Boric acid derivatives, processes for their preparation and use

Abstract

The application discloses a boronic acid derivative, a preparation method and application thereof, and particularly discloses a compound shown in formula (I), an optical isomer or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This invention relates to the compound represented by formula (I), its optical isomers or pharmacologically acceptable salts thereof, and the use of the compound as an antibacterial agent as a β-lactamase inhibitor. Background Technology

[0002] Due to the widespread and excessive use of antibiotics, pathogenic bacteria have rapidly evolved resistance to antimicrobial drugs, resulting in a large number of drug-resistant bacteria, multidrug-resistant bacteria, and even superbugs. Bacterial resistance has become a major challenge in the global public health field.

[0003] β-lactam antibiotics are currently the most prevalent antibacterial drugs in clinical practice, accounting for over 50% of the total market share. β-lactam antibiotics refer to a large class of antibiotics with a β-lactam ring in their chemical structure, including the most commonly used penicillins and cephalosporins, as well as other atypical β-lactam antibiotics such as carbapenems and monocyclic β-lactams. These antibiotics have the advantages of strong bactericidal activity, low toxicity, broad indications, and good clinical efficacy. The mechanisms of action of β-lactam antibiotics are all similar: by inhibiting cell wall peptidoglycan synthase, namely penicillin-binding protein (PBP), they hinder cell wall peptidoglycan synthesis, causing bacterial cell wall defects, bacterial swelling, and lysis.

[0004] One of the main mechanisms of bacterial resistance to β-lactam antibiotics is the production of β-lactamases. To date, more than 2800 β-lactamases have been reported. They differ significantly in origin, substrate, inhibitors, and structure. In 1980, Ambler classified β-lactamases into four classes based on their molecular structure, using amino acid sequence analysis: Class A (penicillinases), Class B (metallo-β-lactamases), Class C (cephalosporinases), and Class D (oxacillinases). Classes A, C, and D contain serine (SBL) as their active group, while Class B contains zinc metalloside (MBL).

[0005] β-lactamase inhibitors bind to β-lactamases, inactivating the enzyme and restoring the antibacterial activity of β-lactam antibiotics. Clinically, they are used in combination with β-lactam antibiotics to inhibit drug-resistant bacteria, reduce dosage, broaden the antibacterial spectrum, and enhance antibacterial activity. To date, the FDA has approved six β-lactamase inhibitors, but all have significant limitations and are ineffective in treating MBL-mediated superbug resistance. Clavulanic acid, sulbactam, and tazobactam only inhibit some class ASBLs; avibactam inhibits class A, C, and D SBLs, but has no effect on pathogens resistant via MBL. MBLs can hydrolyze all β-lactam antibiotics except monocyclic β-lactams, including penicillins, cephalosporins, extended-spectrum cephalosporins, and carbapenems. According to the China Antimicrobial Resistance Surveillance Network (CHINET), in 2018, among clinically isolated bacterial strains in China, the resistance rates of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter bacilli to carbapenem antibiotics such as meropenem reached 26.3%, 25.8%, and 73.9%, respectively. The resistance rate of Klebsiella pneumoniae to meropenem increased from 2.9% in 2005 to 26.3%. Carbapenems are the last line of defense against bacterial infections; once resistance develops, the available drug options are extremely limited, and in some cases, no drugs are available at all. Therefore, there is an urgent clinical need for novel antimicrobial drugs to overcome the treatment dilemma and address the increasingly prominent challenge of drug resistance.

[0006] Bacterial resistance has multiple mechanisms, which can be summarized as follows: (1) Changes in the permeability of the bacterial cell wall or outer membrane, such as decreased expression of porin and increased expression of efflux pumps, prevent or reduce the entry of bacteria into the target site. The outer membrane of Gram-negative bacteria is the first barrier that limits the penetration of β-lactam antibiotics into the bacterial cell; (2) Mutations in target proteins lead to decreased binding affinity to antibiotics, increased target proteins, or the production of new target proteins. For example, methicillin-resistant Staphylococcus aureus is highly resistant due to the production of a new PBP2' between the original PBP2 and PBP3. Low and moderate resistance are due to increased production of PBPs or decreased affinity for methicillin; (3) Bacteria produce β-lactamases, which hydrolyze and inactivate antibiotics or bind to antibiotics, causing them to remain in the extracellular space and unable to bind to target proteins smoothly. The main resistance mechanism of Gram-positive bacteria is the production of β-lactamases and PBP mutations, while the main resistance mechanism of Gram-negative bacteria is the production of β-lactamases. Summary of the Invention

[0007] In a first aspect, the present invention provides a compound of formula (I), an optical isomer thereof, or a pharmacologically acceptable salt thereof. , in, m and n are independently selected from 0, 1 and 2, respectively; T is selected from N and CH; L1 is selected from single bonds, CH2, and The CH2 or It can be replaced by 1, 2, or 3 Rs; R1 is selected from NH2, 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- and C 1-6 Alkyl-NH(C=O)NH-C 1-6 alkyl-, 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 1-6Alkyl groups are optionally substituted with one, two, or three Rs; R2 is selected from H, OH, CN, NH2, and C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R3 is selected from H and C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R4 is selected from H and C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R a R b R c Each of the following is independently selected from H, F, Cl, Br, I, OH, CN, NH2, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, C 6-10 Aryl-C 1-3 Alkyl-, 5- to 10-membered heteroaryl-C 1-3 alkyl- and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, C 6-10 Aryl-C 1-3 Alkyl-, 5- to 10-membered heteroaryl-C 1-3 Alkyl or 5- to 10-membered heteroaryl groups may be substituted with 1, 2 or 3 Rs; L a L b L c One of them is selected from S, and the other two are selected from single bonds; R is independently selected from H, F, Cl, Br, I, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclic group may be optionally substituted with 1, 2 or 3 R's; R' is independently selected from F, Cl, Br, I, OH, CN and NH2; The C 1-6 Heteroalkyl, 3-6 membered heterocyclic or 5-10 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0008] In another aspect of the invention, the invention provides compounds of formula (IA), formula (IB) or formula (IC), their optical isomers or their pharmacologically acceptable salts. , , , in, m and n are independently selected from 0, 1 and 2, respectively; T is selected from N and CH; R1 is selected from NH2, 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- and C 1-6 Alkyl-NH(C=O)NH-C 1-6 alkyl-, 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 1-6Alkyl-, C 1-6 Alkyl-NH(C=O)NH- or C 1-6 Alkyl-NH(C=O)NH-C 1-6 Alkyl groups are optionally substituted with one, two, or three Rs; R2 is selected from H, OH, CN, NH2, and C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R3 is selected from H and C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R4 is selected from H and C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R a R b R c Each of the following is independently selected from H, F, Cl, Br, I, OH, CN, NH2, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, C 6-10 Aryl-C 1-3 Alkyl-, 5- to 10-membered heteroaryl-C 1-3 alkyl- and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, C 6-10 Aryl-C 1-3 Alkyl-, 5- to 10-membered heteroaryl-C 1-3 Alkyl or 5- to 10-membered heteroaryl groups may be substituted with 1, 2 or 3 Rs; R is independently selected from H, F, Cl, Br, I, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclic group may be optionally substituted with 1, 2 or 3 R's; R' is independently selected from F, Cl, Br, I, OH, CN and NH2; L a L b L c Selected from S; The C 1-6Heteroalkyl, 3-6 membered heterocyclic or 5-10 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0009] In some embodiments of the present invention, the R mentioned above is independently selected from H, F, Cl, Br, I, OH, CN, NH2, C. 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 The cycloalkyl and 3- to 6-membered heterocyclic groups may be optionally substituted with 1, 2, or 3 R's, and the remaining variables are as defined in this invention.

[0010] In some embodiments of the present invention, the R mentioned above is independently selected from H, F, Cl, Br, I, OH, CN, NH2, Me, Et, , , , , , and The remaining variables are as defined in this invention.

[0011] In some embodiments of the present invention, R1 is selected from NH2 and C. 1-3 Alkyl, C 1-3 Alkyl-NH-, C 1-3 Alkyl-NH-C 1-3 Alkyl-, C 1-3 Alkyl-NH-C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-(C=O)NH-C 1-3 Alkyl-, C 1-3 Alkyl-NHC(=O)-, C 1-3 Alkyl-(C=O)NH-C 1-3 Alkyl-NH-, C 1-3 Alkyl-NH(C=O)-C 1-3 Alkyl-, NH2(C=O)NH-C 1-3 Alkyl-, NH2(C=N)NH-C 1-3 Alkyl-, C 1-3Alkyl-NH(C=O)NH- and C 1-3 Alkyl-NH(C=O)NH-C 1-3 alkyl-, the C 1-3 Alkyl, C 1-3 Alkyl-NH-, C 1-3 Alkyl-NH-C 1-3 Alkyl-, C 1-3 Alkyl-NH-C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-(C=O)NH-C 1-3 Alkyl-, C 1-3 Alkyl-NHC(=O)-, C 1-3 Alkyl-NH(C=O)-C 1-3 Alkyl-, NH2(C=O)NH-C 1-3 Alkyl-, NH2(C=N)NH-C 1-3 Alkyl-, C 1-3 Alkyl-NH(C=O)NH- or C 1-3 Alkyl-NH(C=O)NH-C 1-3 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs, and other variables are as defined in this invention.

[0012] In some embodiments of the present invention, R1 is selected from NH2, Me, Et, , , , , , , , , and The Me, Et, , , , , , , , , or The variable can be replaced by 1, 2 or 3 Rs, and the remaining variables are as defined in this invention.

[0013] In some embodiments of the present invention, R1 is selected from NH2, Me, Et, , , , , , , , , , , , , , , , , , , , and The remaining variables are as defined in this invention.

[0014] In some embodiments of the present invention, R2 is selected from H, OH, CN, NH2, Me and Et, and the remaining variables are as defined in the present invention.

[0015] In some embodiments of the present invention, R3 is selected from H, Me, and Et, and the remaining variables are as defined in the present invention.

[0016] In some embodiments of the present invention, R4 is selected from H, Me, and Et, and the remaining variables are as defined in the present invention.

[0017] In some embodiments of the present invention, the above-mentioned R a R b R c Each of the following is independently selected from H, F, Cl, Br, I, OH, CN, NH2, and C. 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, phenyl-C 1-3 alkyl-, pyrazol-C 1-3 Alkyl-, imidazolyl-C 1-3 alkyl-, thiazolyl-C 1-3 alkyl-, thiophene-C 1-3 Alkyl, pyrimidinyl-C 1-3 Alkyl, pyrazolyl, imidazolyl, thiazolyl, thiophene, and pyrimidinyl groups, wherein C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, phenyl-C 1-3 alkyl-, pyrazol-C 1-3 Alkyl-, imidazolyl-C 1-3 alkyl-, thiazolyl-C 1-3 alkyl-, thiophene-C 1-3 alkyl-, pyrimidinyl-C 1-3 Alkyl, pyrazolyl, imidazolyl, thiazolyl, thiophene, or pyrimidinyl groups are optionally substituted with 1, 2, or 3 R groups, and the remaining variables are as defined in this invention.

[0018] In some embodiments of the present invention, the above-mentioned R a R b R cEach of the following is independently selected from H, F, Cl, Br, I, OH, CN, NH2, Me, Et, , , , and The Me, Et, , , , or The variable can be replaced by 1, 2 or 3 Rs, and the remaining variables are as defined in this invention.

[0019] In some embodiments of the present invention, the above-mentioned R a R b R c Each of the following is independently selected from H, F, Cl, Br, I, OH, CN, NH2, Me, Et, , , , , , , , , , , , , and The remaining variables are as defined in this invention.

[0020] In some embodiments of the present invention, the above-mentioned R a The variables are selected from H, F, Cl, Br, I, OH, CN, NH2, Me, and Et, and the remaining variables are as defined in this invention.

[0021] In some embodiments of the present invention, the above-mentioned R b Selected from H, F, Cl, Br, I, OH, CN, NH2, Me, Et and The remaining variables are as defined in this invention.

[0022] In some embodiments of the present invention, the above-mentioned R c Selected from H, F, Cl, Br, I, OH, CN, NH2, Me, Et, , , , , , , , , , , , , and The remaining variables are as defined in this invention.

[0023] In some embodiments of the present invention, L1 is selected from single bonds, CH2, and The remaining variables are as defined in this invention.

[0024] In some embodiments of the present invention, the above-mentioned L a and L b Selected from single bond, L c Selected from S, the remaining variables are as defined in this invention.

[0025] In another aspect, the present invention also provides compounds of the following formula, their optical isomers, or their pharmacologically acceptable salts, selected from...

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] .

[0039] In another aspect, the present invention also proposes the use of the aforementioned compounds, their optical isomers, or their pharmacologically acceptable salts in the preparation of medicaments for treating bacterial infections.

[0040] In some embodiments of the invention, the combination of the aforementioned compound, its optical isomer, or a pharmacologically acceptable salt thereof with other β-lactam antibiotics is further included.

[0041] In some embodiments of the present invention, the β-lactam antibiotics are selected from penicillins, cephalosporins, carbapenems, monocyclic β-lactam antibiotics, or combinations thereof.

[0042] In some embodiments of the present invention, the penicillin is selected from acid-resistant penicillin, enzyme-resistant penicillin, ampicillin, amoxicillin, piamoxicillin, carbenicillin, sulfobenzin, ticarcillin, furazolidone, aloxacillin, and piperacillin.

[0043] In some embodiments of the present invention, the cephalosporins are selected from cephalexin, cefradine, cefazolin, cefuroxime, cefamandole, cefaclor, cefotaxime, ceftazidime, cefotaxime, cefoperazone, cefazolin, cefepime, and cefpirome.

[0044] In some embodiments of the present invention, the carbapenems are selected from imipenem, meropenem, panipenem, and biapenem.

[0045] In some embodiments of the present invention, the monocyclic β-lactam is selected from aztreonam.

[0046] Definitions and Explanations

[0047] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0048] As used in this invention, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase "at least one," whether related to or unrelated to those specifically identified elements.

[0049] The term “pharmacologically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0050] The term "pharmacologically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a specific substituent, as discovered in this invention, with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmacologically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmacologically 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, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and also include salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0051] The pharmacologically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. 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 thereof.

[0052] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, ( R )-and( S - Enantiomers, diastereomers, ( D )-Isomer, ( L(Isomers, racemic mixtures thereof, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, are all within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of protection claimed by this invention.)

[0053] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer 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 involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0054] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), Iodine-125 ( 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention. "Optional" or "optionally" means that the events or conditions described below may occur but are not necessary, and the description includes both the occurrence of said events or conditions and the non-occurrence of said events or conditions.

[0055] When the group valence bond is marked with a dashed line " ", for example in " In the diagram, the dashed line indicates the connection point between the group and other parts of the molecule. When a single bond contains a dashed line... ", for example in " In the text, the dashed line represents a single bond or the absence of a bond, which also means "..." "Represents a single key" "or double bond" ".

[0056] The terms “substituted” or “replaced by” refer to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The terms “optionally substituted” or “optionally replaced by” mean that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on a chemically feasible basis.

[0057] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1, 2, or 3 R's, the group can optionally be substituted by 1, 2, or 3 R's, and R' has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0058] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When L1 represents a single bond, it means that the structure is actually .

[0059] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group by any carbon atom on the pyridine ring.

[0060] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is -CH2O-. In this case, -CH2O- can be connected to a phenyl group and a cyclopentyl group in the same direction as the reading order from left to right to form a structure. Alternatively, the phenyl and cyclopentyl groups can be connected in the reverse order of reading from left to right to form the phenyl group. The combination of the linking group, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0061] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “3-6 elemental ring” refers to a “ring” with 3-6 atoms arranged around it.

[0062] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g., hypo-C6 alkyl groups). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, , , , , , , , , , , , wait.

[0063] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 C 3-4 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g., alkyl groups). C 1-4 Examples of alkyl groups include, but are not limited to, CH3, , , , , wait.

