Boric acid β-lactamase inhibitor and use thereof

Abstract

The present invention relates to the pharmaceutical field, and provides a boric acid β-lactamase inhibitor or a use thereof. The boric acid β-lactamase inhibitor is a compound shown in formula (I), or an optical isomer or a pharmaceutically acceptable salt thereof: formula (I). The ultra-broad-spectrum boric acid β-lactamase inhibitor of the present invention has an inhibition effect on A, B, C, and D enzymes, and carbapenem drug-resistant bacteria such as Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii, and Pseudomonas aeruginosa.

Description

Boric acid beta-lactamase inhibitors and uses thereof TECHNICAL FIELD

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

[0002] The long-term abuse of antibiotics has led to the enhancement of bacterial drug resistance, and antibiotic resistance (AMR) has become one of the important public health problems threatening global human health. A study commissioned by the British government shows that AMR causes about 700,000 deaths worldwide each year, and is expected to cause 10 million deaths worldwide each year and a cumulative economic loss of 100 trillion US dollars by 2050.

[0003] Drug-resistant bacteria, in a broad sense, are a general term for pathogenic bacteria that have developed resistance to antibacterial drugs. In 2017, the WHO issued a bulletin classifying clinically important drug-resistant bacteria according to the degree of harm to the human body, pointing out that new antibacterial drugs are urgently needed to combat infections caused by important drug-resistant bacteria, among which the pathogenic bacteria listed as requiring urgent and priority attention are carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Enterobacteriaceae (CRE), and third-generation cephalosporin-resistant Enterobacteriaceae (3GCephRE). The latest WHO data on drug resistance shows that among countries reporting microbial drug resistance using the Global Antimicrobial Resistance Surveillance System (GLASS), the resistance rate to ciprofloxacin was 8.4% to 92.9% for Escherichia coli and 4.1% to 79.4% for Klebsiella pneumoniae. Data from the Chinese Bacterial Drug Resistance Surveillance Network in 2022 shows that the drug resistance rate of Gram-negative bacteria in China was 71.4%, and that of Gram-positive bacteria was 28.6%. The top five isolated bacteria were Escherichia coli (18.96%), Klebsiella pneumoniae (14.12%), Staphylococcus aureus (8.93%), Pseudomonas aeruginosa (7.96%), and Acinetobacter baumannii (7.28%).

[0004] In the face of such a serious threat of antibiotic-resistant bacteria, the speed of new antibiotic development is far slower than the emergence of drug resistance. If antibiotics are continued to be misused, there will be fewer and fewer effective drugs available in the future, leading to the emergence of "superbugs", making it more difficult to diagnose and treat organ transplants, intensive care and other clinical conditions, leading to the emergence of the "post-antibiotic" era. Globalization has greatly facilitated the spread of drug-resistant bacteria. Horizontal transfer of drug resistance genes is the cause of most current antimicrobial drug resistance. Beta-lactam antibiotics are the most widely used antibiotics in clinical practice (such as cephalosporins, carbapenems, etc.), which have good antibacterial effect on both gram-positive and gram-negative bacteria, and have the advantages of good clinical efficacy, low toxicity, and wide indications. Beta-lactam antibiotics mainly inhibit the catalytic activity of bacterial cell wall mucin synthetase (i.e. penicillin binding protein, abbreviated as PBP), thereby preventing cell wall mucin synthesis, leading to bacterial cell wall defects, bacterial lysis and death. However, today's highly resistant beta-lactam antibiotic-resistant "super" bacteria are emerging and rapidly spreading worldwide, and have become one of the main sources of difficult-to-treat infections at home and abroad. Therefore, it is urgent to solve the problem of beta-lactam antibiotic resistance.

[0005] In the face of the urgent problem of antibiotic resistance in clinical practice, it is necessary to develop new inhibitors. SUMMARY

[0006] In view of the above technical status, the present application provides a new generation of boronic acid beta-lactamase inhibitor, which has inhibitory effect on A, B, C and D enzymes, and carbapenem-resistant bacteria such as Klebsiella pneumoniae, Escherichia coli, Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii and Pseudomonas aeruginosa, and has a super broad-spectrum beta-lactamase inhibitor.

[0007] The present application provides a boronic acid beta-lactamase inhibitor, which is a compound represented by formula (I), an optical isomer or a pharmaceutically acceptable salt thereof:

[0008] wherein,

[0009] X is C, O or N;

[0010] Y is B, N or P;

[0011] Z is O, S, B or N;

[0012] R1 is H, wherein E is selected from alkenyl or alkynyl;

[0013] R2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C1-6 alkoxy or nothing; or

[0014] R1, R2and the atoms to which they are attached form a ring: wherein R a , R b each independently is selected from H, deuterium, hydroxyl, thiol, cyano, alkylthio, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, haloaryl, arylheteroaryl or haloarylheteroaryl;

[0015] R3is H or hydroxyl;

[0016] R4is carboxyl, sulfonic acid, amide or sulfonamide;

[0017] k is 0, 1, 2, 3, 4, 5 or 6; as an illustrative example, when k is 0, the corresponding moiety is a single bond;

[0018] R5, R6, R7, R8each independently is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, haloaryl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 haloepoxyalkyl, C 3-8 epoxyalkyl, arylheteroaryl, or haloarylheteroaryl, and the like;

[0019] A ring is selected from C 3-8 carbocyclic, C 3-8 carbocyclic, aromatic, arylheteroaromatic, spirocyclic, spiroheterocyclic or bridged cyclic;

[0020] In the present application, as one of the embodiments, the A ring is unsubstituted or substituted with one, two identical or different, or three or more identical, partially identical or completely different substituents selected from deuterium, halogen, hydroxyl, thiol, cyano, alkylthio, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 epoxyalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkyl, aryl, haloaryl, arylheteroaryl, haloarylheteroaryl; as one of the embodiments, further preferably the A ring is unsubstituted or substituted with one, two identical or different, or three or more identical, partially identical or completely different substituents selected from deuterium, methyl, ethyl, propyl, cyclopropyl, F, Cl;

[0021] In the present application, as one of the embodiments, when the A ring is a heterocarbocyclic ring, an aromatic heterocyclic ring, or a spiro heterocyclic ring, it includes one heteroatom, two same or different heteroatoms, or three or more same, partially same, or completely different heteroatoms, and the heteroatom is selected from O, N, or S;

[0022] In the present application, as one of the embodiments, in the compound represented by formula (I), the optical isomer, or the pharmaceutically acceptable salt thereof, the A ring is selected from:

[0023] wherein,

[0024] M and G are each independently selected from CH2, O, S, or NH;

[0025] n is 1, 2, 3, 4, 5, or 6;

[0026] j is 0, 1, 2, 3, 4, 5, or 6;

[0027] R c is selected from H, halogen, deuterium, hydroxyl, thiol, cyano, alkylthio, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 epoxyalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkylaryl, halogenated aryl, arylhetero, halogenated arylhetero, when j is 2, R c are the same or different; when j is 3, 4, 5, or 6, R c are the same, partially same, or completely different.

[0028] In the present application, as one of the embodiments, in the compound represented by formula (I), the optical isomer, or the pharmaceutically acceptable salt thereof, in the A ring, R c is selected from H, halogen, deuterium, hydroxyl, thiol, cyano, -C(=O)-R j , alkylthio, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 epoxyalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkylaryl, halogenated aryl, arylhetero, halogenated arylhetero;

[0029] wherein, R j is selected from -NR d R f , C 1-6 alkyl, C 1-6 alkoxy, C3-6 Epoxyalkyl, C 3-6 Cycloalkyl, aryl, aromatic heteroyl, wherein the alkyl, alkoxy, cycloalkyl, epoxyalkyl, aryl, aromatic heteroyl can be atomized by one or more halogens, cyano, hydroxyl, nitro, C2-C6 alkenyl, C3-C6 alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, aryl, haloaryl, aryl or haloaryl; wherein, R d R f Each is independently selected from H, deuterium, hydroxyl, mercapto, cyano, alkyl sulfide, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cyclohexaalkyl, aryl, halogenated aryl, aromatic heteroyl or halogenated aromatic heteroyl.

[0030] In this invention, as one embodiment, in the compound, optical isomer, or pharmaceutically acceptable salt of formula (I), ring A, wherein R... c It can be methyl, cyclopropyl, dimethyl, ethyl, or fluorine.

[0031] In this invention, as one embodiment, in the compound, optical isomer, or pharmaceutically acceptable salt thereof represented by formula (I), the A ring is:

[0032] In this invention, as one embodiment, in the compound, optical isomer, or pharmaceutically acceptable salt of formula (I), when R1, R2 and the atoms they are connected to form a ring: And R a R b When both are H or deuterium, the A ring is selected from...

[0033] In this invention, as one embodiment, in the compound, optical isomer, or pharmaceutically acceptable salt of formula (I), R1, R2, and the atoms to which they are attached form a ring:

[0034] In this invention, as one embodiment, the borate β-lactamase inhibitor is a compound of formula (I), an optical isomer, or a pharmaceutically acceptable salt thereof:

[0035] wherein

[0036] X is C, O or N;

[0037] Y is B, N or P;

[0038] Z is O, S, B or N;

[0039] R1is H, wherein E is selected from alkenyl or alkynyl;

[0040] R2is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or is absent;

[0041] R3is H or hydroxyl;

[0042] R4is carboxyl, sulfonic acid, amido or sulfonamido;

[0043] L1is H or

[0044] f, n, i are each independently 1, 2, 3, 4, 5 or 6;

[0045] k is 0, 1, 2, 3, 4, 5 or 6;

[0046] R5, R6, R7, R8are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, haloaryl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 halocycloalkenyl, C 3-8 cycloalkenyl, arylhetero, or halogenarylhetero;

[0047] A ring is selected from C 3-8 carbocyclic, C 3-8 carbocyclic, aromatic, arylheterocyclic, spirocyclic, spiroheterocyclic, or bridged cyclic; said A ring is unsubstituted or substituted with one, two identical or different, or three or more identical, partially identical or completely different substituents selected from the group consisting of deuterium, halogen, hydroxyl, thiol, cyano, alkylthio, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 epoxyalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkylaryl, haloaryl, arylhetero, halogenarylhetero.

[0048] In the present application, as one of the embodiments, in the compound represented by formula (I), the optical isomer or the pharmaceutically acceptable salt thereof, the A ring is unsubstituted or substituted with one, two identical or different, or three or more identical, partially identical or completely different substituents selected from the group consisting of deuterium, methyl, ethyl, propyl, cyclopropyl, F, Cl;

[0049] In the present application, as one of the embodiments, in the compound represented by formula (I), the optical isomer or the pharmaceutically acceptable salt thereof, when the A ring is a heterocarbocyclic ring, an aromatic heterocyclic ring or a spiro heterocyclic ring, it includes one heteroatom, two identical or different heteroatoms, or three or more identical, partially identical or completely different heteroatoms, and the heteroatom is selected from O, N or S.

[0050] In the present application, as one of the embodiments, in the compound represented by formula (I), the optical isomer or the pharmaceutically acceptable salt thereof, the A ring is selected from:

[0051] wherein,

[0052] M and G are each independently selected from CH2, O, S or NH;

[0053] n is 1, 2, 3, 4, 5 or 6;

[0054] j is 0, 1, 2, 3, 4, 5 or 6;

[0055] R c selected from H, halogen, deuterium, hydroxyl, thiol, cyano, -C(=O)-R j , alkylthio group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 epoxyalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkylaryl, halogenated aryl, arylhetero group, halogenated arylhetero group;

[0056] R j selected from -NR d R f , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 epoxyalkyl, C 3-6 cycloalkyl, aryl, arylhetero group, and the alkyl, alkoxy, cycloalkyl, epoxyalkyl, aryl, arylhetero group can be substituted with one or more halogen, cyano, hydroxyl, nitro, C2-C6 alkenyl, C 1-6 alkyl, C 1-6 alkoxy, C1-6 haloalkyl, C 1-6 haloalkoxy, aryl, haloaryl, araheteroaryl or haloaraheteroaryl; wherein R d , R f each independently is selected from H, deuterium, hydroxyl, thiol, cyano, alkylthio, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloheteroalkyl, C 3-6 halocycloheteroalkyl, aryl, haloaryl, araheteroaryl or haloaraheteroaryl.

[0057] In the present application, as one of the embodiments, when j is 2, R c are the same or different; when j is 3, 4, 5 or 6, R c are the same, partially the same or completely different.

[0058] In the present application, as one of the embodiments, in the ring A in the compound represented by formula (I), optical isomer or pharmaceutically acceptable salt thereof, R c is methyl, cyclopropyl, dimethyl, ethyl or fluorine.

[0059] In the present application, as one of the embodiments, in the compound represented by formula (I), optical isomer or pharmaceutically acceptable salt thereof, the ring A is:

[0060] In another aspect of the present application, the boronic acid type β-lactamase inhibitor is a compound represented by formula (II), optical isomer or pharmaceutically acceptable salt thereof:

[0061] wherein,

[0062] X is C, O or N;

[0063] Y is B, N or P;

[0064] Z is O, S, B or N;

[0065] a is 0, 1, 2, 3 or 4, preferably a is 1 or 2;

[0066] M, Q are each independently C, O, S or N, and M, Q are not the same atom;

[0067] R1, R2 and the atoms to which they are attached form a ring of: wherein R a , R beach independently selected from H, deuterium, hydroxyl, thiol, cyano, alkylthio, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, haloaryl, arahetero, or haloarahetero;

[0068] R3is H or hydroxyl;

[0069] R4is preferably carboxyl, sulfonic acid, amide, or sulfonamide;

[0070] e is 0, 1, 2, or 3;

[0071] R M is H, halo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, which alkylalkoxy can be substituted with any one or more halo.

[0072] In the present application, as one of the embodiments, in the compound represented by the formula (II), the optical isomer, or the pharmaceutically acceptable salt thereof, when M is a C atom, Q is not an O atom.

[0073] In the present application, as one of the embodiments, in the compound represented by the formula (II), the optical isomer, or the pharmaceutically acceptable salt thereof, when Q is a C atom, M is not an O atom.

[0074] In the present application, as one of the embodiments, in the compound represented by the formula (II), the optical isomer, or the pharmaceutically acceptable salt thereof, when R M is a methyl group, a dimethyl group, a cyclopropyl group, or an ethyl group.

[0075] The present application further provides a boronic acid type β-lactamase inhibitor, which is a compound represented by the formula (III), the optical isomer, or the pharmaceutically acceptable salt thereof:

[0076] wherein,

[0077] X is C, O, or N;

[0078] Y is B, N, or P;

[0079] Z is O, S, B, or N;

[0080] M and Q are each independently C, O, S, or N, and M and Q are not the same atom;

[0081] R1and R2, together with the atom to which they are attached, form a ring: wherein, R a , Rb each independently selected from H, deuterium, hydroxyl, thiol, cyano, alkylthio, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, haloaryl, heteroaryl, or halo-heteroaryl;

[0082] R3is H or hydroxyl;

[0083] R4is preferably carboxyl, sulfonic acid, amide, or sulfonamide;

[0084] e is 0, 1, 2, or 3;

[0085] R M halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, the alkylalkoxy group can be substituted with any one or more halogens; as an embodiment, R M is preferably methyl, dimethyl, cyclopropyl, or ethyl.

[0086] In the present application, as an embodiment, in the compound represented by formula (III), the optical isomer, or the pharmaceutically acceptable salt thereof, R M is methyl, dimethyl, cyclopropyl, or ethyl.

[0087] In the present application, the C 1～6 alkyl group, as an illustrative example, includes, but is not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl, isohexyl, 3-methylpentyl, 2-ethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, or cyclohexyl, and the like.

[0088] In the present application, as an embodiment, the C 1-6 alkoxy group, as an illustrative example, includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, isobutoxy, n-butoxy, sec-butoxy, t-butoxy, cyclobutoxy, pentoxy, isopentoxy, cyclopentoxy, hexoxy, isohexoxy, 3-methylpentoxy, 2-ethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, or cyclohexoxy, and the like.

[0089] In the present application, as an embodiment, the C 1-6Halogenated alkyl groups, including but not limited to halogenated methyl, halogenated ethyl, halogenated propyl, halogenated isopropyl, halogenated cyclopropyl, halogenated isobutyl, halogenated n-butyl, halogenated sec-butyl, halogenated tert-butyl, halogenated cyclobutyl, halogenated pentyl, halogenated isopentyl, halogenated cyclopentyl, halogenated hexyl, halogenated isohexyl, halogenated 3-methylpentyl, halogenated 2-ethylbutyl, halogenated 2,2-dimethylbutyl, halogenated 2,3-dimethylbutyl, or halogenated cyclohexyl, etc.

[0090] In this invention, as one embodiment, the saturated or unsaturated C 3-8 Carbon ring, C 3-8 Carbon heterocycles, halogenated C 3-8 Carbocyclic rings, halogenated C 3-8 The carbon heterocycle, by way of example, can be cyclopropane, cyclopropylene, cyclobutane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, etc., wherein one, two, or more carbon atoms in the ring are each independently substituted by O, N, or S.

[0091] In this invention, as one embodiment, the aryl, halogenated aryl, aromatic heterol, or halogenated aromatic heterol can be phenyl, halogenated phenyl, imidazolyl, furanyl, pyrazinyl, thiazolyl, thiophene, oxazolyl, pyrroleyl, thiophene, pyrimidinyl, pyrazolyl, thiadiazolyl, triazolyl, halogenated imidazolyl, halogenated furanyl, halogenated pyrazinyl, halogenated thiazolyl, halogenated thiophene, halogenated oxazolyl, halogenated pyrroleyl, halogenated thiophene, halogenated pyrimidinyl, halogenated pyrazolyl, halogenated thiadiazolyl, halogenated triazolyl, etc.

[0092] In this invention, as one embodiment, the C 2～6 The olefin group, as an example, can be including but not limited to vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptenyl, octadienyl, or isopreneyl.

[0093] In this invention, as one embodiment, the C 2～6 The alkyne group, as an example, can be ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0094] In this invention, as one embodiment, the C 1～5 Alkyl groups, as an example, include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, etc.

[0095] In this invention, the halogens, halogenated or halogenated substances mentioned above are, as examples, including but not limited to F, Cl, Br or I.

[0096] In the present application, as one of the embodiments, the pharmaceutically acceptable salt includes pharmaceutically acceptable base salt, as an exemplary illustration, the base includes but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc.

[0097] In the present application, as one of the embodiments, the pharmaceutically acceptable salt includes pharmaceutically acceptable acid salt, as an exemplary illustration, the acid includes but is not limited to inorganic acid or organic acid, the inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid. The organic acid includes but is not limited to citric acid, oxalic acid, lactic acid, etc.

[0098] In the present application, in some embodiments, the compound of formula (I) is selected from:

[0099] In the present application, in some embodiments, the compound of formula (I) is selected from:

[0100] The present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound, its optical isomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0101] The compound of the present application, its optical isomer or pharmaceutically acceptable salt thereof, and its pharmaceutical composition can be used alone or in combination with one or more other drugs, and can be mixed into a preparation or formulated into a separate preparation for simultaneous use.

[0102] In some embodiments, the above-mentioned pharmaceutical composition further comprises other drugs or pharmaceutically active ingredients, including but not limited to penicillins (penicillin, amoxicillin, ampicillin, piperacillin, azlocillin, mezlocillin, sulbactam, etc.), cephalosporins (cephalothin, cefazolin, cefradine, cephalexin, cefamandole, cefuroxime, cefaclor, cefotaxime, ceftriaxone, ceftazidime, cefixime, cefpirome, cefepime, cefpirome, etc.), carbapenems (meropenem, imipenem, biapenem, etc.), monobactams (aztreonam), etc.

[0103] The present application provides a use of the above-mentioned compound, its optical isomer or pharmaceutically acceptable salt in the preparation of a drug for treating bacterial infection.

[0104] In the present application, as one of the embodiments, the infection includes but is not limited to infection caused by Klebsiella pneumoniae, Escherichia coli, Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii or Pseudomonas aeruginosa, etc.

[0105] The new generation of acid beta-lactamase inhibitors has inhibitory effect on A, B, C and D enzymes, and has inhibitory effect on carbapenem-resistant bacteria such as Klebsiella pneumoniae, Escherichia coli, Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii and Pseudomonas aeruginosa, has super broad-spectrum beta-lactamase inhibitor, meets the clinical demand of therapeutic drugs for diseases caused by bacterial infection, and has great clinical value. DETAILED DESCRIPTION

[0106] The following examples are used to further illustrate the present application, but in no way limit the effective range of the present application.

[0107] Example 1

[0108] Step 1: Preparation of 4-(2-hydroxyethyl)phenyl acetate (compound 1-2)

[0109] 4-(2-hydroxyethyl)phenol (compound 1-1, 85.40 g, 0.60 mol) was added to a mixture of Ac2O (63.10 g, 0.60 mol) and K2CO3 (102.50 g, 0.70 mol). The reaction was terminated after stirring at room temperature for 16 hours. The reaction solution was suction filtered with diatomite and concentrated under vacuum to obtain a colorless oil of the crude product (compound 1-2, 100 g, 0.50 mol, 80% yield), which was directly used in the next step.

[0110] 1H NMR (400 MHz, CDCl3) δ 7.24-7.17 (m, 2H), 7.03-6.96 (m, 2H), 3.78 (dd, J = 13.2, 6.4 Hz, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.51 (s, 1H), 2.28 (s, 3H).

[0111] Step 2: Preparation of isochromen-7-yl acetate (compound 1-3)

[0112] Under nitrogen protection at 0°C, BF3·Et2O (261.10 g, 0.80 mol) was added dropwise to a solution of 4-(2-hydroxyethyl)phenyl acetate (compound 1-2, 61.00 g, 0.30 mol), (CH2O)n (45.70 g, 0.50 mol) in DCM (600 mL). The mixture was reacted at room temperature for 3 hours and terminated. The pH value of the solution was adjusted to 7 with 20% NaHCO3 solution. Extraction was performed with ethyl acetate, washed with brine, dried with sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EtOAc / PE = 0%-5%) to obtain the target product (compound 1-3, 50 g, 0.20 mol, 61% yield) as a colorless oil.

[0113] 1H NMR (400 MHz, CDC13) δ 7.12 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 8.0, 2.0 Hz, 1H), 6.72 (s, 1H), 4.75 (s, 2H), 3.96 (t, J = 5.6 Hz, 2H), 2.83 (t, J = 5.6 Hz, 2H), 2.28 (s, 3H).

[0114] Step 3: Preparation of isochroman-7-ol (Compound 1-4)

[0115] To a solution of isochroman-7-yl acetate (Compound 1-3, 55 g, 0.28 mol) in MeOH (400 mL) was added sodium hydroxide (17.10 g, 0.42 mmol) and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was concentrated to remove the organic solvent. The pH was adjusted to 2-3 with 2N HC1. White solid was precipitated and was suction filtered. The filter cake was washed with water and petroleum ether and dried to give the target product (Compound 1-4, 23 g, 0.13 mol, 48% yield) as a white solid.

[0116] 1H NMR (400 MHz, CDC13) δ 6.97 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.0, 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 5.83 (s, 1H), 4.71 (s, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.78 (t, J = 5.6 Hz, 2H).

