CN117777172A - Benzo five-membered ring boric acid ester-3-carboxylic acid compound and application thereof - Google Patents
Benzo five-membered ring boric acid ester-3-carboxylic acid compound and application thereof Download PDFInfo
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- CN117777172A CN117777172A CN202311525208.0A CN202311525208A CN117777172A CN 117777172 A CN117777172 A CN 117777172A CN 202311525208 A CN202311525208 A CN 202311525208A CN 117777172 A CN117777172 A CN 117777172A
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- Prior art keywords
- compound
- carboxylic acid
- mmol
- benzo
- alkyl
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- 125000005605 benzo group Chemical group 0.000 title claims abstract description 32
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 title claims description 7
- 239000004327 boric acid Substances 0.000 title claims description 7
- 108060004734 metallo-beta-lactamase Proteins 0.000 claims abstract description 45
- 102000020235 metallo-beta-lactamase Human genes 0.000 claims abstract description 45
- 102000006635 beta-lactamase Human genes 0.000 claims abstract description 26
- 241000894006 Bacteria Species 0.000 claims abstract description 24
- 108090000204 Dipeptidase 1 Proteins 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 23
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 claims abstract description 20
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 7
- -1 guanidino, mercapto Chemical class 0.000 claims description 104
- 159000000000 sodium salts Chemical group 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 101000740455 Klebsiella pneumoniae Metallo-beta-lactamase type 2 Proteins 0.000 claims description 12
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims description 12
- 229960002260 meropenem Drugs 0.000 claims description 12
- 101710150697 Inositol monophosphatase 1 Proteins 0.000 claims description 11
- 101710126181 Insulin-like growth factor 2 mRNA-binding protein 1 Proteins 0.000 claims description 11
- 102100029083 Minor histocompatibility antigen H13 Human genes 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 101000702393 Homo sapiens Signal peptide peptidase-like 2B Proteins 0.000 claims description 5
- 102100030404 Signal peptide peptidase-like 2B Human genes 0.000 claims description 5
- 230000003115 biocidal effect Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 239000003781 beta lactamase inhibitor Substances 0.000 claims description 4
- 229940126813 beta-lactamase inhibitor Drugs 0.000 claims description 4
- GASFVSRUEBGMDI-UHFFFAOYSA-N n-aminohydroxylamine Chemical compound NNO GASFVSRUEBGMDI-UHFFFAOYSA-N 0.000 claims description 4
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 claims description 4
- BZTQQYSGANYKMQ-UHFFFAOYSA-N NC(N(NN)O)=N Chemical compound NC(N(NN)O)=N BZTQQYSGANYKMQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 198
- 239000011734 sodium Substances 0.000 abstract description 118
- 229940079593 drug Drugs 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 13
- 239000003112 inhibitor Substances 0.000 abstract description 11
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 9
- 206010059866 Drug resistance Diseases 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 3
- 229910052708 sodium Inorganic materials 0.000 abstract description 3
- 229940124350 antibacterial drug Drugs 0.000 abstract description 2
- XTVMVZRNDOSPTI-UHFFFAOYSA-N oxaborole-3-carboxylic acid Chemical compound OC(=O)C1=BOC=C1 XTVMVZRNDOSPTI-UHFFFAOYSA-N 0.000 description 240
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
- 230000015572 biosynthetic process Effects 0.000 description 91
- 238000003786 synthesis reaction Methods 0.000 description 90
- 238000010189 synthetic method Methods 0.000 description 89
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 49
- 102000004190 Enzymes Human genes 0.000 description 29
- 108090000790 Enzymes Proteins 0.000 description 29
- 238000001308 synthesis method Methods 0.000 description 29
- 230000002401 inhibitory effect Effects 0.000 description 18
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 239000002132 β-lactam antibiotic Substances 0.000 description 8
- 229940124586 β-lactam antibiotics Drugs 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000010290 biphenyl Nutrition 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- YCISNMVJZZPXBG-UHFFFAOYSA-N 1-(2-bromo-4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(C)=O)C(Br)=C1 YCISNMVJZZPXBG-UHFFFAOYSA-N 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
