.98 μL). The reaction was stirred at 25°C for 1 hour. The reaction mixture was lyophilized to afford the desired product 36 (68.0 mg, 69.09% yield, 2Na) as a yellow solid. 1 HNMR: ES20989-771-P1C(MeOD,400MHz)δ6.78(d,J=7.6Hz,1H),6.65(d,J=7.6Hz,1H),3.69(t,J=4.6Hz,4H),3.58(s,2H),2.62(br t, J=6.9Hz, 2H), 2.50 (br s, 4H), 0.46 (br t, J=6.9Hz, 2H); LCMS: ES20989-771-P1A, RT=0.495min, m / z=292.2(M+H) + .

[0656] Example 37

[0657] Step 1: Preparation of compound 37-2

[0658] 4-Bromo-3-(methoxymethoxy)benzyl alcohol (8.00 g, 32.3 mmol) was dissolved in N,N-dimethylformamide (160 mL) at 0°C. Sodium hydride (1.94 g, 48.5 mmol, 60% purity) was then added, and the reaction was stirred at 0°C for 0.5 hours. 2,2-Difluoroethyl trifluoromethanesulfonate (8.32 g, 38.8 mmol) was added to the reaction solution. The reaction was stirred at 25°C for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution (300 mL). The mixture was extracted with ethyl acetate (100 mL x 3), and the organic layer was washed with saturated sodium chloride solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 37-2 (6.5 g, 64.5% yield) as a colorless oil. 1 HNMR: ES25406-60-P1A (CDCl3, 400MHz) δ7.54 (d, J = 8.1Hz, 1H), 7.15 (d, J = 1.7Hz, 1H), 6.89 (dd, J = 1.7, 8 .1Hz,1H),6.08-5.75(m,1H),5.27(s,2H),4.57(s,2H),3.70(dt,J=4.1,14.0Hz,2H),3.57-3.52(m,3H).

[0659] Step 2: Preparation of compound 37-3

[0660] 1-Bromo-4-((2,2-difluoroethoxy)methyl)-2-(methoxymethoxy)benzene (6.50 g, 20.8 mmol) was added to a solution of dichloromethane (35 mL) and trifluoroacetic acid (35 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with saturated sodium carbonate (50 mL) and adjusted to pH 8, then extracted with dichloromethane (40 mL x 2). The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 37-3 (5.15 g, crude product) as a yellow oil. 1 HNMR: ES20978-780-P1 (CDCl3, 400MHz) δ7.45 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6. 80(dd,J=1.9,8.1Hz,1H),6.06-5.82(m,1H),4.55(s,2H),3.69(dt,J=4.0,13.9Hz,3H).

[0661] Step 3: Preparation of compound 37-4

[0662] To a solution of 2-bromo-5-((2,2-difluoroethoxy)methyl)phenol (5.15 g, 19.2 mmol) in dichloromethane (60 mL) were added 4-dimethylaminopyridine (117.7 mg, 964.1 μmol) and di-tert-butyl dicarbonate (4.63 g, 21.1 mmol). The reaction was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to yield a crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 37-4 (4.9 g, 69.2% yield) as a yellow solid. 1 HNMR: ES20978-784-P1 (CDCl3, 400MHz) δ7.60 (d, J = 8.1Hz, 1H), 7.21 (d, J = 2.0Hz, 1H), 7.1 1(dd,J=2.0,8.3Hz,1H),6.08-5.74(m,1H),4.59(s,2H),3.76-3.65(m,2H),1.58(s,9H).

[0663] Step 4: Preparation of compound 37-5

[0664] At -70°C under nitrogen, lithium diisopropylamide (2M, 7.84 mL) was dissolved in tetrahydrofuran (50 mL), followed by a solution of tert-butyl 2-bromo-5-((2,2-difluoroethoxy)methyl)phenyl carbonate (4.8 g, 13.0 mmol) in tetrahydrofuran (20 mL). The reaction was stirred at -70°C for 2 hours. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction mixture at 5-10°C, followed by extraction with ethyl acetate (75 mL x 2) and concentration under reduced pressure to afford the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 37-5 (870 mg, 18.1% yield) as a yellow oil. 1 HNMR: ES20978-787-P1 (CDCl3, 400MHz) δ12.00 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.02 (d, J =8.4Hz,1H),6.09-5.77(m,1H),4.85(s,2H),3.74(dt,J=4.0,13.9Hz,2H),1.65(s,9H).

[0665] Step 5: Preparation of compound 37-6

[0666] To a solution of tert-butyl 3-bromo-6-((2,2-difluoroethoxy)methyl)-2-hydroxybenzoate (870 mg, 2.37 mmol) in tetrahydrofuran (15 mL) at 0°C was added sodium hydride (189.5 mg, 4.74 mmol, 60% purity). The mixture was stirred at 0°C for 0.5 hours, followed by the addition of bromomethyl methyl ether (444.1 mg, 3.55 mmol). The reaction was stirred at 25°C for 2 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (30 mL) at 25°C and then extracted with ethyl acetate (30 mL x 2). The organic layer was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 37-6 (850 mg, 87.2% yield) as a yellow oil. 1 HNMR: ES20978-789-P1 (CDCl3, 400MHz) δ7.59 (d, J = 8.3Hz, 1H), 7.08 (d, J = 8.3Hz, 1H),6.03-5.72(m,1H),5.16(s,2H),4.62(s,2H),3.71-3.58(m,5H),1.61(s,9H).

[0667] Step 6: Preparation of compound 37-7

[0668] Tert-butyl 3-bromo-6-((2,2-difluoroethoxy)methyl)-2-(methoxymethoxy)benzoate (225 mg, 547.1 μmol) was dissolved in water (1 mL) and dioxane (5 mL). Catalyst XPhos Pd G3 (23.1 mg, 27.3 μmol), potassium vinyl trifluoroborate (109.9 mg, 820.7 μmol), and anhydrous cesium carbonate (356.53 mg, 1.09 mmol) were added. The reaction was stirred at 110°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 2). The organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 37-7 (117 mg, 29.8% yield) as a yellow oil. 1HNMR: ES20978-799-P1(CDCl3,400MHz)δ7.55(d,J=8.1Hz,1H),7.16(d,J=8.1Hz,1H),7.05(dd,J=11.1,17.7Hz,1H),6.03-5.85(m,1H ),5.79-5.73(m,1H),5.36(dd,J=1.0,11.1Hz,1H),5.04(s,2H),4.65(s,2H),3.64(dt,J=4.1,13.9Hz,2H),3.58(s,3H),1.61(s,9H).

[0669] Step 7: Preparation of compound 37-8

[0670] To a solution of tert-butyl 6-((2,2-difluoroethoxy)methyl)-2-(methoxymethoxy)-3-vinylbenzoate (117 mg, 326.4 μmol) in dichloromethane (3 mL) was added 2-diphenylphosphino(diphenyl)phosphine (7.80 mg, 19.5 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (83.5 mg, 652.9 μmol), and cycloocta-1,5-dieneiridium chloride (6.58 mg, 9.79 μmol). The reaction was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (4 mL x 2). The organic layer was washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash silica gel chromatography to give the desired product 37-8 (130 mg, 81.8% yield) as a yellow oil. 1 HNMR: ES20978-801-P1 (CDCl3, 400MHz) δ7.26 (s, 1H), 7.08 (d, J = 7.9Hz, 1H), 6.02-5.68 (m, 1H), 5.04 (s ,2H),4.62(s,2H),3.67-3.53(m,5H),2.86-2.78(m,2H),1.60(s,9H),1.23(s,13H),1.18-1.09(m,2H).

[0671] Step 8: Preparation of compound 37

[0672] Trifluoroacetic acid (515.7 mg, 4.52 mmol) was added to a solution of tert-butyl 6-((2,2-difluoroethoxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (110 mg, 226.1 μmol) in dichloromethane (2 mL). The reaction was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was diluted with water (1 mL) and acetonitrile (1 mL), and 1 M sodium hydroxide (1 mL) was added to pH 9. The product was purified by reverse-phase HPLC to afford the desired product 37 (16 mg, 24.7% yield) as a white solid. 1 HNMR: ES20978-805-P1 (MeOH, 400MHz) δ7.00-6.94 (m, 1H), 6.77 (d, J = 7.6Hz, 1H), 6.13-5.80 (m, 1H), 4.78 (s, 2H), 3.74-3.64 (m, 3H), 2.65 (br t,J=7.1Hz,2H),0.56(br t,J=7.1Hz,2H).

[0673] Step 9: Preparation of compound 37a

[0674] 7-((2,2-difluoroethoxy)methyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (16.8 mg, 58.7 μmol) was added to a 1 M NaOH solution (117.4 μL). The reaction was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (10 mL), washed with ethyl acetate (5 mL x 2), and lyophilized to afford the desired product 37a (16 mg, 82.0% yield, 2Na) as a yellow solid. 1 HNMR: ES20978-808-P1B (MeOH, 400MHz) δ6.79 (d, J = 7.7Hz, 1H), 6.57 (d, J = 7.6Hz, 1H), 6.09-5.74 (m, 1H), 4.62 (s, 2H), 3.63 (d t, J=4.2, 14.4Hz, 2H), 2.61 (t, J=6.9Hz, 2H), 0.45 (t, J=7.0Hz, 2H); LCMS: ES20978-808-P1B1, RT=2.028min, m / z=287.1(M+H) + .

[0675] Example 38

[0676] Step 1: Preparation of compound 38-2

[0677] To a solution of 2,2,2-trifluoroethanol (1.81 g, 18.0 mmol) in N,N-dimethylformamide (50 mL) at 0°C under nitrogen was added sodium hydride (1.20 g, 30.0 mmol, 60% purity). The mixture was reacted at 0°C under nitrogen for 0.5 hours, followed by the addition of a solution of 2-bromo-5-bromomethylphenol (4 g, 15.0 mmol) in N,N-dimethylformamide (10 mL). The reaction was stirred at 25°C for 16 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (80 mL) at 25°C and then extracted with ethyl acetate (40 mL x 2). The organic layer was washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash silica gel chromatography to yield the desired product 38-2 (2.4 g, 55.9% yield) as a yellow oil. 1 HNMR: ES20978-818-P1 (CDCl3, 400MHz) δ7.46 (d, J = 8.1Hz, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.80 (dd, J = 2.0, 8.3Hz, 1H), 4.61 (s, 2H), 3.87-3.77 (m, 2H).

[0678] Step 2: Preparation of compound 38-3

[0679] To a solution of 2-bromo-5-((2,2,2-trifluoroethoxy)methyl)phenol (2.4 g, 8.42 mmol) in dichloromethane (30 mL) were added 4-dimethylaminopyridine (51.4 mg, 420.9 μmol) and di-tert-butyl dicarbonate (2.02 g, 9.26 mmol). The reaction was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 38-3 (2.3 g, 70.9% yield) as a yellow oil. 1 HNMR: ES20978-824-P1 (CDCl3, 400MHz) δ7.61 (d, J = 8.1Hz, 1H), 7.21 (d, J = 2.0Hz, 1H), 7.12 (dd, J=1.9, 8.3Hz, 1H), 4.66 (s, 2H), 3.85 (q, J=8.6Hz, 2H), 1.58 (s, 9H).

[0680] Step 3: Preparation of compound 38-4

[0681] To a solution of tert-butyl 2-bromo-5-((2,2,2-trifluoroethoxy)methyl)phenyl carbonate (1.9 g, 4.93 mmol) in tetrahydrofuran (40 mL) at -78°C under nitrogen was added lithium diisopropylamide (2 M, 3.70 mL). The reaction was stirred at -78°C for 2 hours, then warmed to 20°C and stirred for 0.5 hours. Saturated ammonium chloride (50 mL) was slowly added to the reaction mixture at 5-10°C with stirring, followed by extraction with ethyl acetate (40 mL x 2) and concentration under reduced pressure to yield the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 38-4 (130 mg, 6.84% yield) as a yellow oil. 1 HNMR: ES20978-832-P1 (CDCl3, 400MHz) δ 12.04 (s, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.01 (d, J = 8.4Hz, 1H), 4.91 (s, 2H), 3.94-3.84 (m, 2H), 1.64 (s, 9H).