[0064] Unless otherwise specified, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heterogroup. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 Heteroalkyl; in other embodiments, the heteroalkyl group is C10. 1-3Heteroalkyl. Heteroatoms or heteroatomic groups can be located in any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a conventional expression and refers to those alkyl groups that are attached to the rest of the molecule by an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and at most two heteroatoms can be consecutive, such as -CH2-NH-OCH3.

[0065] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and butoxy (including...). n -Butyloxy, isobutyloxy, s -butoxy and t -butoxy), pentoxy (including n -pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0066] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkoxy groups, etc. C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0067] Unless otherwise specified, the term "C" 1-6"Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylamino groups, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0068] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0069] Unless otherwise specified, the term "C" 1-6 "Alkylthio" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-6 Alkyl thio groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylthio groups, etc. C 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0070] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-3 Alkyl thio groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkylthio groups, etc. C 1-3Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0071] Unless otherwise specified, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be specific points or ranges of any two points, such as 3, 4, 5, or 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 (e.g., 3, 4, 5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., preferably cycloalkyl; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0072] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0073] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms (which can be specific points or intervals consisting of any two points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), of which 1 to 4 are heteroatoms; preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include aziridine, pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, or pyrrolyl. Polycyclic heterocyclic groups include heterocyclic groups of spirocyclic, fused, and bridged rings.

[0074] Unless otherwise specified, the term "3-6 membered heterocyclic group" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding this "3-6 membered heterocyclic group," the heteroatom can occupy the connection position between the heterocyclic group and the rest of the molecule. The 3-6 membered heterocyclic group includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic groups, etc. Examples of 3-6 membered heterocyclic groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0075] The term "aryl" refers to a 6- to 20-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably 6-membered, such as phenyl and naphthyl. The aryl group includes those fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include: , , , , , and .

[0076] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0077] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furanyl, thiophene, thiazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: , , , , , and .

[0078] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, and heterocyclic alkylthio.

[0079] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole groups (including...). N -pyrroleyl, 2-pyrroleyl and 3-pyrroleyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazoleyl (including... N -imidazolium, 2-imidazolium, 4-imidazolium and 5-imidazolium, etc.), oxazolium (including 2-oxazolium, 4-oxazolium and 5-oxazolium, etc.), triazolium (1 H -1,2,3-triazolyl, 2 H -1,2,3-triazolyl, 1 H -1,2,4-triazolyl and 4 H-1,2,4-triazolyl, tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0080] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It 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 rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also include any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 5-10-membered, 6-7-membered, 6-8-membered, 6-9-membered, and 6-10-membered rings, etc.

[0081] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0082] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0083] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0084] Compounds are named according to conventional naming principles in the art or using ChemDraw® software; commercially available compounds are named according to the supplier catalog. Detailed Implementation

[0085] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, experimental methods in the following embodiments are generally performed under conventional conditions for such reactions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise stated, liquid ratios are volume ratios.

[0086] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0087] The following abbreviations are used in this invention: 9-BBN represents 9-boronbicyclo(3,3,1)-nonane; Boc2O represents ditert-butyl dicarbonate; B2Pin2 represents pinacol diboronate; DCM represents dichloromethane; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DIEA represents N,N-diisopropylethylamine; DMP represents Dys-Martin reagent; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; HBF4PCy3 represents tricyclohexyltetrafluoroborate; LDA represents lithium diisopropylaminoacetate; NaClO2 represents sodium chlorite; NFSI represents N-fluorobis(benzenesulfonamide); NMM represents N-methylmorpholine; PhI(OAc)2 represents diethyl iodophenyl ester; Pd(OAc)2 represents palladium acetate; Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; THF represents tetrahydrofuran; Ti(OEt)4 represents ethyl titanate.

[0088] Example 1: Synthesis of Compound 1

[0089] Step 1: Preparation of Compound 1B

[0090] Compound 1A (20 g, 105 mmol) and DMAP (1.3 g, 10.5 mmol) were dissolved in DCM (200 mL). A solution of Boc₂O (28 g, 126 mmol) in DCM (20 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for about 1 hour, and TLC showed that the reaction was complete. The solution was evaporated to dryness under reduced pressure and separated by column chromatography (9 / 1 pentane / ethyl acetate) to give a pale yellow solid, compound 1B (28 g, 82%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.78 (dd, J = 8.9, 5.9 Hz, 1H), 7.47 (dd, J =9.2, 3.0 Hz, 1H), 7.19 (ddd, J = 8.9, 8.2, 3.0 Hz, 1H), 1.50 (s, 9H).

[0091] Step 2: Preparation of compound 1C

[0092] Under anhydrous and oxygen-free conditions, compound 1B (29.1 g, 100 mmol) was dissolved in anhydrous THF (250 mL). Under argon protection, LDA solution (52.5 mL, 2.5 M hexane solution) was added dropwise within the range of -60 °C to -70 °C (note: internal temperature), controlling the internal temperature not to exceed -60 °C. The reaction was carried out with stirring at low temperature for two hours until completion (LC-MS detection). After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride aqueous solution (250 mL) at 0 °C, and extracted with ethyl acetate. The organic phase was washed twice with saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtration, the solution was evaporated under reduced pressure and separated by column chromatography (9 / 1 pentane / dichloromethane) to give a white solid compound 1C (29 g, 100%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.87 (s, 1H), 7.72 (dd, J = 8.9, 6.0 Hz, 1H), 6.76 (dd, J = 9.8, 8.9 Hz, 1H), 1.55 (s, 9H). LC-MS m / z = 234.9[M+H-56] + .

[0093] Step 3: Preparation of Compound 1D

[0094] Compound 1C (6.8 g, 22.3 mmol) was dissolved in DMF (40 mL), and sodium methanethiol (3.1 g, 44.6 mmol) was added. The mixture was reacted overnight at 80 °C. Ethyl acetate (200 mL) was added, and the organic phase was washed twice with saturated sodium chloride aqueous solution. The mixture was evaporated to dryness under reduced pressure and separated by column chromatography (9 / 1 pentane / dichloromethane) to give a clear oily compound 1D (3.8 g, 54%). 1 H NMR (400 MHz, DMSO-) d 6) δ 10.31 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 6.79 (d, J =8.5 Hz, 1H), 2.43 (s, 3H), 1.55 (s, 9H). LC-MS m / z = 263.0 [M+H-56] + .

[0095] Step 4: Preparation of compound 1E

[0096] Compound 1D (8.0 g, 25.8 mmol), potassium carbonate (5.3 g, 38.7 mmol), and acetone (30 mL) were mixed. Iodomethane (7.3 g, 51.6 mmol) was added dropwise over approximately 20 minutes with stirring at room temperature (8 °C). The mixture was stirred overnight at room temperature. The inorganic salts were filtered through diatomaceous earth, concentrated under reduced pressure, and separated by column chromatography (9 / 1 pentane / dichloromethane) to give a white crystalline compound 1E (8.2 g, 98%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.66 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 3.80 (s, 3H), 2.48 (s, 3H), 1.55 (s, 9H).

[0097] Step 5: Preparation of compound 1F

[0098] Compound 1E (4.3 g, 12.8 mmol), potassium ethylenetrifluoroborate (3.4 g, 25.5 mmol), Pd(dppf)Cl2 (1.1 g, 1.27 mmol), anhydrous isopropanol (30 mL), and anhydrous triethylamine (3.2 g, 31.9 mmol) were added sequentially to a two-necked flask. The mixture was then subjected to freeze-drying under dry ice / ethanol bath for 10 minutes to displace argon gas. The temperature was raised to between 85 °C and 90 °C (external temperature), and the mixture was stirred for 16 hours. The solution was initially orange-red, turning dark after about half an hour of reaction. After the reaction was complete, the mixture was filtered through diatomaceous earth, concentrated directly, and separated by column chromatography (95 / 5 to 90 / 10 pentane / ethyl acetate) to give a pale yellow oily compound 1F (2.3 g, 64%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 6.83 (dd, J = 17.7, 11.1 Hz, 1H), 5.87 (dd, J = 17.7, 1.3 Hz, 1H), 5.37 (dd, J = 11.1, 1.3 Hz, 1H), 3.70 (s, 3H), 2.48 (s, 3H), 1.55 (s, 9H). LC-MS m / z = 225.0 [M+H-56] + .

[0099] Step 6: Preparation of Compound 1G

[0100] Under anhydrous and oxygen-free conditions, compound 1F (2.3 g, 8.21 mmol) was dissolved in anhydrous THF (10 mL). Under argon protection, 9-BBN (50 mL, 25 mmol, 0.5 M THF solution) was added dropwise within a temperature range of 0 °C (note: internal temperature), controlling the internal temperature to not exceed 0 °C. After the addition was complete, the mixture was slowly brought back to room temperature, and the reaction was stirred for approximately 16 hours until completion. The reaction was quenched by adding hydrogen peroxide solution (50 mL) and 30% sodium hydroxide solution (55 mL) at 0 °C. The organic phase was extracted and collected, washed twice with saturated sodium bisulfite aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography (4 / 1 pentane / ethyl acetate) to give a white solid compound 1G (1.6 g, 69%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.30 (d, J = 8.2 Hz, 1H), 7.09 (d, J =8.2 Hz, 1H), 4.03 (s, OH), 3.73 (s, 3H), 3.60 (td, J = 7.0, 5.2 Hz, 2H), 2.71(t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.54 (s, 9H). LC-MS m / z = 321.2 [M+Na] + .

[0101] Step 7: Preparation of compound 1H

[0102] Compound 1G (1.5 g, 5.0 mmol) was dissolved in DCM (10 mL), and DMP (2.6 g, 6.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The turbid solution was filtered, and the mother liquor was washed with dichloromethane and saturated sodium bicarbonate aqueous solution to approximately pH 10. The organic phase was washed once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure, and separated by column chromatography (70 / 30 pentane / ethyl acetate) to give a colorless oily compound 1H (1.0 g, 48%). LC-MS m / z = 241.0 [M+H-56] + .

[0103] Step 8: Preparation of Compound 1I

[0104] Compound 1H (2 g, 6.76 mmol) and R-tert-butylsulfinamide (1 g, 8.25 mmol) were dissolved in anhydrous THF (10 mL). Ethyl titanate (2.5 g, 65% purity, 10.1 mmol) was added at room temperature, and the mixture was stirred for 15 minutes. The solution was added dropwise to a saturated sodium chloride aqueous solution, precipitating a large amount of pale yellow solid. After filtration through diatomaceous earth and washing with ethyl acetate, the organic phase was extracted and collected. The aqueous phase was washed twice with ethyl acetate. The combined organic phases were washed twice with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated under reduced pressure, and separated by column chromatography (4 / 1 dichloromethane / ethyl acetate) to give a pale yellow oily compound 1I (310 mg, 40%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.98 (t, J = 4.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 3.86 (dd, J = 4.4, 1.2 Hz, 2H), 3.71 (s, 3H), 2.45 (s, 3H), 1.54 (s, 9H), 1.08 (s, 9H). LC-MS m / z = 344.2 [M+H-56] + .

[0105] Step 9: Preparation of Compound 1J

[0106] Tricyclohexyltetrafluoroborate (5.6 mg, 0.015 mmol), copper sulfate (0.5 mL, 0.015 mmol, 30 mM aqueous solution), benzylamine (6.8 mg, 0.015 mmol), and toluene (0.36 mL) were added to a vial and stirred for 10 minutes. Substrate 1I (450 mg, 1.27 mmol) and pinacol diboryl ester (646 mg, 2.54 mmol) were dissolved in toluene (0.8 mL) and added to the above system in one batch. The mixture was stirred vigorously for 4 hours. The solution was filtered through a short-path silica gel column, evaporated to dryness under reduced pressure, and separated by reverse-phase column chromatography to give a yellow oily compound 1J (230 mg, 53%). LC-MS m / z = 528.2 [M+1] + .

[0107] Step 10: Preparation of compound 1K

[0108] Compound 1J (400 mg, 0.76 mmol) was added to dioxane (2 mL), followed by 1 M dioxane hydrochloride solution (0.9 mL, 0.90 mmol). The mixture was stirred at room temperature for 15 minutes. The solution was evaporated to dryness under reduced pressure to give compound 1K, which was used directly in the next step. LC-MS m / z = 342.2 [M+H-82] + .

[0109] Step 11: Preparation of compound 1M

[0110] Compound 1K (240 mg, 0.61 mmol), HATU (290 mg, 0.76 mmol), and NMM (100 mg, 0.91 mmol) were dissolved in DCM (3 mL) and reacted at room temperature for 90 min. Then, compound 1L (240 mg, 0.61 mmol) was added, and the reaction was continued at room temperature for 30 min. The mixture was evaporated to dryness under reduced pressure and separated by reverse-phase column chromatography (5% to 100% water / acetonitrile) to give a yellow oily compound 1M (100 mg, 30%). LC-MS m / z = 806.4 [M+1] + .

[0111] Step 12: Preparation of Compound 1

[0112] Compound 1M (40 mg, 0.05 mmol) was dissolved in DCM (1.5 mL) under nitrogen protection, and boron trichloride (0.35 mL, 0.35 mmol, 1 M dichloromethane solution) was added dropwise at -78 °C. The mixture was stirred at room temperature for 30 minutes. The solution was quenched with deionized water (1 mL), and the aqueous phase was washed with DCM (1 mL). After separating the aqueous phase, compound 1 (7 mg, 10%) was prepared by high performance liquid chromatography. 1 H NMR (400 MHz, D2O) δ 7.14 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 8.1 Hz,1H), 3.34 – 3.16 (m, 4H), 3.08 (d, J = 3.5 Hz, 1H), 2.83 – 2.62 (m, 3H), 2.31(s, 3H), 2.21 (dd, J = 13.9, 4.3 Hz, 1H), 1.99 (dd, J = 13.8, 7.8 Hz, 1H),1.73 (ddt, J= 13.2, 6.7, 3.1 Hz, 2H), 1.36 – 1.23 (m, 2H), 1.18 – 1.05 (m,1H), 0.95 (dd, J = 12.5, 3.8 Hz, 1H), 0.82 – 0.71 (m, 1H), 0.60 (dd, J =12.8, 3.2 Hz, 1H), 0.27 (dd, J = 13.3, 3.3 Hz, 1H). LC-MS m / z = 436.2 [M+1] + .

[0113] Example 2: Synthesis of Compound 2

[0114] Step 1: Preparation of compound 2A

[0115] Compound 1J (230 mg, 0.5 mmol) was dissolved in anhydrous THF (3 mL), and (1S,2S,3R,5S)-(+)-2,3-pinenediol (128 mg, 0.75 mmol) was added. The mixture was heated to 60 °C and stirred for 2 hours. After concentration, the solution was diluted with ethyl acetate, water was added, and the organic phase was extracted and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure, and separated by reversed-phase column chromatography to give an oily compound 2A (300 mg, 100%). 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 4.29 – 4.19 (m, 1H), 3.82 (s, 3H), 3.38 (q, J =8.4, 7.6 Hz, 2H), 3.09 (d, J = 6.0 Hz, 1H), 2.99 (dd, J = 13.5, 7.4 Hz, 1H), 2.44 (s, 3H), 2.27 (ddd, J = 13.4, 8.9, 2.4 Hz, 1H), 2.17 – 2.05 (m, 1H),1.97 (t, JLC-MS m / z = 580.4[M+1] + .

[0116] Step 2: Preparation of compound 2B

[0117] Compound 2B was prepared according to the synthetic protocol of Compound 1K in Example 1. Compound 2B was obtained from Compound 2A (150 mg, 0.28 mmol), and the crude product was used directly in the next step. LC-MS m / z = 476.2 [M+1] + .

[0118] Step 3: Preparation of Compound 2D

[0119] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 2D (12 mg, 82%) was obtained as a pale yellow powder from compound 2B (30 mg, 0.063 mmol) and compound 2C (23 mg, 0.07 mmol). LC-MS m / z = 786.8 [M+H-100] + .