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- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- UJSSRKRHXCIJRN-UHFFFAOYSA-N 1-(2-bromo-4-methoxyphenyl)ethanol Chemical compound COC1=CC=C(C(C)O)C(Br)=C1 UJSSRKRHXCIJRN-UHFFFAOYSA-N 0.000 description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 239000011701 zinc Substances 0.000 description 3
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101100026178 Caenorhabditis elegans egl-3 gene Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
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- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
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- IOOWNWLVCOUUEX-WPRPVWTQSA-N 2-[(3r,6s)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid Chemical compound OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1 IOOWNWLVCOUUEX-WPRPVWTQSA-N 0.000 description 1
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- QHDYEBDDCPGWCC-UHFFFAOYSA-M [Br-].[Mg+]C=1C=CSC=1 Chemical compound [Br-].[Mg+]C=1C=CSC=1 QHDYEBDDCPGWCC-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 229960002379 avibactam Drugs 0.000 description 1
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004197 benzothien-3-yl group Chemical group [H]C1=C(*)C2=C([H])C([H])=C([H])C([H])=C2S1 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 description 1
- 235000014304 histidine Nutrition 0.000 description 1
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- HTJPDOPKPWUNBX-UHFFFAOYSA-M magnesium;2h-thiophen-2-ide;bromide Chemical compound [Mg+2].[Br-].C=1C=[C-]SC=1 HTJPDOPKPWUNBX-UHFFFAOYSA-M 0.000 description 1
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- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 1
- DTKMKZYEOXZPQZ-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=C[C-]=C1 DTKMKZYEOXZPQZ-UHFFFAOYSA-M 0.000 description 1
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 description 1
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 1
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- SCPBADGYTPFIQF-UHFFFAOYSA-N methyl 2-(2-bromophenyl)-2-oxoacetate Chemical compound COC(=O)C(=O)C1=CC=CC=C1Br SCPBADGYTPFIQF-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a benzo five-membered ring borate-3-carboxylic acid compound and application thereof, belonging to the technical field of antibacterial drugs. The structure of the compound is shown as a formula I. The compound has good broad-spectrum inhibition activity on metal beta-lactamase and/or serine beta-lactamase, particularly has half inhibition concentration of B1 subtype metal beta-lactamase reaching sodium mole or picomole level, and lays a material foundation for research and development of related medicines. In addition, the compound has excellent antibacterial activity on various drug-resistant bacteria, can reverse the drug resistance of carbapenem-resistant bacteria, and has great potential in preparing inhibitors of metallo beta-lactamase and/or serine beta-lactamase and drugs for reversing the drug resistance of carbapenem-resistant bacteria.
Description
Technical Field
The invention belongs to the technical field of antibacterial medicines, and particularly relates to a benzo five-membered ring borate-3-carboxylic acid compound and application thereof.
Background
Beta-lactam antibiotics are the most widely used small molecular antibacterial drugs clinically at present, and carbapenem drugs are called as the last anti-infection line and are used for treating multi-drug resistant bacterial infection and severe infection. However, due to the abuse of antibiotics, many pathogens develop resistance to β -lactam antibiotics, the main reason for which is the formation of β -lactamase, thereby destroying the β -lactam ring of the antibiotic essential for inhibiting bacterial activity. In the 80 s of the 20 th century Ambler classified β -lactamase into 4 classes, a-D, based on its amino acid sequence homology, which acted by different mechanisms depending on their active site characteristics. Class a, class C and class D molecules have Serine at their active sites and use Serine hydrolysis mechanisms, such beta-lactamases are collectively referred to as Serine beta-lactamases (SBL), whereas class B molecules contain zinc ions at their active sites, which contribute to substrate catalysis, such as NDM, IMP and VIM, so such beta-lactamases are also known as Metallo-beta-lactamases (MBL).