[0682] Step 4: Preparation of compound 38-5

[0683] To a solution of tert-butyl 3-bromo-6-((2,2,2-trifluoroethoxy)methyl)-2-hydroxybenzoate (130 mg, 337.5 μmol) in tetrahydrofuran (3 mL) at 0°C under nitrogen was added sodium hydride (27.0 mg, 675.0 μmol, 60% purity). The mixture was stirred at 0°C under nitrogen for 0.5 hours, followed by the addition of bromomethyl methyl ether (63.2 mg, 506.2 μmol). The reaction was stirred at 25°C for 2 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride (5 mL) at 25°C and then extracted with ethyl acetate (3 mL x 3). The organic layer was washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to afford the desired product 38-5 (110 mg, 75.9% yield) as a yellow oil. 1 HNMR: ES20978-836-P1 (CDCl3, 400MHz) δ7.62-7.58 (m, 1H), 7.09 (d, J = 8.1Hz, 1H), 5.16(s,2H),4.70-4.65(m,2H),3.86-3.76(m,2H),3.67-3.62(m,3H),1.60(s,9H).

[0684] Step 5: Preparation of compound 38-6

[0685] Tert-butyl 3-bromo-6-((2,2,2-trifluoroethoxy)methyl)-2-(methoxymethoxy)benzoate (110 mg, 256.2 μmol) was dissolved in water (0.4 mL) and dioxane (2 mL). Catalyst Pd(dppf)Cl2 (9.38 mg, 12.8 μmol), potassium vinyl trifluoroborate (51.4 mg, 384.4 μmol), and triethylamine (51.8 mg, 512.5 μmol) were added. The reaction was stirred at 110°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (4 mL x 2). The organic layer was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 38-6 (57 mg, 59.1% yield) as a yellow oil. 1 HNMR: ES20978-838-P1(CDCl3,400MHz)δ7.56(d,J=8.1Hz,1H),7.18(d,J=8.1Hz,1H),7.05(dd,J=11.1,17.7Hz,1H),5 .77(d,J=17.7Hz,1H),5.37(d,J=11.0Hz,1H),5.04(s,2H),4.71(s,2H),3.84-3.74(m,2H),3.58(s,3H),1.61(s,9H).

[0686] Step 6: Preparation of compound 38-7

[0687] To a solution of tert-butyl 6-((2,2,2-trifluoroethoxy)methyl)-2-(methoxymethoxy)-3-vinylbenzoate (57 mg, 151.4 μmol) in dichloromethane (2 mL) was added 2-diphenylphosphino(diphenyl)phosphine (3.62 mg, 9.09 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (38.7 mg, 302.9 μmol), and cycloocta-1,5-dieneiridium chloride (3.05 mg, 4.54 μmol). The reaction was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (4 mL x 2). The organic layer was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to give the target product 38-7 (52 mg, 68.0% yield) as a yellow oil. 1HNMR: ES20978-839-P1 (CDCl3, 400MHz) δ7.29 (s, 1H), 7.10 (d, J = 7.9Hz, 1H), 5.04 (s, 2H), 4.68 (s, 2H), 3. 76(q,J=8.8Hz,2H),3.63-3.56(m,3H),2.87-2.80(m,2H),1.60(s,9H),1.23(s,12H),1.16-1.11(m,3H).

[0688] Step 7: Preparation of compound 38

[0689] Trifluoroacetic acid (117.5 mg, 1.03 mmol) was added to a solution of tert-butyl 6-((2,2,2-trifluoroethoxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)vinylbenzoate (52 mg, 103.1 μmol) in dichloromethane (1 mL). The reaction was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was dissolved in water (1 mL) and acetonitrile (1 mL), and 1 M sodium hydroxide (1 mL) was added to adjust the pH to 9. The crude product was purified by reverse-phase HPLC to afford the desired product 38 (14 mg, 44.6% yield) as a white solid. 1 HNMR: ES20978-841-P1 (MeOD, 400MHz) δ7.14 (d, J = 7.6Hz, 1H), 6.99-6.90 (m, 1H), 5.02 (s, 2H), 4.03-3.92 (m, 3H), 2.68 (br t,J=6.9Hz,2H),0.64(t,J=7.2Hz,2H).

[0690] Step 8: Preparation of compound 38a

[0691] 7-((2,2,2-trifluoroethoxy)methyl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborol-8-carboxylic acid (14 mg, 46.0 μmol) was added to a 1 M sodium hydroxide solution (92.10 μL). The reaction was stirred at 25°C for 2 hours. The reaction mixture was lyophilized to afford the desired product 38a (14 mg, 86.8% yield, 2Na) as a white solid. 1HNMR: ES20978-847-P1 (MeOD, 400MHz) δ6.81 (d, J = 7.6Hz, 1H), 6.58 (d, J = 7.6Hz, 1H), 4.68 (s, 2H), 3.86 (q, J = 9. 2Hz, 2H), 2.62 (t, J = 6.9Hz, 2H), 0.45 (t, J = 7.0Hz, 2H); LCMS: ES20978-847-P1A2, RT = 2.277min, m / z = 303.0 (MH) + .

[0692] Example 39

[0693] Step 1: Preparation of compound 39-2

[0694] 2-Bromo-5-hydroxymethylphenol (5.0 g, 24.63 mmol) was added to a solution of isopropanol (50 mL) and phosphoric acid (50 mL). The reaction was stirred at 90°C for 48 hours. The reaction mixture was treated with ethyl acetate (150 mL) and water (150 mL), then adjusted to pH 8 with saturated aqueous sodium carbonate. The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crude product. The crude product was purified by flash silica gel chromatography to yield the target compound 39-2 (2.0 g, 33.13% yield) as a yellow oil. 1 HNMR: ES20989-789-P1A (CDCl3, 400MHz) δ7.43 (d, J = 8.2Hz, 1H), 7.05 (d, J = 1.7Hz, 1H), 6.82 (d d,J=1.8,8.1Hz,1H),5.54(s,1H),4.46(s,2H),3.69(spt,J=6.1Hz,1H),1.23(d,J=6.1Hz,6H).

[0695] Step 2: Preparation of compound 39-3

[0696] To a solution of 2-bromo-5-isopropoxyphenol (2.00 g, 8.16 mmol) in dichloromethane (40 mL) were added 4-dimethylaminopyridine (49.8 mg, 407.98 μmol) and di-tert-butyl dicarbonate (1.96 g, 8.98 mmol). The reaction was stirred at 25°C for 16 hours. The reaction mixture was concentrated and purified by flash silica gel chromatography to afford the target compound 39-3 (2.8 g, 99.40% yield) as a yellow oil.

[0697] Step 3: Preparation of compound 39-4

[0698] To a solution of lithium diisopropylamide (2M, 5.87 mL) in tetrahydrofuran (30 mL) was slowly added a solution of tert-butyl 2-bromo-5-(isopropoxy)phenyl carbonate (2.7 g, 7.82 mmol) in tetrahydrofuran (10 mL) at -78°C under nitrogen. The reaction was stirred at -78°C for 1 hour. Saturated aqueous ammonium chloride (40 mL) was slowly added to the reaction mixture at 5-10°C, stirred, and extracted with ethyl acetate (20 mL x 2). The organic layer was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain the target compound 39-4 (500.0 mg, 18.52% yield) as a yellow oil. 1 HNMR: ES20989-803-P1A (CDCl3, 400MHz) δ 11.43 (s, 1H), 7.71 (d, J = 8.1Hz, 1H), 6.86 (d, J = 8.1Hz, 1H), 3.92 (s, 3H), 1.65-1.52 (m, 9H).

[0699] Step 4: Preparation of compound 39-5

[0700] To a solution of tert-butyl 3-bromo-6-((isopropoxy)methyl)-2-hydroxybenzoate (500.0 mg, 1.45 mmol) in tetrahydrofuran (10 mL) at 0°C under nitrogen was added sodium hydride (115.8 mg, 60% purity). The mixture was stirred at 0°C for 0.5 hours. Bromomethyl methyl ether (217.19 mg, 1.74 mmol) was added to the solution at 0°C. The reaction was stirred at 25°C for 1 hour. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL) at 25°C, followed by extraction with ethyl acetate (10 mL x 2). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by flash silica gel chromatography to yield the desired product 39-5 (420.0 mg, 74.49% yield) as a yellow oil. 1 HNMR: ES20989-805-P1A (CDCl3, 400MHz) δ7.57 (d, J = 8.1Hz, 1H), 7.16 (d, J = 8.4Hz, 1H), 5.18-5.13(m,2H),4.51(s,2H),3.69-3.63(m,4H),1.63(s,9H),1.21(d,J=5.9Hz,6H).

[0701] Step 5: Preparation of compound 39-6

[0702] To a solution of tert-butyl 3-bromo-3-((isopropoxy)methyl)-2-(methoxymethoxy)benzoate (500 mg, 1.03 mmol) in dioxane (8 mL) and water (1.6 mL) was added potassium vinyl trifluoroborate (206.46 mg, 1.54 mmol), triethylamine (207.9 mg, 2.06 mmol), and the catalyst Pd(dppf)Cl2.CH2Cl2 (37.5 mg, 51.3 μmol) in sequence under nitrogen. The reaction was stirred at 110°C for 16 hours. The reaction mixture was treated with ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain the desired product 39-6 (175.0 mg, 50.62% yield) as a yellow oil. 1 HNMR: ES20989-807-P1A (CDCl3, 400MHz) δ7.55 (d, J = 8.1 Hz, 1H), 7.25 ( d, J = 8.1 Hz, 1H), 7.06 ( dd, J = 11.1, 17.7 Hz, 1H), 5.75 ( dd, J = 1.2, 1 7.7Hz,1H),5.34(dd,J=1.1,11.0Hz,1H),5.04(s,2H),4.55(s,2H),3.71-3.62(m,1H),3.59(s,3H),1.63(s,9H),1.21(d,J=6.1Hz,6H).

[0703] Step 6: Preparation of compound 39-7

[0704] To a mixture of tert-butyl 6-((isopropoxy)methyl)-2-(methoxymethoxy)-3-vinylbenzoate (170.0 mg, 505.3 μmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (129.34 mg, 1.01 mmol) in dichloromethane (2 mL) was added cycloocta-1,5-dieneiridium chloride (20.3 mg, 30.3 μmol) and 2-diphenylphosphino(diphenyl)phosphine (24.1 mg, 60.6 μmol) at 25°C under nitrogen. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain the crude product, which was purified by flash silica gel chromatography to obtain the desired product 39-7 (150.0 mg, 323.00 μmol, 63.92% yield) as a light yellow oil. 1HNMR: ES20989-809-P1A (CDCl3, 400MHz) δ7.26 (d, J = 7.9Hz, 1H), 7.16 (d, J = 7.9Hz, 1H), 5.04 (s, 2H), 4.52 (s, 2H), 3.68- 3.62(m,1H),3.61(s,3H),2.92-2.78(m,2H),1.62(s,9H),1.27-1.22(m,12H),1.19(d,J=6.1Hz,6H),1.16-1.10(m,2H).

[0705] Step 7: Preparation of compound 39-8

[0706] To a solution of tert-butyl 6-((isopropoxy)methyl)-2-(methoxymethoxy)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)benzoate (150.0 mg, 323.0 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (368.2 mg, 3.23 mmol) and isobutylboronic acid (32.9 mg, 323.0 μmol) at 25°C. The reaction was stirred at 25°C for 2 hours. The reaction mixture was concentrated, and the crude product was dissolved in water (2 mL) and the pH was adjusted to 10. The desired product 39-8 (70.0 mg, 82.07% yield) was obtained by preparative purification using reverse-phase HPLC as a white solid. 1 HNMR: ES20989-812-P1A (MeOD, 400MHz) δ7.07 (d, J = 7.7Hz, 1H), 6.94 (d, J = 7.6Hz, 1H), 4.82 (s, 2H), 3.82-3.66 (m, 1H), 2.68 (br t,J=7.1Hz,2H),1.22(s,6H),0.62(br t,J=7.1Hz,2H).