[0120] Step 4: Preparation of Compound 2

[0121] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 2 (0.47 mg, 6.7%) was obtained from compound 2D (12 mg, 15 μmol). 1 H NMR (400 MHz, D2O) δ 7.26 (d, J = 8.1 Hz, 1H), 6.97 (d, J =8.1 Hz, 1H), 3.55 – 3.42 (m, 4H), 3.20 (s, 1H), 2.97 (s, 6H), 2.90 – 2.80 (m,3H), 2.45 (s, 3H), 2.40 – 2.30 (m, 1H), 2.18 – 2.07 (m, 1H), 1.87 (d, J =12.0 Hz, 2H), 1.44 (s, 2H), 1.29 – 1.05 (m, 2H), 0.93 (s, 1H), 0.78 (q, J=12.4 Hz, 1H), 0.37 (q, J = 13.2 Hz, 1H). LC-MS m / z = 464.2 [M+H] + .

[0122] Example 3: Synthesis of Compound 3

[0123] Step 1: Preparation of compound 3B

[0124] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 3B (12 mg, 22%) was obtained as a pale yellow powder from compound 2B (30 mg, 0.063 mmol) and compound 3A (23 mg, 0.07 mmol). LC-MS m / z = 772.2 [M+H-100] + .

[0125] Step 2: Preparation of Compound 3

[0126] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 3 (1.3 mg, 21%) was obtained from compound 3B (12 mg, 14 μmol). 1 H NMR (400 MHz, D2O) δ 7.27 (d, J = 8.2 Hz, 1H), 6.97 (d, J =8.2 Hz, 1H), 3.38 (t, J = 3.2 Hz, 4H), 3.20 (s, 1H), 2.89-2.84 (m, 3H), 2.78(s, 3H), 2.44 (s, 3H), 2.39 – 2.30 (m, 1H), 2.12 (dd, J = 13.7, 7.7 Hz, 1H), 1.86 (d, J = 12.1 Hz, 2H), 1.42 (d, J = 12.9 Hz, 2H), 1.28 – 1.16 (m, 1H), 1.10 (tt, J = 13.8, 7.0 Hz, 1H), 0.91 (d, J = 13.3 Hz, 1H), 0.76 (q, J = 12.7Hz, 1H), 0.38 (q, J= 13.0 Hz, 1H). LC-MS m / z = 450.2 [M+1] + .

[0127] Example 4: Synthesis of Compound 4

[0128] Step 1: Preparation of compound 4B

[0129] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 4B (12 mg, 21%) was obtained as a pale yellow powder from compound 2B (30 mg, 0.063 mmol) and compound 4A (23 mg, 0.07 mmol). LC-MS m / z = 772.8 [M+H-100] + .

[0130] Step 2: Preparation of Compound 4

[0131] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 4 (4.3 mg, 68%) was obtained from compound 4B (12 mg, 14 μmol). 1 H NMR (400 MHz, D2O) δ 7.26 (dd, J = 8.1, 2.8 Hz, 1H), 6.94(dd, J = 8.2, 2.8 Hz, 1H), 3.20 (s, 1H), 3.08 (dd, J = 9.4, 7.4 Hz, 4H), 2.86(d, J = 3.5 Hz, 2H), 2.74 (d, J = 10.3 Hz, 1H), 2.43 (d, J = 2.8 Hz, 3H), 2.32 (d, J = 14.1 Hz, 1H), 2.16 – 1.95 (m, 3H), 1.82 (d, J = 12.2 Hz, 2H), 1.39 (d, J = 12.4 Hz, 2H), 1.17 (q, J = 12.5 Hz, 1H), 1.04 (q, J = 12.6 Hz, 1H), 0.90 (d, J = 13.4 Hz, 1H), 0.71 (q, J= 12.9 Hz, 1H), 0.33 (q, J = 13.2Hz, 1H). LC-MS m / z = 450.2 [M+1] + .

[0132] Example 5: Synthesis of Compound 5

[0133] Step 1: Preparation of compound 5B

[0134] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 5B (20 mg, 41%) was obtained as a pale yellow oil from compound 2B (30 mg, 0.063 mmol) and compound 5A (65 mg, 0.21 mmol). LC-MS m / z = 758.4 [M+H] + .

[0135] Step 2: Preparation of Compound 5

[0136] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 5 (5.7 mg, 50%) was obtained from compound 5B (20 mg, 0.026 mmol). 1 H NMR (400 MHz, D2O) δ 7.10 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.31 – 3.15 (m, 2H), 3.09 (d, J = 3.6 Hz, 1H), 3.01 (m, 2H), 2.92 (t, J = 8.0 Hz, 2H), 2.82 – 2.65 (m, 3H), 2.51 (m, 1H), 2.37 – 2.22 (m,4H), 1.97 (m, 3H), 1.62 – 1.37 (m, 2H), 1.06-1.00 (m, 2H), 0.66 – 0.48 (m,1H). LC-MS m / z = 436.2 [M+1] + .

[0137] Example 6: Synthesis of Compound 6

[0138] Step 1: Preparation of compound 6B

[0139] Compound 6A (20 g, 86.96 mmol) was dissolved in DMF (200 mL), and PhI(OAc)2 (28 g, 87 mmol), I2 (22 g, 87 mmol), and Pd(OAc)2 (970 mg, 4.4 mmol) were added. The reaction was carried out at 100 °C for 16 hours. The mixture was concentrated under reduced pressure and separated by column chromatography (7 / 3 pentane / ethyl acetate) to give a black oily compound 6B (24 g, 75%). 1 H NMR (400MHz, DMSO- d 6) δ 13.79 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz,1H), 3.80 (s, 3H). LC-MS m / z = 340.9 [M+H-18] + .

[0140] Step 2: Preparation of compound 6C

[0141] Compound 6C (14 g, 87%) was prepared according to the synthetic protocol of Compound 1B in Example 1. From Compound 6B (13.8 g, 38.8 mmol), a colorless oily compound 6C was obtained. 1 H NMR (400 MHz, DMSO- d 6) δ 7.56 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 1.57 (s, 9H). LC-MS m / z = 340.9 [M+H-72] + .

[0142] Step 3: Preparation of compound 6D

[0143] Compound 6C (6 g, 14.5 mmol) was dissolved in toluene (50 mL), and KSAc (6 g, 52 mmol), 1,10-o-phenanthroline (290 mg, 1.6 mmol), and CuI (160 mg, 0.8 mmol) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. The mixture was concentrated under reduced pressure and separated by column chromatography (9 / 1 pentane / ethyl acetate) to give a black oily compound 6D (3.7 g, 54%). 1 H NMR (400 MHz, DMSO-) d 6) δ 7.82 (d, J= 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 3.83(s, 3H), 2.51 (q, J = 1.9 Hz, 3H), 1.52 (s, 9H). LC-MS m / z = 244.9 [M+H-116] + .

[0144] Step 4: Preparation of compound 6E

[0145] Compound 6D (3.2 g, 8.9 mmol) was dissolved in THF (10 mL), and 3M NaOH aqueous solution (10 mL, 26.7 mmol) was added. The reaction was carried out at room temperature for 2 hours. Then EtI (2.1 mL, 26.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The inorganic salt was filtered through diatomaceous earth, concentrated under reduced pressure, and separated by column chromatography (9 / 1 pentane / ethyl acetate) to give a colorless liquid compound 6E (2.7 g, 80%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.66 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5Hz, 1H), 3.80 (s, 3H), 2.97 (d, J = 7.3 Hz, 2H), 1.55 (s, 9H), 1.19 (t, J =7.3 Hz, 3H). LC-MS m / z = 291.0 [M+H-56] + .

[0146] Step 5: Preparation of compound 6F

[0147] Compound 1F was prepared according to the synthetic protocol of Example 1. A pale yellow oily compound 6F (1.9 g, 70%) was obtained from compound 6E (2.7 g, 1.0 mmol). 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 8.3, 0.5 Hz, 1H), 6.84 (dd, J = 17.7, 11.2 Hz, 1H), 5.89 (dd, J= 17.8, 1.3 Hz, 1H), 5.39 (dd, J = 11.1, 1.2 Hz, 1H), 3.70 (s, 3H), 2.96 (d, J = 7.3 Hz, 2H), 1.54 (s, 9H), 1.20 (t, J = 7.3 Hz, 3H). LC-MS m / z = 239.0 [M+H-56] + .

[0148] Step 6: Preparation of compound 6G

[0149] Compound 1G was prepared according to the synthetic protocol of Example 1. A colorless oily compound 6G (700 mg, 70%) was obtained from compound 6F (1 g, 3.4 mmol). 1 H NMR (400 MHz, DMSO- d 6) δ 7.30 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 4.72 (t, J = 5.3 Hz, 1H), 3.73 (s, 3H), 3.61 (d, J = 5.3 Hz, 2H), 2.90 (d, J = 7.3 Hz, 2H), 2.72 (s, 2H), 1.54 (s, 9H), 1.17 (t, J = 7.3 Hz, 3H). LC-MS m / z = 335.2 [M+Na] + .

[0150] Step 7: Preparation of compound 6H

[0151] Compound 1H was prepared according to the synthetic protocol of Example 1. A pale yellow oily compound 6H (75 mg, 60%) was obtained from compound 6G (120 mg, 0.38 mmol). 1 H NMR (400 MHz, DMSO- d 6) δ 9.66 (t, J = 1.6 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 3.77 (d, J= 1.6 Hz,2H), 3.65 (s, 3H), 2.95 (q, J = 7.3 Hz, 2H), 1.54 (s, 9H), 1.18 (d, J = 7.6Hz, 3H). LC-MS m / z = 333.2 [M+Na] + .

[0152] Step 8: Preparation of compound 6I

[0153] Compound 1I was prepared according to the synthetic protocol of Example 1. A pale yellow oil, 6I (20 mg, 20%), was obtained from compound 6H (80 mg, 0.26 mmol). LC-MS m / z = 358.2 [M+H-56] + .

[0154] Step 9: Preparation of compound 6J

[0155] Compound 1J was prepared according to the synthetic protocol of Example 1. Compound 6J was obtained from compound 6I (80 mg, 0.193 mmol), and the crude product was used directly in the next step. LC-MS m / z = 542.3 [M+H] + .

[0156] Step 10: Preparation of compound 6K

[0157] Compound 6K was prepared according to the synthetic protocol of Example 1. Compound 6K was obtained from compound 6J (15 mg, 0.03 mmol), and the crude product was used directly in the next step. LC-MS m / z = 356.1 [M+H-82] + .

[0158] Step 11: Preparation of compound 6L

[0159] Compound 1M was prepared according to the synthetic protocol of Example 1. A yellow oily compound 6I (10 mg, 45%) was obtained from compound 6K (8 mg, 0.024 mmol) and compound 1L (12 mg, 0.03 mmol). LC-MS m / z = 820.4 [M+H] + .

[0160] Step 12: Preparation of Compound 6

[0161] Compound 6 was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 6 (0.6 mg, 10%) was obtained from L of Compound 6 (10 mg, 0.012 mmol). 1H NMR (400 MHz, D2O) δ 7.06 (d, J = 8.0 Hz, 1H), 6.90 (d, J =8.1 Hz, 1H), 3.23 (h, J = 6.6 Hz, 4H), 3.04 (s, 1H), 2.90 – 2.68 (m, 5H), 2.20 (dd, J = 13.7, 4.5 Hz, 1H), 1.98 (dd, J = 13.7, 7.7 Hz, 1H), 1.75 (s,2H), 1.32 (d, J = 12.8 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H), 1.03 – 0.93 (m,1H), 0.80 (d, J = 13.7 Hz, 1H), 0.63 (d, J = 12.5 Hz, 1H), 0.35 (d, J = 11.7Hz, 1H). LC-MS m / z = 450.2 [M+H] + .

[0162] Example 7: Synthesis of Compound 7

[0163] Step 1: Preparation of compound 7B

[0164] Compound 1B was prepared according to the synthetic protocol of Example 1. Compound 7B (82 g, 98%) was obtained as a pale yellow solid from compound 7A (60 g, 238 mmol). 1 H NMR (400 MHz, CDCl3-d) d 7.55 (m, 2H), 7.01 (d, J =8.0 Hz, 1H), 1.58 (s, 9H).

[0165] Step 2: Preparation of compound 7C

[0166] Under anhydrous and oxygen-free conditions, compound 7B (82 g, 232 mmol) was dissolved in anhydrous THF (500 mL). Under argon protection, a solution of n-butyllithium (98 mL, 245 mmol, 2.5 M pentane) was added dropwise within a temperature range of -70 °C (note: internal temperature), controlling the internal temperature to not exceed -60 °C. After the addition was complete, the mixture was slowly brought back to room temperature, and the reaction was stirred for 2 hours until completion. After concentrating the solution, ethyl acetate (400 mL) was added, and the reaction was quenched by adding saturated ammonium chloride aqueous solution (500 mL) dropwise at 0 °C. The organic phase was extracted and collected, washed twice with saturated sodium chloride aqueous solution, and dried over sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and separated by column chromatography (90 / 10 pentane / dichloromethane) to give a white solid, compound 7C (55 g, 87%). 1 H NMR (400 MHz, CDCl3) d 11.76(s, 1H), 7.72 (m, 2H), 6.76 (t, J = 7.9 Hz, 1H), 1.62 (s, 9H). LC-MS m / z =219.0 [M+H] + .

[0167] Step 3: Preparation of compound 7D

[0168] Compound 1E was prepared according to the synthetic protocol of Example 1. Compound 7D (55 g, 95%) was obtained as a white crystalline form from compound 7C (55 g, 201 mmol). 1 H NMR (400 MHz, DMSO-d6) d 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.68 (dd, J = 7.7, 1.6 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 3.88 (s, 3H), 1.61 (s, 9H). LC-MS m / z = 231.0 [M+H] + .

[0169] Step 4: Preparation of compound 7E

[0170] Compound 1F was prepared according to the synthetic protocol of Example 1. A pale yellow oily compound 7E (15 g, 90%) was obtained from compound 7D (20 g, 69.6 mmol). 1 H NMR (400 MHz, DMSO- d 6) d7.78 (dd, J = 7.8, 1.7 Hz, 1H), 7.53 (dd, J = 7.6, 1.7 Hz, 1H), 7.20 (td, J = 7.7, 0.6 Hz, 1H), 6.96 (dd, J = 17.8, 11.2 Hz, 1H), 5.90 (dd, J = 17.8, 1.3 Hz, 1H), 5.41 (dd, J =11.1, 1.3 Hz, 1H), 3.74 (s, 3H), 1.55 (s, 9H). LC-MS m / z = 179.1 [M+H] + .

[0171] Step 5: Preparation of compound 7F

[0172] p-Benzoquinone (2.65 g, 24.5 mmol), Pd(MeCN)₂Cl₂ (164 mg, 0.63 mmol), and tert-butanol (100 mL) were mixed and heated to 85 °C (outer temperature) with stirring. Under anaerobic conditions, compound 7E (5.0 g, 21.3 mmol) and water (0.4 mL, 22.2 mmol) were added, and the reaction was carried out for half an hour. The reaction was confirmed to be complete by TLC. After cooling, the mixture was concentrated under reduced pressure and separated by column chromatography (90 / 10 pentane / ethyl acetate) to give a pale yellow oily compound 7F (2.9 g, 70%). 1 H NMR (400 MHz, DMSO- d 6) d 9.68 (t, J = 1.6 Hz, 1H), 7.57 (dd, J = 7.7, 1.8 Hz, 1H), 7.44 (dd, J =7.5, 1.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 3.80 (d, J = 1.6 Hz, 2H), 3.68(s, 3H), 1.55 (s, 9H).

[0173] Step 6: Preparation of compound 7G

[0174] Compound 7F (4.9 g, 19.4 mmol) and NaH₂PO₄ (2.8 g, 23.3 mmol) were added to tert-butanol / water (20 mL / 10 mL) under ice bath conditions, followed by the addition of 2-methyl-2-butene (6.2 mL, 58.2 mmol), and then NaClO₂ (2.2 g, 24.3 mmol) in portions. The mixture was brought to room temperature and stirred for 2 hours. The pH was adjusted to 2–3 with 2M hydrochloric acid, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give compound 7G (5.3 g, 100%), a pale yellow oil. 1 H NMR (400 MHz, DMSO-) d 6) d 12.37 (s, 1H), 7.53 (dd, J = 7.7, 1.8 Hz, 1H), 7.43 (dd, J = 7.5, 1.9 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 3.71 (s, 3H), 1.55 (s, 9H).LC-MS m / z = 211.1 [M+H] + .