[0117] Step 4: Preparation of 8-bromo isochroman-7-ol (Compound 1-5)

[0118] To a solution of isochroman-7-ol (Compound 1-4, 20 g, 0.13 mol) in DMF (200 mL) was slowly added NBS (23.70 g, 0.13 mol) at 0 °C under nitrogen protection. The mixture was kept at 0 °C for 2 hours and then quenched. The reaction was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EtOAc / PE = 0% - 10%) to give the target product (Compound 1-5, 35 g, 0.12 mmol, 91% yield) as a colorless oil.

[0119] 1H NMR (400 MHz, CDC13) δ 7.00 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.56 (s, 1H), 4.68 (s, 2H), 3.91 (t, J = 5.6 Hz, 2H), 2.78 (t, J = 5.6 Hz, 2H).

[0120] Step 5: Preparation of 8-bromo-7-(methoxymethoxy)isochromene (Compound 1-6)

[0121] To a solution of 8-bromo-isochroman-7-ol (Compound 1-5, 17 g, 0.07 mol) in DCM (150 mL) was added DIEA (19.20 g, 0.14 mol) and bromo(methoxy)methane (13.90 g, 0.11 mol) slowly at 0 °C under nitrogen protection. The mixture was reacted at 25 °C for 2 hours to terminate. The reaction solution was added with water, extracted with ethyl acetate. Washed with brine, dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (EtOAc / PE = 0% - 3%) to obtain the target product (Compound 1-6, 17 g, 0.05 mmol, 75% yield) as colorless oil.

[0122] 1H NMR (400 MHz, CDC13) δ 7.01 (q, J = 8.4 Hz, 2H), 5.22 (s, 2H), 4.71 (s, 2H), 3.95 - 3.86 (m, 2H), 3.52 (s, 2H), 2.79 (t, J = 5.6 Hz, 2H).

[0123] Step 6: Preparation of 7-(methoxymethoxy)isochromene-8-carboxylic acid (Compound 1-7)

[0124] To a solution of 8-bromo-7-(methoxymethoxy)isochromene (Compound 1-6, 27 g, 0.09 mol) in super dry THF (500 mL) was added n-BuLi (2.5 M in hexane, 79 mL, 0.19 mmol) slowly dropwise at -78 °C under nitrogen protection. After addition, the reaction solution was kept stirring at -78 °C for 1 hour. Then dry ice (130.5 g, 2.90 mol) was added slowly. After addition, the reaction solution was slowly warmed to room temperature and stirred for 16 hours to terminate the reaction. The reaction solution was quenched with a small amount of NH4Cl solution, concentrated to obtain the crude target product 1-7 which was directly used in the next step.

[0125] Step 7: Preparation of 7-hydroxyisochromene-8-carboxylic acid (Compound 1-8)

[0126] The crude 7-(methoxymethoxy)isochromene-8-carboxylic acid (compound 1-7) was dissolved in DCM (500 mL) at room temperature, and TFA (100 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 5 hours. The reaction was terminated. The reaction solution was concentrated. The crude product was purified by reverse phase column (C 18 chromatography column eluted with 0% to 70% ACN in H2O with 0.1% formic acid to give the target compound (compound 1-8, 14 g, 0.06 mol, 65% yield) as a white solid.

[0127] 1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.81 (s, 2H), 3.79 (t, J = 5.6 Hz, 2H), 2.71 (t, J = 5.6 Hz, 2H).

[0128] Step 8: Preparation of 6-bromo-7-hydroxyisochroman-8-carboxylic acid (compound 1-9)

[0129] To a solution of 7-hydroxy-3,4-dihydro-lH-2-benzopyran-8-carboxylic acid (compound 1-8, 20 g, 0.10 mol) in DCM was added NBS (11 g, 0.06 mol), and the mixture was stirred at 25 °C for 2 hours. The organic phase was concentrated, and the crude product was purified by silica gel chromatography (PE / EtOAc = 15: 1) to give the target product (compound 1-9, 5.0 g, 0.02 mol, yield 16.02%) as a white solid.

[0130] 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 4.83 (s, 2H), 3.78 (t, J = 5.6 Hz, 2H), 2.74 (t, J = 5.6 Hz, 2H).

[0131] Step 9: Preparation of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)isochroman-8- carboxylate (compound 1-10)

[0132] Step 1: Preparation of 6-bromo-7-hydroxyisochromene-8-carboxylic acid (Compound 1-9)

[0133] 1H NMR (400 MHz, CDC13) δ 7.42 (s, 1H), 4.75 (d, J = 11.4 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 1.57 (s, 9H), 1.55 (s, 9H).

[0134] Step 10: Preparation of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)isochromene-8-carboxylate (Compound 1-12)

[0135] Step 10: Preparation of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)isochromene-8-carboxylate (Compound 1-12)

[0136] 1H NMR (400 MHz, CDC13) δ 7.40 (s, 2H), 7.40 (d, J = 2.0 Hz, 1H), 6.13 (d, J = 2.0 Hz, 1H), 4.81 (s, 2H), 3.93 (t, J = 5.8 Hz, 2H), 2.86 (t, J = 5.8 Hz, 2H), 1.57 (s, 9H), 1.54 (s, 9H), 1.27 (s, 12H).

[0137] Step 11: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-6-((Z)-2-((3aS,4R,6R)- 3a,5,5-trimethylhexahydro-4,6-methanobenz[d][l,3,2]dioxaborol-2-yl)vinyl)isochroman-8- carboxylate (Compound 1-13)

[0138] tert-Butyl (E)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)vinyl)isochroman-8-carboxylate (Compound 1-12, 750 mg, 1.92 mmol) and tris(2- phenylpyridine)iridium (251.54 mg, 0.38 mmol) were added into MeCN (15 mL) and stirred at 25 °C under nitrogen protection with light (450 nm) for 16 h. The mixture was purified by silica gel column chromatography (PE / EtOAc = 10: 1) to give the target product (Compound 1-13, 474 mg, 1.21 mmol, 63.20% yield) as yellow oil.

[0139] 1H NMR (400 MHz, CDC13) δ 7.42 (s, 1H), 7.13 (d, J = 14.8 Hz, 1H), 5.70 (d, J = 14.8 Hz, 1H), 4.83 (s, 2H), 3.94 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 1.56 (s, 9H), 1.50 (s, 9H), 1.25 (s, 12H).

[0140] Step 12: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-6-((Z)-2-((3aS,4R,6R)- 3a,5,5-trimethylhexahydro-4,6-methanobenz[d][l,3,2]dioxaborol-2-yl)vinyl)isochroman-8- carboxylate (Compound 1-14)

[0141] To a solution of (Z)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)vinyl)isochroman-8-carboxylic acid tert-butyl ester (Compound 1-13, 410 mg, 1.05 mmol), Pd(OAc)2(23.57 mg, 0.11 mmol) and CH2N2(freshly prepared, 7 mL, 0.6 M in Et2O) in THF (3 mL) was stirred at -10 °C for 2 h, then at 25 °C for 14 h. The mixture was diluted with EtOAc, washed with H2O, and dried over Na2SO4. The organic phase was concentrated to dryness, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 10:1) to give the target product (Compound 1-14, 215 mg, 0.53 mmol, 50.62% yield) as yellow oil.

[0142] 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 4.77 (t, J = 10.6 Hz, 2H), 3.91 (t, J = 5.6 Hz, 2H), 2.80 (d, J = 4.0 Hz, 2H), 2.18 (dd, J = 16.6, 7.6 Hz, 1H), 1.55 (d, J = 4.8 Hz, 18H), 1.26 (m, 2H), 1.08 (d, J = 6.2 Hz, 6H), 0.95 (s, 6H), 0.39 (td, J = 9.6, 7.2 Hz, 1H).

[0143] Step 13: Preparation of 7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclopropyl)isochroman-8-carboxylic acid tert-butyl ester (Compound 1)

[0144] To a solution of 7-{[(tert-butoxy)carbonyl]oxy}-6-(2-methylcyclopropyl)-3,4-dihydro-1H- 2-benzopyran-8-carboxylic acid tert-butyl ester (Compound 1-14, 100 mg, 0.25 mmol) and methylboronic acid (50.40 mg, 0.85 mmol) in THF (1 mL) was added concentrated hydrochloric acid (1 mL) at 0 °C. The mixture was stirred at 25 °C under nitrogen protection for 2 h. The reaction was blown with nitrogen to remove the hydrochloric acid, then diluted with C 18 Purification by reverse phase column chromatography (eluted with 0.1% TFA in 0-40% MeCN / H2O) gave the final product (Compound 1, 10 mg, 0.03 mmol, 14% yield) as a white solid.

[0145] LCMS (ESI) m / z = 261.05 [M+H] + .

[0146] 1 H NMR (400 MHz, MeOD) d 7.17 (s, 1H), 4.71 (d, J = 3.0 Hz, 2H), 3.91 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.26 (td, J = 8.2, 4.2 Hz, 1H), 1.32 (ddd, J = 11.2, 7.8, 3.6 Hz, 1H), 0.57 (ddd, J = 10.4, 8.2, 6.2 Hz, 1H), 0.37 (m, 1H).

[0147] Example 2

[0148] Step 1: Preparation of methyl 3-(3-methoxyphenoxy)propanoate (Compound 2-3)

[0149] To a mixture of 3-methoxyphenol (Compound 2-1, 20 g, 0.16 mol) and methyl acrylate (Compound 2-2, 16.64 g, 0.19 mol) was added hydroquinone (0.18 g, 1.61 mmol), the reaction was heated to 110 °C in an oil bath, then sodium pieces (0.19 g, 8 mmol) was added, after that the reaction was stirred at 110 °C for 50 hours. After the reaction was completed, the reaction was quenched with water, then the solution was adjusted to weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 2-3, 12.50 g, 36.90% yield) as a white solid.

[0150] 1 H NMR (400 MHz, CDCl3) d 7.17 (t, J = 8.2 Hz, 1H), 6.55 - 6.49 (m, 2H), 6.47 (t, J = 2.4 Hz, 1H), 4.23 (t, J = 6.4 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 2.80 (t, J = 6.4 Hz, 2H).

[0151] Step 2: Preparation of 4-(3-methoxyphenoxy)-2-methylbutan-2-ol (Compound 2-4)

[0152] To a solution of methyl 3-(3-methoxyphenoxy)propanoate (compound 2-3, 12.50 g, 59.50 mmol) in tetrahydrofuran (80 mL) was added methyl magnesium bromide (50 mL, 3 mol / L) at 0 °C. The reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction solution was quenched with water, extracted, dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 0-20% EtOAc in PE) to give the product (compound 2-4, 12 g, 96% yield) as a white solid.

[0153] 1 H NMR (400 MHz, CDCl3) δ 7.18 (td, J = 8.2, 1.0 Hz, 1H), 6.55-6.45 (m, 3H), 4.16 (td, J = 6.2, 1.0 Hz, 2H), 3.78 (d, J = 1.1 Hz, 3H), 2.33 (s, 1H), 1.99 (dd, J = 9.0, 3.4 Hz, 2H), 1.31 (d, J = 1.0 Hz, 6H).

[0154] Step 3: Preparation of 7-methoxy-4,4-dimethylchroman (compound 2-5)

[0155] To a solution of 4-(3-methoxyphenoxy)-2-methylbutan-2-ol (compound 2-4, 13 g, 61.8 mmol) in methylsulfonic acid (100 mL) was added phosphorus pentoxide (26.32 g, 185.40 mmol) at 0 °C. The reaction was stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into ice water, extracted, washed, dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 0-10% EtOAc in PE) to give the product (compound 2-5, 6.80 g, 57.20% yield) as a colorless oily liquid.

[0156] 1 H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.6 Hz, 1H), 6.49 (dd, J = 8.6, 2.8 Hz, 1H), 6.36 (d, J = 2.8 Hz, 1H), 4.23-4.17 (m, 2H), 3.76 (s, 3H), 1.82 (dd, J = 6.0, 4.8 Hz, 2H), 1.32 (s, 6H).

[0157] Step 4: Preparation of 4,4-dimethylchroman-7-ol (compound 2-6)

[0158]

[0159] To a solution of 7-methoxy-4,4-dimethylchroman (compound 2-5, 6.80 g, 35.40 mmol) in dichloromethane (50 mL) was added BBr3(42.50 mL, 1 M in DCM) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with water, extracted, washed, dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-20% EtOAc in PE) to give the product (compound 2-6, 5.20 g, 82.37% yield) as a colorless oily liquid.

[0160] 1 H NMR (400 MHz, CDCl3) d 7.10 (d, J = 8.4 Hz, 1H), 6.40 (dd, J = 8.4, 2.6 Hz, 1H), 6.28 (d, J = 2.6 Hz, 1H), 5.00 (s, 1H), 4.20-4.15 (m, 2H), 1.83-1.77 (m, 2H), 1.29 (s, 6H).

[0161] Step 5: Preparation of tert-butyl (4,4-dimethylchroman-7-yl) carbonate (compound 2-7)

[0162] To a solution of 4,4-dimethylchroman-7-ol (compound 2-6, 5.20 g, 29.20 mmol) and Boc20 (8.28 g, 37.96 mmol) in DCM (40 mL) was added DMAP (0.36 g, 2.92 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (compound 2-7, 7 g, 86.16% yield) as a colorless oily liquid.

[0163] 1 H NMR (400 MHz, CDCl3) d 7.22 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.4 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.20-4.15 (m, 2H), 1.85-1.78 (m, 2H), 1.54 (s, 9H), 1.31 (s, 6H).

[0164] Step 6: Preparation of tert-butyl 7-hydroxy-4,4-dimethylchroman-8-carboxylate (compound 2-8)

[0165] To a solution of tert-butyl (4,4-dimethylchroman-7-yl) carbonate (compound 2-7, 7 g, 25.10 mmol) in THF (50 mL) was added LDA (20 mL, 2M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction, the reaction mixture was quenched with water, extracted, washed, dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to afford the product (compound 2-8, 3.60 g, 51.63% yield) as a colorless oily liquid.

[0166] 1 H NMR (400 MHz, CDCl3) d 11.24 (s, 1H), 7.36-7.19 (d, J = 8.6 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 4.33-4.15 (m, 2H), 1.83-1.78 (m, 2H), 1.59 (s, 9H), 1.28 (s, 6H).

[0167] Step 7: Preparation of tert-butyl 6-bromo-7-hydroxy-4,4-dimethylchroman-8- carboxylate (compound 2-9)

[0168] To a solution of tert-butyl 7-hydroxy-4,4-dimethylchroman-8-carboxylate (compound 2-8, 3.50 g, 12.60 mmol) in DMF (30 mL) was added NBS (2.47 g, 13.86 mmol) portion wise. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was quenched with water, extracted, washed, dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to afford the product (compound 2-9, 3.60 g, 80.20% yield) as a colorless oily liquid.

[0169] 1 H NMR (400 MHz, CDCl3) d 11.83 (s, 1H), 7.49 (s, 1H), 4.39-4.11 (m, 2H), 1.83-1.77 (m, 2H), 1.59 (s, 9H), 1.29 (s, 6H).

[0170] Step 8: Preparation of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-4,4- dimethylchroman-8-carboxylate (compound 2-10)

[0171] To a solution of tert-butyl 6-bromo-7-hydroxy-4,4-dimethylchroman-8-carboxylate (compound 2-9, 3.50 g, 9.80 mmol) and Boc20 (2.57 g, 11.76 mmol) in DCM (40 mL) was added DMAP (0.12 g, 0.98 mmol) and the reaction was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product as colorless oil (compound 2-10, 4.0 g, 89.15% yield).

[0172] 1 H NMR (400 MHz, CDC13) δ 7.43 (s, 1H), 4.24 - 4.19 (m, 2H), 1.85 - 1.78 (m, 2H), 1.56 (d, J = 2.4 Hz, 18H), 1.31 (s, 6H).

[0173] Step 9: Preparation of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6- (2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)chroman-8-carboxylate (compound 2-12)

[0174] To a solution of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-4,4-dimethylchroman-8- carboxylate (compound 2-10, 3.80 g, 8.30 mmol), vinylboronic acid pinacol ester (compound 2-11, 1.92 g, 12.45 mmol) and triethylamine (1.68 g, 16.60 mmol) in toluene (40 mL) was added Pd(tBu3P)2 (0.42 g, 0.83 mmol). The mixture was stirred at 80 °C under nitrogen for 3 h. After completion of the reaction, the reaction was filtered over celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to give the product as colorless oil (compound 2-12, 3.0 g, 68.48% yield).

[0175] LCMS (ESI) m / z = 374.70 [M-155] +

[0176] Step 10: Preparation of tert-butyl (Z)-7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)chroman-8-carboxylate (compound 2-13)

[0177] To a solution of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)chromane-8-carboxylate (compound 2-12, 2.50 g, 4.70 mmol) in acetonitrile (30 mL) was added fac-Ir(ppy)3 (0.31 g, 0.47 mmol) under nitrogen at room temperature. The mixture was stirred under a blue LED lamp (450 nm) for 16 h. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was rotary evaporated under reduced pressure, and purified by silica gel column (eluent: 0-15% EtOAc in PE) to give the product (compound 2-13, 2.0 g, 51.36% yield, 75% purity) as yellow oil.

[0178] 1 H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.08 (d, J = 15.2 Hz, 1H), 5.54 (d, J = 15.2 Hz, 1H), 4.28-4.16 (m, 2H), 1.82 (dd, J = 10.4, 5.2 Hz, 2H), 1.56 (s, 9H), 1.51 (s, 9H), 1.35 (s, 6H), 1.26 (s, 12H).

[0179] Step 11: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-((Z)-2-((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxolan-2-yl)vinyl)chromane-8-carboxylate (compound 2-15)

[0180] To a solution of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)chromane-8-carboxylate (compound 2-12, 2.50 g, 4.70 mmol) in acetonitrile (30 mL) was added fac-Ir(ppy)3 (0.31 g, 0.47 mmol) under nitrogen at room temperature. The mixture was stirred under a blue LED lamp (450 nm) for 16 h. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was rotary evaporated under reduced pressure, and purified by silica gel column (eluent: 0-15% EtOAc in PE) to give the product (compound 2-13, 2.0 g, 51.36% yield, 75% purity) as yellow oil.

[0181] LCMS (ESI) m / z = 605.30 [M+Na] + .

[0182] Step 12: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(2- ((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxol-2- yl)cyclopropyl)chroman-8-carboxylate (Compound 2-16)

[0183] To a solution of tert-butyl 7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-((Z)-2- ((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxol-2- yl)vinyl)chroman-8-carboxylate (Compound 2-15, 1.20 g, 2.10 mmol) and palladium acetate (20 mg, 0.1 mmol) in tetrahydrofuran (20 mL) was added freshly prepared diazomethane (21 mL, ~1 M in ether) slowly at -30 °C under nitrogen protection. The reaction was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to give the product as colorless oil (Compound 2-16, 0.8 g, 65.15% yield).

[0184] LCMS (ESI) m / z = 619.35 [M+Na] + .

[0185] Step 13: Preparation of 2-hydroxy-8,8-dimethyl-l,la,2,7,8,9b-hexahydro-6H- cyclopropa[3,4][l,2]oxazaborino[5,6-g]chromene-4-carboxylic acid (Compound 2)

[0186] To a solution of tert-butyl 7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(2- ((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxol-2- yl)cyclopropyl)chroman-8-carboxylate (Compound 2-16, 0.10 g, 0.17 mmol) and isobutylboronic acid (34.10 mg, 0.34 mmol) in tetrahydrofuran (1 mL) was added concentrated hydrochloric acid (1 mL), the reaction was stirred at room temperature for 2 h. After the reaction was completed, the crude product was purified by C 18 column (eluted with 5-35% MeCN / H2O with 0.1% TFA in water) to give the product as white solid (Compound 2, 25 mg, 51.74% yield).

[0187] 1 H NMR (400 MHz, MeOD) δ 7.28 (s, 1H), 4.18 (dd, J = 5.8, 4.6 Hz, 2H), 2.27 - 2.13 (m, 1H), 1.89 - 1.74 (m, 2H), 1.32 (s, 6H), 1.29 - 1.19 (m, 1H), 0.51 (m, 1H), 0.30 (s, 1H).

[0188] Example 3

[0189] Step 1: Preparation of 7-hydroxy-3,3-dimethylchroman-4-one (Compound 3-2)

[0190] Dissolve 7-hydroxychroman-4-one (Compound 3-1, 10 g, 60.9 mmol), iodomethane (43.24 g, 304.5 mmol) in tetrahydrofuran (150 mL) and cool to -78 °C, then add 1M potassium tert-butoxide solution (243.6 mL, 243.6 mmol) dropwise. The reaction solution is stirred at -70 °C for 4 hours under nitrogen protection. After the reaction is completed, quench with saturated ammonium chloride solution, extract with ethyl acetate, wash, dry, filter, and concentrate. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain the target compound (Compound 3-2, 8.9 g, 72.25% yield) as a yellow solid.

[0191] 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 8.6, 2.4 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 5.93 (s, 1H), 4.13 (s, 2H), 1.20 (s, 6H).

[0192] Step 2: Preparation of 3,3-dimethylchroman-7-ol (Compound 3-3)

[0193] Dissolve 7-hydroxy-3,3-dimethylchroman-4-one (Compound 3-2, 1.0 g, 5.20 mmol) in trifluoroacetic acid solution (10 mL), and add triethylsilane (2.42 g, 20.81 mmol) dropwise. Stir the reaction solution at room temperature for 17 hours. After the reaction is completed, adjust the pH to 7 with saturated sodium carbonate solution, extract with ethyl acetate, wash, dry, filter, and concentrate. Purify the crude product by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain the target compound (Compound 3-3, 0.75 g, 72.80% yield) as a colorless oily liquid.

[0194] 1 H NMR (400 MHz, CDC13) δ 6.85 (d, J = 8.4 Hz, 1H), 6.37 (dd, J = 8.4, 2.6 Hz, 1H), 6.32 (d, J = 2.6 Hz, 1H), 3.72 (s, 2H), 2.46 (s, 2H), 1.01 (s, 6H).

[0195] Step 3: Preparation of tert-butyl (3,3-dimethylchroman-7-yl) carbonate (Compound 3-4)

[0196] Step 3: Preparation of tert-butyl (3,3-dimethylchroman-7-yl) carbonate (Compound 3-4)

[0197] 1 H NMR (400 MHz, CDC13) δ 6.85 (d, J = 8.4 Hz, 1H), 6.37 (dd, J = 8.4, 2.6 Hz, 1H), 6.32 (d, J = 2.6 Hz, 1H), 3.72 (s, 2H), 2.46 (s, 2H), 1.01 (s, 6H).

[0198] Step 4: Preparation of tert-butyl 7-hydroxy-3,3-dimethylchromen-8-carboxylate (Compound 3-5)

[0199] Step 3: Preparation of tert-butyl (3,3-dimethylchroman-7-yl) carbonate (Compound 3-4)

[0200] 1H NMR (400 MHz, CDC13) δ 11.22 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.76 (s, 2H), 2.45 (s, 2H), 1.59 (s, 9H), 1.00 (s, 6H).

[0201] Step 5: Preparation of tert-butyl 6-bromo-7-hydroxy-3,3-dimethyltryptophan-8- carboxylate (Compound 3-6)

[0202] Tert-butyl 7-hydroxy-3,3-dimethyltryptophan-8-carboxylate (Compound 3-5, 135 mg, 0.49 mmol) was dissolved in DMF (3 mL) at room temperature, and NBS (90.64 mg, 0.51 mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was diluted with water, extracted with ethyl acetate, washed, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:0) to obtain the target compound (Compound 3-6, 0.16 g, 87.83% yield) as a yellow oily liquid.