[0707] Step 8: Preparation of compound 39

[0708] To a solution of 7-(isopropoxy)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborolane-8-carboxylic acid (70.0 mg, 265.07 μmol) in water (10 mL) was added 1 M sodium hydroxide solution (530 μL) and stirred at room temperature for 1 hour. The mixture was lyophilized to afford the desired product 39 (70.0 mg, 85.17% yield, 2Na) as a brown solid. 1HNMR: ES20989-818-P1A (MeOD, 400MHz) δ6.80 (d, J = 7.6Hz, 1H), 6.63 (d, J = 7.6Hz, 1H), 4.58 (s, 2H), 3.73 (spt, J = 6.1Hz, 1H), 2.62 (br t, J=7.0Hz, 2H), 1.19 (d, J=6.1Hz, 6H), 0.47 (br t, J=6.9Hz, 2H); LCMS: ES20989-818-P1B, RT=0.597min, m / z=265.2(M+H) + .

[0709] Example 40

[0710] Step 1: Preparation of compound 40-2

[0711] Compound 40-1 (100.0 mg, 173.6 μmol, 1 eq, HCl) was dissolved in dichloromethane (1 mL). Triethylamine (26.3 mg, 260.4 μmol, 36.2 μL, 1.5 eq) and isopropyl isocyanate (17.7 mg, 208.3 μmol, 20.4 μL, 1.2 eq) were added at 0°C. Stirring was continued at 30°C for 1 h. The mixture was washed with 1N hydrogen chloride (2 mL) and saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, compound 40-2 (0.1 g, crude product), as a yellow oil. LCMS: ES20978-188-P1A1, RT = 1.15 min, m / z = 625.2 (M+H). +

[0712] Step 2: Preparation of compound 40-3

[0713] Compound 40-2 (0.1 g, 160.1 μmol, 1 eq) was dissolved in methanol (2 mL). 10% palladium on carbon (160.1 μmol, 1 eq) was added and hydrogen gas (323.4 μg, 160.1 μmol, 1 eq) was added. Stirring was continued at 25°C for 16 h. Filtration and vacuum concentration were performed to obtain the crude product, compound 40-3 (60 mg, crude product), as a yellow oil. 1 HNMR: ES20978-189-P1(DMSO,400MHz)δ7.69-7.59(m,1H),7.42-7.30(m,1H),6.8 7-6.74(m,1H),3.17(s,3H),1.25-1.15(m,13H),1.09-0.97(m,10H),0.80(s,4H).

[0714] Step 3: Preparation of compound 40

[0715] Compound 40-3 (60 mg, 135.0 μmol, 1 eq) was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). Isobutylboric acid (27.5 mg, 270.0 μmol, 2 eq), triethylsilane (6.19 mg, 27.0 μmol, 0.2 eq), and trifluoroacetic acid (3.08 mg, 27.0 μmol, 2.00 μL, 0.2 eq) were added, and the mixture was stirred at 25°C for 16 h. The residue was collected by filtration and concentrated in vacuo. It was purified by preparative HPLC to afford Compound 40 (2.7 mg, 9.24 μmol, 6.85% yield) as a white solid. 1 HNMR: ES20989-190-P1A (MeOD, 400MHz) δ7.85 (dd, J=1.5, 7.9Hz, 1H), 7.34 (br d, J=7.0Hz, 1H), 6.97 (t, J=7.6Hz, 1H), 3.94-3.57 (m, 1H), 3.22 (br s,1H),2.88(br s,2H),1.23-0.73(m,6H); LCMS: ES20989-190-P1A, RT=1.15min, m / z=204.4(M+H) + .

[0716] Example 41

[0717] Step 1: Preparation of compound 41-2

[0718] Compound 41-1 (55.0 g, 361.4 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL), and di-tert-butyl dicarbonate (315.5 g, 1.45 mol, 332.1 mL, 4 eq), 4-dimethylaminopyridine (13.2 g, 108.4 mmol, 0.3 eq), and tert-butanol (400 mL) were added. Stirring was continued at 60°C for 16 h. The residue was collected by vacuum concentration and purified by flash silica gel chromatography to obtain compound 41-2 (25.0 g, 81.07 mmol, 22.43% yield) as a colorless oil. 1 HNMR: ES20989-169-P1A (CDCl3, 400MHz) δ7.76 (br d, J=7.8Hz, 1H), 7.38 (br d,J=7.4Hz,1H),7.23-7.12(m,1H),2.33-2.24(m,3H),1.59(d,J=3.4Hz,18H).

[0719] Step 2: Preparation of compound 41-3

[0720] Compound 41-2 (5.00 g, 16.2 mmol, 1 eq) was dissolved in carbon tetrachloride (50 mL). Azobisisobutyronitrile (266.2 mg, 1.62 mmol, 0.1 eq) and N-bromosuccinimide (3.03 g, 17.0 mmol, 1.05 eq) were added at 25°C. Stirring was continued at 80°C for 16 h. The residue was collected by vacuum concentration and recrystallized from n-hexane (8 mL) to obtain compound 41-3 (3.0 g, crude product) as a yellow solid. 1 HNMR: ES20989-171-P1A (CDCl3, 400MHz) δ7.81 (dd, J=1.7, 7.8Hz, 1H), 7.48 (dd ,J=1.7,7.7Hz,1H),7.20-7.14(m,1H),4.50-4.39(m,2H),1.55-1.44(m,18H).

[0721] Step 3: Preparation of compound 41-4

[0722] Compound 41-3 (3.33 g, 9.30 mmol, 1.2 eq) and potassium acetate (2.28 g, 23.2 mmol, 3 eq) were dissolved in 1,4-dioxane (30 mL). DPPF palladium dichloride (566.8 mg, 774.6 μmol, 0.1 eq) was added at 25°C under nitrogen. Stirring was continued at 100°C for 16 h. The product was filtered through celite and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography to afford compound 41-4 (2.2 g, 4.52 mmol, 58.39% yield) as a yellow oil. 1 HNMR: ES20989-173-P1A (CDCl3, 400MHz) δ7.72 (dd, J=1.5, 7.8Hz, 1H), 7.43 (dd, J=1.3, 7.6Hz, 1H), 7.16 (t, J=7.7Hz, 1H), 7.12 (br s,1H),4.32-4.25(m,1H),2.36-2.26(m,3H),2.26-2.19(m,1H),2.13-2.01(m,1H),1.99-1. 80(m,3H),1.57(d,J=2.1Hz,18H),1.45-1.37(m,4H),1.32-1.26(m,4H),0.89-0.80(m,4H).

[0723] Step 4: Preparation of compound 41-5

[0724] Dissolve dichloromethane (349.23 mg, 4.11 mmol, 264.57 uL, 2.0 eq) in tetrahydrofuran (10 mL). Slowly add n-butyllithium (2.5 M, 2.06 mL, 2.5 eq) along the inner wall of the flask at -100°C, maintaining the temperature below -90°C. Stirring is continued at -100°C for 30 minutes. Then, compound 41-4 (1.0 g, 2.06 mmol, 1 eq) in tetrahydrofuran (2.0 mL) is added at -90°C. Zinc chloride (1 M, 6.17 mL, 3 eq) is added to the reaction system at -90°C. The temperature is raised to 25°C and stirring is continued for 16 hours. The residue is concentrated in vacuo and purified by flash silica gel chromatography to obtain compound 41-5 (520.0 mg, crude product) as a colorless oil. 1 HNMR: ES20989-175-P1A (CDCl3, 400MHz) δ7.83 (dd, J=1.5, 7.8Hz, 1H), 7.50 (dd, J=1.3, 7.6Hz, 1H), 7. 22(t,J=7.7Hz,1H),4.43-4.32(m,1H),3.69(dd,J=7.0,8.9Hz,1H),3.26(dd,J=6.8,14.2Hz,1H),3.08 (dd,J=9.0,14.2Hz,1H),2.42-2.29(m,1H),2.28-2.17(m,1H),2.09(t,J=5.4Hz,1H),1.96-1.87(m,2 H), 1.58 (d, J = 3.5Hz, 19H), 1.43-1.39 (m, 3H), 1.31 (s, 3H), 1.13 (d, J = 11.0Hz, 1H), 0.91-0.81 (m, 3H).

[0725] Step 5: Preparation of compound 41-6

[0726] Compound 41-5 (50.0 mg, 93.48 μmol, 1 eq) was dissolved in N,N-dimethylformamide (1 mL). Methanol (4.49 mg, 140.22 μmol, 5.67 μL, 1.5 eq) was added, followed by potassium carbonate (51.68 mg, 373.92 μmol, 4 eq). Stirring was continued at 50°C for 1 h. The residue was concentrated in vacuo and purified by flash silica gel chromatography to afford compound 41-6 (15.0 mg, 28.28 μmol, 30.25% yield) as a yellow oil. 1HNMR: ES20989-200-P1A (CDCl3, 400MHz) δ7.69 (dd, J=1.7, 7.8Hz, 1H), 7.52-7.45 (m, 1H), 7 .10(t,J=7.8Hz,1H),4.28-4.18(m,1H),3.35(t,J=6.8Hz,1H),3.29-3.21(m,3H),2.93-2.8 6(m,2H),2.29-2.18(m,1H),2.15-2.03(m,1H),1.97(t,J=5.5Hz,1H),1.89-1.73(m,2H),1. 49(d,J=3.8Hz,18H),1.33-1.26(m,3H),1.24-1.12(m,3H),0.99-0.90(m,1H),0.75(s,3H).

[0727] Step 6: Preparation of compound 41-7

[0728] Compound 41-6 (10.0 mg, 18.85 μmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and isobutylboronic acid (3.84 mg, 37.70 μmol, 2 eq) was added, followed by 36.5% hydrogen chloride (102.00 mg, 1.02 mmol, 100 μL, 36.5% purity, 54.17 eq). Stirring was continued at 25°C for 16 h. The residue was collected by vacuum concentration and purified by preparative HPLC to obtain white compound 41 (1.0 mg, 4.50 μmol, 23.89% yield). 1 HNMR: ES20989-205-P1A (MeOH, 400MHz) δ7.76 (br s, 1H), 7.43-7.29 (m, 1H), 6.93-6.74 (m, 1H), 3.50-3.34 (m, 2H), 3.21-3.04 (m, 3H).

[0729] Example 42

[0730] Step 1: Preparation of compound 42-2

[0731] To a solution of 2-bromo-5-methylphenol (200 g, 1.1 mol) and di-tert-butyl dicarbonate (245 g, 1.1 mol) in dichloromethane (2000 mL) was added 4-dimethylaminopyridine (13 g, 0.1 mol) and allowed to react at room temperature for 0.5 hours. The reaction solution was washed with hydrochloric acid (1 N), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the target compound 42-2 (270 g, 79.1% yield) as a yellow liquid.1 H NMR (400 MHz, DMSO- d6 )δ7.57(d,J=8.0Hz,1H),7.19(s,1H),7.06(d,J=7.6Hz,1H),2.29(s,3H),1.48(d,J=11.1Hz,9H).

[0732] Step 2: Preparation of compound 42-3

[0733] To a solution of tert-butyl 2-bromo-5-methylphenyl carbonate (50 g, 0.17 mol) in tetrahydrofuran (500 mL) at -60°C under nitrogen was added lithium diisopropylamide (105 mL, 0.21 mol, 2 M). The mixture was allowed to react at -60°C for 16 hours. The reaction solution was adjusted to pH 2-3 with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 50:1) to afford the target compound 42-3 (17.50 g, 35% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ12.12 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H), 1.63 (s, 9H).

[0734] Step 3: Preparation of compound 42-4

[0735] To a solution of tert-butyl 3-bromo-2-hydroxy-6-methylbenzoate (93 g, 0.3 mol) and di-tert-butyl dicarbonate (85 g, 0.4 mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine (4.0 g, 0.03 mol) and allowed to react at room temperature for 0.5 hours. The reaction solution was washed with hydrochloric acid (1N), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford the target compound 42-4 (110 g, 78.7% yield) as a yellow liquid. 1 H NMR (400MHz, MeOD) δ7.48 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 2.33 (s, 3H), 1.58 (s, 9H), 1.56 (s, 9H).

[0736] Step 4: Preparation of compound 42-5

[0737] To a solution of tert-butyl 3-bromo-2-((tert-butoxycarbonyl)oxy)-6-methylbenzoate (15.0 g, 39.0 mmol) in carbon tetrachloride (15 ml) at 25°C under nitrogen was added NBS (8.0 g, 44.0 mmol) and BPO (900 mg, 3.90 mmol). The mixture was stirred at 80°C for 16 hours. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 30:1) to afford the target compound 42-5 (10.0 g, 48.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d6 )δ7.84(d,J=8.4Hz,1H),7.45(d,J=8.4Hz,1H),4.70(s,2H),1.55(s,9H),1.50(s,9H).