MBL is divided into 3 subclasses according to its substrate characteristics and gene sequence similarity: b1, B2 and B3. The B1 subclass includes most metallo beta-lactamases, such as the B.cereus produced II enzyme (BcII), the Ccra produced by Bacteroides fragilis (also known as CfiA), the B.meningitidis produced enzyme BlaB, the IND-1 produced by Flavobacterium indoxacum, and the NDM, IMP and VIM classes found in Pseudomonas aeruginosa, serratia viscosa, klebsiella pneumoniae, acinetobacter baumannii all belong to this subclass. NDM class, IMP class and VIM class are currently the most clinically relevant MBL, hydrolyzableAll bicyclic beta lactam antibiotics. These enzymes have 3 histidines and 1 cysteine residue involved in the active site Zn 2+ And/or binding of water molecules, the activity of which can be inhibited by EDTA, a metal ion depriving agent, and Zn is added 2+ The activity can be recovered after that. Most of the B1 subclasses MBLs are plasmid-mediated. Subclass B2 includes enzymes CphA/CphA2 produced by Aeromonas, imiS and SFH-1 produced by Serratia spp. Only one Zn 2+ An active site, which hydrolyzes carbapenem antibiotics. The B3 subclass includes L1 enzymes of stenotrophomonas maltophilia, which have very low amino acid homology with other metalloenzymes, and hydrolyzes carbapenem antibiotics.
The combination of a beta-lactamase inhibitor and a beta-lactam antibiotic is one of the main methods for overcoming bacterial resistance, and the principle is that the beta-lactamase inhibitor prevents the hydrolysis of the beta-lactam antibiotic by the enzyme, so that the antibiotic plays an original antibacterial role. Currently, 6 SBL inhibitors, including clavulanic acid, sulbactam, tazobactam, avibactam, vaborbactam and Relebactam, are approved for use in combination with various beta-lactam antibiotics, respectively, to increase the antibacterial activity of the beta-lactam antibiotics against drug-resistant bacteria and to overcome the problem of beta-lactam antibiotic resistance. However, these SBL-targeting drug molecules are almost ineffective against MBL-expressing drug-resistant bacteria.
MBL-producing resistant bacteria continue to emerge and spread in recent years and are resistant to almost all beta-lactam antibiotics, threatening the life health of humans worldwide. Although a large number of MBL inhibitors have been reported to date, and some inhibitors also exhibit better in vitro and in vivo activity, no MBL inhibitors have been approved for clinical use until now and there are few drugs entering clinical studies.
The patent application No. 202110444405.4 reports a 3- (alpha-acrylic acid) substituted five-membered cyclic borate derivative with the structure of The 3- (alpha-acrylic acid) substituted five-membered cyclic borate derivative has good inhibitory activity on MBL, but the inhibitory activity can not meet the requirements, in particularThe inhibitory activity against MBL of the B1 subclass is to be further improved.
Disclosure of Invention
The invention aims to provide a benzo five-membered ring borate-3-carboxylic acid compound and application thereof in preparing inhibitors of beta-lactamase and/or serine beta-lactamase and medicines for reversing drug resistance of carbapenem resistant bacteria.
The invention provides a benzo five-membered ring boric acid ester-3-carboxylic acid compound, a stereoisomer or a salt thereof, wherein the structure of the benzo five-membered ring boric acid ester-3-carboxylic acid compound is shown as a formula I:
wherein R is 1 Selected from unsubstituted or R 3 The substituted following groups: c (C) 1-6 Alkyl, phenyl, heteroaryl, fused ring alkyl, heterofused ring group, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl; r is R 3 Selected from hydroxy, amino, amide, guanidino, mercapto, halogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, phenyl;
n is selected from 0, 1 or 2;
m is selected from 0, 1, 2, 3 or 4;
R 2 each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio groups.
Further, the structure of the benzo five-membered ring boric acid ester-3-carboxylic acid compound is shown as a formula II:
wherein R is 1 Selected from unsubstituted or R 3 The substituted following groups: c (C) 1-6 Alkyl, phenyl, heteroaryl, fused ring alkyl, fused ring group, 3-6 membered saturated cycloalkyl, 3-6 membered saturatedAnd a heterocyclic group; r is R 3 Selected from hydroxy, amino, amide, guanidino, mercapto, halogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, phenyl;
m is selected from 0, 1, 2, 3 or 4;
R 2 each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio groups.