[0175] Step 7: Preparation of compound 7H

[0176] Compound 7G (5.3 g, 19.4 mmol) was dissolved in acetone (60 mL), and K₂CO₃ (6.2 g, 58.2 mmol) was added. MeI (6.4 g, 58.2 mmol) was added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the organic phases were combined. The mixture was concentrated under reduced pressure and separated by column chromatography (90 / 10 pentane / ethyl acetate) to give a pale yellow oily compound 7H (3.2 g, 59%). 1 H NMR (400 MHz, DMSO- d 6) d 7.55 (dd, J = 7.7, 1.8 Hz, 1H), 7.45 (dd, J = 7.5, 1.8 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 3.71 (s, 2H), 3.70(s, 3H), 3.62 (s, 3H), 1.54 (s, 9H). LC-MS m / z = 225.1 [M+H] + .

[0177] Step 8: Preparation of compound 7I

[0178] Compound 7H (24.5 g, 87.4 mmol) was dissolved in formic acid (100 mL), stirred at room temperature for 3 hours, and concentrated under reduced pressure to give a white solid compound 7I (19.5 g, 100%). 1 H NMR (400 MHz, DMSO- d 6) d 12.98 (m, 1H), 7.63 (dd, J = 7.8, 1.8 Hz, 1H), 7.45 (dd, J = 7.5, 1.8 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 3.70 (s, 5H), 3.62 (s, 3H).

[0179] Step 9: Preparation of compound 7J

[0180] Compound 7I (10.0 g, 44.6 mmol), diethyl iodophenyl ester (14.4 g, 44.6 mmol), iodine (11.3 g, 44.6 mmol), and palladium acetate (500 mg, 2.23 mmol) were placed in a 250 mL single-necked flask, and DMF (90 mL) was added. o The mixture was stirred at C for 20 hours. After the solvent was evaporated under reduced pressure, it was diluted with ethyl acetate, and a saturated aqueous solution of sodium thiosulfate was added and stirred until the solution turned orange-yellow. The organic phase was separated, the pH was adjusted to approximately 3, and the mixture was washed once with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain the crude compound. The crude compound was dissolved in tert-butanol (100 mL), and Boc₂O (50 mL, 200 mmol) and DMAP (530 mg, 4.4 mmol) were added. The mixture was stirred at 80 °C for 2 hours. The solution was concentrated under reduced pressure and separated by column chromatography (90 / 10 pentane / ethyl acetate) to give a pale yellow oily compound 7J (6.5 g, 36%). 1 H NMR (400 MHz, DMSO- d 6) d 7.59 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 3.69 (s, 5H), 3.63 (s,3H), 1.57 (s, 9H). LC-MS m / z = 351.0 [M+H-56] + .

[0181] Step 10: Preparation of compound 7K

[0182] Compound 7J (4.9 g, 12.1 mmol) was dissolved in THF (36 mL), and lithium hydroxide (2 N aqueous solution, 12.1 mL, 24.2 mmol) was added. The mixture was heated to 40 °C and stirred for 1.5 h until the reaction was complete. After cooling to room temperature, the pH was adjusted to 2 with 1.0 M hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate and washed with saturated sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure to give compound 7K (4.6 g, 97%). 1 H NMR (400 MHz, DMSO- d 6) d 12.49 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 3.70 (s, 3H), 3.57 (s, 2H), 1.57 (s, 9H). LC-MS m / z = 410.0 [M+NH4] + .

[0183] Step 11: Preparation of compound 7L

[0184] Compound 7K (4.6 g, 12 mmol) was dissolved in DCM (60 mL), and N,N-diisopropylethylamine (4.0 mL, 24 mmol) was added. Isobutyl chloroformate (2.36 mL, 18.2 mmol) was added dropwise with stirring at 0°C. The reaction was continued to be stirred at room temperature for 1 hour until complete. The mixture was washed once with water, dried over a vacuum, and concentrated to give the crude compound (5.77 g). 1 H NMR (400 MHz, CDCl3) d 7.52 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 3.89(d, J = 6.6 Hz, 2H), 3.82 (s, 3H), 3.63 (s, 2H), 1.91 (dt, J = 13.4, 6.7 Hz,1H), 1.63 (s, 9H), 0.90 (d, J= 6.7 Hz, 6H). The crude compound (5.77 g) was dissolved in tetrahydrofuran (30 mL), and LiBH4 (1.3 g, 60 mmol) was added. The mixture was stirred at 40 °C for 2 hours, and then LiBH4 (1.3 g, 60 mmol) was added again, and the mixture was stirred for another 4 hours until the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was carefully quenched with water at 0 °C. The filter cake was then quenched in methanol. The filtrate was extracted with ethyl acetate and 15% NaOH aqueous solution. The organic phase was collected, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and separated by column chromatography (70 / 30 pentane / ethyl acetate) to give 7 L (4.8 g, 90%) of an oily compound. 1 H NMR (400 MHz, DMSO- d 6) d 7.52 (d, J = 8.1 Hz, 1H), 7.10 (d, J =8.1 Hz, 1H), 4.73 (t, J = 5.3 Hz, 1H), 3.73 (s, 3H), 3.60 (td, J = 6.9, 5.2Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 1.56 (s, 9H). LC-MS m / z = 305.0 [M+H-74] + .

[0185] Step 12: Preparation of compound 7M

[0186] Compound 1H was prepared according to the synthetic protocol of Example 1. A colorless oily compound 7M (3.1 g, 65%) was obtained from compound 7L (4.8 g, 12.8 mmol). 1 H NMR (400 MHz, DMSO- d 6) d 9.66 (s, 1H), 7.61 (d, J =8.0 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 3.78 (d, J = 1.5 Hz, 2H), 3.65 (s,3H), 1.56 (s, 9H). LC-MS m / z = 303.0 [M+H-74] + .

[0187] Step 13: Preparation of compound 7N

[0188] Compound 1I was prepared according to the synthetic protocol of Example 1. Oily compound 7N (2.8 g, 72%) was obtained from compound 7M (3.1 g, 8.18 mmol). 1 H NMR (400 MHz, DMSO- d 6) d 7.99 (t, J = 4.2 Hz, 1H), 7.60(d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 3.87 (d, J = 4.3 Hz, 2H), 3.71(s, 3H), 1.56 (s, 9H), 1.07 (s, 9H). LC-MS m / z = 424.2 [M+H-56] + .

[0189] Step 14: Preparation of compound 7O

[0190] Compound 1J was prepared according to the synthetic protocol of Example 1. Compound 7O (4.1 g, 100%) was obtained from compound 7N (3.3 g, 6.78 mmol), and the crude product was used directly in the next step. LC-MS m / z = 608.2 [M+H] + .

[0191] Step 15: Preparation of compound 7P

[0192] Compound 2P was prepared according to the synthetic protocol of Compound 2A in Example 2. Compound 7P (1.9 g, 43%) was obtained from Compound 7O (4.1 g, 6.78 mmol). LC-MS m / z = 580.4 [M+1] + .

[0193] Step 16: Preparation of compound 7Q

[0194] Compound 1K was prepared according to the synthetic protocol of Example 1. Compound 7Q (1.6 g, 100%) was obtained from compound 7P (1.94 g, 2.94 mmol), and the crude product was used directly in the next step. LC-MS m / z = 556.2 [M+1] + .

[0195] Step 17: Preparation of compound 7R

[0196] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 7Q (1.6 g, 2.94 mmol) and compound 1L (941 mg, 2.35 mmol) yielded a pale yellow solid, compound 7R (1.6 g, 70%). 1 H NMR (400 MHz, CDCl3) d 7.50 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.77-6.67 (m, 1H), 4.75(s, 1H), 4.26 (dd, J = 8.7, 2.1 Hz, 1H), 3.79 (s, 3H), 3.20-3.18 (m, 4H), 2.95 – 2.75 (m, 3H), 2.41 – 2.32 (m, 2H), 2.15 (dd, J = 13.9, 8.3 Hz, 3H), 2.02 (t, J LC-MS m / z = 938.2 [M+1] + .

[0197] Step 18: Preparation of compound 7S

[0198] Compound 7R (109 mg, 0.116 mmol), CuI (4 mg, 0.012 mmol), 1,10-phenanthroline (8 mg, 0.029 mol), and potassium thioacetate (33 mg, 0.29 mmol) were placed in a 10 mL Schlenk tube, purged with argon gas, and anhydrous 1,4-dioxane (0.6 mL) was added. The mixture was heated to 100 °C and stirred for 16 hours. The mother liquor was filtered to remove insoluble matter, concentrated under reduced pressure, and preparatively isolated by high performance liquid chromatography to obtain compound 7S (30 mg, 29%). 1 H NMR (400 MHz, CDCl3) d 7.28(d, J = 8.0 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 4.81 (s, 1H), 4.29 (dd,J = 8.6, 2.1 Hz, 1H), 3.81 (s, 3H), 3.20-3.18 (m, 4H), 3.03 – 2.85 (m, 3H), 2.40 (s, 3H), 2.37 – 2.15 (m, 5H), 2.05 (d, J = 3.4 Hz, 1H), 1.94 –1.69 (m, 7H), 1.58 (s, 9H), 1.49 – 1.39 (m, 24H), 1.27 (d, J = 11.6 Hz, 3H), 1.15 – 0.99 (m, 2H), 0.88 (s, 3H). LC-MS m / z = 886.8 [M+1] + .

[0199] Step 19: Preparation of compound 7T

[0200] Compound 7S (30 mg, 0.034 mmol) was dissolved in THF (0.2 mL), and 2N NaOH (22 μL, 0.068 mmol) was added. The mixture was heated to 40 °C and stirred for 1 hour. 2-Iodopropane (0.1 mL, 0.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour until the reaction was complete. The reaction was quenched with 0.1N hydrochloric acid, and the pH was adjusted to approximately 5. The reaction mixture was extracted with ethyl acetate / water, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and preparatively separated by high-performance liquid chromatography (HPLC) to obtain compound 7T (10 mg, 33%). LC-MS m / z = 886.5 [M+1] + .

[0201] Step 20: Preparation of Compound 7

[0202] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 7 (1.4 mg, 27%) was obtained from compound 7T (10 mg, 0.011 mmol). 1 H NMR (400 MHz, D2O) d 7.10 (d, J = 8.0 Hz, 1H), 7.03 – 6.99(m, 1H), 3.39 – 3.21 (m, 5H), 3.11 – 3.06 (m, 1H), 2.87 – 2.73 (m, 3H), 2.27– 2.19 (m, 1H), 2.02 (dd, J= 13.8, 8.0 Hz, 1H), 1.88 – 1.72 (m, 3H), 1.38(d, J = 13.6 Hz, 2H), 1.13 (ddt, J = 19.0, 6.7, 2.0 Hz, 6H), 1.05 (dd, J =12.4, 3.6 Hz, 1H), 0.81 (d, J = 13.4 Hz, 1H), 0.55 (dd, J = 79.8, 12.7 Hz,2H). LC-MS m / z = 464.2 [M+1] + .

[0203] Example 8: Synthesis of Compound 8

[0204] Step 1: Preparation of compound 8A

[0205] Compound 7S (76 mg, 0.086 mmol) was dissolved in methanol (0.5 mL), and cesium carbonate (42 mg, 0.129 mmol) was added. After purging with argon, the mixture was stirred at room temperature for 15 minutes. Ethyl acetate (10 mL) and 0.1N hydrochloric acid (10 mL) were added, and the reaction mixture was extracted. The organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give compound 8A (65 mg, 90%). LC-MS m / z = 884.4 [M+H] + .

[0206] Step 2: Preparation of compound 8B

[0207] Compound 8A (65 mg, 0.077 mmol), copper acetate (14 mg, 0.077 mmol), 2,2'-bipyridine (12 mg, 0.077 mmol), cesium carbonate (27 mg, 0.077 mmol), and cyclopropylboronic acid (10 mg, 0.116 mmol) were placed in a reaction flask, and 1,2-dichloroethane (1 mL) was added. The mixture was heated to 70 °C and stirred for 4 hours, then quenched with 0.1 N hydrochloric acid. After extraction with dichloromethane (10 mL) and 0.1 N dilute hydrochloric acid (10 mL), the organic phase was collected, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and separated by reversed-phase column chromatography to give compound 8B (10 mg, 15%). LC-MS m / z = 884.6 [M+H] + .

[0208] Step 2: Preparation of Compound 8

[0209] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 8 (0.8 mg, 16%) was obtained from compound 8B (10 mg, 0.011 mmol). 1 H NMR (400 MHz, D2O) d 7.32 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 3.29 – 3.21 (m, 4H), 3.12 (m, 1H), 2.80 (d, J = 5.3 Hz, 3H), 2.23 (s, 1H), 2.10 – 1.98 (m, 2H), 1.79 (s, 2H), 1.33 (s, 2H), 1.14 (d, J =12.0 Hz, 1H), 1.02 (d, J = 7.6 Hz, 3H), 0.80 (d, J = 13.6 Hz, 1H), 0.66 (d, J = 13.2 Hz, 1H), 0.59 (d, J = 5.5 Hz, 1H), 0.48 – 0.31 (m, 2H). LC-MS m / z =462.2 [M+H] + .

[0210] Example 9: Synthesis of Compound 9

[0211] Step 1: Preparation of compound 9A

[0212] Compound 9A (10 mg, 25%) was prepared according to the synthetic protocol of Compound 8B in Example 8. Compound 9A (10 mg, 25%) was obtained from Compound 8A (36 mg, 0.043 mmol). LC-MS m / z = 924.4 [M+H] + .

[0213] Step 2: Preparation of Compound 9

[0214] Compound 9 was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 9 (1.5 mg, 21%) was obtained from Compound 9A (12 mg, 14 μmol). 1 H NMR (400 MHz, D2O) δ 7.43 (d,J = 2.0 Hz, 1H), 6.92 (d, J =8.1 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 8.0 Hz, 1H), 3.52 (s,3H), 3.22 -3.18 (m, 4H), 3.00 (m, 1H), 2.79 (m, 1H), 2.69 – 2.61 (m, 2H),2.18 – 2.11 (m, 1H), 1.90 (dd, J = 14.1, 8.2 Hz, 1H), 1.75 (s, 2H), 1.29 (d, J = 14.0 Hz, 2H), 1.14 – 0.92 (m, 2H), 0.73 – 0.52 (m, 2H), 0.49 – 0.37 (m,1H). LC-MS m / z = 502.2 [M+H] + .

[0215] Example 10: Synthesis of Compound 10

[0216] Step 1: Preparation of Compound 10A

[0217] Compound 7S (50 mg, 0.056 mmol) was dissolved in methanol (0.5 mL), and cesium carbonate (30 mg, 0.085 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Bromopentane (50 mg, 0.338 mmol) was added, and the mixture was stirred at room temperature for 16 hours until the reaction was complete. The reaction was quenched with 0.1 N hydrochloric acid, and the pH was adjusted to approximately 3. The reaction mixture was extracted with ethyl acetate / water, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and preparatively separated by high-performance liquid chromatography (HPLC) to obtain compound 10A (40 mg, 78%). LC-MS m / z = 660.0 [M+H-252] + .

[0218] Step 2: Preparation of Compound 10

[0219] Compound 10 (6.6 mg, 24%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 10A (40 mg, 0.056 mmol) was used to obtain Compound 10 (6.6 mg, 24%). 1 H NMR (400 MHz, D2O) d 7.06 (d, J= 8.0 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 3.52 (m, 1H), 3.23 (m, 4H), 3.05 (d, J = 3.5 Hz, 1H), 2.83 –2.68 (m, 3H), 2.22 – 2.15 (m, 1H), 2.01– 1.69 (m, 6H), 1.59 – 1.29 (m, 7H),1.05 (m, 2H), 0.76 (dt, J = 14.0, 3.3 Hz, 1H), 0.60 (dd, J = 12.7, 3.3 Hz, 1H), 0.39 (dd, J = 13.1, 3.3 Hz, 1H). LC-MS m / z = 490.2 [M+H] + .