[0738] Step 5: Preparation of compound 42-6

[0739] Sodium (590 mg, 26.0 mmol) was dissolved in anhydrous methanol (60 mL) at room temperature, and tert-butyl 3-bromo-6-(bromomethyl)-2-((tert-butoxycarbonyl)oxy)benzoate (8.0 g, 17.0 mmol) was added. The mixture was stirred at 80°C for 3 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain the target compound 42-6 (5.0 g, 62.8% yield) as a colorless liquid. 1 H NMR (400MHz, DMSO) δ7.84 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 4.70 (s, 2H), 1.55 (s, 9H), 1.50 (s, 9H).

[0740] Step 6: Preparation of compound 42-7

[0741] To a solution of activated zinc powder (1.9 g, 30 mmol) and (2S)-4-(bromomethyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.0^{2,6}]decane (300 mg) in anhydrous tetrahydrofuran (5 mL) was added diisobutylaluminum hydride (0.5 mL, 0.52 mmol, 1.0 M in Toluene) at room temperature. After the mixture was stirred at room temperature for 5 min, a solution of (2S(-4-(bromomethyl(-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.0^{2,6}]decane (2.70 g, 11.25 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise to the mixture. The reaction mixture was heated to 50° C. and stirred for 1 h. The clear solution on the upper layer was transferred to 3-bromo-2-((tert-butoxycarbonyl)oxy)-6-(methoxymethyl)benzyl alcohol. A solution of tert-butyl benzoate (3.10 g, 7.5 mmol) and bis(tri-tert-butylphosphine)palladium (96 mg, 0.19 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain the target compound 42-7 (3.0 g, 67.8% yield) as a colorless liquid. LCMS (ESI) m / z = 548.30 [M+18] +

[0742] Step 7: Preparation of compound 42-8

[0743] To a solution of dichloromethane (100 mg, 1.17 mmol) in anhydrous tetrahydrofuran (5 mL) at -100°C was added n-butyllithium (2.5 M in hexane, 0.32 mL, 0.8 mmol) dropwise under nitrogen. The mixture was stirred at this temperature for 30 minutes, and then a solution of tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(methoxymethyl)-3-(((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)methyl)benzoate (311 mg, 0.59 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain the target compound 42-8 (290 mg, 77% yield) as a yellow liquid. LCMS: EC2514-5-P1B, m / z = 596.30 [M+18] +

[0744] Step 8: Preparation of compound 42-9

[0745] To a solution of tert-butyl 2-((tert-butoxycarbonyl)oxy)-3-((2S)-2-chloro-2-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)ethyl)-6-(methoxymethyl)benzoate (1.20 g, 2.1 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (550 mg, 4 mmol) and methanol (100 mg, 3.15 mmol). The mixture was allowed to react at 50°C for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to afford the target compound 42-9 (0.6 g, 47.6% yield) as a colorless liquid. LCMS (ESI): m / z = 597.25 [M+23] + .

[0746] Step 9: Preparation of compound 42

[0747] To a solution of tert-butyl 2-((tert-butoxycarbonyl)oxy)-3-((2R)-2-methoxy-2-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)ethyl)-6-(methoxymethyl)benzoate (130 mg, 0.22 mmol) in tetrahydrofuran (5 mL) at 0°C was added isobutylboronic acid (46 mg, 0.45 mmol) and concentrated hydrochloric acid (2.5 mL). The mixture was stirred at 25°C for 3 hours. The reaction mixture was lyophilized, and the pH was adjusted to 9.5 by adding 1 M sodium hydroxide. Water and acetone were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filter cake was collected and lyophilized to obtain the target compound 42 (20 mg, 29.92% yield) as a white solid. LCMS(ESI)m / z=533.25[M-2Na+H] + ; 1 H NMR (400MHz, D2O) δ6.94 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.43–4.25 (m, 2H), 3.23 (d, J = 18.4 Hz, 6H), 2.84 (dd, J = 49.6, 13.6 Hz, 3H).

[0748] Example 43

[0749] Step 1: Preparation of compound 43-2

[0750] Sodium metal (0.44 g, 19.2 mmol) was added to anhydrous methanol (20 mL). Once the sodium metal was completely dissolved, tert-butyl 3-bromo-6-bromomethyl-2-(tert-butoxycarbonyl)oxy)benzoate (3.0 g, 6.4 mmol) was added. The mixture was reacted in an oil bath at 80°C for 2 hours. After completion of the reaction, the mixture was concentrated and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to obtain the target compound 43-2 (1.80 g, 67.4% yield) as a white solid. LCMS (ESI) m / z = 436.10 [M+18] + .

[0751] Step 2: Preparation of compound 43-3

[0752] Under nitrogen, to a solution of tert-butyl 3-bromo-2-(tert-butoxycarbonyl)oxy)-6-methoxymethylbenzoate (3.0 g, 7.2 mmol) and bis[(-)pinanediol]diboronate (3.9 g, 10.8 mmol) in dioxane (25 mL) were added Pd(dppf)Cl2 (0.26 g, 0.36 mmol) and potassium acetate (1.40 g, 14.4 mmol). The reaction was stirred at 95°C under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain the target compound 43-3 (2.60 g, 70.1% yield) as a light green oil. 1 H NMR (400MHz, CDCl3) δ7.81(d,J=7.8Hz,1H),7.30(d,J=7.8Hz,1H),4.55(d,J=1.0Hz,2H),4.41(dd,J=8.8,1.6Hz,1H),3.35(s,3H),2.44–2. 31(m,1H),2.20(m,1H),2.11(t,J=5.4Hz,1H),2.02–1.85(m,2H),1.58 (s,9H),1.54(d,J=2.4Hz,9H),1.46(s,3H),1.30(s,3H),0.87(s,3H).

[0753] Step 3: Preparation of compound 43-4

[0754] Under nitrogen, to a mixture of tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(methoxymethyl)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methylbenzo[d][1,3,2]dioxin-2-yl)benzoate (0.50 g, 0.96 mmol) and ((2-bromoallyl)oxy)methyl)benzene (0.28 g, 1.25 mmol) in tetrahydrofuran (6 mL) and water (2 mL) was added Pd(PPh3)4 (56 mg, 0.05 mmol) and sodium carbonate (0.51 g, 4.83 mmol). The reaction was stirred at 80°C under nitrogen for 12 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain the target compound 43-4 (0.26 g, 54.7% yield) as a colorless oily liquid. 1 H NMR (400MHz, CDCl3) δ7.44–7.20(m,7H),5.56(s,1H),5.34(s,1H),4.57(s,2H),4.54(s,2H),4.25(s,2H),3.36(s,3H),1.58(s,9H),1.48(s,9H).

[0755] Step 4: Preparation of compound 43-5

[0756] At -15 ° C, to a solution of tert-butyl 3-(3-(benzyloxy)prop-1-en-2-yl)-2-(tert-butoxycarbonyl)oxy)-6-(methoxymethyl)benzoate (1.0 g, 2.1 mmol) in tetrahydrofuran (15 mL), a borane dimethyl sulfide solution (0.16 mL, 2 mol / L) was slowly added. The reaction was returned to room temperature and stirred for 2 hours. After the reaction was completed, water (5 mL) was added under ice bath conditions to quench the reaction and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain the crude intermediate. The crude intermediate was dissolved in tetrahydrofuran (10 mL), and then (1S,2S,3R,5S)-(+)-2,3-pinanediol (0.5 g, 3.2 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction, the reaction mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain the target compound 43-5 (0.65 g, 26% yield, 56% purity) as a colorless oil. LCMS (ESI) m / z = 487.20 [M+23] + .

[0757] Step 5: Preparation of compound 43-6

[0758] Tert-butyl 3-(1-benzyloxy)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborol-2-yl)propyl-2-yl)-2-(tert-butoxycarbonyl)oxy)-6-(methoxymethyl)benzoate (0.40 g, 0.6 mmol) was dissolved in anhydrous methanol (5 mL). 10% Pd / C (30 mg) and Pd(OH)2 / C (30 mg) were added. The reaction was stirred at room temperature under a hydrogen atmosphere (15 psi) for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 43-6 (0.26 g, 75.2% yield) as a colorless oil. 1 H NMR (400MHz, DMSO) δ7.39 (dd, J=8.0, 5.4Hz, 1H), 7.24 (dd, J=8.0, 3.0Hz, 1H), 4.70 (s, 1H), 4.40 ( s,2H),4.21(d,J=8.2Hz,1H),3.48(s,1H),3.41(s,1H),3.24(t,J=3.6Hz,3H),3.09–2.95(m,1H), 2.23(dd,J=23.2,10.0Hz,1H),2.04(dd,J=9.8,6.0Hz,1H),1.88(dd,J=9.4,5.0Hz,1H),1.80(dd, J=17.8,5.6Hz,1H),1.50(s,9H),1.47(s,9H),1.23(dd,J=8.0,6.8Hz,6H),0.78(d,J=4.0Hz,3H).

[0759] Step 6: Preparation of compound 43-7

[0760] Tert-butyl 2-(tert-butoxycarbonyl)oxy)-3-(1-hydroxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborol-2-yl)propan-2-yl)-6-(methoxymethyl)benzoate (0.46 g, 0.80 mmol) and cesium carbonate (0.39 g, 1.20 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and trimethyloxonium tetrafluoroborate (0.18 g, 1.20 mmol) was added. The reaction was stirred at room temperature under nitrogen for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to obtain the target compound 43-7 (0.35 g, 73.6% yield) as a colorless oil. LCMS (ESI) m / z = 606.30 [M+18]+ .

[0761] Step 7: Preparation of compound 43

[0762] Tert-butyl 2-(tert-butoxycarbonyl)oxy)-3-(1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborol-2-yl)propyl-2-yl)-6-methoxymethylbenzoate (50 mg, 0.085 mmol) and isobutylboronic acid (17.29 mg, 0.17 mmol) were dissolved in anhydrous tetrahydrofuran (1 mL), and concentrated hydrochloric acid (1 mL, 12 mol / L) was slowly added dropwise. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was purified by preparative HPLC (C18, acetonitrile and water as mobile phases, containing 0.1% trifluoroacetic acid) to obtain the title compound 43 (8 mg, 32% yield) as a white solid. 1 HNMR(400MHz,MeOD)δ7.22(d,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H),4.49(q,J=12.2Hz,2H),3.43(d,J =4.8Hz,2H),3.41–3.38(m,1H),3.34(s,3H),3.26(s,3H),1.12(m,2H); LCMS(ESI)=m / z=280.60[M+H] + .

[0763] Step 8: Preparation of compounds 43-7a and 43-7b

[0764] Tert-butyl 2-(tert-butoxycarbonyl)oxy)-3-(1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborol-2-yl)propyl-2-yl)-6-methoxymethylbenzoate (0.38 g, 0.65 mmol) was dissolved in ethanol at a sample concentration of 10 mg / mL. The chiral isomers were separated by SFC using an SFC preparation apparatus and a chiral column Unichiral CMD-5H (mobile phase 95% CO2 / 5% ethanol, flow rate 120 mL / min). The corresponding resolved fractions were collected and the solvent was removed under reduced pressure to obtain the products of isomers 43-7a (peak 1, 130 mg) and 43-7b (peak 2, 80 mg).

[0765] Step 9: Preparation of compound 43a

[0766] (2-(tert-Butoxycarbonyl)oxy)-3-((2R)-1-methoxy-3-(3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborol-2-yl)propyl-2-yl)-6-(methoxymethyl)benzoate (130 mg, 0.22 mmol) and isobutylboronic acid (44.80 mg, 0.44 mmol) were dissolved in anhydrous tetrahydrofuran (1.5 mL). Concentrated hydrochloric acid (1.5 mL, 12 mol / L) was slowly added dropwise. The reaction was stirred at room temperature for 3 hours to terminate. After completion of the reaction, the reaction mixture was purified by preparative HPLC (C18, acetonitrile and water as mobile phases containing 0.1% trifluoroacetic acid) to obtain the title compound 43a (15 mg, 24.2% yield) as a white solid. 1 H NMR (400MHz, MeOD) δ7.22(d,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H),4.49(m,2H),3.43(d,J=4 .6Hz,2H),3.33(s,3H),3.25(s,3H),3.11(s,1H),1.12(m,2H); LCMS(ESI)m / z=280.70[M+H] + .