Further, the R 1 Selected from unsubstituted or R 3 The substituted following groups: c (C) 1-4 Alkyl, phenyl,4-5 membered saturated cycloalkyl, 4-5 membered saturated heterocyclyl; r is R 3 Selected from halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl;
m is selected from 0, 1 or 2;
R 2 each independently selected from halogen, C 1-4 An alkoxy group.
Further, the structure of the benzo five-membered ring borate-3-carboxylic acid compound is shown in a formula III:
wherein R is 3 Selected from hydroxy, amino, guanidino, amide, mercapto, halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl;
m is selected from 0, 1 or 2;
R 2 each independently selected from C 1-4 An alkoxy group;
preferably, the halogen substituted C 1-4 Alkyl is CF 3 。
Further, the benzo five-membered ring borate-3-carboxylic acid compound is selected from the group consisting of:
further, the salt is sodium salt, and the salt of the benzo five-membered ring borate-3-carboxylic acid compound is selected from the group consisting of:
the invention also provides a pharmaceutical composition, which is a preparation prepared by taking the benzo five-membered ring borate-3-carboxylic acid compound, the stereoisomer or the salt thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the benzo five-membered ring borate-3-carboxylic acid compound, the stereoisomer or the salt thereof in preparing a beta-lactamase inhibitor.
The invention also provides application of the benzo five-membered ring borate-3-carboxylic acid compound, the stereoisomer or the salt thereof and carbapenem antibiotics in preparing medicines for resisting carbapenem resistant bacteria; preferably, the carbapenem antibiotic is meropenem and/or the carbapenem-resistant bacterium is a beta-lactamase-expressing bacterium.
Further, the beta-lactamase is a metallo beta-lactamase, a serine beta-lactamase, or a metallo beta-lactamase and a serine beta-lactamase;
preferably, the metallo-beta-lactamase is a B1 subclass metallo-beta-lactamase, more preferably, the B1 subclass metallo-beta-lactamase is selected from the group consisting of VIM-1, VIM-2, VIM-5, NDM-1, NDM-5, IMP-1, IMP-4.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1-6 Alkyl refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms.
"heteroaryl" refers to a heteroaromatic group containing at least one heteroatom, where the heteroatom includes, but is not limited to, oxygen, sulfur, nitrogen. For example
"fused ring alkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.
"heterofused ring group" refers to a polycyclic heterocyclic group having two rings sharing two adjacent carbon or heteroatom. For example
"3-6 membered saturated cycloalkyl" refers to a saturated cycloalkyl group having 3-6 ring carbon atoms.
"3-6 membered saturated heterocyclic group" refers to a saturated heterocyclic group having 3 to 6 ring atoms, which contain at least one heteroatom.
"halogen" is fluorine, chlorine, bromine or iodine.
The invention is innovatively introduced in the 3-positionCarboxyl groups, which form new skeleton derivatives of benzo five-membered ring borates-3-carboxylic acids, have very excellent MBL inhibitory activity, especially on half Inhibitory Concentration (IC) of B1 subclass MBL 50 ) The sodium mole or picomole level is achieved, and a material foundation is laid for the research and development of related medicines.
The compound has good and broad-spectrum inhibition activity on metal beta-lactamase and/or serine beta-lactamase, and can be used for preparing the inhibitor of the metal beta-lactamase and/or serine beta-lactamase. The compound has excellent antibacterial activity on various drug-resistant bacteria, can reverse the drug resistance of carbapenem-resistant bacteria, and has great potential in preparing inhibitors of beta-lactamase and/or serine beta-lactamase and drugs for reversing the drug resistance of carbapenem-resistant bacteria.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The following are the preparation methods of the intermediate compounds:
1. intermediate compound a:2- (2-bromophenyl) -2-oxoacetic acid methyl ester
Step 1: synthesis of 2- (2-bromophenyl) -2-glyoxylic acid (A-2)
Compound A-1 (25 g,125 mmol) was dissolved in dry pyridine (62.5 ml), selenium dioxide (21 g,187.5 mmol) was added, reacted under argon atmosphere at 100℃for 15h, after TLC monitoring the reaction was complete, cooled to room temperature, without further purification, to give a crude product solution of intermediate A-2.