[0220] Example 11: Synthesis of Compound 11

[0221] Step 1: Preparation of compound 11A

[0222] Compound 11A was prepared according to the synthetic protocol of Example 10. Compound 11A (40 mg, 79%) was obtained from compound 7S (50 mg, 0.056 mmol). LC-MS m / z = 908.2 [M+H] + .

[0223] Step 2: Preparation of Compound 11

[0224] Compound 11 (3.1 mg, 12%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 11A (44 mg, 0.052 mmol) was used to obtain Compound 11 (3.1 mg, 12%). 1 H NMR (400 MHz, D2O) d 7.10 (dd, J = 8.0, 1.6 Hz, 1H), 7.03– 6.98 (m, 1H), 5.95 (ddt, J= 57.5, 56.0, 2.7 Hz, 1H), 3.33 – 3.18 (m, 6H), 3.06 (m, 1H), 2.75-2.65 (m, 3H), 2.24 – 2.16 (m, 1H), 2.02 – 1.90 (m, 1H), 1.86 – 1.71 (m, 2H), 1.33 (d, J LC-MS m / z = 486.1 [M+H] + .

[0225] Example 12: Synthesis of Compound 12

[0226] Step 1: Preparation of Compound 12A

[0227] Compound 10A was prepared according to the synthetic protocol of Example 10. Compound 12A (27 mg, 52%) was obtained from compound 7S (50 mg, 0.056 mmol). LC-MS m / z = 926.4 [M+H] + .

[0228] Step 2: Preparation of Compound 12

[0229] Compound 12 (3.3 mg, 23%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 12A (27 mg, 0.029 mmol) was used to obtain Compound 12 (3.3 mg, 23%). 1 H NMR (400 MHz, D2O) d 7.14 – 7.01 (m, 2H), 3.69 – 3.49 (m,2H), 3.21 (tt, J = 7.4, 3.7 Hz, 4H), 3.05 (dd, J = 3.7, 1.7 Hz, 1H), 2.82 –2.69 (m, 3H), 2.19 (ddd, J = 13.8, 4.9, 1.7 Hz, 1H), 2.01 – 1.89 (m, 1H), 1.86 – 1.71 (m, 2H), 1.39 – 1.27 (m, 2H), 1.05 (ddd, J= 50.0, 12.5, 3.8 Hz,2H), 0.75 – 0.67 (m, 1H), 0.51 (ddd, J = 65.0, 12.6, 3.3 Hz, 2H). LC-MS m / z =504.4 [M+H] + .

[0230] Example 13: Synthesis of Compound 13

[0231] Step 1: Preparation of compound 13A

[0232] Compound 10A was prepared according to the synthetic protocol of Example 10. Compound 13A (20 mg, 39%) was obtained from compound 7S (50 mg, 0.056 mmol). LC-MS m / z = 900.4 [M+H] + .

[0233] Step 2: Preparation of Compound 13

[0234] Compound 13 (2.2 mg, 21%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 13A (20 mg, 0.022 mmol) was used to obtain Compound 13 (2.2 mg, 21%). 1 H NMR (400MHz, D2O): 7.05 (d, J = 8.0 Hz, 1H), 6.93 (d, J= 8.0 Hz, 1H), 3.27-3.18 (m, 4H), 3.05-3.03 (m, 1H), 2.79-2.72 (m, 4H), 2.63-2.53 (m, 1H), 2.22-2.17 (m, 1H), 2.01-1.95 (m, 1H), 1.80 – 1.71 (m, 2H), 1.65-1.60 (m, 1H), 1.34-1.31 (m, 2H), 1.13-0.98 (m, 2H),0.82 (dd, J = 8.0,4.0 Hz, 6H), 0.80-0.75(m, 1H), 0.68-0.55(m, 1H), 0.40-0.28(m, 1H). LC-MS m / z= 478.2 [M+H] + .

[0235] Example 14: Synthesis of Compound 14

[0236] Step 1: Preparation of compound 14A

[0237] Compound 10A was prepared according to the synthetic protocol of Example 10. Compound 14A (20 mg, 38%) was obtained from compound 7S (50 mg, 0.0564 mmol). LC-MS m / z = 934.4 [M+H] + .

[0238] Step 2: Preparation of Compound 14

[0239] Compound 14 (2.8 mg, 26%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 14A (50 mg, 0.056 mmol) was used to obtain Compound 14 (2.8 mg, 26%). 1 H NMR (400MHz, D2O): 7.25-7.13 (m, 5H), 7.02 (d, J = 8.0Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.07 - 4.00 (m, 2H), 3.30 - 3.18 (m, 4H), 3.07 - 3.03 (m, 1H), 2.85 - 2.67 (m, 3H), 2.27 - 2.15 (m, 1H), 2.01 - 1.95(m, 1H), 1.85 - 1.70 (m, 2H), 1.40 - 1.25 (m, 2H),1.20 - 0.95 (m, 2H), 0.82- 0.73 (m, 1H), 0.70 - 0.55 (m, 1H), 0.42 - 0.28 (m, 1H). LC-MS m / z = 512.2[M+H] + .

[0240] Example 15: Synthesis of Compound 15

[0241] Step 1: Preparation of Compound 15A

[0242] Compound 10A was prepared according to the synthetic protocol of Example 10. Compound 15A (29 mg, 58%) was obtained from compound 7S (50 mg, 0.056 mmol). LC-MS m / z = 900.4 [M+H] + .

[0243] Step 2: Preparation of Compound 15

[0244] Compound 15 (6.0 mg, 39%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 15A (29 mg, 0.032 mmol) was used to obtain Compound 15 (6.0 mg, 39%). 1 H NMR (400 MHz, D2O) d 7.13 – 6.88 (m, 2H), 3.30 – 3.18 (m,4H), 3.11 (q, J = 6.6 Hz, 1H), 3.04 (s, 1H), 2.83 – 2.68 (m, 3H), 2.22 – 2.14(m, 1H), 1.97 (dd, J = 13.9, 7.9 Hz, 1H), 1.85 – 1.69 (m, 2H), 1.53 – 1.25(m, 4H), 1.04 (d, J = 6.6 Hz, 5H), 0.86 – 0.72 (m, 4H), 0.66 – 0.54 (m, 1H), 0.43 (tt, J = 14.1, 6.9 Hz, 1H). LC-MS m / z = 478.4 [M+H] + .

[0245] Example 16: Synthesis of Compound 16

[0246] Step 1: Preparation of compound 16A

[0247] Compound 10A was prepared according to the synthetic protocol of Example 10. Compound 16A (29 mg, 58%) was obtained from compound 7S (50 mg, 0.056 mmol). LC-MS m / z = 900.4 [M+H] + .

[0248] Step 2: Preparation of Compound 16

[0249] Compound 16 was prepared according to the synthetic protocol of Example 1, Compound 16 (6.4 mg, 42%) was obtained from Compound 16A (29 mg, 0.032 mmol). LC-MS m / z = 900.4 [M+H] + . 1 H NMR (400 MHz, D2O) δ 7.05 (d, J = 7.9 Hz, 1H), 6.97 (d, J= 7.8 Hz, 1H), 3.29 – 3.17 (m, 4H), 3.11 (d, J =6.5 Hz, 1H), 3.04 (d, J = 1.9 Hz, 1H), 2.73 (t, J = 4.1 Hz, 3H), 2.22 – 2.15(m, 1H), 1.97 (dd, J = 13.9, 7.9 Hz, 1H), 1.86 – 1.69 (m, 2H), 1.47 – 1.26(m, 4H), 1.17 – 0.96 (m, 5H), 0.76 (q, J = 7.5 Hz, 4H), 0.61 (td, J = 12.8,3.4 Hz, 1H), 0.47 – 0.35 (m, 1H). LC-MS m / z = 478.4 [M+H] + .

[0250] Example 17: Synthesis of Compound 17

[0251] Step 1: Preparation of compound 17A

[0252] Compound 10A was prepared according to the synthetic protocol of Example 10. Compound 17A (20 mg, 38%) was obtained from compound 7S (50 mg, 0.056 mmol). LC-MS m / z = 914.4 [M+H] + .

[0253] Step 2: Preparation of Compound 17

[0254] Compound 17 (3.1 mg, 30%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 17A (20 mg, 0.021 mmol) was used to obtain Compound 17 (3.1 mg, 30%). 1H NMR (400MHz, D2O): 7.02 (d, J = 8.0 Hz, 1H), 6.97 (d, J =8.0 Hz, 1H), 3.30-3.16 (m, 4H), 3.05-2.93 (m, 2H), 2.85-2.65 (m, 3H), 2.22-2.12 (m, 1H), 2.03-1.91 (m, 1H), 1.85-1.67 (m, 2H), 1.54-1.24 (m, 6H), 1.18-0.95 (m, 2H), 0.85-0.70 (m, 7H), 0.67-0.52(m, 1H), 0.50-0.35(m, 1H). LC-MS m / z = 492.2 [M+H] + .

[0255] Example 18: Synthesis of Compound 18

[0256] Step 1: Preparation of compound 18A

[0257] Compound 10A was prepared according to the synthetic protocol of Example 10. Compound 18A (20 mg, 38%) was obtained from compound 7S (50 mg, 0.0564 mmol). LC-MS m / z = 948.6 [M+H] + .

[0258] Step 2: Preparation of Compound 18

[0259] Compound 18 (2.8 mg, 26%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 18A (20 mg, 0.021 mmol) was used to obtain Compound 18 (2.8 mg, 26%). 1H NMR (400MHz, D2O): 7.25-7.07 (m, 5H), 6.97 (d, J = 8.0Hz, 0.5H), 6.95 - 6.87 (m, 1H), 6.70 - 6.55 (d, J = 8.0 Hz, 0.5H), 4.42 - 4.30(m, 1H), 3.35 - 2.95 (m, 5H), 2.85 - 2.60 (m, 3H), 2.20 - 2.15 (m, 1H), 2.05- 1.87 (m, 1H), 1.86 - 1.65 (m, 2H), 1.50 - 1.40 (m, 3H), 1.40 - 1.20 (m,2H),1.15 - 0.90 (m, 2H), 0.80 - 0.50(m, 2H), 0.45 - 0.25(m, 1H). LC-MS m / z =526.3 [M+H] + .

[0260] Example 19: Synthesis of Compound 19

[0261] Step 1: Preparation of compound 19A

[0262] Compound 6E was prepared according to the synthetic protocol of Example 6. Compound 6D (5.5 g, 15 mmol) yielded a yellow oily compound 19A (3.0 g, 51%). 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.03 (dd, J = 9.2, 6.4 Hz, 1H), 3.98 – 3.88 (m,4H), 3.88 – 3.82 (m, 1H), 3.80 – 3.74 (m, 1H), 3.69 (dd, J = 9.2, 5.2 Hz,1H), 2.31 – 2.22 (m, 1H), 1.96 – 1.88 (m, 1H), 1.62 (s, 9H). LC-MS m / z =331.0 [M+H-56] + .

[0263] Step 2: Preparation of compound 19B

[0264] Compound 1F was prepared according to the synthetic protocol of Example 1. Compound 19B (1.8 g, 69%) was obtained from compound 19A (3.0 g, 7.7 mmol) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 0.8 Hz, 1H), 6.92 (dd, J = 17.6, 11.2 Hz, 1H), 5.78 (dd, J = 17.6, 1.2 Hz, 1H), 5.37 (dd, J = 11.2, 1.2 Hz, 1H), 4.04 (dd, J = 9.2, 6.4Hz, 1H), 3.98 – 3.92 (m, 1H), 3.88 – 3.82 (m, 1H), 3.80 (s, 4H), 3.70 (dd, J = 9.2, 5.2 Hz, 1H), 2.31 – 2.21 (m, 1H), 1.98 – 1.88 (m, 1H), 1.63 (s, 9H). LC-MS m / z = 281.1 [M+H-56] + .

[0265] Step 3: Preparation of compound 19C

[0266] Compound 1G was prepared according to the synthetic protocol of Example 1. A colorless oily compound 19C (1.2 g, 62%) was obtained from compound 19B (1.9 g, 5.5 mmol). 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 1.2 Hz, 2H), 4.03 (dd, J = 9.2, 6.4 Hz, 1H), 3.97 – 3.92 (m, 1H), 3.90 – 3.81 (m, 6H), 3.79 – 3.67 (m, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.30 – 2.21 (m, 1H), 1.96 –1.89 (m, 1H), 1.63 (s, 9H). LC-MS m / z = 281.1 [M-73] + .

[0267] Step 4: Preparation of compound 19D

[0268] Compound 1H was prepared according to the synthetic protocol of Example 1. A colorless oily compound 19D (0.65 g, 56%) was obtained from compound 19C (1.2 g, 3.3 mmol). 1 H NMR (400 MHz, CDCl3) δ 9.73 (t, J = 2.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.05 (dd, J = 9.2, 6.4Hz, 1H), 3.95 (m, 1H), 3.89 – 3.84 (m, 1H), 3.79 (s, 4H), 3.73 – 3.68 (m,3H), 2.33 – 2.22 (m, 1H), 1.98 – 1.90 (m, 1H), 1.63 (s, 9H). LC-MS m / z =279.1 [M-73] + .

[0269] Step 5: Preparation of compound 19E

[0270] Compound 1I was prepared according to the synthetic protocol of Example 1. A colorless oily compound 19E (0.55 g, 67%) was obtained from compound 19D (0.65 g, 1.8 mmol). 1 H NMR (400 MHz, CDCl3)δ 8.11 (t, J = 4.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.03 (dd, J = 9.2, 6.4Hz, 1H), 3.98 – 3.91 (m, 1H), 3.83 (d, J = 9.6 Hz, 6H), 3.79 – 3.75 (m, 1H), 3.72 – 3.68 (m, 1H), 2.31 – 2.22 (m, 1H), 1.93 (dd, J= 7.6, 5.2 Hz, 1H),1.62 (s, 9H), 1.19 (s, 9H). LC-MS m / z = 400.2 [M+H-56] + .

[0271] Step 6: Preparation of compound 19F

[0272] Compound 1J was prepared according to the synthetic protocol of Example 1. Compound 19F (600 mg, 86%) was obtained as a yellow oil from compound 19E (550 mg, 1.2 mmol). LC-MS m / z = 584.4 [M+H] + .

[0273] Step 7: Preparation of compound 19G

[0274] Compound 2A was prepared according to the synthetic protocol of Example 2. Oily compound 19G (260 mg, 41%) was obtained from compound 19F (600 mg, 1.0 mmol). LC-MS m / z = 636.4 [M+H] + .

[0275] Step 8: Preparation of compound 19H

[0276] Compound 1K was prepared according to the synthetic protocol of Example 1. Compound 19H, a pale yellow oil, was obtained from compound 19G (260 mg, 0.41 mmol). The crude product was used directly in the next step. LC-MS m / z = 398.2 [M-133] + .

[0277] Step 9: Preparation of compound 19I

[0278] Compound 1M was prepared according to the synthetic protocol of Example 1. A pale yellow oil, compound 19I (20 mg, 38%), was obtained from compound 19H (45 mg, 0.08 mmol) and compound 1L (23 mg, 0.06 mmol). LC-MS m / z = 914.5 [M+H] + .