[0767] Step 10: Preparation of compound 43b

[0768] 2-(tert-Butyloxycarbonyl)oxy)-3-((2S)-1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborol-2-yl)propyl-2-yl)-6-(methoxymethyl)benzoate (80 mg, 0.14 mmol) and isobutylboronic acid (27.67 mg, 0.27 mmol) were dissolved in anhydrous tetrahydrofuran (1 mL), and concentrated hydrochloric acid (1 mL, 12 mol / L) was slowly added dropwise. The reaction was stirred at room temperature for 3 hours to terminate. After completion of the reaction, the reaction mixture was purified by preparative HPLC (C18, acetonitrile and water as mobile phases, containing 0.1% trifluoroacetic acid) to obtain the title compound 43b (8 mg, 21% yield) as a white solid. 1 H NMR (400MHz, MeOD) δ7.22(d,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H),4.49(q,J=12.2Hz,2H),3.43(d,J =4.6Hz,2H),3.33(s,3H),3.26(s,3H),3.11(s,1H),1.21–1.05(m,2H); LCMS(ESI)m / z=280.70[M+H] + .

[0769] Example 44

[0770] Step 1: Preparation of compound 44-2

[0771] At 0°C under nitrogen, benzyl alcohol (2.97 g, 0.028 mol) was dissolved in tetrahydrofuran (60 mL), and sodium hydride (1.10 g, 0.028 mol) was added. The reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of 2,3-dibromo-1-propene (5.0 g, 0.028 mol). The reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 50:1) to afford the target compound 44-2 (3.0 g, 47.60% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.25–7.36(m,5H),5.96(d,J=1.6Hz,1H),5.65(d,J=1.6Hz,1H),4.56(s,2H),4.13(s,2H).

[0772] Step 2: Preparation of compound 44-4

[0773] At room temperature, under nitrogen, tert-butyl 3-bromo-2-((tert-butoxycarbonyl)oxy)-6-(ethoxymethyl)benzoate (3.50 g, 8.1 mmol) was dissolved in 1,4-dioxane (0 mL). Bis[(-)pinanediol]diboronate (4.35 g, 12.2 mmol), Pd(dppf)Cl2 (0.59 g, 0.81 mmol), and potassium acetate (1.59 g, 16.2 mmol) were added. The reaction mixture was reacted at 100°C under nitrogen for 16 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain the target compound 44-4 (3.0 g, 62.96% yield) as a yellow oil. 1H NMR(400MHz, CDCl3) δ7.81(d,J=7.7Hz,1H),7.33(d,J=7.7Hz,1H),4.59(s,2H), 4.41(dd,J=8.7,1.8Hz,1H),3.50(q,J=7.0Hz,2H),2.41–2.32(m,1H),2.24–2.16 (m,1H),2.13–2.09(m,1H),1.97–1.85(m,2H),1.58(s,9H),1.52(d,J=10.2Hz,9H ), 1.44 (d, J = 10.3Hz, 3H), 1.30 (s, 3H), 1.22 (dd, J = 8.8, 5.2Hz, 4H), 0.87 (s, 3H).

[0774] Step 3: Preparation of compound 44-5

[0775] At room temperature, under nitrogen, tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(ethoxymethyl)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)benzoate (2.0 g, 3.8 mmol) was dissolved in tetrahydrofuran (30 mL) and water (5 mL). ((2-bromoallyl)oxy)methyl)benzene (1.29 g, 5.7 mmol), Pd(PPh3)4 (0.44 g, 0.38 mmol), and sodium carbonate (2.01 g, 19.0 mmol) were added. The reaction mixture was reacted at 80°C under nitrogen for 18 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain the target compound 44-5 (1.20 g, 60.35% yield) as a yellow oily liquid. LCMS (ESI) m / z = 516.35.

[0776] Step 4: Preparation of compound 44-6

[0777] To a solution of tert-butyl 3-(3-(benzyloxy)prop-1-en-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-(ethoxymethyl)benzoate (1.20 g, 2.4 mmol) in ultra-dry tetrahydrofuran (20 mL) at -15°C was added a solution of borane dimethyl sulfide (2.4 mL, 2.4 mmol, 2 M) dropwise. The mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction was quenched with water, extracted with ethyl acetate, dried, filtered, and concentrated. The crude product was dissolved in tetrahydrofuran (20 mL), and (+)-pinanediol (0.82 g, 4.8 mmol) was added. The reaction mixture was allowed to react at room temperature for 15 hours. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford the target compound 44-6 (0.60 g, 33.33% yield) as a yellow oil. LCMS (ESI) m / z=696.40.

[0778] Step 5: Preparation of compound 44-7

[0779] To a solution of tert-butyl 3-(1-(benzyloxy)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-(ethoxymethyl)benzoate (0.60 g, 0.88 mmol) in methanol (20 mL) was added 10% palladium on carbon (120 mg) and palladium hydroxide on carbon (60 mg) at room temperature. The mixture was allowed to react at room temperature for 2 hours under a hydrogen atmosphere. The mixture was filtered through celite, dried, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to afford the target compound 44-7 (0.40 g, 75.32% yield) as a yellow oil. LCMS (ESI) m / z = 606.45 [M+H2O] + .

[0780] Step 6: Preparation of compounds 44-8a and 44-8b

[0781] To a solution of tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(ethoxymethyl)-3-(1-hydroxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (0.40 g, 0.68 mmol) in ultra-dry tetrahydrofuran (8 mL) was added trimethyloxytetrafluoroborate (0.15 g, 1.01 mmol) and cesium carbonate (0.33 g, 1.01 mmol) under nitrogen at room temperature. The reaction was stirred at room temperature for 16 hours. The mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to afford a mixture of compounds 44-8a and 44-8b (230 mg) as a colorless liquid. The isomers were prepared by chiral separation column (Column: UniChiral CMD-5H.4.6*250mm, Mobile Phase: 95% n-Hexane / 5% IPA) to obtain compound 44-8a (80 mg, 19.56%) and target compound 44-8b (80 mg, 19.56% yield) as colorless liquids. 1 H NMR (400MHz, CDCl3) 44-8a: δ7.35 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 4.56 (d, J = 1.2 Hz, 2H), 4.2 0(dd,J=8.7,1.8Hz,1H),3.49(dt,J=14.0,5.5Hz,3H),3.36(d,J=6.1Hz,2H),3.28(s,3H),2 .38–2.19(m,1H),2.11(dt,J=10.7,4.9Hz,1H),1.98(t,J=5.5Hz,1H),1.82(d,J=20.5Hz,2 H),1.58(s,9H),1.54(s,9H),1.31(s,4H),1.26(s,7H),1.20(t,J=7.0Hz,4H),0.82(s,3H); 1H NMR (400MHz, CDCl3) 44-8b: δ7.34(d,J=8.1Hz,1H),7.28(s,1H),4.56(d,J=1.7Hz,2H),4.20 (dd,J=8.7,1.8Hz,1H),3.48(dt,J=14.0,4.6Hz,3H),3.41–3.33(m,2H),3.29(s,3H),2.25(d t,J=23.1,10.3Hz,1H),2.07(dt,J=19.1,7.2Hz,1H),1.98(t,J=5.5Hz,1H),1.86–1.70(m,2 H),1.57(s,10H),1.54(s,9H),1.31(s,3H),1.25(s,6H),1.20(t,J=7.0Hz,4H),0.81(s,3H).

[0782] Step 7: Preparation of compound 44a

[0783] Tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(ethoxymethyl)-3-((2S)-1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (70 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), and concentrated hydrochloric acid (0.1 mL) and isobutylboronic acid (24 mg, 0.23 mmol) were added. The reaction was stirred at 25°C for 3 hours. The crude product was purified by preparative HPLC (C18, acetonitrile and water as mobile phases containing 0.1% trifluoroacetic acid) to afford the title compound 44a (28 mg, 77.93% yield) as a white solid. LCMS (ESI) m / z = 294.75 [M+H]+. 1 H NMR (400MHz, MeOD) δ7.21(d,J=7.7Hz,1H),7.01(d,J=7.8Hz,1H),4.54(q,J=12.1Hz,2H),3.51(q,J=7 .0Hz,2H),3.43(d,J=4.6Hz,2H),3.26(s,3H),3.11(s,1H),1.20(t,J=7.0Hz,3H),1.17–1.04(m,2H).

[0784] Step 8: Preparation of compound 44b

[0785] Tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(ethoxymethyl)-3-((2R)-1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (50 mg, 0.083 mmol) was dissolved in tetrahydrofuran (1 mL), and concentrated hydrochloric acid (0.5 mL) and isobutylboronic acid (17 mg, 0.16 mmol) were added. The reaction was stirred at 25°C for 3 hours. The crude product was purified by preparative HPLC (C18, acetonitrile and water as mobile phases containing 0.1% trifluoroacetic acid) to afford the title compound 44b (10 mg, 39.37% yield) as a white solid. LCMS (ESI) m / z = 294.65 [M+H]+. 1 H NMR (400MHz, MeOD) δ7.21(d,J=7.7Hz,1H),7.01(d,J=7.8Hz,1H),4.54(q,J=12.1Hz,2H),3.51(q,J =7.0Hz,2H),3.43(d,J=4.6Hz,2H),3.26(s,3H),3.11(s,1H),1.23–1.17(m,3H),1.17–1.07(m,2H).

[0786] Example 45

[0787] Step 1: Preparation of compound 45-2

[0788] At room temperature, tert-butyl 3-bromo-2-((tert-butoxycarbonyl)oxy)-6-(cyclopropyloxymethyl)benzoate (4.50 g, 10.13 mmol) was dissolved in 1,4-dioxane (40 mL). Bis((+)-pyrandiol)diborate (5.43 g, 15.16 mmol), Pd(dppf)Cl2 (0.37 g, 0.51 mmol), and potassium acetate (2.97 g, 30.31 mmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 17 hours. After cooling to room temperature, the mixture was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain the target compound 45-2 (3.30 g, 54.46% yield) as a yellow oil. 1H NMR(400MHz, CDCl3)δ7.80(d,J=8.0Hz,1H),7.31(d,J=7.6Hz,1H),4.69–4.57(m,2H),4.4 1(dd,J=8.8,1.8Hz,1H),3.33(tt,J=6.0,3.0Hz,1H),2.36(ddd,J=13.6,8.8,2.0Hz,1H), 2.20(dtd,J=8.0,6.2,2.0Hz,1H),2.11(t,J=5.2Hz,1H),2.02–1.87(m,2H),1.59(s,9H), 1.54(s,9H),1.46(s,3H),1.30(s,4H),0.87(s,3H),0.64–0.58(m,2H),0.49–0.41(m,2H).

[0789] Step 2: Preparation of compound 45-3

[0790] At room temperature, under nitrogen, tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(cyclopropyloxymethyl)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)benzoate (3.59 g, 6.61 mmol) was dissolved in tetrahydrofuran (20 mL) and water (5 mL). ((2-bromoallyl)oxy)methyl)benzene (1.50 g, 6.61 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol), and sodium carbonate (3.50 g, 33.03 mmol) were added. The reaction mixture was reacted at 80°C under nitrogen for 17 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain the target compound 45-3 (1.50 g, 39.95% yield) as a yellow oily liquid. 1 H NMR (400MHz, CDCl3) δ7.36–7.27(m,7H),5.56(s,1H),5.34(s,1H),4.62(s,2H),4.56(s,2H),4.2 4(s,2H),3.39–3.27(m,1H),1.59(s,9H),1.48(s,9H),0.67–0.57(m,2H),0.46(q,J=6.0Hz,2H).