Step 2: synthesis of methyl 2- (2-bromophenyl) -2-oxoacetate (A)
Form 4A molecular sieves (750 mg) were added to the crude product solution of A-2 above, dry methanol (100 ml) was added, cooled to 0deg.C, thionyl chloride (50 ml) was slowly added dropwise, after the reaction was allowed to proceed to room temperature for 16h, after TLC monitoring the reaction was complete, a mixed solution of perchloric acid (15 ml), acetonitrile (300 ml), water (30 ml) was added, stirring was continued at room temperature overnight, then quenching with saturated sodium bicarbonate, extraction with ethyl acetate and water, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was removed by evaporation, and column chromatography gave intermediate A (20 g, 66%). ESI-MS: [ M+H ] + ]:243.0,245.0
2. Intermediate compound B:2- (2-bromo-4-fluorophenyl) -2-oxoacetic acid methyl ester
Step 1: synthesis of 2- (2-bromo-4-fluorophenyl) -2-oxoacetic acid (B-2)
Starting from compound B-1 (8.68 g,40 mmol), a similar synthesis of intermediate A-2 was performed to give a crude product solution of intermediate B-2.
Step 2: synthesis of methyl 2- (2-bromo-4-fluorophenyl) -2-oxoacetate (B)
Intermediate B (7 g, 67%) was obtained by carrying out a similar synthesis method as intermediate A using intermediate B-2 as a starting material. ESI-MS: [ M+H ] + ]:261.0,263.0
3. Intermediate compound C:2- (2-bromo-5-fluorophenyl) -2-oxoacetic acid methyl ester
Step 1: synthesis of 2- (2-bromo-5-fluorophenyl) -2-oxoacetic acid (C-2)
Starting from compound C-1 (8.68 g,40 mmol), a similar synthesis of intermediate A-2 was performed to give a crude product solution of intermediate C-2.
Step 2: synthesis of methyl 2- (2-bromo-5-fluorophenyl) -2-oxoacetate (C)
Intermediate C (7.5 g, 72%) was obtained by carrying out a similar synthesis of intermediate A starting from intermediate C-2. ESI-MS: [ M+H ] + ]:261.0,263.0
4. Intermediate compound D:2- (2-bromo-4-methoxyphenyl) -2-oxoacetic acid methyl ester
Step 1: synthesis of 1- (2-bromo-4-methoxyphenyl) ethane-1-ol (D-2)
Compound D-1 (10 g,46.5 mmol) was dissolved in dry tetrahydrofuran (47 ml), methyl magnesium bromide (1.0M in THF) (19 ml,56 mmol) was slowly added dropwise at 0deg.C under argon atmosphere, then the reaction was continued to room temperature for 2h, after completion of TLC monitoring the reaction, saturated ammonium chloride solution was added for quenching, ethyl acetate and water extraction, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the excess solvent was evaporated to give the crude product of intermediate D-2.
Step 2: synthesis of 1- (2-bromo-4-methoxyphenyl) ethan-1-one (D-3)
The crude product of intermediate D-2 was dissolved in dry dichloromethane (216 ml), DMP (28 g,65 mmol) was added, reacted overnight at room temperature, after completion of TLC monitoring the reaction, dichloromethane and water were extracted, saturated sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride were washed respectively, dried over anhydrous sodium sulfate, the solvent was then spun dry, and column chromatography gave intermediate D-3 (5 g).
Step 3: synthesis of 2- (2-bromo-4-methoxyphenyl) -2-oxoacetic acid (D-4)
Starting from intermediate D-3 (5 g,21.8 mmol), a similar synthesis of intermediate A-2 was performed to give a crude product solution of intermediate D-4.