[0279] Step 10: Preparation of Compound 19

[0280] Compound 19 was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 19 (5.8 mg, 60%) was obtained from Compound 19I (20 mg, 0.02 mmol). 1 H NMR (400 MHz, D2O) δ 7.08 (d, J= 8.0 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 3.84 (td, J = 9.0, 7.0 Hz, 3H), 3.71 (td, J = 8.3, 5.8 Hz,1H), 3.57 – 3.53 (m, 1H), 3.26 – 3.20 (m, 4H), 3.05 (dd, J = 3.7, 1.7 Hz, 1H), 2.76 (dt, J = 14.9, 3.5 Hz, 3H), 2.29 – 2.15 (m, 2H), 1.98 (dd, J =14.0, 8.0 Hz, 1H), 1.83 – 1.72 (m, 3H), 1.38 – 1.26 (m, 2H), 1.13 (td, J =12.4, 3.4 Hz, 1H), 1.04 – 0.94 (m, 1H), 0.75 (dt, J = 13.6, 3.4 Hz, 1H), 0.63(td, J = 12.7, 3.4 Hz, 1H), 0.40 (qd, J = 13.3, 3.4 Hz, 1H). LC-MS m / z =492.2 [M+H] + .

[0281] Example 20: Synthesis of Compound 20

[0282] Step 1: Preparation of compound 20A

[0283] Compound 20A (5.5 g, 85%) was prepared according to the synthetic protocol of compound 6E in Example 6. Compound 20A was obtained from compound 6D (6.5 g, 17.9 mmol) 1 H NMR (400 MHz, DMSO- d 6) δ 7.67 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.49-3.42 (m, 1H), 1.55 (s, 9H), 1.21 (d, J= 6.7 Hz, 6H). LC-MS m / z =306.0 [M+H-56] + .

[0284] Step 2: Preparation of compound 20B

[0285] Compound 1F was prepared according to the synthetic protocol of Example 1. Compound 20B (3.3 g, 80%) was obtained from compound 20A (5.5 g, 15.3 mmol), which was a pale yellow oil. 1 H NMR (400 MHz, DMSO- d 6) δ 7.67 – 7.62 (m, 1H),7.29 (d, J = 8.2 Hz, 1H), 6.85 (dd, J = 17.8, 11.1 Hz, 1H), 5.92 (dd, J =17.7, 1.2 Hz, 1H), 5.42 (dd, J = 11.2, 1.2 Hz, 1H), 3.71 (s, 3H), 3.49-3.46(m, 1H), 1.55 (s, 9H), 1.21 (d, J = 6.7 Hz, 6H). LC-MS m / z = 253.0 [M+H-56] + .

[0286] Step 3: Preparation of compound 20C

[0287] Prepared according to the synthetic protocol of compound 1G in Example 1. Compound 20B (3.8 g, 12.2 mmol) yielded a pale yellow oily compound 20C (2.8 g, 70%). LC-MS m / z = 271.2 [M+H-56] + .

[0288] Step 4: Preparation of compound 20D

[0289] Compound 1H was prepared according to the synthetic protocol of Example 1. Compound 20C (2.8 g, 8.59 mmol) yielded a pale yellow oily compound 20D (1.4 g, 50%). 1 H NMR (400 MHz, DMSO- d 6) δ 9.70 – 9.66 (m, 1H),7.29 (d, J= 1.3 Hz, 2H), 3.78 (m, 2H), 3.66 (s, 3H), 3.45-3.38 (m, 1H), 1.55(s, 9H), 1.21 (d, J = 6.7 Hz, 6H). LC-MS m / z = 269.2 [M+H-56] + .

[0290] Step 5: Preparation of compound 20E

[0291] Compound 1I was prepared according to the synthetic protocol of Example 1. Compound 20E (1.2 g, 60%) was obtained from compound 20D (1.4 g, 4.32 mmol) as a pale yellow oil. 1 H NMR (400 MHz, DMSO- d 6) δ 8.01 (t, J = 4.4 Hz, 1H), 7.30 (q, J = 8.0 Hz, 2H),4.06 – 4.00 (m, 1H), 3.89 – 3.87 (m, 1H), 3.72(s, 3H), 3.44-3.36 (m, 1H), 1.54 (d, J = 1.5 Hz, 9H), 1.20 – 1.17 (m, 6H),1.07 (s, 9H). LC-MS m / z =372.2[M+H-56] + .

[0292] Step 6: Preparation of compound 20F

[0293] Compound 1J was prepared according to the synthetic protocol of Example 1. Compound 20F was obtained from compound 20E (920 mg, 2.15 mmol), and the crude product was used directly in the next step. LC-MS m / z = 556.6 [M+H] + .

[0294] Step 7: Preparation of Compound 20G

[0295] Prepared according to the synthetic protocol of compound 2A in Example 2. Oily compound 20G (450 mg, 45% yield in two steps) was obtained from crude compound 20F. LC-MS m / z = 608.4 [M+H] + .

[0296] Step 8: Preparation of compound 20H

[0297] Compound 1K was prepared according to the synthetic protocol of Example 1. Compound 20H (370 mg, 100%) was obtained from compound 20G (450 mg, 0.74 mmol), and the crude product was used directly in the next step. LC-MS m / z = 370.2 [M-133] + .

[0298] Step 9: Preparation of compound 20J

[0299] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 20J (40 mg, 45%) was obtained as a pale yellow powder from compound 20H (75 mg, 0.15 mmol) and compound 20I (40 mg, 0.10 mmol). LC-MS m / z = 886.4 [M+1] + .

[0300] Step 10: Preparation of Compound 20

[0301] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 20 (2.3 mg, 10%) was obtained from compound 20J (40 mg, 0.045 mmol). 1 H NMR (400 MHz, D2O) δ 7.02 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 3.22 (s, 6H), 3.02 (d, J = 3.1 Hz, 1H), 2.76 (m, 4H), 2.13(tt, J = 11.9, 3.2 Hz, 1H), 1.61 (d, J = 12.9 Hz, 3H), 1.36 – 1.29 (m, 1H), 1.07 (dd, J = 6.7, 4.9 Hz, 6H), 1.01 (ddd, J = 12.3, 9.0, 3.7 Hz, 2H), 0.92 –0.81 (m, 2H). LC-MS m / z = 464.2 [M+1] + .

[0302] Example 21: Synthesis of Compound 21

[0303] Step 1: Preparation of compound 21B

[0304] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 21B (30 mg, 29%) was obtained from compound 20H (75 mg, 0.15 mmol) and compound 21A (45 mg, 0.12 mmol). LC-MS m / z = 872.4 [M+H] + .

[0305] Step 2: Preparation of Compound 21

[0306] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 21 (7.8 mg, 51%) was obtained from compound 21B (30 mg, 0.034 mmol). 1 H NMR (400 MHz, D2O) δ 7.14 (d, J = 7.6 Hz, 1H), 7.03 (m, J = 7.9, 1.8 Hz, 1H), 3.40 (m, 1H), 3.33 – 3.27 (m, 4H), 3.12 (m, 1H), 3.09 –3.00 (m, 1H), 2.90 (d, J = 7.6 Hz, 1H), 2.86 – 2.76 (m, 2H), 2.45 – 2.11 (m,4H), 1.95-1.90 (m, 1H), 1.72 – 1.59 (m, 1H), 1.52 – 1.29 (m, 1H), 1.25-1.15(m, 7H). LC-MS m / z = 449.8 [M+H] + .

[0307] Example 22: Synthesis of Compound 22

[0308] Step 1: Preparation of compound 22B

[0309] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 22B (40 mg, 40%) was obtained as a pale yellow oil from compound 20H (75 mg, 0.15 mmol) and compound 22A (40 mg, 0.10 mmol). LC-MS m / z = 900.4 [M+H] + .

[0310] Step 2: Preparation of Compound 22

[0311] Compound 22 (1.9 mg, 10%) was prepared according to the synthetic protocol of Compound 1 in Example 1. Compound 22 was obtained from Compound 22B (10 mg, 0.01 mmol) as 1.9 mg (10%). Diastereomer 22-D1 (0.8 mg): 1 H NMR (400 MHz, D2O) δ 7.17 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 3.39 - 3.29 (m, 6H), 3.15 - 3.12(m, 1H), 2.90 - 2.81 (m, 3H), 2.44 (t, J LC-MS m / z =478.2 [M+H] + Diastereomer 22-D2 (1.1 mg): 1 H NMR (400 MHz, D2O) δ 7.18 (d, J =8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.45 - 3.29 (m, 6H), 3.10 - 3.05 (m,1H), 2.90 - 2.75 (m, 3H), 2.20 - 2.15 (m, 1H), 1.90 - 1.75 (m, 2H), 1.55 -1.50 (m, 1H), 1.25 – 1.15 (m, 8H), 1.06 (d, J = 8.0 Hz, 3H), 1.00 – 0.90 (m,1H), 0.87– 0.79 (m, 1H), 0.35– 0.25 (m, 1H). LC-MS m / z = 478.2 [M+H] + .

[0312] Example 23: Synthesis of Compound 23

[0313] Step 1: Preparation of compound 23B

[0314] Compound 1B was prepared according to the synthetic protocol of Example 1. Compound 23B (62 g, 99%) was obtained as a pale yellow solid from compound 23A (45 g, 167.3 mmol). 1 H NMR (400MHz, DMSO- d 6 ) δ 7.82 (d, J = 7.9 Hz, 2H), 1.53(s, 9H). LC-MS m / z = 314.9 [M-55] + .

[0315] Step 2: Preparation of compound 23C

[0316] Compound 1D was prepared according to the synthetic protocol of Example 1. Compound 23B (20 g, 54.3 mmol) yielded a white solid compound 23C (23 g, 100%), which was used directly in the next step. 1 H NMR (400MHz, DMSO- d 6 ) δ 7.60(s, 2H), 2.47 (s, 3H), 1.52 (s, 9H). LC-MS m / z = 399.2 [M+H] + .

[0317] Step 3: Preparation of compound 23D

[0318] Compound 7C was prepared according to the synthetic protocol of Example 7. Compound 23C (23.0 g, 57.8 mmol) yielded a white solid compound 23D (16.2 g, 88%). 1 H NMR (400MHz, DMSO- d 6 ) δ 11.27 (s, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 4.0 Hz, 1H)), 2.49 (s, 3H), 1.59 (s, 9H). LC-MS m / z = 263.0 [M+H-56] + .

[0319] Step 4: Preparation of compound 23E

[0320] Compound 1E was prepared according to the synthetic protocol of Example 1. Compound 23E (4.3 g, 95%) was obtained as a white crystalline solid from compound 23D (4.8 g, 15.1 mmol).1 H NMR (400 MHz, DMSO- d 6) δ 7.68 (d, J = 4.0Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H), 3.79 (s, 3H), 2.51 (s, 3H), 1.55 (s, 9H).LC-MS m / z = 279.0 [M+H-56] + .

[0321] Step 5: Preparation of compound 23F

[0322] Compound 1F was prepared according to the synthetic protocol of Example 1. Compound 23F (2.3 g, 64%) was obtained from compound 23E (4.3 g, 12.8 mmol), yielding a pale yellow oily compound 23F. 1 H NMR (400 MHz, DMSO- d 6) δ 7.62 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 4.0 Hz, 1H), 6.90 (dd, J = 17.8, 11.2 Hz, 1H), 5.97 (dd, J = 17.7, 1.2 Hz, 1H), 5.42 (dd, J = 11.1, 1.1 Hz, 1H), 3.70 (s, 3H), 2.51 (s,3H), 1.55 (s, 9H). LC-MS m / z = 225.2 [M+H-56] + .

[0323] Step 6: Preparation of compound 23G

[0324] Compound 1G was prepared according to the synthetic protocol of Example 1. Compound 23F (2.3 g, 8.21 mmol) yielded a white solid, compound 23G (1.6 g, 69%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.52 (d, J = 4.0 Hz, 1H), 7.29 ((d, J = 4.0 Hz, 1H), 3.88 (t, J = 6.5 Hz, 2H), 3.85 (s, 3H), 2.93(t,J = 6.5 Hz, 2H), 2.50 (s, 3H), 1.63 (s, 9H). LC-MS m / z = 243.0 [M+H-56] + .

[0325] Step 7: Preparation of compound 23H

[0326] Compound 1H was prepared according to the synthetic protocol of Example 1. A colorless oily compound 23H (1.3 g, 90%) was obtained from compound 23G (1.5 g, 5.0 mmol). LC-MS m / z = 241.0 [M+H-56] + .

[0327] Step 8: Preparation of compound 23I

[0328] Compound 1I was prepared according to the synthetic protocol of Example 1. A colorless oily compound 23I (2.8 g, 72%) was obtained from compound 23H (3.1 g, 8.18 mmol). LC-MS m / z = 400.2 [M+H] + .

[0329] Step 8: Preparation of compound 23J

[0330] Compound 1J was prepared according to the synthetic protocol of Example 1. A yellow oily compound 23J (150 mg, 53%) was obtained from compound 23I (180 mg, 0.45 mmol). LC-MS m / z = 528.2 [M+H] + .

[0331] Step 9: Preparation of compound 23K

[0332] Compound 1K was prepared according to the synthetic protocol of Example 1. Crude compound 23K (118 mg, 100%) was obtained from compound 23J (150 mg, 0.28 mmol) and used directly in the next step. LC-MS m / z = 342.1 [M-82] + .

[0333] Step 10: Preparation of compound 23L

[0334] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 23L (190 mg, 82%) was obtained from compound 23K (150 mg, 0.28 mmol) and compound 1L (120 mg, 0.28 mmol). LC-MS m / z = 706.4 [M+H-100] + .

[0335] Step 11: Preparation of Compound 23

[0336] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 23 (5.6 mg, 38%) was obtained from compound 23L (30 mg, 34 μmol). 1 H NMR (400 MHz, D2O) δ 7.61 (s, 1H), 7.31 (s, 1H), 3.30-3.24(m, 4H), 3.18 (s, 1H), 2.85 – 2.80 (m, 2H), 2.79 – 2.68 (m, 1H), 2.39 (s,3H), 2.24 – 2.27 (m, 1H), 2.06 – 2.01 (m, 1H), 1.84 – 1.73 (m, 2H), 1.37 –1.33 (m, 1H), 1.26 (m, 1H), 1.16 – 1.10 (m, 1H), 0.96 – 0.93 (m, 1H), 0.72 –0.68 (m, 1H), 0.59 – 0.52 (m, 1H), 0.48 – 0.39 (m, 1H). LC-MS m / z = 436.1 [M+H] + .

[0337] Example 24: Synthesis of Compound 24

[0338] Step 1: Preparation of Compound 24A

[0339] Compound 1G was prepared according to the synthetic protocol of Example 1. Oily compound 24A (5.8 g, 85%) was obtained from compound 7E (6.5 g, 27 mmol). 1 H NMR (400MHz, CDCl3) d 7.63 (dd, J = 1.8, 7.8 Hz, 1H), 7.36 (dd, J = 1.8, 7.5 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 3.92 - 3.82 (m,5H), 2.95 (t, J = 6.5 Hz, 2H), 1.62 (s, 9H). LC-MS m / z = 275.1 [M+Na] + .

[0340] Step 2: Preparation of compound 24B

[0341] Compound 24A (10.0 g, 39.4 mmol) was dissolved in formic acid (100 mL), stirred at room temperature for 1 hour, and the reaction solution was concentrated to obtain compound 24B (8.8 g, 100%), which was used directly in the next step. 1 H NMR (400 MHz, DMSO- d 6) δ12.95 (s, 1H, -COOH), 8.19 (s, 1H), 7.58 (dd, J = 7.7, 1.8 Hz, 1H), 7.46 (dd, J = 7.6, 1.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 4.37 – 4.28 (m, 2H), 3.77 (s,3H), 2.97 (t, J = 6.8 Hz, 2H).

[0342] Step 3: Preparation of compound 24C

[0343] Compound 24B (8.8 g, 39 mmol), diethyl iodophenyl ester (12.6 g, 39 mmol), iodine (9.9 g, 39 mmol), palladium acetate (438 mg, 1.95 mmol), and tetrabutylammonium iodide (14.4 g, 39 mmol) were added to 1,2-dichloroethane (100 mL) and stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was washed with an aqueous sodium bisulfite solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 24C (13.6 g, 100%). The crude product was used directly in the next step. LC-MS m / z = 351.2 [M+H] + .