[0203] 1 H NMR (400 MHz, CDC13) δ 11.22 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.76 (s, 2H), 2.45 (s, 2H), 1.59 (s, 9H), 1.00 (s, 6H).

[0204] Step 6: Preparation of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-3,3- dimethyltryptophan-8-carboxylate (Compound 3-7)

[0205] Tert-butyl 6-bromo-7-hydroxy-3,3-dimethyltryptophan-8-carboxylate (Compound 3-6, 0.16 g, 0.45 mmol) was dissolved in dichloromethane (3 mL), and Boc20 (0.12 g, 0.54 mmol) and DMAP (5.47 mg, 0.04 mmol) were added. The reaction was stirred at 25°C for 1 hour. After the reaction was completed, the reaction was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain the target compound (Compound 3-7, 0.21 g, 97.39% yield) as a colorless oily liquid.

[0206] LCMS (ESI) m / z = 300.95 [M-155]+.

[0207] Step 7: Preparation of (E)-7-((tert-butoxycarbonyl)oxy)-3,3-dimethyl-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl) tryptophan tert-butyl ester-8-carboxylic acid (Compound 3-9)

[0208] To a solution of 6-bromo-7-((tert-butoxycarbonyl)oxy)-3,3-dimethyl tryptophan tert-butyl ester-8-carboxylic acid (Compound 3-7, 0.21 g, 0.46 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Compound 3-8, 0.09 g, 0.60 mmol) in super dry toluene (10 mL) was added Pd(t-Bu3P)2(25.92 mg, 0.05 mmol) and triethylamine (0.09 g, 0.92 mmol) under nitrogen protection. The reaction was stirred at 80 °C for 4 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature, filtered over celite and the filtrate was concentrated. The crude was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4: 1) to give the target compound (Compound 3-9, 0.11 g, 42.90% yield) as a yellow oily liquid.

[0209] 1 H NMR (400 MHz, CDC13) δ 7.30 (d, J = 18.4 Hz, 1H), 7.26 (s, 1H), 5.98 (d, J = 18.4 Hz, 1H), 3.79 (s, 2H), 2.52 (s, 2H), 1.56 (s, 9H), 1.54 (s, 9H), 1.26 (s, 12H), 1.02 (s, 6H).

[0210] Step 8: Preparation of (Z)-7-((tert-butoxycarbonyl)oxy)-3,3-dimethyl-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl) tryptophan tert-butyl ester-8-carboxylic acid (Compound 3-10)

[0211] (E)-7-((tert-butoxycarbonyl)oxy)-3,3-dimethyl-6-(2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)vinyl)tryptophan tert-butyl ester-8-carboxylic acid (Compound 3-9, 0.11 g, 0.21 mmol) was dissolved in acetonitrile (3 mL) at room temperature, fac-Ir(ppy)3 (13.58 mg, 0.02 mmol) was added. The reaction was placed under nitrogen protection and stirred at 25 °C for 16 h under blue light (450 nm) irradiation. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4: 1) to obtain the target compound (Compound 3-10, 90 mg, 69.53% yield) as a yellow oily liquid.

[0212] 1 H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.06 (d, J = 14.4 Hz, 1H), 5.56 (d, J = 14.4 Hz, 1H), 3.79 (s, 2H), 2.48 (s, 2H), 1.56 (s, 9H), 1.50 (s, 9H), 1.25 (s, 12H), 1.02 (s, 6H).

[0213] Step 9: Preparation of 7-((tert-butoxycarbonyl)oxy)-3,3-dimethyl-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)tryptophan tert-butyl ester-8- carboxylic acid (Compound 3-11)

[0214] (Z)-7-((tert-butoxycarbonyl)oxy)-3,3-dimethyl-6-(2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)vinyl)tryptophan tert-butyl ester-8-carboxylic acid (Compound 3-10, 0.09 g, 0.17 mmol) and palladium acetate (1.9 mg, 0.0.1 mmol) were dissolved in tetrahydrofuran (3 mL) under nitrogen protection at -40 °C, and freshly prepared diazomethane in ether (1.7 mL, concentration about 1 mol / L) was added dropwise. After the reaction was stirred at -20 °C for 2 h, it was slowly raised to room temperature and continued to react for 12 h. The reaction was filtered with diatomite, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1) to obtain the target compound (Compound 3-11, 30 mg, 30.82% yield) as a colorless oily liquid.

[0215] 1H NMR (400 MHz, CDC13) δ 6.90 (s, 1H), 3.73 (s, 2H), 2.46 (s, 2H), 2.09 (dd, J = 16.8, 8.0 Hz, 1H), 1.55 (s, 18H), 1.09 (s, 6H), 1.06 - 1.00 (m, 2H), 1.00 (s, 6H), 0.97 (s, 6H), 0.32 (td, J = 10.0, 7.6 Hz, 1H).

[0216] Step 10: Preparation of 2-hydroxy-7,7-dimethyl-l,la,2,7,8,9b-hexahydro-6H- cyclopropyl[3,4][l,2]oxazino[5,6-g]chromene-4-carboxylic acid (Compound 3)

[0217] Step 10: Preparation of 2-hydroxy-7,7-dimethyl-l,la,2,7,8,9b-hexahydro-6H- cyclopropyl[3,4][l,2]oxazino[5,6-g]chromene-4-carboxylic acid (Compound 3) 18 Step 10: Preparation of 2-hydroxy-7,7-dimethyl-l,la,2,7,8,9b-hexahydro-6H- cyclopropyl[3,4][l,2]oxazino[5,6-g]chromene-4-carboxylic acid (Compound 3)

[0218] LCMS (ESI) m / z = 288.60 [M+H]+

[0219] 1 H NMR (400 MHz, MeOD) δ 7.01 (s, 1H), 3.75 (s, 2H), 2.50 (s, 2H), 2.17 (td, J = 8.0, 4.0 Hz, 1H), 1.35 - 1.22 (m, 1H), 1.01 (s, 6H), 0.61 - 0.40 (m, 1H), 0.31 (s, 1H).

[0220] Example 4

[0221] Step 1: Preparation of tert-butyl 7-((tert-butoxy carbonyl)oxy)-4,4-dimethyl-6-(2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ethyl)chroman-8-carboxylate (Compound 4-1)

[0222] To a solution of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)chromane-8-carboxylate (compound 2-12, 0.30 g, 0.57 mmol) in methanol (7 mL) was added 10% palladium on carbon (50 mg) and the reaction was stirred at room temperature under hydrogen (30 psi) for 4 hours. After completion of the reaction, the reaction was filtered over celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to give a colorless oily liquid (compound 4-1, 0.23 g, 76.38% yield).

[0223] LCMS (ESI) m / z = 377.10 [M-155] + .

[0224] Step 2: Preparation of 2-hydroxy-6,6-dimethyl-3,4,7,8-tetrahydro-2H,6H- [1,2]oxaborino[5,6-g]chromene-10-carboxylic acid (compound 4)

[0225] To a solution of tert-butyl 7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborinane-2-yl)ethyl)chromane-8-carboxylate (compound 4-1, 0.20 g, 0.38 mmol) and isobutylboronic acid (76.58 mg, 0.75 mmol) in tetrahydrofuran (1 mL) was added concentrated hydrochloric acid (1 mL) and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was purified by C 18 column (eluted with 5-35% MeCN / H2O with 0.1% TFA in water) to give the product as a white solid (compound 4, 20 mg, 19.28% yield).

[0226] LCMS (ESI) m / z = 276.65 [M+H] + .

[0227] 1 H NMR (400 MHz, MeOD) δ 7.23 (s, 1H), 4.47 - 4.05 (m, 2H), 2.66 (t, J = 7.4 Hz, 2H), 1.86 (s, 2H), 1.31 (s, 6H), 1.06 (t, J = 7.8 Hz, 2H).

[0228] Example 5

[0229] Step 1: Preparation of (E)-(3-(2-hydroxy-4-methoxyphenyl)but-2-en-1-yl)oxonium + 2-(4-hydroxybutan-2-yl)-5-methoxyphenol (Compound 5-2)

[0230] To a solution of 7-methoxy-4-methyl-2H-methylene-2-one (Compound 5-1, 70.00 g, 368.42 mmol) in THF was added LiAlH4(14.00 g, 368.4 mmol) in portions at 0 °C under nitrogen protection. The mixture was stirred at 0 °C for 1 h. To the mixture was added H2O (14 mL), 15% NaOH solution (14 mL) and H2O (42 mL) slowly. After the addition, the solution was stirred at 25 °C for 30 min. Then Na2SO4was added and stirred for 30 min, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: 15-30% EtOAc in PE) to give the product (Compound 5-2, 30.0 g, 41.97% yield) as colorless oil.

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 6.34 (dd, J = 8.3, 2.5 Hz, 1H), 5.50 (td, J = 6.5, 1.4 Hz, 1H), 4.35 (s, 1H), 3.71 (d, J = 6.4 Hz, 2H), 3.68 (s, 3H), 1.92 (d, J = 1.1 Hz, 3H).

[0232] Step 2: Preparation of 2-(4-hydroxybutan-2-yl)-5-methoxyphenol (Compound 5-3)

[0233] To a solution of (E)-(3-(2-hydroxy-4-methoxyphenyl)but-2-en-1-yl)oxonium and 2-(4-hydroxybutan-2-yl)-5-methoxyphenol (Compound 5-2, 30.00 g, 154.64 mmol) in MeOH was added 10% Pd / C (3.26 g). The mixture was evacuated and backfilled with hydrogen three times, then charged with hydrogen. The resulting mixture was stirred at room temperature for 2 h. Then the mixture was filtered through celite and concentrated, the residue was purified by silica gel column chromatography (eluent: 15-30% EtOAc in PE) to give the product (Compound 5-3, 25.00 g, 74.24% yield) as colorless oil.

[0234] 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.33 (dt, J = 8.3, 2.5 Hz, 2H), 4.29 (t, J = 5.1 Hz, 1H), 3.65 (s, 3H), 3.31 (dt, J = 7.7, 5.6 Hz, 2H), 3.05 (dd, J = 14.2, 7.1 Hz, 1H), 1.78 - 1.56 (m, 2H), 1.10 (d, J = 7.0 Hz, 3H).

[0235] Step 3: Preparation of 7-methoxy-4-methylchroman (Compound 5-4)

[0236] A solution of 2-(4-hydroxybutan-2-yl)-5-methoxyphenol (Compound 5-3, 25.00 g, 127.40 mmol), PPh3(35.09 g, 133.77 mmol) and DIAD (28.34 g, 140.14 mmol) in THF was heated at 60 °C for 4 h. The mixture was filtered through celite and concentrated. The crude product was purified by flash column chromatography (eluent: PE) to give the target product (Compound 5-4, 18.00 g, 71.35% yield) as colorless oil.

[0237] 1 H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 8.5 Hz, 1H), 6.46 (dd, J = 8.5, 2.6 Hz, 1H), 6.35 (d, J = 2.6 Hz, 1H), 4.24 - 4.09 (m, 2H), 3.75 (s, 3H), 2.88 (dd, J = 13.2, 6.6 Hz, 1H), 2.10 - 2.01 (m, 1H), 1.73 - 1.64 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H).

[0238] Step 4: Preparation of 4-methylchroman-7-ol + 4-(4-bromobutan-2-yl)benzene-1,3-diol (Compound 5-5 + Compound 5-5A)

[0239] To a solution of 7-methoxy-4-methylchroman (Compound 5-4, 18.00 g, 101.00 mmol) in DCM was added BBr3(121 mL, 1 M in DCM) dropwise at 0 °C under nitrogen protection. The mixture was stirred at 0 °C for 1 h. The mixture was quenched with H2O and extracted with DCM, washed with brine, dried over sodium sulfate, concentrated to give the crude product (Compound 5-5 + Compound 5-5A mixture, 18.00 g), which was used for the next step without further purification.

[0240] Compound 5-5: 1 H NMR (400 MHz, CDC13) δ 7.00 (d, J = 8.3 Hz, 1H), 6.38 (dd, J = 8.3, 2.6 Hz, 1H), 6.28 (d, J = 2.6 Hz, 1H), 4.73 (s, 1H), 4.22 - 4.10 (m, 2H), 2.88 (dd, J = 13.2, 6.6 Hz, 1H), 2.08 - 2.02 (m, 1H), 1.68 (dtd, J = 10.0, 6.9, 3.2 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H).

[0241] Compound 5-5A: 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.98 (s, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 6.16 (dd, J = 8.2, 2.4 Hz, 1H), 3.38 (dd, J = 7.3, 2.0 Hz, 3H), 3.08 (dd, J = 14.2, 7.1 Hz, 1H), 2.10 (td, J = 14.3, 7.5 Hz, 1H), 1.94 (dd, J = 14.0, 7.2 Hz, 1H), 1.12 (d, J = 7.0 Hz, 3H).

[0242] Step 5: Preparation of 4-methylchroman-7-ol (Compound 5-5)

[0243] To a solution of 4-methylchroman-7-ol and 4-(4-bromobutan-2-yl)benzene-1,3-diol (mixture of Compound 5-5 + Compound 5-5A, 18.00 g) in DMF was added Cs2C03(31.87 g, 97.80 mmol). The mixture was stirred at room temperature for 1 h. The residue was extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the target product (Compound 5-5, 15.00 g, 76.22% yield) as a white solid.

[0244] 1H NMR (400 MHz, CDC13) δ 7.00 (d, J = 8.3 Hz, 1H), 6.38 (dd, J = 8.3, 2.6 Hz, 1H), 6.28 (d, J = 2.6 Hz, 1H), 4.73 (s, 1H), 4.22 - 4.10 (m, 2H), 2.88 (dd, J = 13.2, 6.6 Hz, 1H), 2.08 - 2.02 (m, 1H), 1.68 (dtd, J = 10.0, 6.9, 3.2 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H).

[0245] Step 6: Preparation of tert-butyl 7-hydroxy-4-methylchroman-8-carboxylate (Compound 5-7)

[0246] To a solution of 4-methylchroman-7-ol (Compound 5-5, 15.00 g, 91.40 mmol) and DMAP (2.23 g, 18.28 mmol) in DCM was added Boc20 (23.94 g, 109.68 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 5-6, 18.00 g, 74.60%) as colorless oil.

[0247] 1 H NMR (400 MHz, CDC13) δ 7.00 (d, J = 8.3 Hz, 1H), 6.38 (dd, J = 8.3, 2.6 Hz, 1H), 6.28 (d, J = 2.6 Hz, 1H), 4.73 (s, 1H), 4.22 - 4.10 (m, 2H), 2.88 (dd, J = 13.2, 6.6 Hz, 1H), 2.08 - 2.02 (m, 1H), 1.68 (dtd, J = 10.0, 6.9, 3.2 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H).

[0248] Step 7: Preparation of tert-butyl 7-hydroxy-4-methylchroman-8-carboxylate (Compound 5-7)

[0249] To a solution of (4-methylchroman-7-yl) tert-butyl carbonate (compound 5-6, 18.00 g, 68.10 mmol) in THF was added LDA (41 mL, 2 M in THF) dropwise at -40 °C under nitrogen protection. The mixture was stirred at -40 °C for 5 h. Quenched with H2O and extracted with EtOAc, washed with brine, dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (eluent: PE) to give the target product (compound 5-7, 13.00 g, 65.05% yield) as colorless oil.

[0250] 1 H NMR (400 MHz, CDCl3) d 11.29 (s, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 4.23 - 4.16 (m, 2H), 2.85 (dd, J = 12.9, 6.5 Hz, 1H), 2.13 - 1.98 (m, 1H), 1.73 - 1.64 (m, 1H), 1.59 (s, 9H), 1.27 (d, J = 7.0 Hz, 3H).

[0251] Step 8: Preparation of 6-bromo-7-hydroxy-4-methylchroman-8-carboxylic acid tert-butyl ester (compound 5-8)

[0252] To a solution of 7-hydroxy-4-methylchroman-8-carboxylic acid tert-butyl ester (compound 5-7, 13.00 g, 49.2 mmol) in DMF was added NBS (9.19 g, 51.66 mmol) portionwise. The mixture was stirred at room temperature for 2 h. The residue was extracted with EtOAc, washed with water and brine, dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (eluent: PE) to give the target product (compound 5-8, 16.00 g, 85.37% yield) as white solid.

[0253] 1 H NMR (400 MHz, CDCl3) d 11.88 (s, 1H), 7.39 (s, 1H), 4.20 (d, J = 4.8 Hz, 2H), 2.86 (dd, J = 13.0, 6.6 Hz, 1H), 2.04 (dt, J = 11.7, 6.9 Hz, 1H), 1.73 - 1.65 (m, 1H), 1.59 (s, 9H), 1.28 (d, J = 7.0 Hz, 3H).

[0254] Step 9: Preparation of 6-bromo-7-hydroxy-4-methylchroman-8-carboxylic acid (compound 5-9)

[0255] To a solution of 6-bromo-7-hydroxy-4-methylchromo-8-carboxylic acid tert-butyl ester (Compound 5-8, 15.00 g, 43.70 mmol) in DCM (150 mL) was added TFA (30 mL) at room temperature. The reaction was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and washed with DCM to give the target product (Compound 5-9, 12.00 g, 86.04% yield) as a white solid.

[0256] 1 H NMR (400 MHz, CDCl3) δ 12.75 (s, 1H), 7.54 (s, 1H), 4.52 - 4.43 (m, 2H), 2.94 (dd, J = 13.1, 6.5 Hz, 1H), 2.25 - 2.14 (m, 1H), 1.82 (dtd, J = 14.2, 6.2, 4.0 Hz, 1H), 1.34 (d, J = 7.0 Hz, 3H).

[0257] Step 10: Preparation of 6-bromo-4,8,8-trimethyl-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-10-one (Compound 5-10)

[0258] To a solution of 6-bromo-7-hydroxy-4-methylchromo-8-carboxylic acid (Compound 5-9, 12.00 g, 41.80 mmol) in TFA (23.83 g, 209.00 mmol) was added TFAA (15.80 g, 75.24 mmol) and acetone (7.28 g, 125.40 mmol). The reaction was stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure and the pH was adjusted to 8 with saturated Cs2CO3. The mixture was washed with DCM, filtered, and the filtrate was evaporated to dryness to give the target product (Compound 5-10, 2.20 g, 14.59% yield) as a white solid.

[0259] 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 4.37 (t, J = 5.3 Hz, 2H), 2.91 (d, J = 6.5 Hz, 1H), 2.10 (dd, J = 14.0, 5.8 Hz, 1H), 1.77 (d, J = 5.2 Hz, 1H), 1.74 (s, 6H), 1.32 (d, J = 7.0 Hz, 3H).

[0260] Step 11: Preparation of (E)-3-(4,8,8-trimethyl-10-oxo-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-6-yl)acrylic acid (Compound 5-12)

[0261] A solution of 6-bromo-4,8,8-trimethyl-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-10-one (compound 5-10, 2.20 g, 6.70 mmol), acrylic acid (compound 5-11, 1.45 g, 20.10 mmol), Pd2(dba)3(0.61 g, 0.67 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.39 g, 1.34 mmol) and N,N-dicyclohexylmethylamine (3.93 g, 20.10 mmol) in dioxane was heated at 100 °C for 8 h under nitrogen atmosphere. After cooling to ambient temperature, the mixture was filtered through celite and concentrated. The crude product was purified by column chromatography (eluting with 5-95% MeCN / H2O containing 0.1% formic acid) to afford the target product (compound 5-12, 1.70 g, 71.64% yield) as a white solid. 18 The product was purified by reverse phase column (eluting with 5-95% MeCN / H2O containing 0.1% formic acid) to afford the target product (compound 5-12, 1.70 g, 71.64% yield) as a white solid.

[0262] 1 H NMR (400 MHz, CDC13) δ 7.87 (d, J = 16.1 Hz, 1H), 7.56 (s, 1H), 6.41 (d, J = 16.1 Hz, 1H), 4.44 (t, J = 5.4 Hz, 2H), 2.99 - 2.90 (m, 1H), 2.17 - 2.10 (m, 1H), 1.81 (d, J = 4.9 Hz, 1H), 1.76 (s, 6H), 1.36 (d, J = 7.0 Hz, 3H).

[0263] Step 12: Preparation of 2,3-dibromo-3-(4,8,8-trimethyl-10-oxo-3,4-dihydro- 2H,10H-[1,3]dioxolo[4,5-h]chromen-6-yl)propionic acid (compound 5-13)

[0264] To a solution of (E)-3-(4,8,8-trimethyl-10-oxo-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-6-yl)acrylic acid (compound 5-12, 1.70 g, 5.30 mmol) in chloroform was added dropwise bromine (2.54 g, 15.90 mmol) at 0 °C. The reaction solution was stirred at 0 °C for 1 h and then concentrated under reduced pressure to afford the dibromo intermediate (compound 5-13, 2.4 g, 94.73% yield) as a yellow solid, which was used for the next step without further purification.

[0265] LCMS (ESI) m / z = 429.10 [M+H] + .

[0266] Step 13: Preparation of (Z)-6-(2-bromovinyl)-4,8,8-trimethyl-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-10-one (Compound 5-14)

[0267] To a solution of 2,3-dibromo-3-(4,8,8-trimethyl-10-oxo-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-6-yl)propanoic acid (Compound 5-13, 2.40 g, 5.02 mmol) in DMF was added triethylamine (1.07 g, 10.60 mmol) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 4 h. It was extracted with EtOAc and washed with 0.1 N HC1 and water. The mixture was dried over Na2S04and concentrated. The crude product was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the target product (Compound 5-14, 1.40 g, 64.15% yield) as colorless oil.

[0268] 1 H NMR (400 MHz, CDC13) δ 7.28 (s, 1H), 7.10 (d, J = 14.0 Hz, 1H), 6.77 (d, J = 14.0 Hz, 1H), 4.38 (dd, J = 6.8, 4.2 Hz, 2H), 2.91 (dd, J = 12.8, 6.4 Hz, 1H), 2.16 - 2.07 (m, 1H), 1.81 - 1.76 (m, 1H), 1.73 (s, 6H), 1.33 (d, J = 7.0 Hz, 3H).

[0269] Step 14: Preparation of 4,8,8-trimethyl-6-((Z)-2-((3aR,4R,6R,7aS)-3a,5,5- trimethylhexahydro-4,6-methanopyran-2-yl)vinyl)-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-10-one (Compound 5-15)

[0270] A solution of (Z)-6-(2-bromovinyl)-4,8,8-trimethyl-3,4-dihydro-2H,10H- [1,3]dioxolo[4,5-h]chromen-10-one (compound 5-14, 1.30 g, 3.70 mmol), bis(-)- pinanediol diboron (1.99 g, 5.55 mmol), PdCl2(dppf) (0.27 g, 0.37 mmol) and KOAc (0.73 g, 7.40 mmol) in dioxane was heated at 60 °C for 2 h under nitrogen protection. After cooling to ambient temperature, the mixture was filtered through celite and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the target product (compound 5-15, 0.70 g, 32.43% yield) as colorless oil.

[0271] LCMS (ESI) m / z = 453.30 [M+H] + .