[0791] Step 3: Preparation of compound 45-4

[0792] To a solution of tert-butyl 3-(3-(benzyloxy)prop-1-en-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-(cyclopropyloxymethyl)benzoate (1.40 g, 2.73 mmol) in ultra-dry tetrahydrofuran (15 mL) at -15°C was added a solution of borane dimethyl sulfide (2.1 mL, 4.10 mmol, 2 M). The mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction was quenched with water, extracted with ethyl acetate, dried, filtered, and concentrated. The crude product was dissolved in tetrahydrofuran (15 mL), and (+)-pinanediol (0.70 g, 4.10 mmol) was added. The reaction mixture was allowed to react at room temperature for 17 hours. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford the target compound 45-4 (0.60 g, 30.12% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.41–7.27(m,7H),4.60(d,J=2.0Hz,2H),4.51–4.41(m,2H),3. 64–3.56(m,1H),3.53–3.36(m,2H),3.35–3.25(m,1H),2.30–2.16(m,1H),1.94(t,J= 5.2Hz,1H),1.79(s,1H),1.71(dd,J=15.0,6.8Hz,1H),1.58(s,18H),1.28–1.25(m,6 H), 1.23 (s, 3H), 1.20 (s, 2H), 0.78 (s, 3H), 0.64–0.55 (m, 2H), 0.43 (q, J = 6.2Hz, 2H).

[0793] Step 4: Preparation of compound 45-5

[0794] To a solution of tert-butyl 3-(1-(benzyloxy)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-(cyclopropyloxymethyl)benzoate (0.65 g, 0.94 mmol) in methanol (8 mL) was added 10% palladium on carbon (65 mg) and palladium hydroxide on carbon (65 mg) at room temperature. The mixture was allowed to react at room temperature under hydrogen atmosphere for 3 hours. The mixture was filtered through celite, dried, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford the target compound 45-5 (0.50 g, 84.03% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ7.33 (dd, J=18.0, 8.0Hz, 2H), 4.60 (d, J=2.8Hz, 2H), 4.21 ( t,J=7.4Hz,1H),3.71(s,2H),3.42–3.20(m,2H),2.33–2.19(m,1H),2.03–1.93(m ,2H),1.84(s,1H),1.80–1.69(m,1H),1.59(s,9H),1.54(s,9H),1.31(d,J=2.0H z, 4H), 1.26 (s, 6H), 0.81 (d, J = 4.8Hz, 3H), 0.64–0.56 (m, 2H), 0.50–0.40 (m, 2H).

[0795] Step 5: Preparation of compound 45-6

[0796] To a solution of tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(cyclopropyloxymethyl)-3-(1-hydroxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (0.50 g, 0.83 mmol) in ultra-dry tetrahydrofuran (8 mL) was added trimethyloxytetrafluoroborate (0.18 g, 1.25 mmol) and cesium carbonate (0.41 g, 1.25 mmol) at room temperature under nitrogen. The reaction was stirred at room temperature for 17 hours. The mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford the target compound 45-6 (0.27 g, 50.13% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ7.34(dd,J=8.0,4.4Hz,1H),7.28(d,J=4.4Hz,1H),4.66–4.52(m,2H),4.20(d,J=7.4Hz ,1H),3.50(dd,J=6.8,4.0Hz,1H),3.41–3.34(m,2H),3.34–3.30(m,1H),3.28(d,J=3.2Hz,3H),2.37–2.20(m ,1H),2.20–2.07(m,1H),1.98(t,J=5.2Hz,1H),1.84(s,1H),1.76(t,J=15.0Hz,1H),1.58(d,J=0.6Hz,9H),1 .54(s,9H),1.31(s,3H),1.26(t,J=5.0Hz,6H),0.81(d,J=2.6Hz,3H),0.63–0.55(m,2H),0.48–0.39(m,2H).

[0797] Step 6: Preparation of compound 45

[0798] Tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(cyclopropyloxymethyl)-3-(1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (0.1 g, 0.16 mmol) was dissolved in tetrahydrofuran (1.5 mL), and concentrated hydrochloric acid (0.75 mL) and isobutylboronic acid (33.13 mg, 0.32 mmol) were added. The reaction was stirred at 25°C for 3 hours. The crude product was purified by preparative HPLC (C18 column, acetonitrile and water as mobile phases containing 0.1% trifluoroacetic acid) to afford the title compound 45 (22.61 mg, 43.66% yield) as a white solid. LCMS (ESI) m / z = 306.7 [M+H]+. 1 H NMR (400MHz, MeOD) δ7.24(d,J=7.6Hz,1H),7.04(d,J=7.8Hz,1H),4.60(q,J=11.6Hz,2H),3.45(d,J=4.6Hz,2H),3. 38(ddd,J=9.2,6.0,3.0Hz,1H),3.28(s,3H),3.13(s,1H),1.28–1.12(m,2H),0.71–0.57(m,2H),0.54–0.43(m,2H).

[0799] Example 46

[0800] Step 1: Preparation of compound 46-2

[0801] To a solution of 2-fluoroethanol (1.50 g, 0.02 mol) in THF (50 mL) was added NaH (0.62 g, 0.03 mol), and the mixture was stirred at 0°C for 0.5 h. Then, tert-butyl 3-bromo-6-(bromomethyl)-2-((tert-butoxycarbonyl)oxy)benzoate (10.93 g, 0.02 mol) was added, and the mixture was stirred at 25°C under N2 protection for 15.5 h. Water was added to the mixture, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was dissolved in DCM, and Boc2O and DMAP were added. The mixture was stirred at 25°C for 3 h. The reaction solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 5:1) to obtain the target compound 46-2 (2.20 g, 0.49 mmol, 20.94% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ7.61 (d, J = 8.4Hz, 1H), 7.26 (d, J = 8.4Hz, 1H), 4.65 (s, 2H) ,4.62(m,1H),4.51(m,1H),3.73(m,1H),3.66(m,1H),1.58(s,9H),1.56(s,9H).

[0802] Step 2: Preparation of compound 46-3

[0803] Tert-butyl 3-bromo-2-((tert-butoxycarbonyl)oxy)-6-((2-fluoroethoxy)methyl)benzoate (3.0 g, 0.64 mmol), bis((+)-pyrandiol)diboronate (2.98 g, 0.83 mmol), Pd(dppf)Cl2 (0.23 g, 0.03 mmol), and potassium acetate (1.88 g, 1.92 mmol) were added to dioxane (50 mL) and stirred at 100°C under N2 protection for 16 hours. Water was added to the mixture and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10:1) to obtain the target compound 46-3 (0.45 g, 0.08 mmol, 12.50% yield) as a pale yellow oil. LCMS (ESI) m / z = 571.15 [M+H] + .

[0804] Step 3: Preparation of compound 46-4

[0805] Tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-((2-fluoroethoxy)methyl)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)benzoate (2.70 g, 0.49 mmol), ((2-bromoallyl)oxy)methyl)benzene (1.67 g, 0.74 mmol), Pd(PPh3)4 (0.28 g, 0.02 mmol), and Na2CO3 (2.60 g, 2.45 mmol) were added to THF (40 mL) and H2O (8 mL). The reaction solution was stirred at 80°C under N2 atmosphere for 16 hours. Water was added to the mixture, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc=15:1) to obtain the target compound 46-4 (0.4 g, 0.08 mmol, yield 16.33%) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.39 (d, J = 7.8Hz, 1H), 7.29 (m, 6H), 5.49 (s, 1H), 5.21 (s, 1H), 4.5 5(m,3H),4.45(m,3H),4.17(s,2H),3.65(m,1H),3.57(m,1H),1.46(s,9H),1.37(s,9H).

[0806] Step 4: Preparation of compound 46-5

[0807] Tert-butyl 3-(3-(benzyloxy)prop-1-en-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-((2-fluoroethoxy)methyl)benzoate (1.04 g, 2.00 mmol) was added to THF (10 mL), BH3-Me2S (1.5 mL) was added at -10 ° C, and the mixture was stirred at room temperature for 2 hours under N2 atmosphere. Water was added to the mixture and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product and (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol (513 mmol, 3.01 mmol) were then added to THF (5 mL) and stirred at room temperature for 14 hours under N2 atmosphere. Water was added to the mixture and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 15:1) to obtain the target compound 46-5 (400 mg, 0.57 mmol, 28.25% yield) as a light yellow oil. LCMS (ESI) m / z = 541.20 [M+H] + .

[0808] Step 5: Preparation of compound 46-6

[0809] Tert-butyl 3-(1-(benzyloxy)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-((2-fluoroethoxy)methyl)benzoate (600 mg, 0.86 mmol) and 10% Pd / C (229 mg, 2.15 mmol) were added to MeOH (30 mL). The reaction solution was stirred at 25°C under a H2 atmosphere for 3 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10:1) to afford the target compound 46-6 (220 mg, 0.33 mmol, 37.90% yield) as a colorless oil. LCMS (ESI) m / z = 624.25 [M+H] + .

[0810] Step 6: Preparation of compound 46-7

[0811] Tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-((2-fluoroethoxy)methyl)-3-(1-hydroxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanebenzo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (170 mg, 0.28 mmol), trimethyloxytetrafluoroborate (62 mg, 0.42 mmol) and Cs2CO3 (137 mg, 0.42 mmol) were added to THF (5 mL) and stirred at room temperature under N2 protection for 4 hours. Water was added to the mixture and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc=10:1) to obtain the target compound 46-7 (130 mg, 0.21 mmol, yield 74.77%) as a colorless oil. LCMS (ESI) m / z=643.15 [M+H] + .

[0812] Step 7: Preparation of Compound 46

[0813] To a solution of tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-((2-fluoroethoxy)methyl)-3-(1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (100 mg, 0.16 mmol) and isobutylboronic acid (32.80 mg, 0.32 mmol) in THF (2 mL) was added concentrated HCl (2 mL) at 0°C. The reaction solution was stirred at 25°C under N2 protection for 2 hours. The mixture was purified by Prep-HPLC (ACN-H2O (0.1% TFA)) to give the title compound 46 (9.70 mg, 0.03 mmol, 17.65% yield) as a white solid. LCMS (ESI) m / z = 313.05 [M+H] + . 1 H NMR (400MHz, MeOD) δ7.23(d,J=7.8Hz,1H),7.04(d,J=7.8Hz,1H),4.62(dd,J=14.6,8.6Hz,2H),4.59(m,1H),4.47 (m,1H),3.72(m,1H),3.65(m,1H),3.44(d,J=4.6Hz,2H),3.26(s,3H),3.12(s,1H),1.13(qd,J=16.0,5.4Hz,2H).

[0814] Example 47

[0815] Step 1: Preparation of compound 47-2

[0816] At room temperature, under nitrogen, tert-butyl 3-bromo-2-((tert-butoxycarbonyl)oxy)-6-(isopropoxymethyl)benzoate (2.50 g, 5.60 mmol) was dissolved in 1,4-dioxane (25 mL). Bis((+)-pyrandiol) diborate (3.00 g, 8.40 mmol), Pd(dppf)Cl2 (0.20 g, 0.28 mmol), and potassium acetate (1.65 g, 16.80 mmol) were added. The reaction mixture was reacted at 100°C under nitrogen for 17 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate, 10:1) to afford the target compound 47-2 (2.20 g, 68.41% yield) as a yellow oil. 1H NMR (400MHz, CDCl3) δ7.81(d,J=7.6Hz,1H),7.38(d,J=7.8Hz,1H),4.41(d,J=7 .2Hz,1H),3.62(dt,J=12.2,6.0Hz,1H),2.44–2.31(m,1H),2.24–2.15(m,1H),2 .11(t,J=5.2Hz,1H),1.97(d,J=14.8Hz,1H),1.91(s,1H),1.58(s,9H),1.53(s, 9H), 1.46 (s, 3H), 1.30 (s, 4H), 1.26 (s, 2H), 1.18 (d, J = 6.0Hz, 6H), 0.87 (s, 3H).

[0817] Step 2: Preparation of compound 47-3

[0818] At room temperature, under nitrogen, tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(isopropoxymethyl)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)benzoate (2.40 g, 4.40 mmol) was dissolved in tetrahydrofuran (16 mL) and water (4 mL). ((2-bromoallyl)oxy)methyl)benzene (1.00 g, 4.40 mmol), Pd(PPh3)4 (0.25 g, 0.22 mmol), and sodium carbonate (2.33 g, 22.02 mmol) were added. The reaction mixture was reacted at 80°C under nitrogen for 17 hours. After cooling to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 10:1) to obtain the target compound 47-3 (1.0 g, 42.00% yield) as a yellow oily liquid. 1 H NMR (400MHz, CDCl3) δ7.39–7.27(m,7H),5.56(d,J=1.6Hz,1H),5.33(s,1H),4.58(s,2H),4.57(s ,2H),4.24(s,2H),3.64(dt,J=12.2,6.0Hz,1H),1.58(s,9H),1.48(s,9H),1.18(d,J=6.0Hz,6H).