[0344] Step 4: Preparation of compound 24D

[0345] Compound 24C (13.6 g, 39 mmol) was dissolved in tert-butanol (250 mL), and Boc2O (67 mL, 295 mmol) and DMAP (720 mg, 5.9 mmol) were added. The mixture was heated to 80 °C and stirred for 2 hours. After concentration under reduced pressure, the mixture was separated by column chromatography (90 / 10 pentane / ethyl acetate) to give an oily compound 24D (11.4 g, 50%). 1 H NMR (400 MHz, DMSO- d6) δ 8.20 (s, 1H), 7.79 (dd, J = 19.9, 2.3 Hz, 2H), 4.31 (t, J = 6.7 Hz, 2H), 3.75 (s,3H), 2.93 (t, J = 6.7 Hz, 2H), 1.54 (s, 9H).

[0346] Step 5: Preparation of compound 24E

[0347] At room temperature, NaOH (2.2 g, 55 mmol) was added to a THF / H₂O (160 mL, 3:1) solution of compound 24D (11 g, 27 mmol), and the mixture was heated to 60 °C for 2 hours. TLC showed that the starting material disappeared and a new spot formed. The organic phase was separated, concentrated under reduced pressure, and separated by column chromatography (100 / 0 to 70 / 30 pentane / ethyl acetate) to give a colorless oily compound 24E (10 g, 98%). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 2.4 Hz, 1H), 7.66 (d, J =2.4 Hz, 1H), 3.87 – 3.83 (m, 5H), 2.88 (t, J = 6.5 Hz, 2H), 1.60 (s, 9H).

[0348] Step 5: Preparation of compound 24F

[0349] Compound 1H was prepared according to the synthetic protocol of Example 1. Compound 24E (6.4 g, 17 mmol) yielded a pale yellow oily compound 24F (5.3 g, 83%). 1 H NMR (400 MHz, Chloroform- d ) δ 9.72 (t, J = 1.6Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 3.78 (s, 3H), 3.68 (d, J = 2.0 Hz, 2H), 1.60 (s, 9H).

[0350] Step 6: Preparation of compound 24G

[0351] Compound 1I was prepared according to the synthetic protocol of Example 1. Compound 24F (5.3 g, 14 mmol) yielded a pale yellow oily compound 24G (5.5 g, 82%). 1 H NMR (400 MHz, Chloroform- d ) δ 8.10 (t, J = 4.4Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 3.82 (d, J = 6.4Hz, 5H), 1.60 (s, 9H), 1.18 (s, 9H).

[0352] Step 7: Preparation of compound 24H

[0353] Prepared according to the synthetic protocol of compound 1J in Example 1. Compound 24G (6.0 g, 12 mmol) yielded a pale yellow oily compound 24H (7.5 g, 100%), the crude product of which was used directly in the next step. LC-MS m / z = 608.0 [M+H] + .

[0354] Step 8: Preparation of compound 24I

[0355] Compound 2A was prepared according to the synthetic protocol of Example 2. Compound 24I (7.6 g, 96%) was obtained from compound 24H (7.5 g, 12 mmol). 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 4.24 (dd, J = 8.8, 2.0 Hz, 1H), 4.00 (dt, J = 10.0, 5.2 Hz,1H), 3.84 (s, 3H), 3.38 (d, J = 1.6 Hz, 2H), 3.16 (m, 1H), 2.98 – 2.90 (m,1H), 2.70 (d, J = 6.4 Hz, 1H), 2.51 – 2.43 (m, 1H), 2.22 (d, J= 2.4 Hz, 2H),2.17 – 2.09 (m, 1H), 1.58 (s, 9H), 1.31 (s, 3H), 1.18 (s, 9H), 0.94 (s, 3H),0.81 (s, 3H).

[0356] Step 9: Preparation of compound 24J

[0357] Compound 24J (6.4 g, 100%) was prepared according to the synthetic protocol of Compound 1K in Example 1. Compound 24J was obtained from Compound 24I (7.6 g, 11.5 mmol), and the crude product was used directly in the next step. LC-MS m / z = 556.0 [M+H] + .

[0358] Step 10: Preparation of compound 24K

[0359] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 24K (5.1 g, 73%) was obtained from compound 24J (6.4 g, 11.5 mmol) and compound 1L (3 g, 7.5 mmol). 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 6.61 (s, 1H), 4.26 (dd, J = 8.8,2.0 Hz, 1H), 3.79 (s, 3H), 3.20 (s, 4H), 2.93 – 2.78 (m, 3H), 2.41 – 2.30 (m,1H), 2.19 – 2.10 (m, 3H), 2.00 (d, J = 5.6 Hz, 1H), 1.93 – 1.68 (m, 11H), 1.60 (s, 9H), 1.47 (s, 9H), 1.43 (s, 9H), 1.27 (d, J = 12.0 Hz, 6H), 1.06 (d, J = 13.2 Hz, 2H), 0.87 (s, 3H). LC-MS m / z = 938.2 [M+H] + .

[0360] Step 11: Preparation of compound 24L

[0361] Compound 7S was prepared according to the synthetic protocol of Example 7. Compound 24K (300 mg, 0.3 mmol) was used to obtain a pale red solid compound 24L (250 mg, 94%). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 2.4 Hz,1H), 7.26 (s, 1H), 7.18 (s, 1H), 4.29 (dd, J = 8.8, 2.0 Hz, 1H), 3.86 (s,4H), 3.25 – 3.18 (m, 4H), 3.10 – 3.03 (m, 1H), 2.84 (d, J = 11.6 Hz, 1H), 2.70 (t, J = 12.8 Hz, 1H), 2.45 (s, 3H), 2.41 – 2.31 (m, 1H), 2.20 – 2.15 (m,3H), 2.05 -2.01 (m, 6H), 1.91 – 1.69 (m, 6H), 1.60 (s, 9H), 1.46 (s, 9H),1.43 (d, J = 1.6 Hz, 9H), 1.27 (d, J = 14.4 Hz, 6H), 1.07 (s, 2H), 0.88 (s, 3H). LC-MS m / z = 886.4 [M+H] + .

[0362] Step 11: Preparation of compound 24M

[0363] Compound 7T was prepared according to the synthetic protocol of Example 7. Compound 24M (40 mg, 100%) was obtained from compound 24L (40 mg, 0.045 mmol), and the crude product was used directly in the next step. LC-MS m / z = 872.4 [M+H] + .

[0364] Step 12: Preparation of Compound 24

[0365] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 24 (5.7 mg, 29%) was obtained from compound 24M (40 mg, 0.045 mmol). 1 H NMR (400 MHz, D2O) δ 7.61 (d, J = 2.4 Hz, 1H), 7.30 (d,J = 2.4 Hz, 1H), 3.22 (s, 4H), 3.18-3.12 (m, 1H), 2.89 – 2.66 (m, 5H), 2.25-2.20 (m, 1H), 1.98 (dd, J = 14.0, 8.0 Hz, 1H), 1.82-1.75 (m, 1H), 1.73 – 1.65(m, 1H), 1.35-1.30 (m, 1H), 1.26-1.21 (m, 1H), 1.13-1.06 (m, 4H), 0.95-0.86(m, 1H), 0.67-0.61(m, 1H), 0.48 - 0.45 (m, 2H). LC-MS m / z = 450.2 [M+H] + .

[0366] Example 25: Synthesis of Compound 25

[0367] Step 1: Preparation of compound 25A

[0368] Compound 7T was prepared according to the synthetic protocol of Example 7. Compound 25A (40 mg, 100%) was obtained from compound 24L (40 mg, 0.045 mmol), and the crude product was used directly in the next step. LC-MS m / z = 886.4 [M+H] + .

[0369] Step 2: Preparation of Compound 25

[0370] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 25 (2.2 mg, 11%) was obtained from compound 25A (40 mg, 0.045 mmol). 1 H NMR (400 MHz, D2O) δ 7.77 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 3.34 – 3.22 (m, 5H), 3.19 (s, 1H), 2.87 (t, J = 3.6 Hz, 2H),2.81 – 2.70 (m, 1H), 2.33 – 2.21 (m, 1H), 2.02 (dd, J = 14.0, 8.0 Hz, 1H),1.83-1.73 (m, 2H), 1.39 (d,J = 13.6 Hz, 1H), 1.33 – 1.23 (m, 1H), 1.13 (d, J = 6.8 Hz, 7H), 1.02 – 0.89 (m, 1H), 0.71 (d, J = 13.2 Hz, 1H), 0.56-0.48 (m,2H). LC-MS m / z = 464.2 [M+H] + .

[0371] Example 26: Synthesis of Compound 26

[0372] Step 1: Preparation of compound 26B

[0373] Compound 1B was prepared according to the synthetic protocol of Example 1. Compound 26B (16.8 g, 98%) was obtained from compound 26A (10 g, 76.9 mmol) as a colorless, clear liquid. 1 H NMR (400 MHz, CDCl3) δ 7.15 (dt, J = 9.9, 8.9 Hz, 1H), 7.06 (ddd, J = 10.8, 6.7, 2.8 Hz, 1H), 6.92 (dddd, J = 9.0, 3.6,2.8, 1.8 Hz, 1H), 1.55 (s, 9H). 19 F NMR (377 MHz, CDCl3) d -134.61, -141.12.

[0374] Step 2: Preparation of compound 26C

[0375] Compound 1C was prepared according to the synthesis scheme of Compound 1C in Example 1. The oily liquid compound 26C (10.4 g, 87%) was obtained from compound 26B (10 g, 76.9 mmol). 1 H NMR (400 MHz, DMSO- d 6) d 10.39 (s, -OH, 1H), 7.36 (dt, J = 10.6, 9.3 Hz, 1H), 6.70 (ddd, J = 9.2, 3.7, 2.0 Hz, 1H), 1.52(s, 9H). 19F NMR (377 MHz, DMSO- d 6) d -140.04, -150.47.

[0376] Step 3: Preparation of compound 26D

[0377] Compound 26C (700 mg, 3.04 mmol) and NBS (568 mg, 3.19 mmol) were dissolved in acetonitrile (6 mL). The mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure and separated by column chromatography (9 / 1 pentane / ethyl acetate) to give an oily compound 26D (783 mg, 83%). 1 H NMR (400 MHz, DMSO- d 6 ) d 10.75 (s, 1H), 8.01 (dd, J = 10.1,8.5 Hz, 1H), 1.55 (s, 9H). 19 F NMR (377 MHz, DMSO- d 6) d -136.71, -146.33.

[0378] Step 4: Preparation of compound 26E

[0379] Compound 1E was prepared according to the synthetic scheme of Example 1. A transparent, colorless, oily compound 26E (1.1 g, 87%) was obtained from compound 26D (1.21 g, 3.91 mmol). 1 H NMR (400 MHz, CDCl3) d 7.42 (dd, J = 9.3,8.2 Hz, 1H), 3.90 (s, 3H), 1.60 (s, 9H). 19 F NMR (377 MHz, Chloroform- d ) d -137.88 (d, J = 22.1 Hz), -139.08 (d, J = 22.2 Hz).

[0380] Step 5: Preparation of compound 26F

[0381] Compound 1F was prepared according to the synthesis scheme of Compound 1F in Example 1. Colorless oily compound 26F (4.3 g, 56%) was obtained from compound 26E (9.2 g, 28.5 mmol). 1 H NMR (MHz, DM400 SO- d 6) d 7.87 (dd, J = 11.9, 9.3Hz, 1H), 6.81 (ddd, J = 17.7, 11.2, 1.6 Hz, 1H), 5.98 (d, J = 17.6 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 3.74 (s, 3H), 1.55 (s, 9H). 19 F NMR (377 MHz, DMSO- d 6) d -140.53 (d, J = 24.2 Hz), -141.95 (d, J = 23.8 Hz).

[0382] Step 6: Preparation of compound 26G

[0383] Under ice bath conditions, isopropyl mercaptan (2.9 mL, 31.2 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and sodium hydride (1.25 g, 60% wt, 31.2 mmol) was added in portions, with stirring for 1 hour. Compound 26F (4.22 g, 15.6 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) was added, and the mixture was stirred at room temperature for 18 hours. After concentrating the reaction mixture, ethyl acetate (100 mL) and water (60 mL) were added. The organic phase was extracted, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and separated by column chromatography (95 / 5 pentane / ethyl acetate) to give compound 26G (4.61 g, 91%). 1 H NMR (400 MHz, DMSO- d 6) d 7.65 (d, J = 10.1 Hz, 1H), 6.83 (ddd, J =17.7, 11.2, 1.7 Hz, 1H), 6.06 (dd, J = 17.7, 1.0 Hz, 1H), 5.52 (dd,J = 11.1,1.0 Hz, 1H), 3.70 (s, 3H), 3.37 (p, J = 6.7 Hz, 1H), 1.56 (s, 9H), 1.18 (d, J = 6.6 Hz, 6H). 19 F NMR (377 MHz, DMSO- d 6) d -111.30.

[0384] Step 7: Preparation of compound 26H

[0385] The compound 1G was prepared according to the synthesis scheme of Example 1. The colorless oily compound 26H (3.8 g, 87%) was obtained from compound 26G (4.2 g, 12.7 mmol). 1 H NMR (400 MHz, DMSO- d 6) d 7.29 (d, J = 9.9 Hz, 1H), 4.77 (t, J = 5.2 Hz, 1H), 3.72 (s, 3H), 3.66 (td, J = 6.7, 5.2 Hz, 2H), 3.31 (d, J = 6.7 Hz, 1H), 2.75 (t, J = 6.7 Hz, 2H), 1.56 (s, 9H), 1.17 (d, J= 6.6 Hz, 6H). 19 F NMR (377 MHz, DMSO- d 6) d -112.05.

[0386] Step 8: Preparation of compound 26I

[0387] Compound 26I (2.0 g, 100%) was prepared according to the synthetic protocol of Compound 1H in Example 1. The crude product was used directly in the next step. LC-MS m / z = 287.4 [M+H-56] + .

[0388] Step 9: Preparation of compound 26J

[0389] Compound 26J (1.2 g, 47%) was prepared according to the synthesis scheme of compound 1I in Example 1. Compound 26I (2.0 g, 5.8 mol) was used to obtain compound 26J (1.2 g, 47%). 1 H NMR (400 MHz, DMSO- d 6) d 8.04 (t, J = 4.0 Hz, 1H), 7.34( d , J = 9.4 Hz, 1H), 3.92 (t, J = 4.5 Hz, 2H), 3.70 (s, 3H), 3.38-3.34 (m,1H), 1.55 (s, 9H), 1.16 (t, J = 4.0 Hz, 6H), 1.05 (s, 9H). 19 F NMR (377 MHz, DMSO- d 6) d -111.59. LC-MS m / z = 389.8 [M-55] + .

[0390] Step 10: Preparation of compound 26K

[0391] Prepared according to the synthetic protocol of compound 1J in Example 1. A light brown oily compound 26K (1.6 g, 100%) was obtained from compound 26J (1.2 g, 2.76 mol), and the crude product was used directly in the next step. LC-MS m / z = 574.3 [M+H] + .

[0392] Step 11: Preparation of compound 26L

[0393] Compound 2A was prepared according to the synthetic protocol of Example 2. A pale yellow oily compound 26L (0.83 g, 48%) was obtained from compound 26K (1.6 g, 2.76 mol). LC-MS m / z = 626.4 [M+H] + .

[0394] Step 12: Preparation of compound 26M

[0395] Compound 1K was prepared according to the synthetic protocol of Example 1. Compound 26M (54 mg, 100%) was obtained from compound 26L (65.4 mg, 0.104 mol), and the crude product was used directly in the next step. LC-MS m / z = 522.0 [M+H] + .

[0396] Step 13: Preparation of compound 26N

[0397] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 26N (35 mg, 37%) was obtained as a pale yellow powder from compound 26M (54 mg, 0.104 mmol) and compound 1L (45 mg, 0.112 mmol). LC-MS m / z = 904.4 [M+H] + .