Step 4: synthesis of methyl 2- (2-bromo-4-methoxyphenyl) -2-oxoacetate (D)
Intermediate D (2.4 g, 41%) was obtained by carrying out a similar synthesis of intermediate A starting from intermediate D-4. ESI-MS: [ M+H ] + ]:273.0,275.0
5. Intermediate compound G-M1: synthesis of thiophen-2-yl magnesium bromide
Activated magnesium turnings (292 mg,12 mmol) were added to dry tetrahydrofuran (10 ml), and after a few drops of 1, 2-dibromoethane were added at 70℃under argon atmosphere, compound G-1 (0.86 ml,10 mmol) was slowly added dropwise, and the reaction was continued for 2 hours after initiation, and cooled to room temperature to give a tetrahydrofuran solution (10mmol,1.0M in THF) of intermediate G-M1.
6. Intermediate compound G-M2: synthesis of (4-fluorophenyl) magnesium bromide
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Starting from compound G-2 (1.1 ml,10 mmol), intermediate G-M2 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
7. Intermediate compound G-M3: synthesis of (3-fluorophenyl) magnesium bromide
Starting from compound G-3 (1.1 ml,10 mmol), intermediate G-M3 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
8. Intermediate compound G-M4: synthesis of 3- (trifluoromethyl) phenylmagnesium bromide
Starting from compound G-4 (1.4 ml,10 mmol), intermediate G-M4 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
9. Intermediate compound G-M5: synthesis of (4-methoxyphenyl) magnesium bromide
Starting from compound G-5 (1.25 ml,10 mmol), intermediate G-M5 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
10. Intermediate compound G-M6: synthesis of (3-methoxyphenyl) magnesium bromide
Starting from compound G-6 (1.26 ml,10 mmol), intermediate G-M6 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
11. Intermediate compound G-M7: synthesis of (4-methylphenyl) magnesium bromide
Starting from compound G-7 (1.35 ml,10 mmol), intermediate G-M7 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
12. Intermediate compound G-M8: synthesis of (3-methylthiophenyl) magnesium bromide
Starting from compound G-8 (1.34 ml,10 mmol), intermediate G-M8 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
13. Intermediate compound G-M9: synthesis of (3-biphenylyl) magnesium bromide
Starting from compound G-9 (1.67 ml,10 mmol), intermediate G-M9 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
14. Intermediate compound G-M10: synthesis of (3-chlorophenyl) magnesium bromide
Starting from compound G-10 (1.2 ml,10 mmol), intermediate G-M10 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
15. Intermediate compound G-M11: synthesis of (3-methylthiophene-2-yl) magnesium bromide
Starting from compound G-11 (1.1 ml,10 mmol), intermediate G-M11 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
16. Intermediate compound G-M12: synthesis of benzo [ b ] thiophen-2-yl magnesium bromide
Starting from compound G-12 (2.13G, 10 mmol), intermediate G-M12 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
17. Intermediate compound G-M13: synthesis of benzo [ b ] thiophen-3-yl magnesium bromide
Starting from compound G-13 (2.13G, 10 mmol), intermediate G-M13 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
18. Intermediate compound G-M14: synthesis of furan-2-yl magnesium bromide
Starting from compound G-14 (0.88 ml,10 mmol), intermediate G-M14 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
19. Intermediate compound G-M15: synthesis of thiophen-3-yl magnesium bromide
To an isopropyl magnesium chloride solution (5 ml,2M in THF) was slowly added dropwise compound G-15 (0.93 ml,10 mmol) at 0 ℃ under argon atmosphere, followed by reaction at 40 ℃ for 3h, and cooled to room temperature to give intermediate G-M15 in tetrahydrofuran (10mmol,1.0M in THF) 20. Intermediate compound G-M16: synthesis of cyclobutyl magnesium bromide
Starting from compound G-16 (0.94 ml,10 mmol), intermediate G-M16 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
21. Intermediate compound G-M17: synthesis of cyclopentylmagnesium bromide
Starting from compound G-17 (1.1 ml,10 mmol), intermediate G-M17 (10mmol,1.0M in THF) was obtained according to a similar synthetic method as intermediate G-M1.