[0272] Step 15: Preparation of 4,8,8-trimethyl-6-(2-((3aR,4R,6R,7aS)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxol-2-yl)cyclopropyl)-3,4- dihydro-2H,10H-[1,3]dioxolo[4,5-h]chromen-10-one (compound 5-16)

[0273] To a solution of 4,8,8-trimethyl-6-((Z)-2-((3aR,4R,6R,7aS)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxol-2-yl)vinyl)-3,4-dihydro- 2H,10H-[1,3]dioxolo[4,5-h]chromen-10-one (compound 5-15, 0.70 g, 1.55 mmol) and Pd(OAc)2(17.37 mg, 0.08 mmol) in THF was added slowly dropwise diazomethane (15.4 mL, freshly prepared, ca. 0.6 M in diethyl ether) at -10 °C under nitrogen protection, the solution was slowly warmed to room temperature and stirred for 12 h, then concentrated and dried. The crude product was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the target product (compound 5-16, 0.45 g, 53.00% yield) as colorless oil.

[0274] LCMS (ESI) m / z = 467.15 [M+H] + .

[0275] Step 16: Preparation of compound 5-17-P1, 5-17-P2, 5-17-P3, 5-17-P4

[0276] A mixture of compound 5-16 (4.9 g, 3.26 mmol) was dissolved in isopropanol (100 mg / mL), filtered and purified by HPLC prep (eluted with 95% n-hexane / 5% isopropyl alcohol at a flow rate of 25 mL / min) to give 5-17-P1 (1.0 g) as a colorless oil, 5-17-P2 (690 mg) as a colorless oil, 5-17-P3 (1.1 g) as a colorless oil, and 5-17-P4 (690 mg) as a colorless oil.

[0277] Step 17: Preparation of compounds 5-P1, 5-P2, 5-P3, 5-P4

[0278] A solution of compound 5-17-P1 (1.0 g, 1.72 mmol) and methylboronic acid (206 mg, 3.43 mmol) in tetrahydrofuran (5 mL) was added with concentrated hydrochloric acid (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and purified by C 18 column (eluted with 5%-95% MeCN / H2O with 0.1% TFA in water) to give 5-P1 (278 mg, 59.09% yield, free acid) as a yellow solid. 5-P1 was dissolved in 1 M NaOH (2.03 mL), washed with MeCN and lyophilized to give compound 5-P1 (323 mg, 94.76%, disodium salt) as a light yellow solid.

[0279] LCMS (ESI) m / z = 275.05 [M+H] + (free acid). 1 H NMR (400 MHz, D2O) δ 6.95 (s, 1H), 4.17 - 3.96 (m, 2H), 2.82 (dd, J = 13.1, 6.5 Hz, 1H), 2.07 - 1.94 (m, 1H), 1.78 - 1.70 (m, 1H), 1.62 (dtd, J = 9.6, 6.8, 3.1 Hz, 1H), 1.22 (t, J = 10.7 Hz, 3H), 0.82 - 0.67 (m, 1H), 0.25 - 0.08 (m, 2H).

[0280] Compound 5-P2 (203 mg, 86.68%, disodium salt) was obtained from compound 5-17-P2 (690 mg, 1.18 mmol) following the procedure for 5-P1 from 5-17-P1.

[0281] LCMS (ESI) m / z = 275.00 [M+H] + (free acid). 1H NMR (400 MHz, D20) δ 6.97 (s, 1H), 4.21 - 3.98 (m, 2H), 2.86 (dd, J = 13.2, 6.6 Hz, 1H), 2.03 (td, J = 10.7, 5.3 Hz, 1H), 1.76 (td, J = 8.4, 3.6 Hz, 1H), 1.65 (dtd, J = 9.5, 6.8, 2.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H), 0.88 - 0.73 (m, 1H), 0.22 (ddt, J = 15.8, 9.3, 4.8 Hz, 2H).

[0282] Compound 5-P3 (323 mg, 94.76%, disodium salt) was obtained from compound 5-17-P3 (1.0 g, 1.72 mmol) following the procedure for 5-P1.

[0283] LCMS (ESI) m / z = 275.05 [M+H] + (free acid). 1 H NMR (400 MHz, MeOD) δ 6.75 (s, 1H), 4.06 (td, J = 5.0, 4.3, 2.5 Hz, 2H), 2.79 (q, J = 6.5 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.70 - 1.56 (m, 2H), 1.25 (d, J = 6.9 Hz, 3H), 0.77 - 0.66 (m, 1H), 0.31 - 0.17 (m, 2H).

[0284] Compound 5-P4 (203 mg, 86.68%, disodium salt) was obtained from compound 5-17-P4 (690 mg, 1.18 mmol) following the procedure for 5-P1.

[0285] LCMS (ESI) m / z = 275.00 [M+H] + (free acid). 1 H NMR (400 MHz, MeOD) δ 6.75 (s, 1H), 4.12 (ddd, J = 10.9, 8.0, 2.8 Hz, 1H), 4.00 (ddd, J = 10.6, 7.1, 3.1 Hz, 1H), 2.81 (q, J = 6.5 Hz, 1H), 2.00 (dddd, J = 13.7, 8.6, 6.2, 3.3 Hz, 1H), 1.64 (dddt, J = 22.9, 13.4, 6.7, 3.4 Hz, 2H), 1.24 (d, J = 6.9 Hz, 3H), 0.70 (ddd, J = 10.0, 8.0, 2.3 Hz, 1H), 0.31 - 0.16 (m, 2H).

[0286] Example 6

[0287] Step 1: Preparation of 7-bromo-4-methylenechroman (Compound 6-2)

[0288] To a solution of methyltriphenylphosphonium bromide (Compound 6-1, 45.99 g, 128.82 mmol) in THF was added dropwise n-BuLi (2.5 M in hexane, 51.5 mL, 128.82 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 0 °C for 1 h, then a solution of compound 7-bromopyran-4-one (25.00 g, 110.10 mmol) in THF was added. The mixture was stirred at 0 °C for 1 h, then at room temperature for another 1 h. The mixture was quenched with NH4Cl and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over sodium sulfate, concentrated, and purified by column (eluent: PE) to give the product (Compound 6-2, 11.00 g, 44.60% yield) as colorless oil.

[0289] 1 H NMR (400 MHz, CDC13) δ 7.43 - 7.37 (m, 1H), 7.05 - 6.95 (m, 2H), 5.49 (s, 1H), 4.91 (s, 1H), 4.26 - 4.18 (m, 2H), 2.67 (dd, J = 8.1, 3.1 Hz, 2H).

[0290] Step 2: Preparation of 7-bromospiro[chroman-4,1'-cyclopropane] (Compound 6-3)

[0291] CH2I2(52.64 g, 196.43 mmol) was added dropwise to a solution of ZnEt2(1 M in hexane, 98.5 mL, 98.21 mmol) in dichloromethane stirred at -78 °C under nitrogen, and the mixture was stirred at 0 °C for 15 min to form a white precipitate. TFA (11.20 g, 98.21 mmol) was added dropwise to the mixture to form a homogeneous solution, which was stirred at 0 °C for 15 min. Then a solution of compound 7-bromo-4-methylenechroman (Compound 6-2, 11.00 g, 49.11 mmol) in dichloromethane was added, and the resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with saturated aqueous NaHC03solution, extracted with dichloromethane. The combined organic phase was washed with water and brine, dried over sodium sulfate, concentrated. The crude was purified by silica gel column chromatography (eluent: 0-5% EtOAc in PE) to give the product (Compound 6-3, 8.50 g, 72.72% yield) as white solid.

[0292] 1 H NMR (400 MHz, CDC13) δ 6.96 (d, J = 1.8 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.50 (d, J = 8.3 Hz, 1H), 4.31 - 4.23 (m, 2H), 1.88 - 1.80 (m, 2H), 1.02 (q, J = 4.7 Hz, 2H), 0.84 (q, J = 4.7 Hz, 2H).

[0293] Step 3: Preparation of 4,4,5,5-tetramethyl-2-(spiro[chroman-4,1'- cyclopropan]-7-yl)-1,3,2-dioxaborolane (Compound 6-4)

[0294] A solution of 7-bromospiro[chroman-4,1'-cyclopropane] (Compound 6-3, 8.50 g, 35.71 mmol), B2Pin2(18.14 g, 71.42 mmol), Pd(PPh3)2Cl2(2.51 g, 3.57 mmol) and potassium acetate (10.50 g, 107.14 mmol) in dioxane was heated at 80 °C for 12 h under nitrogen protection. After cooling to ambient temperature, the mixture was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 6-4, 8.00 g, 78.33% yield) as a white solid.

[0295] 1 H NMR (400 MHz, CDC13) δ 6.96 (d, J = 1.8 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.50 (d, J = 8.3 Hz, 1H), 4.31 - 4.23 (m, 2H), 1.88 - 1.80 (m, 2H), 1.02 (q, J = 4.7 Hz, 2H), 0.84 (q, J = 4.7 Hz, 2H).

[0296] Step 4: Preparation of spiro[chroman-4,1'-cyclopropan]-7-ol (Compound 6-5)

[0297] To a solution of 4,4,5,5-tetramethyl-2-(spiro[chroman-4,1'-cyclopropan]-7-yl)-1,3,2- dioxaborolane (compound 6-4, 8.00 g, 27.97 mmol) in THF / H2O (2 / 1, 150 mL) was added NaB03*4H20 (12.92 g, 83.92 mmol). The mixture was stirred at room temperature for 1 h. The mixture was quenched with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the product as a white solid (compound 6-5, 4.20 g, 85.32% yield).

[0298] 1 H NMR (400 MHz, CDCl3) δ 6.51 (d, J = 8.2 Hz, 1H), 6.33 (dd, J = 12.1, 2.3 Hz, 2H), 4.57 (s, 1H), 4.30 - 4.23 (m, 2H), 1.86 - 1.79 (m, 2H), 0.98 (q, J = 4.7 Hz, 2H), 0.78 (q, J = 4.6 Hz, 2H).

[0299] Step 5: Preparation of tert-butyl spiro[chroman-4,1'-cyclopropan]-7-yl carbonate (compound 6-6)

[0300] To a solution of spiro[chroman-4,1'-cyclopropan]-7-ol (compound 6-5, 4.20 g, 23.86 mmol) and DMAP (0.29 g, 2.38 mmol) in DCM was added Boc20 (6.24 g, 28.64 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product as a white solid (compound 6-6, 6.20 g, 94.15% yield).

[0301] 1 H NMR (400 MHz, CDCl3) δ 6.63 (d, J = 2.3 Hz, 2H), 4.30 - 4.25 (m, 2H), 1.86 - 1.81 (m, 1H), 1.54 (s, 5H), 1.04 - 1.00 (m, 1H), 0.84 - 0.80 (m, 1H).

[0302] Step 6: Preparation of 7-hydroxyspiro[chroman-4,1'-cyclopropan]-8-carboxylic acid tert-butyl ester (compound 6-7)

[0303] To a solution of tert-butyl spiro[chromane-4,1'-cyclopropane]-7-yl carbonate (compound 6-6, 6.20 g, 22.46 mmol) in THF was added LDA (16.8 mL, 2M in THF) dropwise at -50 °C under nitrogen protection. The mixture was stirred at room temperature for 12 hours. The mixture was quenched with H2O and extracted with EtOAc, washed with brine, dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product as colorless oil (compound 6-7, 5.30 g, 85.50% yield).

[0304] 1 H NMR (400 MHz, CDCl3) d 11.17 (s, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.43 (d, J = 8.7 Hz, 1H), 4.35-4.27 (m, 2H), 1.86-1.79 (m, 2H), 1.60 (s, 9H), 0.96 (q, J = 4.8 Hz, 2H), 0.77 (q, J = 4.8 Hz, 2H).

[0305] Step 7: Preparation of tert-butyl 6-bromo-7-hydroxyspiro[chromane-4,1'- cyclopropane]-8-carboxylate (compound 6-8)

[0306] To a solution of tert-butyl 7-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylate (compound 6-7, 5.30 g, 19.20 mmol) in DMF was added NBS (3.59 g, 20.16 mmol) portionwise. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product as yellow solid (compound 6-8, 6.30 g, 92.69% yield). 1 H NMR (400 MHz, CDCl3) d 11.67 (s, 1H), 6.81 (s, 1H), 4.26-4.23 (m, 2H), 1.77-1.72 (m, 2H), 1.53 (s, 9H), 0.90 (q, J = 4.9 Hz, 2H), 0.74 (q, J = 4.9 Hz, 2H).

[0307] Step 8: Preparation of 6-bromo-7-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylic acid (compound 6-9)

[0308] To a solution of 6-bromo-7-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylic acid tert-butyl ester (compound 6-8, 2.00 g, 5.60 mmol) in DCM (30 mL) was added TFA (6 mL). The reaction was stirred at 25 °C for 1 h. The mixture was quenched with NaHC03and extracted with DCM. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product (compound 6-9, 1.50 g) was used directly for the next step without further purification.

[0309] 1 H NMR (400 MHz, CDC13) δ 12.69 (s, 1H), 11.52 (s, 1H), 7.02 (s, 1H), 4.60 - 4.52 (m, 2H), 1.98 - 1.89 (m, 2H), 1.09 - 1.02 (m, 2H), 0.91 (dd, J = 6.7, 5.0 Hz, 2H).

[0310] Step 9: Preparation of 6-bromo-7-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylic acid methyl ester (compound 6-10)

[0311] A solution of 6-bromo-7-hydroxyspiro[4,1'-cyclopropane]-8-carboxylic acid (compound 6-9, 1.50 g, 5.01 mmol), NaHC03(0.51 g, 6.02 mmol) and Mel (0.85 g, 6.02 mmol) in DMF was stirred at 40 °C for 12 h. It was quenched with H20 and extracted with EtOAc. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the target product (compound 6-10, 1.30 g, 74.51% yield) as a white solid.

[0312] 1 H NMR (400 MHz, CDC13) δ 11.82 (s, 1H), 6.93 (s, 1H), 4.37 - 4.33 (m, 2H), 3.97 (s, 3H), 1.86 - 1.81 (m, 2H), 1.01 - 0.96 (m, 2H), 0.83 (dd, J = 6.5, 4.9 Hz, 2H).

[0313] Step 10: Preparation of 6-bromo-7-((tert-butoxycarbonyl)oxy)spiro[chromane-4,1'- cyclopropane]-8-carboxylic acid methyl ester (compound 6-11)

[0314] To a solution of 6-bromo-7-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylic acid methyl ester (compound 6-10, 1.30 g, 4.15 mmol) and DMAP (0.05 g, 0.41 mmol) in DCM was added Boc20 (1.09 g, 4.98 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product as colorless oil (compound 6-11, 1.60 g, 83.94% yield).

[0315] 1 H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 4.35-4.28 (m, 2H), 3.89 (s, 3H), 1.88-1.81 (m, 2H), 1.55 (s, 11H), 1.04 (dd, J = 6.6, 4.9 Hz, 2H), 0.89 (dd, J = 6.4, 4.8 Hz, 2H).

[0316] Step 11: Preparation of 7-((tert-butoxycarbonyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)spiro[chromane-4,1'-cyclopropane]-8-carboxylic acid methyl ester (compound 6-12)

[0317] A solution of 6-bromo-7-((tert-butoxycarbonyl)oxy)spiro[chromane-4,1'- cyclopropane]-8-carboxylic acid methyl ester (compound 6-11, 1.60 g, 3.87 mmol), B2Pin2 (1.97 g, 7.74 mmol), Pd(dppf)Cl2(0.28 g, 0.39 mmol) and potassium acetate (1.14 g, 11.62 mmol) in dioxane was heated at 100 °C for 12 h under nitrogen atmosphere. After cooling to ambient temperature, the mixture was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the product as white solid (compound 6-12, 0.90 g, 45.45% yield).

[0318] 1 H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 4.35-4.28 (m, 2H), 3.89 (s, 3H), 1.88-1.81 (m, 2H), 1.55 (s, 11H), 1.04 (dd, J = 6.6, 4.9 Hz, 2H), 0.89 (dd, J = 6.4, 4.8 Hz, 2H).

[0319] Step 12: Preparation of 7-((tert-butoxycarbonyl)oxy)-6-hydroxyspiro[chromane-4,1'- cyclopropane]-8-carboxylic acid methyl ester (Compound 6-13)

[0320] To a solution of 7-((tert-butoxycarbonyl)oxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)spiro[chromane-4,1'-cyclopropane]-8-carboxylic acid methyl ester (Compound 6-12, 0.90 g, 1.96 mmol) in THF / H2O (V / V = 2 / 1, 15 mL) was added NaB03*4H20 (0.90 g, 5.87 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was quenched with H20 and extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the product (Compound 6-13, 0.56 g, 73.58% yield) as colorless oil.

[0321] 1 H NMR (400 MHz, CDC13) δ 11.39 (s, 1H), 6.58 (s, 1H), 4.36 - 4.30 (m, 2H), 3.95 (s, 3H), 1.86 - 1.81 (m, 2H), 1.55 (s, 9H), 0.97 (d, J = 1.8 Hz, 2H), 0.81 (d, J = 1.4 Hz, 2H).

[0322] Step 13: Preparation of ((7-((tert-butoxycarbonyl)oxy)-8-(methoxycarbonyl)spiro[chromane- 4,1'-cyclopropane]-6-yl)oxy]methyl)boronic acid (Compound 6-15)

[0323] A solution of 7-((tert-butoxycarbonyl)oxy)-6-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylic acid methyl ester (Compound 6-13, 0.56 g, 1.60 mmol), 2-(iodomethyl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (Compound 6-14, 0.86 g, 3.20 mmol) and potassium carbonate (0.33 g, 2.40 mmol) in acetonitrile was heated at 60 °C for 3 h. After cooling to ambient temperature, the mixture was filtered through celite and concentrated. The crude product was purified by reverse phase column (eluted with 5%-95% MeCN / H20 with 0.1% FA) to give the target product (Compound 6-15, 400 mg, 55.18% yield) as yellow solid.

[0324] 1H NMR (400 MHz, CDC13) δ 6.46 (s, 1H), 5.34 (s, 2H), 4.31 - 4.27 (m, 2H), 3.95 (s, 2H), 3.91 (s, 3H), 1.87 - 1.81 (m, 2H), 1.53 (s, 9H), 1.00 (t, J = 5.7 Hz, 2H), 0.84 (t, J = 5.7 Hz, 2H).

[0325] Step 14: Preparation of 10'-carboxy-2'-dihydroxy-2'-,3',7'-,8'- tetrahydrospiro[cyclopropane-l,6'-[l,4,2]dioxadibydro[5,6-g]chromene]-2'- uridine disodium (Compound 6)

[0326] ((7-((tert-butoxycarbonyl)oxy)-8-(methoxycarbonyl)spiro[chromane-4,l'- cyclopropane]-6-yl)oxy]methylboronic acid (Compound 6-15, 100 mg, 0.25 mmol) was dissolved in 4 M NaOH (2.0 mL) solution at 80 °C and stirred for 2 h. After cooling to ambient temperature, the target product (Compound 6, 30 mg, 43.48% yield) was obtained as a brown solid by purification on a reverse phase column eluting with 5%-95% MeCN / H2O.

[0327] LCMS (ESI) m / z = 277.05 [M+H] + .

[0328] 1 H NMR (400 MHz, D20) δ 5.93 (s, 1H), 4.13 - 4.05 (m, 2H), 3.18 (s, 2H), 1.76 - 1.68 (m, 2H), 0.84 (d, J = 3.8 Hz, 2H), 0.74 (d, J = 4.0 Hz, 2H).

[0329] Example 7

[0330] Step 1: Preparation of 6-bromo-7-hydroxy-4-methyltryptophan-8-carboxylic acid methyl ester (Compound 7-2)

[0331] To a solution of 6-bromo-7-hydroxy-4-methyltryptophan-8-carboxylic acid (compound 5-9, 1.3 g, 4.5 mol) in DMF (10 mL) was added NaHC03(0.45 g, 5.3 mol) and iodomethane (0.77 g, 5.3 mol). The mixture was stirred at room temperature for 3 h. The residue was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 10:1) to give a yellow liquid (compound 7-2, 1.30 g, 91% yield).

[0332] 1 H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 7.40 (s, 1H), 4.21 - 4.08 (m, 2H), 3.77 (s, 3H), 2.85 (dd, J = 12.9, 6.4 Hz, 1H), 1.96 (dd, J = 9.4, 5.0 Hz, 1H), 1.65 - 1.52 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H).

[0333] Step 2: Preparation of 6-bromo-7-((tert-butoxycarbonyl)oxy)-4-methyltryptophan-8- carboxylic acid methyl ester (compound 7-3)

[0334] To a solution of 6-bromo-7-hydroxy-4-methyltryptophan-8-carboxylic acid methyl ester (compound 7-2, 1.30 g, 4.3 mol) and DMAP (0.050 g, 0.4 mol) in DCM (10 mL) was added Boc20 (1.03 g, 4.7 mol). The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA = 10:1) to give the product as a yellow oil (compound 7-3, 1.50 g, 84%).

[0335] 1 H NMR (400 MHz, DMSO) δ 7.64 (d, J = 0.7 Hz, 1H), 4.20 (dd, J = 6.2, 3.7 Hz, 2H), 3.77 (s, 3H), 2.97 (dd, J = 12.8, 6.4 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.72 - 1.56 (m, 1H), 1.47 (s, 9H), 1.28 (d, J = 7.0 Hz, 3H).

[0336] Step 3: Preparation of 7-((tert-butoxycarbonyl)oxy)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)tryptophan-8-carboxylic acid methyl ester (compound 7-4)

[0337] Under nitrogen protection, 6-bromo-7-((tert-butoxycarbonyl)oxy)-4- methyltryptophan-8-carboxylic acid methyl ester (compound 7-3, 1.20 g, 2.99 mmol), pinacol diborane (1.52 g, 5.98 mmol), Pd(dppf)Cl2(0.22 g, 0.30 mmol) and potassium acetate (0.88 g, 8.97 mmol) were dispersed in super dry 1,4 dioxane (15 mL), the reaction was stirred at 100 °C for 17 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound (compound 7-4, 1.0 g, 67.12% yield) as a yellow oily liquid.

[0338] LCMS (ESI) m / z = 466.15 [M+H2O] + .

[0339] Step 4: Preparation of 7-((tert-butoxycarbonyl)oxy)-6-hydroxy-4- methyltryptophan-8-carboxylic acid methyl ester (compound 7-5)

[0340] At room temperature, 7-((tert-butoxycarbonyl)oxy)-4-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)tryptophan-8-carboxylic acid methyl ester (compound 7-4, 0.9 g, 2.01 mmol) was dissolved in tetrahydrofuran (6 mL) and water (3 mL), and sodium perborate tetrahydrate (0.93 g, 6.02 mmol) was added. The reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, ethyl acetate was added for extraction, washed, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound (compound 7-5, 0.52 g, 72.73% yield) as a colorless oily liquid.

[0341] 1 H NMR (400 MHz, CDCl3) δ 11.50 (s, 1H), 7.09 (s, 1H), 4.23 (dd, J = 6.4, 4.0 Hz, 2H), 3.94 (s, 3H), 2.87 (dd, J = 12.8, 6.6 Hz, 1H), 2.14-2.05 (m, 1H), 1.76-1.65 (m, 1H), 1.56 (s, 9H), 1.28 (d, J = 7.0 Hz, 4H).