[0398] Step 14: Preparation of Compound 26

[0399] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 26 (11 mg, 49%) was obtained from compound 26N (40 mg, 0.0465 mmol). 1 H NMR (400 MHz, D2O) δ 6.96 (d, J = 9.1 Hz, 1H), 3.33 –3.20 (m, 5H), 3.03 (d, J = 3.5 Hz, 1H), 2.85 – 2.69 (m, 3H), 2.24 – 2.16 (m,1H), 1.97 (dd, J = 13.8, 8.2 Hz, 1H), 1.80 – 1.75 (m, 2H), 1.36 (d, J = 14.1Hz, 2H), 1.19 – 1.07 (m, 8H), 0.72 (dt, J = 11.0, 3.4 Hz, 1H), 0.67 – 0.47(m, 2H). 19 F NMR (377 MHz, D2O) δ -116.94. LC-MS m / z = 482.4 [M+H] + .

[0400] Example 27: Synthesis of Compound 27

[0401] Step 1: Preparation of compound 27A

[0402] Compound 26H (2.67 g, 7.74 mmol), imidazole (632 mg, 9.29 mmol), and 4-dimethylaminopyridine (94 mg, 0.744 mmol) were dissolved in anhydrous dichloromethane (30 mL). Dimethyl-tert-butylchlorosilane (1.28 g, 8.51 mmol) was added, and the mixture was heated to 35 °C and stirred for 1 hour. The insoluble salts were removed by filtration, and the organic phase was washed twice with 0.1 N hydrochloric acid and once with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and separated by column chromatography (100 / 0 to 95 / 5 pentane / ethyl acetate) to give a clear oily compound 27A (2.77 g, 80%). 1 H NMR (400 MHz, CDCl3) d 7.03 (d, J = 9.4 Hz, 1H), 3.84 (t, J = 6.7 Hz, 2H), 3.80 (s, 3H), 3.41 (p, J = 6.7 Hz, 1H), 2.84 (t, J = 6.7 Hz, 2H), 1.63 (s, 9H), 1.24 (d, J = 6.2 Hz, 6H), 0.87(s, 9H), 0.00 (s, 6H). 19 F NMR (377 MHz, CDCl3) d -111.89.

[0403] Step 2: Preparation of compound 27B

[0404] Compound 27A (2.304 g, 5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under argon protection. A solution of n-butyllithium (6.03 mL, 15 mmol, 2.5 M hexane) was added dropwise at -70 °C. After stirring at -35 °C for 2 hours, N-fluorobis(benzenesulfonamide) (7.88 g, 25 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred for 10 minutes, then heated to 0 °C. The system was quenched dropwise with 0.1 N hydrochloric acid. After slight concentration, ethyl acetate (40 mL) and 15% sodium chloride aqueous solution (30 mL) were added. The organic phase was extracted and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure, and separated by column chromatography to give compound 27B (0.88 g, 37%). LC-MS m / z = 421.2 [M+H-56] + .

[0405] Step 3: Preparation of compound 27C

[0406] Compound 27B (878 mg, 1.84 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (2.76 mL, 2.76 mmol, 1.0 M tetrahydrofuran solution) was added. The mixture was stirred at room temperature for 15 minutes, concentrated under reduced pressure, and separated by column chromatography (70 / 30 pentane / ethyl acetate) to give compound 27C (475 mg, 71%). 1 H NMR (400 MHz, DMSO- d 6) δ4.89 (t, J = 5.6 Hz, 1H, OH), 3.78 (s, 3H), 3.61 (q, J = 6.5 Hz, 2H), 3.43 –3.35 (m, 1H), 2.82 (t, J = 6.6 Hz, 2H), 1.56 (s, 9H), 1.19 (d, J = 6.6 Hz, 6H). 19 F NMR (377 MHz, DMSO- d 6) δ -135.40 (d, J = 25.1 Hz), -135.95 (d, J =25.5 Hz). LC-MS m / z = 307.2 [M+H-56] + .

[0407] Step 4: Preparation of compound 27D

[0408] Compound 27D (250 mg, 75%) was prepared according to the synthetic protocol of Compound 1H in Example 1. Compound 27D was obtained from Compound 27C (440 mg, 0.927 mmol) . LC-MS m / z = 305.0 [M+H-56] + .

[0409] Step 5: Preparation of compound 27E

[0410] Compound 1I was prepared according to the synthetic scheme of Example 1. Compound 27E (145 mg, 45%) was obtained from compound 27D (250 mg, 0.694 mmol). 1 H NMR (400 MHz, DMSO- d 6) d8.12 – 8.08 (m,1H), 3.99 (s, 2H), 3.71 (s, 3H), 3.40 (dt, J = 13.5, 6.7 Hz, 1H), 1.55 (s,9H), 1.19 (s, 3H), 1.17 (s, 3H), 1.03 (s, 9H). 19 F NMR (377 MHz, DMSO- d 6) d -134.55 (d, J = 24.9 Hz), -135.49 (d, J = 24.9 Hz). LC-MS m / z = 408.2 [M+H-56] + .

[0411] Step 6: Preparation of compound 27F

[0412] Compound 1J was prepared according to the synthetic protocol of Example 1. Compound 27F (185 mg, 100%), a pale brown oil, was obtained from compound 27E (145 mg, 0.313 mmol). The crude product was used directly in the next step. LC-MS m / z = 536.3 [M+H-56] + .

[0413] Step 7: Preparation of compound 27G

[0414] Compound 2A was prepared according to the synthetic protocol of Example 2. Compound 27F (185 mg, 0.313 mmol) yielded a pale yellow oily compound 27G (100 mg, 50%). LC-MS m / z = 644.4 [M+H] + .

[0415] Step 8: Preparation of compound 27H

[0416] Prepared according to the synthetic protocol for compound 1K in Example 1. Crude compound 27H (42 mg, 100%) was obtained from compound 27G (50 mg, 0.078 mol), and was used directly in the next step. LC-MS m / z = 405.8 [M-133] + .

[0417] Step 9: Preparation of compound 27I

[0418] Compound 1M was prepared according to the synthetic protocol of Example 1. Compound 27I (25 mg, 50%) was obtained as a pale yellow powder from compound 27H (42 mg, 0.078 mmol) and compound 1L (22 mg, 0.054 mmol). LC-MS m / z = 922.2 [M+H] + .

[0419] Step 10: Preparation of Compound 27

[0420] Compound 1 was prepared according to the synthetic protocol of Example 1. Compound 27 (3.5 mg, 26%) was obtained from compound 27I (25 mg, 0.027 mmol). 1 H NMR (400 MHz, D2O) d 3.38 – 3.30 (m, 1H), 3.22 (q, J =3.3 Hz, 4H), 3.15 – 3.03 (m, 2H), 2.89 – 2.77 (m, 1H), 2.52 (dd, J = 16.1,4.1 Hz, 1H), 2.26 – 2.17 (m, 1H), 1.99 (dd, J = 13.9, 8.3 Hz, 1H), 1.88 –1.69 (m, 2H), 1.46 – 1.30 (m, 2H), 1.20 – 0.99 (m, 8H), 0.82 – 0.53 (m, 3H). 19 F NMR (377 MHz, D2O) d -139.62 (d, J = 24.2 Hz), -140.21 (d, J = 24.1 Hz).LC-MS m / z = 500.2 [M+H] + .

[0421] Test Example 1: Enzyme Activity Test

[0422] Compound stock solution: The compound was prepared as a 50 mM DMSO stock solution. The positive control compound VNRX-5133 was prepared as a 50 mM DMSO stock solution. After aliquoting, the compound stock solutions were stored at -20°C.

[0423] Preparation and storage of antibiotic substrate stock solution: The fluorescent antibiotic substrate FC5 was synthesized internally and prepared into a 2mM stock solution, which was then aliquoted and stored at -20°C.

[0424] β-lactamase preservation: Each β-lactamase was synthesized by Genscript Biotech Inc., aliquoted and stored at -80°C to avoid repeated freeze-thaw cycles.

[0425] Enzyme activity reaction buffer preparation: SBL buffer: PBS pH 7.4, 0.01% (v / v) Triton X-100; MBL buffer: 50Mm HEPES in PBS pH 7.2, 1 μM ZnSO4, 1 μg / mL BSA, 0.01% v / v Triton X-100

[0426] The buffer solution should be stored at 4°C.

[0427] Experimental steps: a) Remove the test compound and buffer solution and allow it to reach room temperature.

[0428] b) Dilute each compound to the initial experimental concentration with DMSO and buffer (Table 1), and then dilute the compound 3-fold to obtain a total of 10 concentrations.

[0429] c) Add the diluted compound to wells 1-20 of the 384-well blackboard in duplicate for each concentration, 5 μL per well. Add 5 μL of DMSO to wells 21-24.

[0430] d) Dilute each enzyme to the experimental concentration in SBL and MBL buffer (Table 1), and finally add 35 μL / well for a total of 22 wells. Add 35 μL of buffer to wells 23 and 24. Wells 21 and 22 are the maximum test values ​​(Max), and wells 23 and 24 are the minimum test values ​​(Min).

[0431] e) Centrifuge rapidly and incubate at room temperature for 10 minutes.

[0432] f) Dilute antibiotic substrate FC5 in buffer to the experimental concentration of each enzyme (Table 1).

[0433] g) After the 384-well plate has finished incubating, add FC-5 to wells 1-24, 10 μL per well. Centrifuge quickly and then transfer to a microplate reader for reading.

[0434] h) Measure the fluorescence intensity under 355nm excitation light / 460nm emission light in an ELISA reader. Measure the fluorescence intensity every three minutes for a total of 10 measurements.

[0435] Table 1: Test Concentration

[0436] Initial enzyme reaction rate V: Subtract the background reading (min well) without enzyme from each fluorescence intensity reading, and then perform linear regression analysis on each compound concentration group. The slope is the initial enzyme reaction rate (V) at each compound concentration.

[0437] Dose-response curves and IC50 calculation of compounds: The initial rate of enzyme reaction under the action of each compound concentration was fitted by nonlinear regression. The half-maximal inhibitory concentration (IC50) of the compound was calculated according to the formula IC50=(1-Vi / V0)x100 (Vi: initial rate of enzyme reaction under each compound concentration; V0: initial rate of enzyme reaction without compound (Max well)). See Table 2. The software used was Graphpadprism 8.

[0438] Table 2: Selected Compounds (IC) in Enzyme Activity Assay Experiments 50 Value (nM)

[0439] As shown in Table 2, the compounds of this invention can effectively inhibit three clinically important β-lactamases: A (KPC-2, CTX-M-15), B (NDM-1, NDM-5, IMP-1, VIM-1, VIM-2), and D (OXA-23, OXA-48, OXA-10), demonstrating a significant advantage in inhibitory activity compared to compound VNRX-5133. The commercially available drug avibactam exhibits good activity against serine β-lactamases (SBL) of types A and C, but shows no inhibitory effect on type B zinc ion β-lactamases (MBL), and also has low inhibitory activity against type D serine β-lactamases.

[0440] Test Example 2: Minimum Inhibitory Concentration (MIC) Test of Compounds on Bacterial Growth

[0441] (1) The main reagents and consumables are shown in Table 3: (2) Table 3

[0442] (2) The strains are shown in Table 4: Table 4

[0443] (3) Experimental methods

[0444] Strain preparation: The test strain was streaked from a -80°C glycerol tube onto a Mueller Hinton II Agar plate. The plate was then incubated at 37°C for 18-24 hours.

[0445] Culture medium preparation: CAMHB (Mueller Hinton II Broth): Dissolve 22 g of powder in 1 L of pure water and sterilize at 121°C for 10 min. Physiological saline: Dissolve 8.5 g of NaCl in 1 L of pure water and sterilize at 121°C for 30 min.

[0446] Preparation of stock solutions of compounds and antibiotics: Dissolve the compounds and antibiotics in DMSO or water to a concentration of 12.8 mg / ml.

[0447] Antibiotic serial dilution: Add 300 μL of CAMHB medium to columns 2-12 of a 96-well deep plate. Add 24 μL of the antibiotic stock solution and 576 μL of CAMHB medium to column 1, mix well, and the concentration is 512 μg / mL. Take 300 μL of the antibiotic solution from column 1 to column 2 and mix well. Repeat this process until column 11. Column 12 is the blank control.

[0448] Dilution of the compound: Dilute the compound 400 times with CAMHB medium to 32 ug / ml.

[0449] Working solution aliquoting: Use a pipette to aliquot 25 μL of antibiotic into each 96-U substrate, and then add 25 μL of the compound to be used in combination to each well. If the antibiotic is used alone, add 25 μL of CAMHB medium.

[0450] Inoculation preparation: Pick 5-6 single colonies from the plate and suspend them in physiological saline. Adjust the bacterial suspension to 0.2 (i.e., 0.5 McFarland turbidity, with a bacterial concentration of approximately 1-2 x 10⁻⁶) using a turbidimeter. 8 (CFU / mL). Dilute the bacterial suspension 100 times with CAMHB medium for later use.

[0451] Inoculation: Transfer 50 μL of inoculum to the above 50 μL compound plate using a pipette.

[0452] Culture: Place the 96-U substrate in a 37℃ incubator and incubate for 18-20 h.

[0453] (4) MIC assessment: After incubation, bacterial growth is visually observed, and the test plate is photographed and archived. The minimum compound concentration at which bacterial growth is completely inhibited is defined as the minimum inhibitory concentration (MIC).

[0454] Table 5: MIC values ​​(ug / mL) of selected compounds in combination with the antibiotics ceftazidime / cefoperazone

[0455] As shown in Table 5, the latest antibiotic combination on the market, avibactam and ceftazidime, is effective against only 3 carbapenem-resistant strains (ATCC-BAA-1705 / 1898, ARLG-1019), and completely ineffective against MBL-producing resistant strains (ARLG-1196 / 2829, ATCC-BAA-2470, NCTC 13439 / 13476). However, the compound of this invention, when combined with cefoperazone, is effective against most of these resistant strains. For example, cefoperazone + compound 7 is effective against 6 out of 7 tested strains (ineffective against NCTC 13476), showing a significant advantage in inhibitory spectrum compared to the combination of avibactam and ceftazidime.

[0456] Table 6: Determination of MIC values ​​(ug / mL) of selected compounds in combination with the antibiotic cefepime / meropenem

[0457] As shown in Table 6, the compounds of this invention, when used in combination with antibiotics, exhibited significant advantages in antibacterial activity and antibacterial spectrum against the aforementioned carbapenem-resistant strains. In particular, compound 10 of this invention, when used in combination with meropenem, was effective against all seven resistant strains (two strains, ATCC-BAA-1705 / 1898, both expressing KPC-2), showing a significant advantage in antibacterial activity and antibacterial spectrum compared to the combination of cefepime and VNRX5133. Compound 19 of this invention, when used in combination with cefepime / meropenem, showed extremely high antibacterial activity against the four selected resistant strains (ATCC-BAA-1705, ARLG-1196, ATCC-BAA-2470, ARLG-2829), also showing a significant advantage in antibacterial activity compared to the combination of cefepime and VNRX5133.

Claims

1. The compound represented by formula (IC), its optical isomer, or a pharmacologically acceptable salt thereof, ， in, m and n are each independently selected from 1; T is selected from CH; R1 is selected from , , or ; R2 is selected from H; R3 is selected from H; R4 is selected from H; R a Selected from H or F; R b Selected from H or F; R c Selected from Me, Et, , , , , , , , , , , , , or ; R is selected from H, Me, or Et; L c Selected from S.

2. The compound according to claim 1, its optical isomer, or a pharmacologically acceptable salt thereof, selected from... 。 3. Use of the compound of any one of claims 1-2, its optical isomer, or its pharmacologically acceptable salt in the preparation of a medicament for treating bacterial infections.

4. The use according to claim 3, wherein, Further including the compound of any one of claims 1-2, its optical isomer or its pharmacologically acceptable salt, and its combination with β-lactam antibiotics.

5. The use according to claim 4, wherein, The β-lactam antibiotics are selected from cephalosporins, carbapenems, or combinations thereof.

6. The use according to claim 5, wherein, The cephalosporins are selected from ceftazidime, cefoperazone, and cefepime.

7. The use according to claim 5, wherein, The carbapenems are selected from meropenem.

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