The following are examples of the preparation of the compounds of the invention.
Example 1:3- (4-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-1) and its sodium salt (J-1-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2- (4-fluorophenyl) -2-glycolate (V-1)
Intermediate A (1.2G, 5 mmol) was dissolved in dry tetrahydrofuran (50 ml), G-M2 (10 ml,1M in THF) was slowly added dropwise at 0deg.C under argon, after which time the reaction was allowed to proceed to room temperature for 3h, after completion of TLC monitoring, saturated ammonium chloride was quenched, extracted with ethyl acetate and water, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was removed by evaporation, and column chromatography gave intermediate V-1 (660 mg, 52%).
Step 2: synthesis of methyl 3- (4-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-1)
Intermediate V-1 (660 mg,2.59 mmol), pinacol biboronate (987 mg,3.89 mmol), pd (PPh) 3 Cl 2 (182 mg,0.26 mmol), potassium acetate (1.02 g,10.3 mmol) was dissolved in dry DMSO (5 ml), reacted for 16h at 90℃under argon, after completion of the TLC monitoring reaction, cooled to room temperature, extracted with dichloromethane and water, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was dried, and column chromatographed to give intermediate L-1 (200 mg, 27%).
Step 3:3- (4-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-1) and its sodium salt (J-1-Na) + ) Is synthesized by (a)
Intermediate L-1 (200 mg,0.7 mmol) was dissolved in methanol (1 ml), aqueous sodium hydroxide (112 mg,2.8 mmol) was added (1 ml), reacted overnight at room temperature, TLC monitored to completion and then added 1N HCl to adjust pH to 1, ethyl acetate and water extraction, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the excess solvent was evaporated, and dichloromethane and N-pentane recrystallized to give Compound J-1(100mg,53％)。 1 H NMR(400MHz,CD 3 OD)δ7.74(d,J＝7.8Hz,1H),7.68(d,J＝7.2Hz,1H),7.59–7.39(m,4H),7.05(t,J＝8.7Hz,2H). 13 C NMR(101MHz,CD 3 OD)δ172.79,163.85,161.41,153.82,136.41,130.96,130.02,128.38,128.34,128.25,124.24,114.76,114.54,88.77.ESI-MS:[M-H 2 O+H + ]:255.1
Dissolving compound J-1 (76 mg,0.28 mmol) in acetonitrile (1 ml) and water (1 ml), adding 1N sodium hydroxide to adjust pH to be 13, reacting for 5h, extracting with ethyl acetate and water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and spin-drying the solvent to obtain compound J-1-Na + (20mg,20％)。
Example 2:3- (3-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-2) and its sodium salt (J-2-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2- (3-fluorophenyl) -2-glycolate (V-2)
Starting from intermediate G-M3 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-2 (480 mg, 58%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- (3-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-2)
Intermediate L-2 (250 mg, 30%) was obtained by a similar synthesis method to intermediate L-1 using intermediate V-2 (900 mg,2.89 mmol) as a starting material.
Step 3:3- (3-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-2) and its sodium salt (J-2-Na) + ) Is synthesized by (a)
Starting from intermediate L-2 (250 mg,0.87 mmol), compound J-2 (110 mg, 46%) was obtained according to a similar synthetic method as intermediate L-1. 1 H NMR(400MHz,CD 3 OD)δ7.79(d,J＝7.8Hz,1H),7.72(d,J＝7.3Hz,1H),7.58(t,J＝7.5Hz,1H),7.47(t,J＝7.3Hz,1H),7.38(dd,J＝12.5,5.6Hz,2H),7.23(d,J＝10.4Hz,1H),7.12–7.02(m,1H). 13 C NMR(101MHz,CD 3 OD)δ172.42,163.83,161.39,153.53,142.93,142.86,131.02,130.09,129.84,129.76,128.46,124.16,121.97,121.94,114.82,114.61,113.16,112.92,88.53.ESI-MS:[M-H 2 O+H + ]:255.1
Starting from compound J-2 (80 mg,0.29 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-2-Na + (20mg,21％)。
Example 3: 6-fluoro-1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-3) and its sodium salt (J-3-Na) + )
Step 1: synthesis of methyl 2- (2-bromo-4-fluorophenyl) -2-hydroxy-2-phenylacetate (V-3)
Starting from phenylmagnesium bromide (10 mmol,1M in THF), intermediate B (1.2 g,5 mmol), intermediate V-3 (1.1 g, 65%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- (3-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-2)
Intermediate L-3 (300 mg, 32%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-3 (1.1 g,3.24 mmol).