[0342] Step 5: Preparation of ((7-((tert-butoxycarbonyl)oxy)-8- (methoxycarbonyl)-4-methylchrom-6-yl)oxy methyl)boronic acid (compound 7-7)

[0343] Under nitrogen protection, methyl 7-((tert-butoxycarbonyl)oxy)-6-hydroxy-4-methyltryptophan-8-carboxylate (compound 7-5, 0.52 g, 1.54 mmol) was dissolved in acetonitrile (10 mL), and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (compound 7-6, 0.82 g, 3.07 mmol) and potassium carbonate (0.32 g, 2.31 mmol) were added. The reaction was stirred at 60 °C for 2 hours under nitrogen protection. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The crude product was analyzed by high performance liquid chromatography (HPLC) (C1). 18 The mobile phase was acetonitrile / water (0.1% formic acid), yielding the target compound (compound 7-7, 0.32 g, 49.93% yield), a yellow solid.

[0344] 1 H NMR(400MHz, CDCl3)δ6.98(s,1H),5.36(s,2H),4.26–4.13(m,2H),3.90(s,3H),3.16– 2.46(m,1H),2.13–1.97(m,1H),1.76–1.65(m,1H),1.54(s,9H),1.29(d,J=7.0Hz,3H).

[0345] Step 6: Preparation of 5,5-dihydroxy-11-methyl-4,7,14-trioxa-5-borontricyclo[8.4.0.0^{3,8}]tetradecane-1,3(8),9-triene-5-directed-2-carboxylic acid disodium salt (compound 7)

[0346] ((7-((tert-Butoxycarbonyl)oxy)-8-(methoxycarbonyl)-4-methylchromium-6-yl)oxymethyl)boronic acid (compound 7-7, 50 mg, 0.13 mmol)) was dissolved in 1.5 mL of 4 M sodium hydroxide solution, and the reaction mixture was stirred at 50 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the crude product was analyzed by high performance liquid chromatography (HPLC). 18 The target compound (compound 7, 3.79 mg, 8.23% yield) was purified using acetonitrile / water as the mobile phase to obtain an orange solid.

[0347] LCMS(ESI)m / z = 265.05[M+H] + .

[0348] 1H NMR (400 MHz, D20) δ 6.44 (d, J = 0.8 Hz, 1H), 4.00 (dddd, J = 28.6, 10.8, 7.4, 3.0 Hz, 2H), 3.20 (d, J = 1.2 Hz, 2H), 2.75 (dq, J = 13.6, 6.8 Hz, 1H), 1.94 (dddd, J = 7.6, 5.8, 4.4, 2.6 Hz, 1H), 1.56 (dtd, J = 10.0, 7.0, 3.0 Hz, 1H), 1.16 (d, J = 7.0 Hz, 3H).

[0349] Example 8

[0350] Step 1: Preparation of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)spiro[chromane- 4,1'-cyclopropane]-8-carboxylate (Compound 8-1)

[0351] To a solution of tert-butyl 6-bromo-7-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylate (Compound 6-8, 3.00 g, 8.47 mmol) and DMAP (0.10 g, 0.85 mmol) in DCM was added Boc20 (2.22 g, 10.17 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE:EA = 10: 1) to give the product (Compound 8-1, 3.30 g, 7.27 mmol, 85.82% yield) as a yellow solid.

[0352] 1 H NMR (400 MHz, CDC13) δ 6.81 (s, 1H), 4.34 - 4.29 (m, 2H), 1.86 - 1.80 (m, 2H), 1.57 (s, 9H), 1.55 (s, 9H), 1.02 (q, J = 4.9 Hz, 2H), 0.87 (q, J = 4.9 Hz, 2H).

[0353] Step 2: Preparation of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1'-cyclopropane]-8- carboxylate (Compound 8-3A)

[0354] A mixture of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)spiro[chromane-4.1'- cyclopropane]-8-carboxylate (compound 8-1, 190 mg, 0.42 mmol), 4.4.5.5-tetramethyl-2- vinyl-1.3.3.2 dioxaborolane (compound 8-2A, 19.32 mg, 0.46 mmol), Pd(t-Bu3P)2 (23.55 mg, 0.05 mmol) and TEA (126.68 mg, 1.25 mmol) in toluene was stirred at 80 °C under N2for 4 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 10:1) to give the target product (compound 8-3A, 170 mg, 0.29 mmol, 69.37% yield) as colorless oil.

[0355] LCMS (ESI) m / z = 373.10 [M+H] + .

[0356] Step 3: Preparation of tert-butyl (Z)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1'-cyclopropane]-8-carboxylate (compound 8-4)

[0357] A mixture of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)vinyl)spiro[cyclopropane-4,1'-cyclopropane]-8-carboxylate (compound 8-3A, 100 mg, 0.19 mmol) and tris(2-phenylpyridine)iridium (12.39 mg, 0.02 mmol) in ACN (10 mL) was stirred at room temperature under blue LED lamp (450 nm) for 16 h. The mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: PE:EA = 5:1) to give the target product (compound 8-4, 40 mg, 0.08 mmol, 40.01% yield) as colorless oil.

[0358] 1 H NMR (400 MHz, CDC13) δ 7.36 (s, 1H), 7.05 (m, 1H), 5.51 (m, 1H), 4.33 (m, 2H), 1.85 (m, 2H), 1.56 (s, 9H), 1.50 (s, 9H), 1.26 (s, 12H), 1.14 (m, 2H), 0.81 (m, 2H).

[0359] Step 4: Preparation of tert-butyl (Z)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1 '-cyclopropane]-8- carboxylate (Compound 8-4A)

[0360] To a solution of tert-butyl (Z)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1 '-cyclopropane]-8- carboxylate (Compound 8-4, 50 mg, 0.09 mmol) and Pd(OAc)2(2.21 mg, 0.01 mmol) in THF (3 mL) was added freshly prepared CH2N2(2 mL, about 0.6 M in Et2O) dropwise at -20 °C under N2protection, the mixture was stirred at -20 °C for 2 h, then stirred at rt for 14 h. The mixture was concentrated under reduced pressure, the crude was purified by silica gel column chromatography (eluent: PE:EA = 10:1) to give the target product (Compound 8-4A, 50 mg, 0.08 mmol, 82.77% yield) as yellow oil. LCMS (ESI) m / z = 387.15 [M+H] + .

[0361] Step 5: Preparation of 2'-hydroxy-1 ',1 a',2',6',7',9b'-hexahydrospiro[cyclopropane-8'- cyclopropane[3,4][1,2]oxaboreindeno[5,6-g]chromene]-4'-carboxylic acid (Compound 8)

[0362] To a solution of tert-butyl (Z)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1 '-cyclopropane]-8- carboxylate (Compound 8-4A, 40 mg, 0.07 mmol) and methylboronic acid (4.87 mg, 0.08 mmol) in THF (1 mL) was added concentrated HC1 (1 mL) at 0 °C, the mixture was stirred at 25 °C under N2protection for 2 h. The mixture was concentrated under reduced pressure, the crude was purified on Biotage Isolera One (C 18 18 column, eluted with 0% - 40% MeCN / H2O containing 0.1% TFA) to give the target product (Compound 8, 3.5 mg, 0.01 mmol, 15.61% yield) as yellow solid.

[0363] LCMS (ESI) m / z = 287.05 [M+H] + .

[0364] 1 H NMR (400 MHz, MeOD) δ 6.69 (s, 1H), 4.26 (m, 2H), 2.16 (td, J = 8.0, 4.2 Hz, 1H), 1.84 (dd, J = 10.6, 5.8 Hz, 2H), 1.25 (m, 1H), 1.03 (d, J = 5.4 Hz, 2H), 0.85 (d, J = 1.8 Hz, 2H), 0.49 (ddd, J = 10.4, 8.4, 6.2 Hz, 1H), 0.28 (s, 1H).

[0365] Example 9

[0366] Step 1: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)spiro[chromane-4,1'-cyclopropane]-8- carboxylate (Compound 9-2)

[0367] A mixture of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1'-cyclopropane]-8- carboxylate (Compound 8-4, 170 mg, 0.32 mmol) and 10% Pd / C (3.42 mg, 0.03 mmol) in MeOH (3 mL) was stirred at 25 °C under H2protection for 16 h. Then the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude product (Compound 9-2, 165 mg, 0.28 mol, 87.01% yield) was obtained as colorless oil, which was used directly for the next step without further purification. LCMS (ESI) m / z = 375.10 [M+H] + .

[0368] Step 2: Preparation of 2'-hydroxy-3',4',7',8'-tetrahydro-2'-spiro[cyclopropane-1,6'- [1,2]oxaborin[5,6-g]chromene]-10'-carboxylic acid (Compound 9)

[0369] To a solution of 7-((tert-butoxycarbonyl)oxy)-6-(2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)ethyl)tert-butyl spiro[4,1'-cyclopropane]-8-carboxylate (compound 9-2, 165 mg, 0.31 mmol) and methylboronic acid (22.41 mg, 0.37 mmol) in THF (2 mL) was added a solution of concentrated HC1 (2 mL) at 0 °C. The mixture was stirred at 25 °C under N2for 2 hours. The crude product was purified on a Biotage Isolera One (C 18 Column, eluted with 0% - 40% MeCN / H2O with 0.1% TFA) to give the target product (compound 9, 20 mg, 0.07 mmol, 23.21% yield) as a yellow solid.

[0370] LCMS (ESI) m / z = 275.05 [M+H] + .

[0371] 1 H NMR (400 MHz, MeOD) d 6.63 (s, 1H), 4.39 (s, 2H), 2.62 (t, J = 7.8 Hz, 2H), 1.88 (m, 2H), 1.02 (m, 5H), 0.85 (q, J = 4.6 Hz, 2H).

[0372] Example 10

[0373] Step 1: Preparation of 4-methyl-2H-chromen-7-ol (compound 10-3)

[0374] DIBAL-H (compound 10-2, 1 M in tetrahydrofuran, 1.70 L, 1.70 mol) was added dropwise slowly at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 4 hours. After the reaction was completed, 5% NaOH aqueous solution / water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1) to give the target compound (compound 10-3, 27.4 g, 30% yield) as a yellow oily liquid.

[0375] 1H NMR (400 MHz, CDC13) δ 7.00 (d, J = 8.3 Hz, 1H), 6.38 (dd, J = 8.3, 2.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 5.43 (td, J = 3.5, 1.7 Hz, 1H), 4.72 (dd, J = 3.6, 1.8 Hz, 2H), 1.98 (dd, J = 3.2, 1.6 Hz, 3H).

[0376] Step 2: Preparation of 4-methylbenzopyran-7-ol (Compound 10-4)

[0377] To a solution of 4-methyl-2H-benzopyran-7-ol (Compound 10-3, 37.0 g, 0.22 mol) in methanol (200 mL) was added 10% Pd / C (2.43 g) at room temperature and the mixture was stirred under hydrogen atmosphere at room temperature for 16 h. The mixture was filtered through celite and the filtrate was concentrated to give a colorless oil (Compound 10-4, 30.0 g, 80% yield) which was used directly in the next step without further purification.

[0378] 1 H NMR (400 MHz, CDC13) δ 7.00 (d, J = 8.3 Hz, 1H), 6.38 (dd, J = 8.3, 2.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 5.43 (td, J = 3.5, 1.7 Hz, 1H), 4.72 (dd, J = 3.6, 1.8 Hz, 2H), 1.98 (dd, J = 3.2, 1.6 Hz, 3H).

[0379] Step 3: Preparation of tert-butyl (4-methylchroman-7-yl) carbonate (Compound 10-5)

[0380] To a solution of 4-methylchroman-7-ol (Compound 10-4, 27.50 g, 167.50 mmol) and DMAP (2.05 g, 16.75 mmol) in DCM was added Boc20 (40.21 g, 184.25 mmol) portion wise. The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product as a colorless oil (Compound 10-5, 42.00 g, 94.87% yield).

[0381] 1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.4, 2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 4.10 - 4.20 (m, 2H), 2.85 - 2.95 (m, 1H), 1.95 - 2.05 (m, 1H), 1.58 - 1.68 (m, 1H), 1.47 (s, 9H), 1.26 (d, J = 6.8 Hz, 3H).

[0382] Step 4: Preparation of tert-butyl 7-hydroxy-4-methyltryptophan-8-carboxylate (Compound 10-6)

[0383] To a solution of tert-butyl (4-methylchroman-7-yl) carbonate (Compound 10-5, 42.00 g, 158.90 mmol) in THF was added LDA (95 mL, 2 M in THF) slowly dropwise under nitrogen protection at -40 °C. The mixture was stirred at -40 °C for 5 h. Quenched with H2O and extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (eluent: PE) to give the target product (Compound 10-6, 33.00 g, 78.60% yield) as colorless oil.

[0384] 1 H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.4, 2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 4.10 - 4.20 (m, 2H), 2.85 - 2.95 (m, 1H), 1.95 - 2.05 (m, 1H), 1.58 - 1.68 (m, 1H), 1.47 (s, 9H), 1.26 (d, J = 6.8 Hz, 3H).

[0385] Step 5: Preparation of tert-butyl 6-bromo-7-hydroxy-4-methyltryptophan-8- carboxylate (Compound 10-7)

[0386] To a solution of tert-butyl 7-hydroxy-4-methyltryptophan-8-carboxylate (Compound 10-6, 60.00 g, 227.00 mmol) in DMF was added NBS (44.44 g, 249.70 mmol) portionwise. The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (eluent: PE) to give the target product (Compound 10-7, 75.00 g, 96.26% yield) as white solid.

[0387] LCMS (ESI) m / z = 288.95 [M-56+H] + .

[0388] Step 6: Preparation of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-4- methylchromane-8-carboxylate (Compound 10-8)

[0389] To a solution of 4-methylchroman-7-ol (Compound 10-7, 75.00 g, 218.50 mmol) and DMAP (2.67 g, 21.85 mmol) in DCM was added Boc20 (52.46 g, 240.35 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-9% EtOAc in PE) to give the product (Compound 10-8, 83.50 g, 94.87% yield) as colorless oil.

[0390] 1 H NMR (400 MHz, DMSO-d6) d 7.58 (s, 1H), 4.16-4.26 (m, 2H), 2.90-3.00 (m, 1H), 1.96-2.06 (m, 1H), 1.61-1.70 (m, 1H), 1.48 (s, 18H), 1.28 (d, J = 7.2 Hz, 3H).

[0391] Step 7: Preparation of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-4-methyl-6-(2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)chromene-8-carboxylate (Compound 10-10)

[0392] To a solution of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-4-methylchromene-8- carboxylate (Compound 10-8, 0.60 g, 1.35 mmol), Compound 10-9 (0.31 g, 2.03 mmol) and triethylamine (0.27 g, 2.70 mmol) in toluene (10 mL) was added Pd(tBu3P)2 (0.07 g, 0.13 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. After completion of the reaction, the reaction was filtered over celite and concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to give the product (Compound 10-10, 0.50 g, 71.6% yield) as colorless oil.

[0393] 1H NMR (400 MHz, CDC13) δ 7.41 (s, 1H), 7.31 (d, J = 18.4 Hz, 1H), 6.01 (d, J = 18.4 Hz, 1H), 4.23 (dd, J = 9.4, 6.2 Hz, 2H), 2.92 (dd, J = 13.0, 6.4 Hz, 1H), 2.06 (dd, J = 6.2, 3.8 Hz, 1H), 1.75 - 1.68 (m, 1H), 1.57 (s, 9H), 1.54 (s, 9H), 1.30 (d, J = 7.0 Hz, 3H), 1.26 (s, 12H).

[0394] Step 8: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-4-methyl-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)tryptophan tert-butyl-8-carboxylate (Compound 10-11)

[0395] To a solution of tert-butyl 7-((tert-butoxycarbonyl)oxy)-4-methyl-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)tryptophan tert-butyl-8-carboxylate (Compound 10-10, 0.50 g, 0.97 mmol) in methanol was added 10% palladium on carbon (50 mg) and the reaction was stirred at room temperature under hydrogen (30 psi) for 4 hours. After completion of the reaction, the reaction was filtered over celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to give a colorless oily liquid (Compound 10-11, 0.35 g, 69.7% yield).

[0396] 1 H NMR (400 MHz, CDC13) δ 7.05 (s, 1H), 4.17 (dt, J = 7.0, 3.6 Hz, 2H), 2.88 (d, J = 6.4 Hz, 1H), 2.62 - 2.49 (m, 2H), 2.05 (m, 1H), 1.77 - 1.66 (m, 1H), 1.56 (s, 9H), 1.54 (s, 9H), 1.29 (d, J = 7.0 Hz, 3H), 1.22 (s, 12H).

[0397] Step 9: Preparation of Compound 10-12-P1, 10-12-P2

[0398] A mixture of compound 10-11 (4 g) was dissolved in isopropanol (150 mg / mL), filtered and purified by HPLC prep (eluted with 95% n-hexane / 5% isopropyl alcohol at a flow rate of 25 mL / min) to give off-white solid 10-12-P1 (1.7 g) and off-white solid 10-12-P2 (1.49 g).

[0399] Step 10: Preparation of compound 10-P1, 10-P2

[0400] To a solution of 10-12-P1 (0.20 g, 0.38 mmol) and isobutylboronic acid (77.47 mg, 0.76 mmol) in tetrahydrofuran (1 mL) was added concentrated hydrochloric acid (1 mL) and the reaction was stirred at room temperature for 2 hours. The reaction was purified by C 18 column purification (eluted with 5%-35% MeCN / H2O with 0.1% TFA in water) to give the product as a white solid (compound 10-P1, 40 mg, 40.1% yield).

[0401] 1 H NMR (400 MHz, MeOD) δ 7.10 (s, 1H), 4.31 (s, 2H), 2.89 (dd, J = 13.0, 6.4 Hz, 1H), 2.65 (t, J = 7.4 Hz, 2H), 2.11 (d, J = 5.2 Hz, 1H), 1.86 - 1.59 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.9 Hz, 2H). LCMS (ESI) m / z = 263.10 [M+H] + .

[0402] Compound 10-P2 (15 mg, 21% yield) was prepared from compound 10-12-P2 (0.14 g, 0.27 mmol) following the procedure for 10-P1 from 10-12-P1. 1 H NMR (400 MHz, MeOD) δ 7.11 (s, 1H), 4.30 (s, 2H), 2.89 (m, 1H), 2.65 (t, J = 7.4 Hz, 2H), 2.10 (s, 1H), 1.74 (s, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.8 Hz, 2H). LCMS (ESI) m / z = 263.10 [M+H] + .

[0403] Example 11

[0404] Step 1: Preparation of 6-bromo-7-hydroxy-4,4-dimethylchromane-8-carboxylic acid (Compound 11-2)

[0405] To a solution of 6-bromo-7-hydroxy-4,4-dimethylchromane-8-carboxylic acid (Compound 2-9, 1.70 g, 4.80 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The reaction was stirred at 25 °C for 1 h. The mixture was quenched with sodium bicarbonate and extracted with dichloromethane. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product (Compound 11-2, 0.90 g) was used directly for the next step without further purification.

[0406] LCMS (ESI) m / z = 299.00 [M-H] + .

[0407] Step 2: Preparation of methyl 6-bromo-7-hydroxy-4,4-dimethylchroman-8- carboxylate (Compound 11-3)

[0408] A solution of 6-bromo-7-hydroxy-4,4-dimethylchromane-8-carboxylic acid (Compound 11-2, 0.89 g, 2.95 mmol), sodium bicarbonate (0.74 g, 8.86 mmol) and iodomethane (0.5 g, 3.5 mmol) in DMF (20 mL) was stirred at 40 °C for 3 h. It was quenched with H2O and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1) to give the target product (Compound 11-3, 0.79 g, 84.81% yield) as a white solid.

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.51 (s, 1H), 4.14 (dd, J = 9.6, 4.4 Hz, 2H), 3.76 (s, 3H), 1.75 - 1.70 (m, 2H), 1.25 (s, 6H).

[0410] Step 3: Preparation of methyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-4,4- dimethylchroman-8-carboxylate (Compound 11-4)

[0411] To a solution of 6-bromo-7-hydroxy-4,4-dimethylchroman-8-carboxylic acid methyl ester (compound 11-3, 0.87 g, 2.76 mmol) and DMAP (0.03 g, 0.27 mmol) in dichloromethane (10 mL) was added Boc20 (0.90 g, 4.14 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10: 1) to give the product (compound 11-4, 0.89 g, 69.87% yield) as colorless oil.

[0412] 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 4.24 - 4.19 (m, 2H), 3.77 (s, 3H), 1.82 - 1.77 (m, 2H), 1.47 (s, 9H), 1.31 (s, 6H).

[0413] Step 4: Preparation of 7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tryptophanic acid-8-carboxylic acid methyl ester (compound 11-5)

[0414] Under nitrogen protection, 6-bromo-7-((tert-butoxycarbonyl)oxy)-4,4-dimethyltryptophanic acid-8-carboxylic acid methyl ester (compound 11-4, 0.70 g, 1.69 mmol), pinacol diborane (0.86 g, 3.37 mmol), Pd(dppf)Cl2(0.12 g, 0.17 mmol) and potassium acetate (0.50 g, 5.06 mmol) were dispersed in super dry 1,4 dioxane (15 mL), the reaction was stirred at 100 °C under nitrogen protection for 17 h. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10: 1) to give the target compound (compound 11-5, 0.43 g, 43.63% yield) as yellow oily liquid.

[0415] LCMS (ESI) m / z = 480.25 [M+H2O] + .

[0416] Step 5: Preparation of 7-((tert-butoxycarbonyl)oxy)-6-hydroxy-4,4-dimethyltryptophanic acid-8-carboxylic acid methyl ester (compound 11-6)

[0417] Methyl 7-((tert-butoxycarbonyl)oxy)-4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)tryptophan-8-carboxylate (Compound 11-5, 0.43 g, 0.92 mmol) was dissolved in tetrahydrofuran (4 mL) and water (2 mL) at room temperature, and sodium perborate tetrahydrate (0.42 g, 2.76 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, washed, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1) to obtain the target compound (Compound 11-6, 0.23 g, 67.46% yield) as a colorless oily liquid.

[0418] LCMS (ESI) cm / z = 297.00 [M-(t-Bu)] + .

[0419] Step 6: Preparation of ((7-((tert-butoxycarbonyl)oxy)-8-(methoxycarbonyl)-4,4- dimethylchroman-6-yl)oxy)methyl)boronic acid (Compound 11-8)

[0420] Methyl 7-((tert-butoxycarbonyl)oxy)-6-hydroxy-4,4-dimethyltryptophan-8- carboxylate (0.20 g, 0.57 mmol) was dissolved in acetonitrile (8 mL) under nitrogen protection, and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 11-7, 0.30 g, 1.14 mmol) and potassium carbonate (0.12 g, 0.85 mmol) were added. The reaction was stirred at 60°C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered with diatomite, and the filtrate was concentrated under vacuum. The crude product was purified by high-performance reverse-phase liquid chromatography (mobile phase: acetonitrile / water (0.1% formic acid)) to obtain the target compound (Compound 11-8, 0.15 g, 61.21% yield) as a white solid. 18

[0421] 1 H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 5.37 (s, 2H), 4.24-4.16 (m, 2H), 3.96 (s, 2H), 3.90 (s, 3H), 1.86-1.78 (m, 2H), 1.54 (s, 9H), 1.30 (s, 9H).