[0819] Step 3: Preparation of compound 47-4

[0820] To a solution of tert-butyl 3-(3-(benzyloxy)prop-1-en-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-(isopropoxymethyl)benzoate (1.0 g, 1.95 mmol) in ultra-dry tetrahydrofuran (10 mL) at -15°C was added a solution of borane dimethyl sulfide (1.9 mL, 3.89 mmol, 2 M). The mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction was quenched with water, extracted with ethyl acetate, dried, filtered, and concentrated. The crude product was dissolved in tetrahydrofuran (10 mL), and (+)-pinanediol (0.50 g, 2.92 mmol) was added. The reaction mixture was allowed to react at room temperature for 17 hours. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford the target compound 47-4 (0.50 g, 29.62% yield) as a colorless oil. LCMS (ESI) m / z = 715.2 [M+Na] + .

[0821] Step 4: Preparation of compound 47-5

[0822] To a solution of tert-butyl 3-(1-(benzyloxy)-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-(isopropoxymethyl)benzoate (0.50 g, 0.72 mmol) in methanol (5 mL) was added 10% palladium on carbon (50 mg) and palladium hydroxide on carbon (50 mg) at room temperature. The mixture was allowed to react under hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered through celite, dried, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford the target compound 47-5 (0.40 g, 76.19% yield) as a colorless oil. LCMS (ESI) m / z = 625.3 [M+Na] + .

[0823] Step 5: Preparation of compound 47-6

[0824] To a solution of tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(isopropoxymethyl)-3-(1-hydroxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (0.40 g, 0.66 mmol) in ultra-dry tetrahydrofuran (8 mL) was added trimethyloxytetrafluoroborate (0.20 g, 1.33 mmol) and cesium carbonate (0.32 g, 0.99 mmol) under nitrogen at room temperature. The reaction was stirred at room temperature for 17 hours. The mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford the target compound 47-6 (0.25 g, 54.97% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.41–7.29(m,2H),4.56(s,2H),4.20(d,J=7.2Hz,1H),3.60(dt,J=12. 0,6.0Hz,1H),3.52–3.47(m,1H),3.39–3.32(m,2H),3.29(d,J=3.2Hz,3H),2.34–2.20(m,1H) ,2.15–2.06(m,1H),1.98(t,J=5.6Hz,1H),1.89–1.81(m,1H),1.81–1.71(m,1H),1.58(s,9H ),1.53(s,9H),1.31(s,3H),1.29–1.21(m,6H),1.17(d,J=6.0Hz,6H),0.81(d,J=2.4Hz,3H).

[0825] Step 6: Preparation of compound 47

[0826] Tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(isopropoxymethyl)-3-(1-methoxy-3-((3aS,4R,6R)-3a,5,5-trimethylhexahydro-4,6-toluo[d][1,3,2]dioxaborolan-2-yl)propan-2-yl)benzoate (0.10 g, 0.16 mmol) was dissolved in tetrahydrofuran (1.5 mL), and concentrated hydrochloric acid (0.75 mL) and isobutylboronic acid (33.03 mg, 0.32 mmol) were added. The reaction was stirred at 25°C for 3 hours. The crude product was purified by preparative HPLC (C18, acetonitrile and water as mobile phases, containing 0.1% trifluoroacetic acid) to afford the title compound 47 (12.97 mg, 25.76% yield) as a white solid. LCMS (ESI) m / z 309=308.7[M+H]+. 1H NMR (400MHz, MeOD) δ7.21(d,J=7.8Hz,1H),7.02(d,J=7.8Hz,1H),4.60–4.49(m,2H),3.67(dt,J=12.2,6.4H z, 1H), 3.43 (d, J = 4.6Hz, 2H), 3.26 (s, 3H), 3.11 (s, 1H), 1.18 (d, J = 6.0Hz, 6H), 1.13 (dd, J = 9.0, 5.4Hz, 2H).

[0827] Example 48

[0828] Step 1: Preparation of compound 48-2

[0829] Sodium lumps (0.90 g, 38.70 mmol) were placed in an isobutanol solution and heated to 50°C until the sodium lumps were completely dissolved. 3-Bromo-6-(bromomethyl)-2-((tert-butoxycarbonyl)oxy)benzene (15.00 g, 12.90 mmol, 40% purity) was added to the reaction solution. The mixture was heated at 50°C for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 100% petroleum ether) to obtain the target compound 48-2 as a yellow oil, which was used directly in the next step (2.60 g).

[0830] Step 2: Preparation of compound 48-3

[0831] To a solution of tert-butyl 3-bromo-2-hydroxy-6-(isobutoxymethyl)benzoate (2.60 g, 2.80 mmol), DMAP (0.03 g, 0.20 mmol), and triethylamine (0.85 g, 8.40 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (0.92 g, 4.20 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 0% to 5%) to obtain the target compound 48-3 (2.00 g, 60.17% yield) as a yellow oily liquid. 1 H NMR(400MHz,DMSO-d6)δ7.80(d,J=8.4Hz,1H),7.33(d,J=8.4Hz,1H),4.47(s,2H),3 .16(d,J=6.4Hz,2H),1.80(m,1H),1.50(d,J=8.8Hz,18H),0.85(s,3H),0.84(s,3H).

[0832] Step 3: Preparation of compound 48-4

[0833] Under nitrogen, tert-butyl 3-bromo-2-((tert-butoxycarbonyl)oxy)-6-(isobutoxymethyl)benzoate (2.30 g, 5.00 mmol), bis((+)-pinenediol)diboron (2.69 g, 7.50 mmol), potassium acetate (0.98 g, 10.00 mmol), and Pd(dppf)Cl2 (0.37 g, 0.50 mmol) were dissolved in dry dioxane (40 mL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated. The residue was purified on a silica gel column (eluent: ethyl acetate:petroleum ether = 0% to 5%) to obtain the target compound 48-4 (1.90 g, 68.00% yield) as a yellow oil. LCMS (ESI) m / z = 576.35 [M+OH] + .

[0834] Step 4: Preparation of compound 48-5

[0835] Under nitrogen at room temperature, tert-butyl 2-((tert-butoxycarbonyl)oxy)-6-(isobutoxymethyl)-3-((3aS,4R,6R)-3A,5,5-trimethylhexahydro-4,6-methylbenzo[d][1,3,2]dioxaborolan-2-yl)benzoate (1.90 g, 3.40 mmol) was dissolved in tetrahydrofuran (50 mL) and water (15 mL). ((2-bromoallyl)oxy)methyl)benzene (1.00 g, 4.42 mmol), Pd(PPh3)4 (0.20 g, 0.17 mmol), and sodium carbonate (1.80 g, 17.00 mmol) were added. The reaction mixture was reacted at 80°C under nitrogen for 16 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 0% to 5%) to obtain the target compound 48-5 (0.90 g, 50.00% yield) as a yellow oily liquid. 1 H NMR (400MHz, CDCl3) δ7.20-7.45(m,7H),5.56(s,1H),5.34(s,1H),4.57(s,4H),4.25(s,2H) ,3.21(d,J=6.8Hz,2H),1.83-1.92(m,1H),1.58(s,9H),1.47(s,9H),0.92(d,J=6.8Hz,6H).

[0836] Step 5: Preparation of compound 48-6

[0837] To a solution of tert-butyl 3-(3-(benzyloxy)prop-1-en-2-yl)-2-((tert-butoxycarbonyl)oxy)-6-(isobutoxymethyl)benzoate (700 mg, 1.33 mmol) in ultra-dry tetrahydrofuran (20 mL) at -15°C was added a 2M borane dimethyl sulfide solution (2.0 mL, 3.98 mmol) dropwise. The mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction was quenched with water, extracted with ethyl acetate, dried, filtered, and concentrated. The crude product was dissolved in tetrahydrofuran (20 mL) and (+)-pinanediol (0.82 g, 4.8 mmol) was added. The reaction mixture was allowed to react at room temperature for 15 hours. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 0% to 10%) to obtain the target compound 48-6 (250 mg, 26.62% yield) as a colorless oil. LCMS (ESI) m / z = 724.30 [M+OH] + .

[0838] Step 6: Preparation of compound 48-7

[0839] To a solution of tert-butyl 3-(...

Claims

1. A β-lactamase inhibitor, which is a compound of formula (I), or an optical isomer or a pharmaceutically acceptable salt thereof: in, The E and G are each independently H, C, N, S elements or do not exist; M is a single bond or C; T is a single bond, or -(CH) m -, wherein m is selected from 0 or 1; X is a single bond, -(CH2) t -, where t is selected from 0 or 1; Y is B, O, or P element; Z is an O, S, B, or N element; L1 is selected from a single bond, halogen, H, -O-, -S-, -CR a R b -、-NH-、-CH2-、-C(O)NR a R b or The group may not exist; L2 is selected from a single bond, H, -C(O)-, -CR a R b -、-CO-、-NR a -、 or does not exist; L3 is selected from H, a single bond, halogen, -O-, -S-, -N-, -C-, -CR a R b - or does not exist; L4 is selected from H, amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-S-、-CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S)-, -NHC(O)-, -NHC(O)NH-, -CH2NR a R b , Single bond or not present; R1 is selected from -H-, -S(O)(O)NR a R b 、-S(O)(O)R a 、-S(O)(O)(CH2) n R a 、-S(O)NR a R b 、-(O)NR a R b 、-CHR a R b 、-C(O)R a 、-C(O)NR a R b 、-COR a 、-CONR a R b 、-NR a COR b , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 3-8 Aromatic heterocyclic ring, C 3-8 Alkyl bridge ring, C 3-8 Epoxyalkyl, C 1-8 Alkyl, aryl or heteroaryl or absent; Preferably, R1 is selected from -H-, -C(O)-aryl, -C(O)NH-C 1-6 Oxoalkyl, -C(O)NH-(CH2) n -cycloalkyl, -C(O)NH-C 1-6 Alkyl, -C(O)N(C 1-6 alkyl)-cycloalkyl, -S(O)(O)-aryl, -S(O)(O)-C 1-6 Alkyl, -S(O)(O)-C 3-8 Cycloalkyl, -S(O)(O)-C 3-8 Heterocycloalkyl, -S(O)(O)-halogenated aromatic ring, -S(O)(O)-(CH2) n - cycloalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 3-8 Aromatic heterocyclic ring, C 3-8 Alkyl bridge ring, C 3-8 Epoxyalkyl, C 1-8 Alkyl, aryl or heteroaryl or absent; R2 is alkyl, -OR a 、-SR a 、-NR a R b , or does not exist; R3 is -H-, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaromatic, or absent; Preferably, the C 1-8 Alkyl, C 1-8 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl is substituted by 1, 2 or 3 F, Cl, Br, I, OH, alkyl or heteroalkyl; It is further preferred that R3 is CH3 or does not exist; R4 is selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -(CH2)n-cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Halogenated alkylthiol, C 1-6 Alkoxy, C 1-6 Alkylthiol, hydroxyl, carboxyl, -O-(CH2) n -Aromatic heterocycle, -O-(CH2) n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、-S-(CH2) n -aromatic heterocyclic ring, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a , C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n -Aryl, -C(O)R a 、-C(O)NR a R b 、-NHCOR a 、-NR a R b , C 3-8 Cycloheteroalkyl, aryl, halogenated aryl and aromatic heterocycle, -(CH2) n -C 3-8 Cycloalkyl, -(CH2) n -Halogenated C 3-8 Cycloalkyl, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -Aryl, -(CH2) n -haloaryl, -(CH2) n -aromatic group, C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH(C=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- and C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl - or absent, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; Among them, the C 1-6 Alkyl, C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NHC(=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- or C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl-optionally substituted with 1, 2 or 3 R a replace; Wherein, the -O-(CH2) n -Aromatic heterocycle, -O-(CH2) n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、-S-(CH2) n -aromatic heterocyclic ring, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a , C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n - aryl is optionally substituted by 1, 2 or 3 Ra; The halogen is -F, -Cl, -Br, -I, or -B; R5 and R6 are each independently H or absent, or R5 and R6 together with the atoms to which they are attached form a C 3-8 Carbon ring, C 3-8 a carbon heterocyclic ring, an aromatic ring, a heteroaromatic ring or a fused ring; R7 is carboxyl, sulfonic acid, amide, sulfonamide, triazole, tetrazole or Or not present; preferably R7 is COOH, SO3H, CONH2、 or does not exist; R8, R9 are each independently selected from H, hydroxyl or absent; R a , R b are each independently a hydrogen atom or an alkyl, halogen, hydroxyl, amino, carbonyl, carboxyl, cyano, deuterated, C 1-6 Alkoxy, aryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Oxoalkyl, C 1-6 Thioalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, halogenated C 3-8 Cycloalkyl, halogenated C 3-8 Epoxyalkyl, C 3-8 Aromatic heterocyclic or halogenated C 3-8 Aromatic heterocyclic group, -(CH2) n -C 3-8 Cycloalkyl, -(CH2) n -Halogenated C 3-8 Cycloalkyl, -(CH2) n -Halogenated aromatic ring, -(CH2) n -Halogenated aromatic heterocycle, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH(C 1-6 alkyl), -C(O)(C 1-6 Alkyl), -C(O)(halogenated C 1-6 Alkyl), -C(O)(halogenated C 3-8 Cycloalkyl), -C(O)(C 3-8 Cycloalkyl), -C(O)NH-C 1-6 Alkyl, -C(O)NH-halogenated C 1-6 Alkyl, -NHCO-haloalkyl, -NHC 3-8 The cycloalkyl group is or is absent, and n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), When m is 1, L2 and R6 are both hydrogen atoms, X is a single bond, Y and Z are each independently selected from B or O atoms, M, E, and G are each independently C, L3 is selected from H, L4 is selected from H, amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S)-, R4 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl, C 3-8 Epoxyalkyl, halogenated C 3-8 The alkylene oxide group, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a replace.

3. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), When t is 1, R5 and R6 are hydrogen atoms or the atoms they are connected to together form a C 3-8 Carbon ring, C 3-8 a carbon heterocyclic ring, an aromatic ring, a heteroaromatic ring or a fused ring; M, E, and G are each independently C or N, T is a single bond, L2 is a hydrogen atom, L1, L3, and L4 are each independently a single bond, -O-, -S-, or -CR a R b -, R1, R3, and R4 are each independently -H-, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated, amino-substituted, cyano-substituted cycloalkyl or aryl or heteroaromatic.

4. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), When t is 1, m is 1, Y is selected from B atoms, Z is selected from O atoms, and R5 and R6 are each independently selected from hydrogen atoms, 1) L1 is H, -O-, -NH-, -CH2-, -C(O)NR a R b , R1 is -S(O)(O)NR a R b 、-S(O)(O)R a 、-S(O)(O)(CH2) n R a 、-S(O)NR a R b 、-C(O)NR a R b 、-CHR a R b 、-C(O)R a 、 C 3-8 Cycloalkyl, C 1-8 Haloalkyl, C 3-8 Heterocyclic group, optionally substituted C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a , halogenated C 3-8 Cycloalkyl, halogenated C 3-8 Epoxyalkyl, C 3-8 Aromatic heterocyclic or halogenated C 3-8 Aromatic heterocyclic ring, C 1-8 Alkyl bridge ring or methyl substituted C 3-8 Cycloalkyl, cyano substituted C 3-8 Cycloalkyl, amino substituted C 3-8 Cycloalkyl groups; L2 and L3 are each independently H; M, E, and G are N, O, S or (-CH2-) i , where i is 1; L4 is a single bond, amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -, -NHC(O)-, -NHC(O)NH-, -O-, -CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S)-, R4 is H, halogen, -CH2(aryl), -CH2(heteroaryl), -CH2(C 1-6 Cycloalkyl), -CH2(C 3-8 Heterocyclyl), optionally substituted C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a Substituted or unsubstituted C 3-8 Cycloalkyl, unsubstituted C 3-8 Epoxyalkyl, halogenated C 3-8 Cycloalkyl or halogenated C 3-8 an alkylene oxide group; or 2) L1 and L3 are hydrogen atoms, L2 is -C(O)-, -CR a R b -, -NRa-, R2 is alkyl, -OR a 、-SR a , -NRaRb group; M, E, G are each independently a C, or N atom; L4 is a single bond, H, amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, -C(S-; optionally substituted C 3-8 Heterocyclic group, optionally substituted C 1-6 Alkyl, the C 1-6 Alkyl, C 3-8 The heterocyclic group is optionally substituted with 1, 2 or 3 R a Substituted or unsubstituted C 3-8 Cycloalkyl, unsubstituted C 3-8 Epoxyalkyl, halogenated C 3-8 Cycloalkyl, halogenated C 3-8 Oxiranyl groups.

5. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), When t=1, m=1, Y is a B atom, Z is an O atom; When R5 and R6 are H or R5, R6 and the atoms to which they are connected form a fused ring or ring system, the fused ring or ring system is preferably a 3-10-membered carbocyclic group or a 3-10-membered heterocyclic group, preferably a 3-7-membered carbocyclic group or a 3-7-membered heterocyclic group including but not limited to: a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring; L3 is O, S, N, or C atom; R3 is C 1-6 Alkyl, C 1-6 heteroalkyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, aryl or heteroaryl is optionally substituted with 1, 2 or 3 F, Cl, Br, I, OH, alkyl or heteroalkyl; L4 is amino, halogen, cyano, hydroxyl, alkynyl, deuterium, thiol, nitro, -NR a -、-O-、-CR a R b -, -S(O)O-, -S(O)(O)-, -S(O)(O)O-, -CO-, -C(O)-, -C(O)O-, -CS-, or -C(S)-, R4 is selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -(CH2)n-cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Halogenated alkylthiol, C 1-6 Alkoxy, C 1-6 Alkylthiol, hydroxyl, carboxyl, -O-(CH2) n -Aromatic heterocycle, -O-(CH2) n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、-S-(CH2) n -aromatic heterocyclic ring, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a , C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n -Aryl, -C(O)R a 、-C(O)NR a R b 、-NHCOR a 、-NR a R b , C 3-8 Cycloheteroalkyl, aryl, halogenated aryl and aromatic heterocycle, -(CH2) n -C 3-8 Cycloalkyl, -(CH2) n -Halogenated C 3-8 Cycloalkyl, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -Aryl, -(CH2) n -haloaryl, -(CH2) n -aromatic group, C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH(C=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- and C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl - or absent, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; Among them, the C 1-6 Alkyl, C 1-6 Alkyl-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-, C 1-6 Alkyl-(C=O)NH-C 1-6 Alkyl-NH-, C 1-6 Alkyl-NHC(=O)-, C 1-6 Alkyl-NH(C=O)-C 1-6 Alkyl-, NH2(C=O)NH-C 1-6 Alkyl-, NH2(C=N)NH-C 1-6 Alkyl-, C 1-6 Alkyl-NH(C=O)NH- or C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl-optionally substituted with 1, 2 or 3 R a replace; Wherein, the -O-(CH2) n -Aromatic heterocycle, -O-(CH2) n -C 3-8 Cycloheteroalkyl, -O-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a 、-S-(CH2) n -aromatic heterocyclic ring, -S-(CH2) n -C 3-8 Cycloheteroalkyl, -S-(CH2) n -C 3-8 Cycloalkyl-R a 、-O-(CH2) n -C 3-8 Cycloheteroalkyl-R a , C 3-8 Cycloheteroalkyl, aromatic heterocycle, -(CH2) n -C 3-8 Cycloheteroalkyl, -(CH2) n -aromatic heteroyl-, -(CH2) n -Aryl is optionally substituted with 1, 2 or 3 R a replace; The halogen is -F, -Cl, -Br, -I, or -B.

6. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), When m=1, i.e. T is -CH-, T, E, G, and M form a six-membered ring, preferably a benzene ring.

7. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), When T is a single bond, the ring containing E, G, and M is a five-membered ring.

8. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), When m=0, that is, T does not exist, E and G do not exist either, and the ring is an open ring.

9. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), L1 is selected from NH, F, H, O, CH3, Or does not exist.

10. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), L2 is selected from H, N, CH2, CH3, -CO-, or NH.

11. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), L3 is selected from H, a single bond, halogen, -O-, -S-, -N-, -C-, -CH3- or is absent; further preferably, the halogen is F, Cl, Br or I.

12. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), L4 is selected from H, F, O, S, CH3, CH2, -NCH3-, NH, -CH2NR a R b Or does not exist.

13. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), R1 is selected from H, -CH3, -CH2F, -CH2Cl, -CHCH3F, -CHF2, -CHOHOH, -CHCNCN, -CH2COCH3, Or does not exist.

14. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), R2 is CH3, CH3O, CH3NH, Or does not exist.

15. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), The R4 is selected from H, -CH3, CH3CH2-, -OCH3, (CH3)2CH2CH2-, -CH2CN, CNCH2CH2-, <h2 style=";text-align:left;direction:ltr">CH3CH2CH2O-, CH3O-, (CH3)2CHCH2O-, CH3CH2O-, (CH3CH2)2CH-,<h2 style=";text-align:left;direction:ltr"> (CH3)2CH-、CH3(CH2)3-、 CH3S-, CH3CH2S-, (CH3)3CO-, (CH3)2CHO-; F2CH-、FCH2CH2-、CF3CH2-、FCH2CH2O-、FCH2CH2O-、F2CHCH2O-、CF3CH2O-; -N(CH3)2、CH3CO-、 F2CHCH2NHCO-、-NHCH2CH(CH3)2、CH3CH2NHCO-、NH2CH2CH2NHCO-、FCH2CH2NHCO-、CF3CH2NHCO-、 CH3NH-, or not present.

16. The β-lactamase inhibitor according to claim 1, characterized in that In the compound of formula (I), R5 and R6 are each independently H or absent, or R5, R6 and the carbon atoms to which they are connected together form cyclopropane, cyclobutane, cyclopentane or cyclohexane.

17. The β-lactamase inhibitor according to claim 1, which is a compound represented by formula I-1, or an optical isomer or a pharmaceutically acceptable salt thereof Said R5 and R6 are as defined in claim 1; Said L1 and L2 are as defined in claim 1; Said R1 and R2 are as defined in claim 1; Said R7 is defined in claim 1; Said L4 is defined in claim 1; The R4 is as defined in claim 1.

18. The β-lactamase inhibitor according to claim 17, wherein The compound represented by formula I-1, or its optical isomers or pharmaceutically acceptable salts, The R5, R6 and the atoms to which they are connected together form a cyclopropyl group; The L1 and L2 are each independently a single bond; Said R1 and R2 are each independently H; The R7 is selected from carboxyl, sulfonic acid, amide, sulfonamide, or tetrazole; The L4 is -CR a R b -, -S-, halogen; The R4 is H, alkyl, cycloalkyl, halogenated alkoxy, or alkoxy.

19. The β-lactamase inhibitor according to claim 18, which is a compound represented by formula I-2, or an optical isomer or a pharmaceutically acceptable salt thereof: Said L4 is defined in claim 1; Said R4 is defined in claim 1; Said R7 is defined in claim 1; The R a , R b As defined in claim 1.

20. The β-lactamase inhibitor according to claim 19, wherein In the compound represented by formula I-2, or its optical isomers or pharmaceutically acceptable salts, The L4 is -CR a R b -; The R4 is selected from -OCH2CH2F, -OCH3, -OCH2CH3; The R7 is a carboxyl group; The R a , R b For H.

21. The compound according to claim 20, which is selected from the following compounds, or optical isomers or pharmaceutically acceptable salts thereof:

22. The β-lactamase inhibitor according to claim 1, which is selected from the following compounds, or optical isomers or pharmaceutically acceptable salts thereof:

23. The β-lactamase inhibitor according to claim 1, wherein the pharmaceutically acceptable salt is an organic salt, an inorganic salt or an amino acid salt; preferably an inorganic salt, and more preferably a sodium salt.

24. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 23, an optical isomer or a pharmaceutically acceptable salt thereof and a β-lactamase antibacterial agent, preferably the β-lactamase antibacterial agent is meropenem, biapenem or imipenem; preferably meropenem.

25. Use of the compound of formula (I) according to any one of claims 1 to 23, or its optical isomers or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 24 in the preparation of drugs for treating bacterial infections.

26. The use according to claim 25, wherein: The bacterial infection-related disease is caused by bacteria expressing β-lactamase.

27. The use according to claim 26, wherein: The bacterial infection-related diseases are diseases caused by Klebsiella pneumoniae and Escherichia coli.

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