[0422] Step 7: Preparation of 5,5-dihydroxy-11,11-dimethyl-4,7,14-trioxo-5-boratricyclo[8.4.0.0^{3,8}]tetradeca-1,3(8),9-trien-5-ium-2-carboxylate disodium salt (Compound 11)​

[0423] ((7-((tert-Butoxycarbonyl)oxy)-8-(methoxycarbonyl)-4,4-dimethylchromium-6-yl)oxymethyl)boronic acid (compound 11-8, 50 mg, 0.12 mmol)) was dissolved in 1.5 mL of 4 M sodium hydroxide solution, and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the crude product was analyzed by high performance liquid chromatography (HPLC). 18 The target compound (compound 11, 1.54 mg, 3.36% yield) was purified by mobile phase (acetonitrile / water) to obtain a white solid.

[0424] LCMS(ESI)m / z=279.05[M+H] + .

[0425] 1 H NMR (400MHz, D2O) δ6.54(s,1H),4.12–3.93(m,2H),3.19(s,2H),1.79–1.62(m,2H),1.18(s,6H).

[0426] Example 12

[0427] Step 1: Preparation of 7-bromo-3-fluoropyran-4-one (compound 12-2)

[0428] Under nitrogen protection, a selective fluorine reagent (46.78 g, 132.16 mmol) and H₂SO₄ (1.08 g, 11.01 mmol) were added to a MeOH solution of 7-bromochrome-4-one (compound 12-1, 25.00 g, 110.13 mmol). The mixture was heated at 50 °C for 24 hours. After cooling to room temperature, the mixture was filtered and concentrated. The residue was diluted with CH₂Cl₂, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: 0-10% EtOAc in PE) to give a white solid product 12-2 (15.00 g, 55.82% yield).

[0429] 1 H NMR (400MHz, CDCl3) for 2: δ7.81–7.72(m,1H),7.26–7.20(m,2H),5.13(ddd,J=46.9,8.7,4.7Hz,1H),4.68–4.53(m,2H).

[0430] Step 2: Preparation of 7-bromo-3,3-difluorochroman-4-one (compound 12-3)

[0431] To a solution of 7-bromo-3-fluorochroman-4-one (compound 12-2, 23.00 g, 93.90 mmol) in DCM was added TBSOTf (37.23 g, 140.85 mmol) and TEA (19.00 g, 187.80 mmol) dropwise at 0 °C under nitrogen protection. The mixture was stirred at room temperature for 3 h. Quenched with saturated Na2CO3, extracted with DCM. The combined organic phase was washed with brine, dried over sodium sulfate, concentrated. The residue was dissolved in ACN, and added with fluorinating reagent (36.59 g, 103.29 mmol). The reaction was stirred at room temperature for 1 h. The mixture was quenched with water, extracted with CH2Cl2. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the target product (compound 12-3, 21.00 g, 76.57% yield) as a white solid.

[0432] 1 H NMR (400 MHz, CDCl3) d 7.83 (d, J = 8.9 Hz, 1H), 7.33-7.28 (m, 2H), 4.58 (t, J = 12.3 Hz, 2H).

[0433] Step 3: Preparation of 7-bromo-3,3-difluoro-4-methylenechroman (compound 12-4)

[0434] To a solution of methyltriphenylphosphonium bromide (34.19 g, 95.76 mmol) in THF was added n-BuLi (2.5 M in hexane, 38 mL, 95.76 mmol) dropwise at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 1 h, then added with a solution of compound 7-bromo-3,3-difluorochroman-4-one (compound 12-3, 21.00 g, 79.80 mmol) in THF. The mixture was stirred at 0 °C for 1 h, then stirred at room temperature for another 1 h. The reaction was quenched by adding NH4Cl, extracted with ethyl acetate. The organic layer was washed with brine, dried, filtered, concentrated. The crude product was purified by silica gel column chromatography (eluent: PE) to give the target product (compound 12-4, 10.0 g, 43.23% yield) as a colorless oil.

[0435] 1 H NMR (400 MHz, CDCl3) d 7.45-7.40 (m, 1H), 7.14 (dd, J = 7.9, 1.6 Hz, 2H), 5.85 (s, 1H), 5.77 (t, J = 2.2 Hz, 1H), 4.24 (t, J = 10.4 Hz, 2H).

[0436] Step 4: Preparation of 7-bromo-3,3-difluorospiro[chromene-4,1'-cyclopropane] (Compound 12-5)

[0437] To a solution of 7-bromo-3,3-difluoro-4-methylenechromonic acid (Compound 12-4, 10.00 g, 38.30 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (14.34 g, 49.79 mmol) in THF was added NaHMDS (2 M in THF, 30.6 mL, 61.28 mmol) dropwise at room temperature under nitrogen protection. The solution was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by reverse phase column (eluted with 5%-95% MeCN / H2O containing 0.1% FA) to give the target product (Compound 12-5, 4.0 g, 37.97% yield) as a yellow solid.

[0438] 1 H NMR (400 MHz, CDCl3) δ 7.10-7.03 (m, 2H), 6.51 (d, J = 8.3 Hz, 1H), 4.24 (t, J = 9.7 Hz, 2H), 1.55-1.50 (m, 2H), 1.09 (d, J = 1.8 Hz, 2H).

[0439] Step 5: Preparation of 2-(3,3-difluorospiro[chromene-4,1'-cyclopropane]-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 12-6)

[0440] A solution of 7-bromo-3,3-difluorospiro[chromene-4,1'-cyclopropane] (Compound 12-5, 4.0 g, 14.50 mmol), B2Pin2 (7.36 g, 29.00 mmol), Pd(PPh3)2Cl2 (1.02 g, 1.45 mmol) and potassium acetate (4.27 g, 43.50 mmol) in dioxane was heated at 80 °C for 12 hours under nitrogen. After cooling to room temperature, the mixture was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 12-6, 5.00 g, 96.55% yield) as a white solid.

[0441] 1H NMR (400 MHz, CDC13) δ 7.36 (d, J = 6.7 Hz, 2H), 6.66 (d, J = 8.1 Hz, 1H), 4.23 (t, J = 9.8 Hz, 2H), 1.54 - 1.51 (m, 2H), 1.32 (s, 12H), 1.14 (d, J = 1.9 Hz, 2H).

[0442] Step 6: Preparation of 3,3-difluorospiro[chromane-4,1'-cyclopropane]-7-ol (Compound 12-7)

[0443] To a solution of 2-(3,3-difluorospiro[chromane-4,1'-cyclopropane]-7-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (Compound 12-6, 5.00 g, 15.50 mmol) in THF / H20 (2 / 1, 60 mL) was added NaB03*4H20 (7.15 g, 46.50 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was quenched with H20, extracted with EtOAc. The combined organic phase was washed with brine, dried, concentrated. The crude was purified by silica gel column chromatography (eluent: 5-15% EtOAc in PE) to give the product (Compound 12-7, 2.50 g, 68.39% yield) as a white solid.

[0444] 1 H NMR (400 MHz, CDC13) δ 6.51 (d, J = 8.5 Hz, 1H), 6.47 - 6.40 (m, 2H), 5.03 (s, 1H), 4.22 (t, J = 9.8 Hz, 2H), 1.45 (q, J = 4.8 Hz, 2H), 1.06 - 1.00 (m, 2H).

[0445] Step 7: Preparation of (3,3-difluorospiro[chromane-4,1'-cyclopropane]-7-yl) tert- butyl carbonate (Compound 12-8)

[0446] To a solution of 3,3-difluorospiro[chromane-4,1'-cyclopropane]-7-ol (Compound 12-7, 2.50 g, 11.80 mmol) and DMAP (0.14 g, 1.18 mmol) in DCM was added Boc20 (3.09 g, 14.16 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 12-8, 3.0 g, 72.88% yield) as a white solid.

[0447] 1H NMR (400 MHz, CDC13) δ 6.77 (q, J = 2.1 Hz, 2H), 6.63 (d, J = 8.4 Hz, 1H), 4.24 (t, J = 9.7 Hz, 2H), 1.55 (s, 9H), 1.50 (d, J = 2.2 Hz, 2H), 1.09 (d, J = 1.9 Hz, 2H).

[0448] Step 8: Preparation of tert-butyl 3,3-difluoro-7-hydroxyspiro[chromane-4,1'- cyclopropane]-8-carboxylate (Compound 12-9)

[0449] To a solution of tert-butyl (3,3-difluorospiro[chromane-4,1'-cyclopropane]-7- yl) carbonate (Compound 12-8, 3.0 g, 9.60 mmol) in THF was added LDA (5.80 mL, 2M in THF) dropwise at -50 °C under nitrogen protection. The mixture was stirred at room temperature for 12 hours. The mixture was quenched with H2O, extracted with EtOAc, washed, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 12-9, 2.00 g, 56.25% yield) as colorless oil.

[0450] 1 H NMR (400 MHz, CDC13) δ 6.77 (q, J = 2.1 Hz, 2H), 6.63 (d, J = 8.4 Hz, 1H), 4.24 (t, J = 9.7 Hz, 2H), 1.55 (s, 9H), 1.50 (d, J = 2.2 Hz, 2H), 1.09 (d, J = 1.9 Hz, 2H).

[0451] Step 9: Preparation of tert-butyl 6-bromo-3,3-difluoro-7-hydroxyspiro[chromane-4,1'- cyclopropane]-8-carboxylate (Compound 12-10)

[0452] To a solution of tert-butyl 3,3-difluoro-7-hydroxyspiro[chromane-4,1'-cyclopropane]-8- carboxylate (Compound 12-9, 2.00 g, 6.40 mmol) in DMF was added NBS (1.20 g, 6.72 mmol) portionwise. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 12-10, 1.40 g, 50.29% yield) as white solid.

[0453] 1H NMR (400 MHz, CDC13) δ 11.97 (s, 1H), 6.89 (s, 1H), 4.27 (t, J = 9.6 Hz, 2H), 1.60 (d, J = 0.5 Hz, 9H), 1.49 (dd, J = 7.3, 5.3 Hz, 2H), 1.04 (s, 2H).

[0454] Step 10: Preparation of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-3,3- difluorospiro[chromane-4,1'-cyclopropane]-8-carboxylate (Compound 12-11)

[0455] To a solution of tert-butyl 6-bromo-3,3-difluoro-7-hydroxyspiro[chromane-4,1'- cyclopropane]-8-carboxylate (Compound 12-10, 1.40 g, 3.60 mmol) and DMAP (0.04 g, 0.36 mmol) in DCM was added Boc20 (0.94 g, 4.32 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: 10-20% EtOAc in PE) to give the product as a white solid (Compound 12-11, 1.70 g, 86.11% yield).

[0456] LCMS (ESI) m / z = 508.00 [M+NH4] + .

[0457] Step 11: Preparation of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-3,3-difluoro-6-(2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1'-cyclopropane]-8- carboxylate (Compound 12-13)

[0458] A solution of tert-butyl 6-bromo-7-((tert-butoxycarbonyl)oxy)-3,3-difluorospiro[chromane- 4,1'-cyclopropane]-8-carboxylate (Compound 12-11, 0.50 g, 1.02 mmol), 4.4,5,5,5- tetramethyl-2-vinyl-1,3,3,2-dioxaborolane (Compound 12-12, 0.19 g, 1.22 mmol), Pd(tBu3P)2 (0.05 g, 0.10 mmol) and TEA (0.21 g, 2.04 mmol) in toluene was heated at 80 °C for 3 h under nitrogen protection. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: 10-20% EtOAc in PE) to give the product as a colorless oil (Compound 12-13, 0.39 g, 61.11% yield).

[0459] 1 H NMR (400 MHz, CDC13) δ 7.30 (s, 0 H), 7.25 (s, 1 H), 6.87 (s, 1 H), 5.99 (d, J = 18.3 Hz, 1 H), 4.29 (t, J = 9.7 Hz, 2 H), 1.57 (s, 9 H), 1.53 (s, 10 H), 1.26 (s, 12 H), 1.09 (d, J = 6.9 Hz, 3 H), 0.87 - 0.84 (m, 2 H).

[0460] Step 12: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-3,3-difluoro-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1'- cyclopropane]-8-carboxylate (Compound 12-14)

[0461] To a solution of tert-butyl (E)-7-((tert-butoxycarbonyl)oxy)-3,3-difluoro-6-(2-(4,4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1'- cyclopropane]-8-carboxylate (Compound 12-13, 390 mg, 0.69 mmol) in ACN was added tris(2-phenylpyridine)iridium (fac-Ir(ppy)3) (45 mg, 0.07 mmol) under nitrogen protection, then placed in blue LED light (450 nm). The reaction was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the product (Compound 12-14, 200 mg, 35.89% yield) as yellow oil.

[0462] 1 H NMR (400 MHz, CDC13) δ 7.38 (s, 1 H), 7.06 (d, J = 15.1 Hz, 1 H), 5.59 (d, J = 15.1 Hz, 1 H), 4.30 (d, J = 9.6 Hz, 2 H), 1.57 (s, 9 H), 1.51 (s, 9 H), 1.26 (s, 12 H), 1.22 (s, 2 H), 0.88 (d, J = 2.9 Hz, 2 H).

[0463] Step 13: Preparation of tert-butyl 7-((tert-butoxycarbonyl)oxy)-3,3-difluoro-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)spiro[chromane-4,1'- cyclopropane]-8-carboxylate (Compound 12-15)

[0464] To a solution of tert-butyl (Z)-7-((tert-butoxycarbonyl)oxy)-3,3-difluoro-6-(2-(4,4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)spiro[chromane-4,1'- cyclopropane]-8-carboxylate (Compound 12-14, 200 mg, 0.35 mmol) and Pd(OAc)2(4.00 mg, 0.02 mmol) in THF was added freshly prepared diazomethane (5.9 mL, ~0.6 M in diethyl ether) dropwise at -10 °C under nitrogen protection. The solution was slowly warmed to room temperature and stirred for 12 h, then concentrated to dryness. The crude product was purified by silica gel column chromatography (eluent: 10-20% EtOAc in PE) to give the target product (Compound 12-15, 120 mg, 52.70% yield) as colorless oil.

[0465] LCMS (ESI) m / z = 596.20 [M+NH4] + .

[0466] Step 14: Preparation of 7',7'-difluoro-2'-hydroxy-1',1a',2',6',7',9b'- hexahydrospiro[cyclopropane-8'-cyclopropane[3,4][1,2]oxabenzindeno[5,6-g]chromene]-4'- carboxylic acid (Compound 12)

[0467] To a solution of tert-butyl 7-((tert-butoxycarbonyl)oxy)-3,3-difluoro-6-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)spiro[chromane-4,1'-cyclopropane]-8- carboxylate (Compound 12-15, 120 mg, 0.21 mmol) in HOAc (1 mL) was added MeB(OH)2(25 mg, 0.42 mmol) and 6 M HCl (1 mL). The reaction mixture was stirred at room temperature for 1 h. The residue was purified by reverse phase column (eluted with 5%-95% MeCN / H2O containing 0.1% TFA) to give the target product (Compound 12, 45 mg, 66.55% yield) as yellow solid.

[0468] LCMS (ESI) m / z = 323.05 [M+H]+.

[0469] 1H NMR (400 MHz, MeOD) δ 6.78 (s, 0H), 4.31 - 4.23 (m, 2H), 2.22 (td, J = 8.0, 4.2 Hz, 0H), 1.45 (dd, J = 6.4, 4.3 Hz, 1H), 1.32 - 1.24 (m, 1H), 1.16 (d, J = 1.7 Hz, 1H), 0.53 (ddd, J = 10.5, 8.2, 6.2 Hz, 1H), 0.30 (dt, J = 6.1, 3.9 Hz, 1H). 19 F NMR (377 MHz, MeOD) δ -114.49 (s, 1H), -115.15 (s, 8H), -115.32 (s, 9H), -115.98 (s, 1H).

[0470] Example 13

[0471] Step 1: Preparation of ethyl 2-(2-acetyl-5-methoxyphenoxy)acetate (compound 13-3)

[0472] To a solution of 2-hydroxy-4-methoxyacetophenone (compound 13-1, 14.0 g, 84.20 mmol) and potassium carbonate (23.37 g, 168.40 mmol) in acetone (250 mL) was added ethyl bromoacetate (compound 13-2, 21.09 g, 126.30 mmol) and the reaction was heated to 65 °C in an oil bath and stirred for 4 h. After the reaction was completed, the reaction solution was filtered through celite and the filtrate was rotary evaporated to give the crude product (compound 13-3, 20 g) which was used directly in the next step without further purification.

[0473] LCMS (ESI) m / z = 253.00 [M+H] + .

[0474] Step 2: Preparation of 2-(2-acetyl-5-methoxyphenoxy)acetic acid (compound 13-4)

[0475] To a solution of ethyl 2-(2-acetyl-5-methoxyphenoxy)acetate (compound 13-3, 20 g, 79.30 mmol) in methanol (80 mL) was added aqueous sodium hydroxide solution (80 mL, 4 mol / L) at 0 °C and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the methanol solvent was removed under reduced pressure and the solution was adjusted to pH about 2 with 6 M hydrochloric acid at this moment a large amount of solid was precipitated. The white solid (compound 13-4, 18 g) was obtained by filtration and used directly in the next step.

[0476] LCMS (ESI) m / z = 224.95 [M+H]+ .

[0477] Step 3: Preparation of 6-methoxy-3-methylbenzofuran (Compound 13-5)

[0478] To a solution of 2-(2-acetyl-5-methoxyphenoxy)acetic acid (Compound 13-4, 18 g, 80.30 mmol) in acetic anhydride (100 mL) was added sodium acetate (46.09 g, 562.10 mmol) at 0 °C. The reaction was stirred at 120 °C in an oil bath for 16 h. After completion of the reaction, the reaction was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 13-5, 12.0 g, 92.16% yield) as a colorless oily liquid.

[0479] 1 H NMR (400 MHz, CDC13) δ 7.37 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.4, 2.2 Hz, 1H), 3.85 (s, 3H), 2.21 (d, J = 1.4 Hz, 3H).

[0480] Step 4: Preparation of 6-methoxy-3-methyl-2,3-dihydrobenzofuran (Compound 13-6)

[0481] To a solution of 6-methoxy-3-methylbenzofuran (Compound 13-5, 12.0 g, 74 mmol) in methanol (120 mL) was added 10% palladium on carbon (1.50 g). The reaction was stirred at room temperature under hydrogen (30 psi) for 12 h. The reaction was filtered over celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 13-6, 11.0 g, 90.47% yield) as a colorless oily liquid.

[0482] 1 H NMR (400 MHz, CDC13) δ 7.01 (dd, J = 8.2, 0.8 Hz, 1H), 6.41 (dd, J = 8.2, 2.4 Hz, 1H), 6.38 (d, J = 2.2 Hz, 1H), 4.68 (t, J = 8.6 Hz, 1H), 4.07 (dd, J = 8.6, 7.4 Hz, 1H), 3.76 (s, 3H), 3.47 (m, 1H).

[0483] Step 5: Preparation of 3-methyl-2,3-dihydrobenzofuran-6-ol (Compound 13-7)

[0484] To a solution of 6-methoxy-3-methyl-2,3-dihydrobenzofuran (Compound 13-6, 10.0 g, 60.90 mmol) in dichloromethane (50 mL) was added BBr3(86 mL, 1 M in DCM) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction was quenched with water, extracted, washed, dried, filtered, and concentrated. The obtained oily liquid was dissolved in DMF (80 mL), and then cesium carbonate (79.37 g, 243.60 mmol) was added. The mixture was stirred at room temperature for another 2 h. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, washed, dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: 0-15% EtOAc in PE) to give the product (Compound 13-7, 3.50 g, 37.42% yield) as a white solid.

[0485] 1 H NMR (400 MHz, CDCl3) δ 6.96 (dd, J = 7.4, 0.8 Hz, 1H), 6.32-6.26 (m, 2H), 4.93 (m, 1H), 4.79 (s, 1H), 3.22 (dd, J = 14.8, 8.7 Hz, 1H), 2.72 (dd, J = 14.8, 7.6 Hz, 1H), 1.45 (d, J = 6.2 Hz, 3H).

[0486] Step 6: Preparation of tert-butyl (3-methyl-2,3-dihydrobenzofuran-6-yl) carbonate (Compound 13-8)

[0487] To a solution of 3-methyl-2,3-dihydrobenzofuran-6-ol (Compound 13-7, 3 g, 20 mmol) and Boc20 (4.37 g, 20 mmol) in DCM (40 mL) was added DMAP (0.24 g, 2 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: 0-10% EtOAc in PE) to give the product (Compound 13-8, 3.50 g, 70% yield) as a white solid.

[0488] 1H NMR (400 MHz, CDC13) δ 7.25 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.4, 2.4 Hz, 1H), 4.29 (m, 1H), 3.20 (dd, J = 14.2, 6.8 Hz, 1H), 3.04 (dd, J = 14.2, 7.4 Hz, 1H), 1.67 (d, J = 6.6 Hz, 3H), 1.55 (s, 9H).

[0489] Step 7: Preparation of tert-butyl 6-hydroxy-3-methyl-2,3-dihydrobenzofuran-7- carboxylate (Compound 13-9)

[0490] To a solution of tert-butyl (3-methyl-2,3-dihydrobenzofuran-6-yl) carbonate (Compound 13-8, 3.50 g, 14 mmol) in THF (30 mL) was added LDA (11.20 mL, 2M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction was allowed to warm up to room temperature slowly and stirred for 2 hours. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 13-9, 1.50 g, 42.85% yield) as a colorless oily liquid.

[0491] 1 H NMR (400 MHz, CDC13) δ 7.25 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.4, 2.4 Hz, 1H), 4.29 (m, 1H), 3.20 (dd, J = 14.2, 6.8 Hz, 1H), 3.04 (dd, J = 14.2, 7.4 Hz, 1H), 1.67 (d, J = 6.6 Hz, 3H), 1.55 (s, 9H).

[0492] Step 8: Preparation of tert-butyl 5-bromo-6-hydroxy-3-methyl-2,3-dihydrobenzofuran-7- carboxylate (Compound 13-10)

[0493] To a solution of tert-butyl 6-hydroxy-3-methyl-2,3-dihydrobenzofuran-7-carboxylate (compound 13-9, 1.50 g, 6 mmol) in DMF (20 mL) was added NBS (1.17 g, 6.60 mmol) portion wise and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to afford the product (compound 13-10, 1.10 g, 56.14% yield) as yellow oily liquid.

[0494] 1 H NMR (400 MHz, CDCl3) δ 11.98 (s, 1H), 7.37 (s, 1H), 5.00 (m, 1H), 3.21 (ddd, J = 15.0, 8.8, 1.0 Hz, 1H), 2.71 (ddd, J = 15.0, 7.6, 1.0 Hz, 1H), 1.60 (s, 9H), 1.46 (d, J = 6.4 Hz, 3H).

[0495] Step 9: Preparation of tert-butyl 5-bromo-6-((tert-butoxycarbonyl)oxy)-3-methyl- 2,3-dihydrobenzofuran-7-carboxylate (compound 13-11)

[0496] To a solution of tert-butyl 5-bromo-6-hydroxy-3-methyl-2,3-dihydrobenzofuran-7- carboxylate (compound 13-10, 1.10 g, 3.30 mmol) and Boc20 (0.86 g, 3.96 mmol) in DCM (16 mL) was added DMAP (0.04 g, 0.33 mmol) and the reaction was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to afford the product (compound 13-11, 1.0 g, 70.18% yield) as colorless oil.

[0497] 1 H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 5.21 - 4.96 (m, 1H), 3.29 (ddd, J = 15.8, 8.8, 1.0 Hz, 1H), 2.78 (ddd, J = 15.8, 7.4, 1.0 Hz, 1H), 1.56 (s, 18H), 1.47 (d, J = 6.3 Hz, 3H).

[0498] Step 10: Preparation of tert-butyl (E)-6-((tert-butoxycarbonyl)oxy)-3-methyl-5-(2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 13-13)

[0499] To a solution of tert-butyl 5-bromo-6-((tert-butoxycarbonyl)oxy)-3-methyl-2,3- dihydrobenfuran-7-carboxylate (Compound 13-11, 0.80 g, 1.86 mmol), Compound 13-12 (0.43 g, 2.80 mmol) and triethylamine (0.38 g, 3.73 mmol) in toluene (10 mL) was added (tBu3P)2Pd (0.09 g, 0.18 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. After completion of the reaction, the reaction was filtered over celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to afford a colorless oily liquid (Compound 13-13, 0.60 g, 64.08% yield).

[0500] 1 H NMR (400 MHz, CDC13) δ 7.46 (s, 1H), 7.38 (d, J = 18.4 Hz, 1H), 5.97 (d, J = 18.4 Hz, 1H), 5.13 - 4.96 (m, 1H), 3.29 (dd, J = 15.4, 8.8 Hz, 1H), 2.78 (dd, J = 15.4, 7.2 Hz, 1H), 1.57 (s, 9H), 1.55 (s, 9H), 1.48 (d, J = 6.4 Hz, 3H), 1.27 (s, 12H).

[0501] Step 11: Preparation of tert-butyl (E)-6-((tert-butoxycarbonyl)oxy)-3-methyl-5-(2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 13-13)

[0502] To a solution of tert-butyl (E)-6-((tert-butoxycarbonyl)oxy)-3-methyl-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenzofuran-7-carboxylate (compound 13-13, 0.60 g, 1.19 mmol) in acetonitrile (12 mL) was added fac-Ir(ppy)3 (0.08 g, 0.12 mmol) under nitrogen at room temperature. The mixture was stirred under a blue LED lamp (450 nm) for 16 h. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to give the product (compound 13-14, 0.30 g, 50% yield) as yellow oil.

[0503] 1 H NMR (400 MHz, CDC13) δ 7.51 (s, 1H), 7.12 (d, J = 14.8 Hz, 1H), 5.56 (d, J = 14.8 Hz, 1H), 5.15 - 4.96 (m, 1H), 3.26 (ddd, J = 15.4, 8.8, 1.0 Hz, 1H), 2.74 (ddd, J = 15.4, 7.4, 1.0 Hz, 1H), 1.56 (s, 9H), 1.51 (s, 9H), 1.48 (d, J = 6.4 Hz, 3H), 1.24 (s, 12H).

[0504] Step 12: Preparation of tert-butyl 6-((tert-butoxycarbonyl)oxy)-3-methyl-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2,3-dihydrobenzofuran-7-carboxylate (compound 13-15)

[0505] To a solution of tert-butyl (Z)-6-((tert-butoxycarbonyl)oxy)-3-methyl-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenzofuran-7-carboxylate (compound 13-14, 0.30 g, 0.60 mmol) and palladium acetate (6.8 mg, 0.03 mmol) in tetrahydrofuran (8 mL) was added freshly prepared diazomethane (6 mL, about 1 M in ether) slowly at -30 °C under nitrogen. The solution was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 0-20% EtOAc in PE) to give the product (compound 13-15, 0.20 g, 64.85% yield) as colorless oil.

[0506] LCMS (ESI) m / z = 539.30 [M+Na] + .

[0507] Step 13: Preparation of 2-hydroxy-7-methyl-1,1a,2,6,7,8b-hexahydrocyclopropa[3,4][1,2]oxazaborole[5,6-f]benzofuran-4-carboxylic acid (Compound 13)

[0508] To a solution of tert-butyl 6-((tert-butoxycarbonyl)oxy)-3-methyl-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2,3-dihydrobenzofuran-7-carboxylate (Compound 13-15, 0.15 g, 0.29 mmol) and isobutylboronic acid (59.23 mg, 0.58 mmol) in tetrahydrofuran (1 mL) was added concentrated hydrochloric acid (1 mL), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was purified by column (eluted with 5% to 40% MeCN / H2O with 0.1% TFA in water) to give the product (Compound 13, 30 mg, 39.72% yield) as a white solid. 18 .

[0509] LCMS (ESI) m / z = 261.10 [M+H] + .

[0510] 1 H NMR (400 MHz, MeOD) d 7.15 (s, 1H), 5.06 - 4.91 (m, 1H), 3.28 - 3.21 (m, 1H), 2.74 (ddd, J = 15.2, 7.5, 3.2 Hz, 1H), 2.19 (m, 1H), 1.47 - 1.38 (t, J = 11.2, 5.6 Hz, 3H), 1.21 (dd, J = 12.2, 4.8 Hz, 1H), 0.53 - 0.45 (m, 1H), 0.40 (m, 1H).

[0511] Example 14

[0512] Step 1-2: Preparation of 6-hydroxy-2-methylbenzofuran-3(2H)-one (Compound 14-4)

[0513] To a solution of 1,3-benzene-diol (compound 14-1, 30.0 g, 272.5 mmol) and AlCl3(36.3 g, 272.5 mmol) in DCE (300 mL) was added 2-chloropropanoyl chloride (compound 14-2, 34.6 g, 272.5 mmol) slowly at 0 °C under nitrogen protection, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice. The mixture was filtered and the filter cake was washed with water. The filter cake was dried to give 2-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (compound 14-3, 22.0 g, 40.26%) as a yellow solid. To a solution of 2-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (24.0 g, 119.6 mmol) in water (200 mL) was added sodium bicarbonate (20.1 g, 239.2 mmol), and the reaction mixture was stirred at 25 °C for 16 hours. The pH of the reaction mixture was adjusted to 6-7, and a white solid precipitated. The mixture was filtered, the filter cake was washed with water and dried to give the product (compound 14-4, 17.0 g, 86.62%) as a white solid.

[0514] 1 H NMR (400 MHz, Methanol-d4) δ 7.47 (d, J = 8.6 Hz, 1H), 6.56 (dd, J = 8.5, 2.0 Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H), 4.66 (q, J = 7.1 Hz, 1H), 1.44 (d, J = 7.1 Hz, 3H).

[0515] Step 3: Preparation of 2-methylbenzofuran-6-ol (compound 14-5)

[0516] To a solution of 6-hydroxy-2-methyl-2H-1-benzofuran-3-one (compound 14-4, 17.0 g, 103.6 mmol) and sodium hydroxide (4.10 g, 103.6 mmol) in ethanol (170 mL) was added sodium borohydride (11.0 g, 290.1 mmol), and stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to 2-3 carefully at 0 °C, extracted with ethyl acetate, washed, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluted with 0% to 10% EtOAc / PE) to give the product (compound 14-5, 11.3 g, 73.65%) as a white solid.

[0517] 1H NMR (400 MHz, CDC13) δ 7.28 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.72 (dd, J = 8.3, 2.3 Hz, 1H), 6.30 - 6.26 (m, 1H), 4.79 (s, 1H), 2.41 (d, J = 1.2 Hz, 3H).

[0518] Step 4-5: Preparation of tert-butyl (2-methyl-2,3-dihydrobenzofuran-6-yl) carbonate (Compound 14-7)

[0519] To a solution of 2-methylbenzofuran-6-ol (Compound 14-5, 15.0 g, 101.2 mmol) in methanol (150 mL) was added 10% palladium on carbon (1.50 g) and the reaction mixture was stirred at room temperature for 3 hours under hydrogen protection. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (150 mL), then Boc20 (26.5 g, 121.4 mmol) and DMAP (1.20 g, 10.1 mmol) were added. The solution was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuum and purified by silica gel column chromatography (eluted with 0% - 10% EtOAc / PE) to give the product as a white solid (Compound 14-7, 21.0 g, 82.91%).

[0520] 1 H NMR (400 MHz, CDC13) δ 7.09 (dd, J = 8.0, 1.3 Hz, 1H), 6.62 (dd, J = 8.0, 2.2 Hz, 1H), 6.56 (d, J = 2.2 Hz, 1H), 4.96 (ddq, J = 8.8, 7.6, 6.3 Hz, 1H), 3.27 (ddd, J = 15.3, 8.8, 1.1 Hz, 1H), 2.77 (ddd, J = 15.4, 7.6, 1.2 Hz, 1H), 1.55 (s, 9H), 1.45 (d, J = 6.3 Hz, 3H).

[0521] Step 6: Preparation of tert-butyl 6-hydroxy-2-methyl-2,3-dihydrobenzofuran-7- carboxylate (Compound 14-8)

[0522] To a solution of tert-butyl (2-methyl-2,3-dihydrobenofuran-6-yl) carbonate (compound 14-7, 10.0 g, 40.0 mmol) in tetrahydrofuran (100 mL) was added LDA (2M in THF, 24 mL) at -78 °C under nitrogen protection, and the reaction mixture was stirred at -78 °C for 0.5 h, then slowly warmed to 25 °C for another 2 h. After the reaction was completed, it was quenched with water at 0 °C carefully, extracted with EtOAc, washed, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluted with 0% - 10% EtOAc / PE) to give the product as colorless oil (compound 14-8, 7.10 g, 71.00%).

[0523] 1 H NMR (400 MHz, CDCl3) δ 11.22 (s, 1H), 7.11 (dd, J = 8.1, 1.2 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.99 (ddq, J = 9.0, 7.6, 6.3 Hz, 1H), 3.19 (ddd, J = 14.8, 8.9, 1.1 Hz, 1H), 2.69 (ddd, J = 14.8, 7.5, 1.1 Hz, 1H), 1.60 (s, 9H), 1.46 (d, J = 6.3 Hz, 3H).

[0524] Step 7: Preparation of tert-butyl 5-bromo-6-hydroxy-2-methyl-2,3-dihydrobenofuran-7- carboxylate (compound 14-9)

[0525] To a solution of tert-butyl 6-hydroxy-2-methyl-2,3-dihydrobenofuran-7-carboxylate (compound 14-8, 2.40 g, 9.60 mmol) in DMF (20 mL) was added NBS (1.90 g, 10.6 mmol), and the reaction mixture was stirred at room temperature for 1 h. Diluted with water, extracted with EtOAc, washed, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluted with 0% - 10% EtOAc / PE) to give the product as white solid (compound 14-9, 2.40 g, 76.04%).

[0526] 1 H NMR (400 MHz, CDCl3) δ 11.22 (s, 1H), 7.11 (dd, J = 8.1, 1.2 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.99 (ddq, J = 9.0, 7.6, 6.3 Hz, 1H), 3.19 (ddd, J = 14.8, 8.9, 1.1 Hz, 1H), 2.69 (ddd, J = 14.8, 7.5, 1.1 Hz, 1H), 1.60 (s, 9H), 1.46 (d, J = 6.3 Hz, 3H).

[0527] Step 8: Preparation of tert-butyl 5-bromo-6-((tert-butoxycarbonyl)oxy)-2-methyl- 2,3-dihydrobenzofuran-7-carboxylate (Compound 14-10)

[0528] To a solution of tert-butyl 5-bromo-6-hydroxy-2-methyl-2,3-dihydrobenzofuran-7- carboxylate (Compound 14-9, 2.40 g, 7.3 mmol) and Boc20 (1.9 g, 8.8 mmol) in DCM (20 mL) was added DMAP (0.10 g, 0.70 mmol) and the reaction mixture was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with 0% - 10% EtOAc / PE) to give the product as a white solid (Compound 14-10, 3.0 g, 95.89%).

[0529] 1 H NMR (400 MHz, CDC13) δ 7.37 (d, J = 1.2 Hz, 1H), 5.12 - 5.00 (m, 1H), 3.29 (ddd, J = 15.7, 8.9, 1.3 Hz, 1H), 2.78 (ddd, J = 15.6, 7.3, 1.3 Hz, 1H), 1.56 (s, 18H), 1.47 (d, J = 6.3 Hz, 3H).

[0530] Step 9: Preparation of tert-butyl (E)-6-((tert-butoxycarbonyl)oxy)-2-methyl-5-(2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenzofuran-7- carboxylate (Compound 14-11)

[0531] To a solution of tert-butyl 5-bromo-6-((tert-butoxy carbonyl)oxy)-2-methyl-2,3- dihydrobenzofuran-7-carboxylate (Compound 14-10, 3.0 g, 6.99 mmol), Compound 13-12 (1.3 g, 8.39 mmol) and triethylamine (1.40 g, 13.98 mmol) in toluene (30 mL) was added Pd(tBu3P)2 (357 mg, 0.70 mmol) and the reaction mixture was heated at 80 °C under nitrogen for 3 h. The reaction mixture was concentrated under reduced pressure and diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2S04and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with 0% - 25% EtOAc / PE) to give the product as a yellow solid (Compound 14-11, 2.50 g, 71.21%).

[0532] 1H NMR (400 MHz, CDC13) δ 7.45 (s, 1H), 7.37 (d, J = 18.3 Hz, 1H), 5.96 (d, J = 18.3 Hz, 1H), 5.03 (dq, J = 8.6, 6.5 Hz, 1H), 3.28 (ddd, J = 15.5, 8.9, 1.2 Hz, 1H), 2.77 (ddd, J = 15.5, 7.3, 1.3 Hz, 1H), 1.56 (s, 9H), 1.54 (s, 9H), 1.47 (d, J = 6.3 Hz, 3H), 1.26 (s, 12H).

[0533] Step 10: Preparation of tert-butyl 6-((tert-butoxycarbonyl)oxy)-2-methyl-5-((E)-2-(((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[l,3,2]dioxol-2-yl)ethenyl)-2,3-dihydrobenfur an-7-carboxylate (Compound 14-12)

[0534] To a solution of tert-butyl (E)-6-((tert-butoxycarbonyl)oxy)-2-methyl-5-(2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)ethenyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 14-11, 500 mg, 1.00 mmol) in THF (5 mL) was added (1R,2R,3S,5R)-(-)-2,3-propanediol (847 mg, 4.98 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluted with 0% - 15% EtOAc / PE) to give the product as a white solid (Compound 14-12, 400 mg, 72.49%).

[0535] LCMS (ESI) m / z = 572.20 [M+H20].

[0536] Step 11: Preparation of tert-butyl 6-((tert-butoxycarbonyl)oxy)-2-methyl-5-((Z)-2-((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[l,3,2]dioxol-2-yl)ethenyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 14-13)

[0537] To a solution of 6-((tert-butoxycarbonyl)oxy)-2-methyl-5-((E)-2-((3aR,4R,6R,7aS)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[l,3,2]dioxol-2-yl)vinyl)-2,3-dihydroben- furan-7-carboxylic acid tert-butyl ester (Compound 14-12, 400 mg, 0.72 mmol) in acetonitrile (15 mL) was added fac-Ir(ppy)3(47 mg, 0.07 mmol) under nitrogen, then the reaction mixture was placed under a blue LED lamp (450 nm) and stirred at room temperature for 5 hours. The reaction mixture was filtered and purified by C 18 Column purification (5% - 95% MeCN / H2O eluting with 0.1% formic acid in water) gave the product as a light yellow solid (Compound 14-13, 290 mg, 72.50%).

[0538] 1 H NMR (400 MHz, CDC13) δ 7.51 (d, J = 4.8 Hz, 1H), 7.14 (d, J = 14.7 Hz, 1H), 5.67 - 5.57 (m, 1H), 5.11 - 4.98 (m, 1H), 4.27 (dd, J = 8.8, 2.0 Hz, 1H), 3.31 - 3.20 (m, 1H), 2.74 (dt, J = 16.1, 7.9 Hz, 1H), 2.35 - 2.27 (m, 1H), 2.23 - 2.16 (m, 1H), 2.01 (s, 1H), 1.90 (dt, J = 5.6, 2.9 Hz, 1H), 1.82 (ddt, J = 14.6, 3.6, 1.9 Hz, 1H), 1.56 (s, 9H), 1.51 (s, 9H), 1.48 (dd, J = 6.3, 3.5 Hz, 3H), 1.38 (d, J = 1.1 Hz, 3H), 1.28 (d, J = 2.0 Hz, 3H), 1.24 - 1.20 (m, 1H), 0.84 (s, 3H).

[0539] Step 12: Preparation of 6-((tert-butoxycarbonyl)oxy)-2-methyl-5-(2-((3aR,4R,6R,7aS)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[l,3,2]dioxol-2-yl)cyclopropyl)-2,3- dihydrobenzofuran-7-carboxylic acid tert-butyl ester (Compound 14-14)

[0540] To a solution of 6-((tert-butoxy carbonyl)oxy)-2-methyl-5-((Z)-2-((3aR,4R,6R,7aS)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxol-2-yl)vinyl)-2,3- dihydrobenzofuran-7-carboxylic acid tert-butyl ester (Compound 14-13, 200 mg, 0.36 mmol) and Pd(OAc)2(4 mg, 0.02 mmol) in THF (2 mL) was added freshly prepared diazomethane (6.0 mL, about 0.6 M in ether) dropwise at -10 °C under nitrogen protection. The solution was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated to dryness, and the crude product was purified by silica gel column chromatography (eluted with 0% - 20% EtOAc / PE) to give the product as a white solid (Compound 14-14, 180 mg, 87.77%).

[0541] LCMS (ESI) m / z = 586.35 [M+H2O].

[0542] Step 13: Preparation of 2-hydroxy-6-methyl-l,la,2,6,7,8b-hexahydrocyclopropyl[3,4][l,2]oxazino[5,6- f]benzofuran-4-carboxylic acid (Compound 14)

[0543] To a solution of 6-((tert-butoxy carbonyl)oxy)-2-methyl-5-(2-((3aR,4R,6R,7aS)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxol-2-yl)cyclopropyl)-2,3- dihydrobenzofuran-7-carboxylic acid tert-butyl ester (Compound 14-14, 170 mg, 0.30 mmol) and MeB(OH)2(36 mg, 0.60 mmol) in THF (1 mL) was added concentrated hydrochloric acid (1 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction was filtered and purified by C 18 column chromatography (eluted with 5% - 95% MeCN / H2O with 0.1% TFA in water) to give the product as a yellow solid (Compound 14, 21 mg, 27.02%).

[0544] LCMS (ESI) m / z = 260.60 [M+H2O].

[0545] 1H NMR (400 MHz, MeOD) δ 7.16 (d, J = 1.4 Hz, 1H), 5.0 - 4.92 (m, 1H), 3.28 - 3.21 (m, 1H), 2.79 - 2.67 (m, 1H), 2.19 (td, J = 8.0, 4.3 Hz, 1H), 1.43 (ddd, J = 6.2, 5.0, 1.0 Hz, 3H), 1.26 - 1.18 (m, 1H), 0.49 (dddd, J = 9.7, 8.5, 6.2, 1.0 Hz, 1H), 0.40 (s, 1H).

[0546] Example 15

[0547] Step 1: Preparation of 2-bromo-l-(2,4-dihydroxyphenyl)butan-l-one (Compound 15-3)

[0548] To a solution of resorcinol (Compound 15-1, 15.0 g, 136.20 mmol) in trifluoromethanesulfonic acid (150 mL) was added 2-bromobutyric acid (Compound 15-2, 22.75 g, 136.20 mmol) and the reaction was stirred at 80 °C after heating in an oil bath for 6 hours. After the reaction was completed, the reaction solution was poured into ice water, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: 0-30% EtOAc in PE) to give the product (Compound 15-3, 23.0 g, 65.14% yield) as a white solid.

[0549] 1 H NMR (400 MHz, CDCl3) δ 12.45 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 6.42 (dd, J = 11.6, 2.4 Hz, 2H), 5.89 (s, 1H), 5.02 (dd, J = 7.6, 6.8 Hz, 1H), 2.31 - 2.11 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H).

[0550] Step 2: Preparation of 2-ethyl-6-hydroxybenzofuran-3(2H)-one (Compound 15-4)

[0551] To a solution of 2-bromo-l-(2,4-dihydroxyphenyl)butan-l-one (compound 15-3, 23.0 g, 88.80 mmol) in water (120 mL) was added sodium bicarbonate (14.92 g, 177.60 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h. After the reaction was completed, a large amount of solid was precipitated. The white solid was filtered and dried (compound 15-4, 12.0 g) to be used directly in the next step.

[0552] LCMS (ESI) m / z = 179.00 [M+H] + .

[0553] Step 3: Preparation of 2-ethylbenzofuran-6-ol (compound 15-5)

[0554] To a solution of 2-ethyl-6-hydroxybenzofuran-3(2H)-one (compound 15-4, 10.0 g, 56.10 mmol) and sodium hydroxide (2.24 g, 56.10 mmol) in water (80 mL) was added sodium borohydride (6.37 g, 168.30 mmol) at 0 °C. The reaction was stirred at 50 °C for 4 h. After the reaction was completed, the solution was adjusted to pH 3 with hydrochloric acid (2 M). The solution was extracted with ethyl acetate, washed, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: 0-20% ethyl acetate in PE) to give the product (compound 15-5, 5.0 g, 54.97% yield) as a colorless oily liquid.

[0555] 1 H NMR (400 MHz, CDC13) δ 7.29 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.72 (dd, J = 8.4, 2.2 Hz, 1H), 6.28 (d, J = 0.8 Hz, 1H), 4.86 (s, 1H), 2.75 (qd, J = 7.4, 0.8 Hz, 2H), 1.31 (t, J = 7.4 Hz, 3H).

[0556] Step 4: Preparation of 2-ethyl-2,3-dihydrobenzofuran-6-ol (compound 15-6)

[0557] To a solution of 2-ethylbenzofuran-6-ol (compound 15-5, 5.0 g, 30.80 mmol) in methanol (40 mL) was added 10% palladium on carbon (0.50 g). The reaction was stirred at room temperature under hydrogen (30 psi) for 4 h. After the reaction was completed, the reaction was filtered over celite. The filtrate was concentrated under reduced pressure. The obtained crude (compound 15-6, 4.50 g) was used directly in the next step without purification.

[0558] LCMS (ESI) m / z = 165.00 [M+H] + .

[0559] Step 5: Preparation of tert-butyl 2-ethyl-2,3-dihydrobenofuran-6-yl carbonate (Compound 15-7)

[0560] To a solution of 2-ethyl-2,3-dihydrobenofuran-6-ol (Compound 15-6, 4.50 g, 27.40 mmol) and Boc20 (7.18 g, 32.88 mmol) in DCM (40 mL) was added DMAP (0.33 g, 2.74 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column (eluent: 0-10% EtOAc in PE) to give the product (Compound 15-7, 4.80 g, 66.46% yield) as a white solid.

[0561] 1 H NMR (400 MHz, CDC13) δ 7.08 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.1 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 4.87 - 4.65 (m, 1H), 3.22 (dd, J = 15.4, 9.0 Hz, 1H), 2.82 (dd, J = 15.4, 7.8 Hz, 1H), 1.83 (m, 1H), 1.74 - 1.65 (m, 1H), 1.55 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H).

[0562] Step 6: Preparation of tert-butyl 2-ethyl-6-hydroxy-2,3-dihydrobenofuran-7- carboxylate (Compound 15-8)

[0563] To a solution of tert-butyl 2-ethyl-2,3-dihydrobenofuran-6-yl carbonate (Compound 15-7, 4.50 g, 17 mmol) in THF (30 mL) was added LDA (13.60 mL, 2M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction was slowly warmed to room temperature and stirred for 2 h. The reaction was quenched with water, extracted with ethyl acetate, washed, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 15-8, 3.80 g, 84.83% yield) as a colorless oily liquid.

[0564] 1H NMR (400 MHz, CDC13) δ 11.25 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 82 Hz, 1H), 4.70 (m, 1H), 3.09 (ddd, J = 14.8, 9.0, 0.8 Hz, 1H), 2.64 (ddd, J = 14.8, 7.6, 0.8 Hz, 1H), 1.79 - 1.69 (m, 1H), 1.62 (m, 1H), 1.53 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H).

[0565] Step 7: Preparation of tert-butyl 5-bromo-2-ethyl-6-hydroxy-2,3-dihydrobenzofuran-7- carboxylate (Compound 15-9)

[0566] To a solution of tert-butyl 2-ethyl-6-hydroxy-2,3-dihydrobenzofuran-7-carboxylate (Compound 15-8, 3.80 g, 14.40 mmol) in DMF (40 mL) was added NBS (3.08 g, 17.28 mmol) portion wise. The reaction was stirred at room temperature for 2 h. The reaction was quenched with water, extracted with ethyl acetate, washed, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product (Compound 15-9, 4.20 g, 84.80% yield) as a colorless oily liquid.

[0567] 1 H NMR (400 MHz, CDC13) δ 11.25 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 82 Hz, 1H), 4.70 (m, 1H), 3.09 (ddd, J = 14.8, 9.0, 0.8 Hz, 1H), 2.64 (ddd, J = 14.8, 7.6, 0.8 Hz, 1H), 1.79 - 1.69 (m, 1H), 1.62 (m, 1H), 1.53 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H).

[0568] Step 8: Preparation of tert-butyl 5-bromo-6-((tert-butoxycarbonyl)oxy)-2-ethyl-2,3- dihydrobenzofuran-7-carboxylate (Compound 15-10)

[0569] To a solution of 5-bromo-2-ethyl-6-hydroxy-2,3-dihydrobenzofuran-7-carboxylic acid tert-butyl ester (compound 15-9, 3.50 g, 10.20 mmol) and Boc20 (2.67 g, 12.24 mmol) in DCM (40 mL) was added DMAP (0.12 g, 1.11 mmol) and the reaction was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: 0-10% EtOAc in PE) to give the product as colorless oil (compound 15-10, 4.0 g, 88.75% yield).

[0570] 1 H NMR (400 MHz, CDC13) δ 7.36 (s, 1H), 4.95 - 4.77 (m, 1H), 3.40 - 3.16 (m, 1H), 2.82 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H), 1.56 (d, J = 1.6 Hz, 18H), 1.01 (t, J = 7.4 Hz, 3H).

[0571] Step 9: Preparation of tert-butyl (E)-6-((tert-butoxycarbonyl)oxy)-2-ethyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenzofuran-7-carboxylate (compound 15-11)

[0572] To a solution of 5-bromo-6-((tert-butoxycarbonyl)oxy)-2-ethyl-2,3-dihydrobenzofuran-7-carboxylic acid tert-butyl ester (compound 15-10, 1.0 g, 2.30 mmol), vinylboronic acid pinacol ester (0.53 g, 3.45 mmol) and triethylamine (0.47 g, 4.60 mmol) in toluene (10 mL) was added (tBu3P)2Pd (0.12 g, 0.23 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. After completion of the reaction, the reaction was filtered over celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-20% EtOAc in PE) to give the product as colorless oily liquid (compound 15-11, 0.70 g, 59.49% yield).

[0573] 1H NMR (400 MHz, CDC13) δ 7.46 (s, 1H), 7.40 (d, J = 18.4 Hz, 1H), 5.96 (d, J = 18.4 Hz, 1H), 4.96 - 4.78 (m, 1H), 3.25 (dd, J = 15.6, 9.0 Hz, 1H), 2.82 (dd, J = 15.8, 7.4 Hz, 1H), 1.85 (m, 1H), 1.71 (m, 1H), 1.56 (d, J = 4.6 Hz, 18H), 1.27 (s, 12H), 1.02 (t, J = 7.4 Hz, 3H).

[0574] Step 10: Preparation of tert-butyl (Z)-6-((tert-butoxycarbonyl)oxy)-2-ethyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 15-12)

[0575] To a solution of tert-butyl (E)-6-((tert-butoxycarbonyl)oxy)-2-ethyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 15-11, 0.70 g, 1.36 mmol) in acetonitrile (12 mL) was added fac-Ir(ppy)3 (0.09 g, 0.14 mmol) at room temperature under nitrogen protection. The mixture was stirred under blue LED lamp (450 nm) for 16 h. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was rotary evaporated under reduced pressure and purified by silica gel column chromatography (eluent: 0-15% EtOAc in PE) to give the product (Compound 15-12, 0.50 g, 71.43% yield) as yellow oil.

[0576] 1 H NMR (400 MHz, CDC13) δ 7.52 (s, 1H), 7.14 (d, J = 14.8 Hz, 1H), 5.56 (d, J = 14.8 Hz, 1H), 4.90 - 4.76 (m, 1H), 3.21 (dd, J = 15.4, 9.0 Hz, 1H), 2.78 (dd, J = 15.4, 7.4 Hz, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.56 (s, 9H), 1.52 (s, 9H), 1.25 (s, 12H), 1.03 (t, J = 7.4 Hz, 3H).

[0577] Step 11: Preparation of tert-butyl 6-((tert-butoxycarbonyl)oxy)-2-ethyl-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 15-13)

[0578] To a solution of tert-butyl (Z)-6-((tert-butoxycarbonyl)oxy)-2-ethyl-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 15-12, 0.37 g, 0.72 mmol) and palladium acetate (8 mg, 0.04 mmol) in tetrahydrofuran (8 mL) was added freshly prepared diazomethane (7 mL, ~1 M in ether) dropwise at -10 °C under nitrogen atmosphere. The solution was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 0-20% EtOAc in PE) to afford the product as colorless oil (Compound 15-13, 0.24 g, 63.15% yield).

[0579] LCMS (ESI) m / z = 553.3 [M+Na] + .

[0580] Step 12: Preparation of 6-ethyl-2-hydroxy-1,1 a,2,6,7,8b-hexahydrocyclopropa[3,4][1,2]oxaboro[5,6- f]benfuran-4-carboxylic acid (Compound 15)

[0581] To a solution of tert-butyl 6-((tert-butoxycarbonyl)oxy)-2-ethyl-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2,3-dihydrobenfuran-7-carboxylate (Compound 15-13, 0.10 g, 0.19 mmol) and isobutylboronic acid (38.43 mg, 0.38 mmol) in tetrahydrofuran (1 mL) was added concentrated hydrochloric acid (1 mL) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was purified by C 18 column (eluted with 5-40% MeCN in H2O with 0.1% TFA in water) to afford the product as white solid (Compound 15, 25 mg, 48.41% yield).

[0582] LCMS (ESI) m / z = 275.05 [M+H] + .

[0583] 1H NMR (400 MHz, MeOD) δ 7.15 (s, 1H), 4.83-4.71 (m, 1H), 3.24-3.17 (m, 1H), 2.79 (dd, J = 15.4, 7.4 Hz, 1H), 2.19 (td, J = 8.2, 5.0 Hz, 1H), 1.88-1.77 (m, 1H), 1.71 (m, 1H), 1.31-1.17 (m, 1H), 1.00 (td, J = 7.4, 2.8 Hz, 3H), 0.49 (m, 1H), 0.40 (s, 1H).

[0584] Experimental Example 1 Mouse Pharmacokinetic Experiment

[0585] Reagents and samples: Compound 5-P1, Compound 10-P1, normal saline, EDTA-2K

[0586] Animals: ICR mice, SPF level

[0587] Test method:

[0588] The pharmacokinetic characteristics of Compound 5-P1 and Compound 10-P1 after intravenous injection were tested by the following method. The ICR male mice in the experiment were fasted and intravenously injected with the above-mentioned Compound 5-P1 and Compound 10-P1 at a concentration of 0.2 mg / mL in clear normal saline solution. Nine mice were cross-sampled at time points of 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h, 0.08 mL of blood was collected and placed in a labeled EDTA-2K anticoagulant tube. The anticoagulant (EDTA-2K) was mixed with the blood by gently inverting the tube. The blood was immediately placed on wet ice, and the plasma was separated by centrifugation within 30 min after blood collection. The separated plasma was placed in a labeled EP tube. The plasma samples were analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated. The pharmacokinetic parameters of Compound 5-P1 and Compound 10-P1 are shown in Table 1.

[0589] Table 1 Mouse pharmacokinetic data of compounds of the application

[0590] The experimental results show that the series of compounds 5-P1 and 10-P1 of the application have good exposure under intravenous administration, and have no obvious toxic side effects and good safety at 1 mg / kg intravenous bolus, and have excellent pharmacokinetic properties.

[0591] Experimental Example 2 Biological activity test: minimum inhibitory concentration test of antibiotics combined with compounds

[0592] 1. Strain preparation

[0593] -80°C glycerol stocks were streaked onto CAMHA, Mueller Hinton II Agar (cation-adjusted), trademark name BD-212322 solid agar medium, and incubated at 35 ± 2°C for 18-24 h.

[0594] 2. Preparation of compound plate

[0595] Meropenem and compounds were prepared as stock solutions at concentrations of 12.8 mg / mL and 1.6 mg / mL, respectively, and stored at -80°C until use.

[0596] On the day of the experiment, meropenem stock solution was prepared in 96-well plates in test medium CAMHB as 11 two-fold serial dilutions of 4-fold working solutions (128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0 ug / mL). Compound stock solution was diluted in a centrifuge tube in test medium CAMHB to a 4-fold working solution (32 ug / mL). Then 25 μL of the 4-fold working solution of meropenem and 25 μL of the 4-fold working solution of compound were transferred to a U-bottom 96-well plate, mixed, and this was the compound plate.

[0597] 3. Preparation of inoculum

[0598] An appropriate amount of solid plate culture (step 1) was resuspended in physiological saline, mixed, and the bacterial suspension was adjusted to ~1 x 10 8 cfu / mL using a turbidimeter. This bacterial suspension was then diluted in test medium CAMHB to ~1 x 10 6 cfu / mL as the inoculum.

[0599] 4. Minimum inhibitory concentration (MIC) determination.

[0600] 50 μL of the bacterial inoculum (step 3) was transferred to the compound plate (step 2) to obtain the test plate. The total volume in each well of the test plate was 100 μL, containing ~5 x 10 5 cfu / mL of bacteria.

[0601] The test concentrations of meropenem were (in μg / mL): 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0; and the test concentration of the compound was 8 μg / mL. Finally, all test plates were incubated at 35 ± 2°C for 20 h.

[0602] Minimum inhibitory concentration (MIC) determination plate reading: After incubation, the test plates were observed by eye, and the lowest drug concentration that completely inhibited bacterial growth was the minimum inhibitory concentration of the compound. The lowest drug concentration that inhibited bacterial growth was defined as the MIC. The results are shown in Table 2.

[0603] Table 2. MIC data of the antibacterial activity of the compounds of this invention in combination with antibiotics against different bacterial strains.

[0604] Note: "NA" indicates not detected; MEM stands for Meropenem.

[0605] As shown in Table 2, the compound of this invention plus meropenem is effective against all drug-resistant strains. The compound of this invention plus meropenem exhibits high antibacterial activity against metalloenzyme-producing Escherichia coli, with a MIC of [missing value]. 50 All are ≤0.5mg / L; the compounds of this invention have strong antibacterial activity against carbapenem-resistant Acinetobacter baumannii strains, with MIC ranges from 1mg / L to 32mg / L; the compounds of this invention plus meropenem have high antibacterial activity against KPC-producing Klebsiella pneumoniae, with MICs ≤0.12mg / L; in particular, the antibacterial activity is most significant when meropenem is used in combination with compounds 5-P1, 5-P4, 9, and 13.

Claims

1. A boronic acid-based beta-lactamase inhibitor which is a compound represented by Formula (I), an optical isomer, or a pharmaceutically acceptable salt thereof: ###00001### (I) ​ wherein, X is C, O or N; Y is B, N or P; Z is O, S, B or N; R1is: H or wherein E is selected from alkenyl or alkynyl; R2is: H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or null; or R1, R2and the atoms to which they are attached form a ring of the following: wherein R a , R b each independently is selected from H, deuterium, hydroxyl, thiol, cyano, alkylthio, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, haloaryl, heteroaryl, or halo-heteroaryl; R3is H or hydroxyl; R4is carboxyl, sulfonic acid, amide or sulfonamide; L1is H or f, n, i are each independently 1, 2, 3, 4, 5 or 6; k is 0, 1, 2, 3, 4, 5 or 6; R5, R6, R7, R8are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, haloaryl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 halocycloalkenyl, C 3-8 cycloalkenyl, arylheterocyclyl or halogenarylheterocyclyl; A ring is selected from C 3-8 carbocyclic, C 3-8 carbocyclic, C 1-6 carbocyclic, C 1-6 carbocyclic, C 1-6 carbocyclic, C 3-8 carbocyclic, C 3-8 carbocyclic, C 3-8 carbocyclic, C 2. The boronic acid-based beta-lactamase inhibitor according to claim 1, characterized in that, in the compound of formula (I), optical isomer or pharmaceutically acceptable salt thereof, the A ring is unsubstituted or substituted with one, two identical or different, or three or more identical, partially identical or completely different substituents selected from the group consisting of deuterium, methyl, ethyl, propyl, cyclopropyl, F or Cl.

3. The boronic acid-based beta-lactamase inhibitor of claim 1, wherein, in the compound of formula (I), optical isomer or pharmaceutically acceptable salt thereof, when the A ring is a heterocarbocyclic ring, aromatic heterocyclic ring, spiro heterocyclic ring, it includes one heteroatom, two identical or different heteroatoms, or three or more identical, partially identical or completely different heteroatoms, and the heteroatom is selected from O, N or S.

4. The boronic acid-based beta-lactamase inhibitor of claim 1, wherein, In the compound of Formula (I), optical isomer, or pharmaceutically acceptable salt thereof, the A ring is selected from: wherein, M, G are each independently selected from CH2, O, S or NH; n is 1, 2, 3, 4, 5 or 6; j is 0, 1, 2, 3, 4, 5 or 6; R c selected from H, halogen, deuterium, hydroxyl, thiol, cyano, -C(=O)-R j , alkylthio, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 epoxyalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkylaryl, haloaryl, heteroaryl, haloheteroaryl; R j -NR d R f , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 epoxyalkyl, C 3-6 cycloalkyl, aryl, arahetero, which alkyl, alkoxy, cycloalkyl, epoxyalkyl, aryl, arahetero can be substituted by one or more halogen, cyano, hydroxy, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, aryl, haloaryl, arahetero or halarahetero; wherein R d , R f are each independently selected from H, deuterium, hydroxy, thiol, cyano, alkylthio, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloheteroalkyl, C 3-6 halocycloheteroalkyl, aryl, haloaryl, arahetero or halarahetero.

5. The boronic acid-based beta-lactamase inhibitor of claim 1, wherein, In the compound of formula (I), optical isomer, or pharmaceutically acceptable salt thereof, when j is 2, R c are the same or different; when j is 3, 4, 5, or 6, R c are the same, partially the same, or completely different.

6. The boronic acid-based beta-lactamase inhibitor of claim 4, wherein In the A ring of the compound of Formula (I), optical isomer, or pharmaceutically acceptable salt thereof, R c is methyl, cyclopropyl, dimethyl, ethyl, or fluoro.

7. The boronic acid-based beta-lactamase inhibitor of claim 1, wherein, In the compound of formula (I), optical isomer, or pharmaceutically acceptable salt thereof, the A ring is:

8. The boronic acid-based beta-lactamase inhibitor of claim 1, wherein, In the compound, optical isomer, or pharmaceutically acceptable salt of formula (I), when R1, R2 and the atoms they are attached to form a ring: And R a R b When both are H or deuterium, the A ring is selected from...

9. The boronic acid-based beta-lactamase inhibitor of claim 1, wherein, In the compound of formula (I), optical isomer, or pharmaceutically acceptable salt thereof, R1, R2and the atoms to which they are attached form a ring:

10. The boronic acid beta-lactamase inhibitor of claim 1, which is a compound represented by Formula (I), an optical isomer, or a pharmaceutically acceptable salt thereof: ###0002### (I). wherein, X is C, O or N; Y is B, N or P; Z is O, S, B or N; R1is: H, wherein E is selected from alkenyl or alkynyl; R2is: H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or absent; R3is H or hydroxyl; R4is carboxyl, sulfonic acid, amide or sulfonamide; L1is H or f, n, i are each independently 1, 2, 3, 4, 5 or 6; k is 0, 1, 2, 3, 4, 5 or 6; R5, R6, R7, R8are each independently selected from the group consisting of: H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, haloaryl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 haloepoxyalkyl, C 3-8 epoxyalkyl, arylheteroaryl or haloarylheteroaryl; A ring is selected from C 3-8 carbocyclic, C 3-8 carbocyclic, C 1-6 carbocyclic, C 1-6 carbocyclic, C 1-6 carbocyclic, C 3-8 carbocyclic, C 3-8 carbocyclic, C 3-8 carbocyclic, C 11. The boronic acid-based beta-lactamase inhibitor according to claim 10, characterized in that, in the compound of formula (I), optical isomer or pharmaceutically acceptable salt thereof, the A ring is unsubstituted or substituted with one, two identical or different, or three or more identical, partially identical or completely different substituents selected from the group consisting of deuterium, methyl, ethyl, propyl, cyclopropyl, F or Cl.

12. The boronic acid-based beta-lactamase inhibitor of claim 10, wherein, in the compound of formula (I), optical isomer or pharmaceutically acceptable salt thereof, when the A ring is a heterocarbocyclic ring, aromatic heterocyclic ring, spiro heterocyclic ring, it includes one heteroatom, two identical or different heteroatoms, or three or more identical, partially identical or completely different heteroatoms, and the heteroatom is selected from O, N or S.

13. The boronic acid-based beta-lactamase inhibitor of claim 10, wherein, In the compound of Formula (I), optical isomer, or pharmaceutically acceptable salt thereof, the A ring is selected from: wherein, M, G are each independently selected from CH2, O, S or NH; n is 1, 2, 3, 4, 5 or 6; j is 0, 1, 2, 3, 4, 5 or 6; R c selected from H, halogen, deuterium, hydroxyl, thiol, cyano, -C(=O)-R j , alkylthio group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 epoxyalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkylaryl, haloaryl, heteroaryl, haloheteroaryl; R j -NR d R f , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 epoxyalkyl, C 3-6 cycloalkyl, aryl, arahetero, which alkyl, alkoxy, cycloalkyl, epoxyalkyl, aryl, arahetero can be substituted by one or more halogen, cyano, hydroxy, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, aryl, haloaryl, arahetero or halohetero; wherein R d , R f are each independently selected from H, deuterium, hydroxy, thiol, cyano, alkylthio, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloheteroalkyl, C 3-6 halocycloheteroalkyl, aryl, haloaryl, arahetero or halohetero; R is the same or different; when j is 2, R c is the same or different; when j is 3, 4, 5 or 6, R c is the same, partially the same or completely different.

14. The boronic acid-based beta-lactamase inhibitor of claim 10, wherein, In the A ring of the compound of formula (I), the optical isomer, or the pharmaceutically acceptable salt thereof, R c is methyl, cyclopropyl, dimethyl, ethyl, or fluoro.

15. The boronic acid-based beta-lactamase inhibitor of claim 10, wherein, In the compound of formula (I), optical isomer, or pharmaceutically acceptable salt thereof, the A ring is:

16. The boronic acid beta-lactamase inhibitor of claim 1, which is a compound represented by Formula (II), an optical isomer, or a pharmaceutically acceptable salt thereof: wherein, X is C, O or N; Y is B, N or P; Z is O, S, B or N; a is 0, 1, 2, 3 or 4, preferably a is 1 or 2; M, Q are each independently C, O, S or N, and M, Q are not the same atom; R1, R2and the atoms to which they are attached form a ring of the following: wherein R a , R b are each independently selected from H, deuterium, hydroxyl, thiol, cyano, alkylthio, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, haloaryl, heteroaryl, or halo-heteroaryl; R3is H or hydroxyl; R4is carboxyl, sulfonic acid, amide or sulfonamide; e is 0, 1, 2 or 3; R M H, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; the alkyl, alkoxy groups can be substituted with any one or more halogens.

17. The boron-based β-lactamase inhibitor according to claim 16, wherein in the compound of formula (II), optical isomer or pharmaceutically acceptable salt thereof, when M is a C atom, Q is not an O atom.

18. The boron-based β-lactamase inhibitor according to claim 16, wherein in the compound of formula (II), optical isomer or pharmaceutically acceptable salt thereof, when Q is a C atom, M is not an O atom.

19. The boronic acid beta-lactamase inhibitor of claim 16, wherein R in the compound of Formula (II), the optical isomer, or the pharmaceutically acceptable salt thereof, is methyl, dimethyl, cyclopropyl, or ethyl. M is methyl, dimethyl, cyclopropyl, or ethyl.

20. The boronic acid-based beta-lactamase inhibitor of claim 1, wherein, for a compound of formula (III), an optical isomer, or a pharmaceutically acceptable salt thereof: wherein, X is C, O or N; Y is B, N or P; Z is O, S, B or N; M or Q are each independently C, O, S or N, and M, Q are not the same atom; R1, R2and the atoms to which they are attached form a ring of the following: wherein R a , R b are each independently selected from H, deuterium, hydroxyl, thiol, cyano, alkylthio, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, haloaryl, heteroaryl, or halo-heteroaryl; R3 is H or hydroxyl; R4 is carboxyl, sulfonic acid, amide or sulfonamide; e is 0, 1, 2 or 3; R M halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, said alkylalkoxy can be substituted with any one or more halogens.

21. The boronic acid beta-lactamase inhibitor of claim 20, wherein R in the compound of Formula (III), the optical isomer, or the pharmaceutically acceptable salt thereof, is methyl, dimethyl, cyclopropyl, or ethyl. M is methyl, dimethyl, cyclopropyl, or ethyl.

22. The compound of claim 1 of formula (I), wherein which is selected from the following compounds:

23. The compound of formula (I) according to claim 1, wherein the compound is selected from the following compounds:

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-23, an optical isomer or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable excipient.

25. The pharmaceutical composition of claim 24, wherein, The pharmaceutical composition further comprises a penicillin such as penicillin, amoxicillin, ampicillin, piperacillin, azlocillin, mezlocillin, sulbactam), a cephalosporin such as cephalothin, cefazolin, ceftizoxime, cefoperazone, cefotaxime, ceftriaxone, ceftazidime, cefixime, cefpirome, cefepime, cefixime, ceftaroline fosamil), a carbapenem such as meropenem, imipenem, biapenem, a monobactam such as aztreonam, or a combination of two or more thereof.

26. Use of a compound of any one of claims 1-23, an optical isomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 24-25 in the manufacture of a medicament for the treatment of a bacterial infection.

27. The use of claim 26, wherein the infection comprises an infection caused by Klebsiella pneumoniae, Escherichia coli, E. coli, Enterobacter cloacae, Acinetobacter baumannii, or Pseudomonas aeruginosa.

28. The pharmaceutical composition of claim 25, wherein the carbapenem comprises meropenem, imipenem, biapenem, ceftazidime, cefepime, cefuroxime, cefaclor, cefotaxime, ceftriaxone, cephalothin, cefazolin, ceftizoxime, cefoperazone, cefixime, ceftaroline fosamil, or aztreonam.

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