Step 3:3- (3-fluorophenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-3) and its sodium salt (J-2-Na) + ) Is synthesized by (a)
Starting from intermediate L-3 (300 mg,1.05 mmol), compound J-2 (150 mg, 53%) was obtained according to a similar synthetic method as intermediate L-1. 1 H NMR(400MHz,CD 3 OD)δ7.75(dd,J＝8.5,4.5Hz,1H),7.44(dd,J＝7.8,1.7Hz,2H),7.37–7.23(m,5H). 13 C NMR(101MHz,CD 3 OD)δ172.68,164.48,162.03,149.42,140.03,128.14,128.07,126.57,126.49,126.00,118.33,118.10,115.42,115.22,89.01.ESI-MS:[M-H 2 O+H + ]:255.1
Starting from compound J-3 (80 mg,0.29 mmol) according to the formulaThe compound J-1-Na was carried out as follows + Similar synthesis method to obtain compound J-3-Na + (25mg,24％)。
Example 4: 5-fluoro-1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-4) and its sodium salt (J-4-Na) + )
Step 1: synthesis of methyl 2- (2-bromo-5-fluorophenyl) -2-hydroxy-2-phenylacetate (V-4)
Starting from phenylmagnesium bromide (10 mmol,1M in THF), intermediate C (1.2 g,5 mmol), intermediate V-4 (1.03 g, 61%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 5-fluoro-1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-4)
Starting from intermediate V-4 (1.03 g,3.04 mmol), intermediate L-4 (280 mg, 32%) was obtained according to a similar synthetic method as intermediate L-1.
Step 3: 5-fluoro-1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-4) and its sodium salt (J-4-Na) + ) Is synthesized by (a)
Starting from intermediate L-3 (280 mg,0.98 mmol), compound J-4 (126 mg, 47%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,CD 3 OD)δ7.60(dd,J＝8.1,5.7Hz,1H),7.39–7.31(m,3H),7.29–7.22(m,3H),7.12-7.06(m,1H). 13 C NMR(101MHz,CD 3 OD)δ172.30,166.21,166.16,163.73,163.69,156.84,156.75,156.45,156.36,139.80,139.49,132.17,132.04,131.95,128.37,128.26,128.23,128.16,125.86,125.79,116.27,116.09,116.05,115.87,111.66,111.57,111.42,111.33,88.89.ESI-MS:[M-H 2 O+H + ]:255.1
Starting from compound J-4 (80 mg,0.29 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-4-Na + (20mg,20％)。
Example 5: 1-hydroxy-6-methoxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-5) and its sodium salt (J-5-Na) + )
Step 1: synthesis of methyl 2- (2-bromo-4-methoxyphenyl) -2-hydroxy-2-phenylacetate (V-5)
Starting from phenylmagnesium bromide (10 mmol,1M in THF), intermediate D (1.2 g,5 mmol), intermediate V-5 (1.2 g, 68%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 5-fluoro-1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-5)
Intermediate L-5 (300 mg, 30%) was obtained by a similar synthesis method as intermediate L-1 starting from intermediate V-5 (1.0 g,3.41 mmol).
Step 3: 5-fluoro-1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-5) and its sodium salt (J-5-Na) + ) Starting from intermediate L-5 (300 mg,1 mmol), compound J-5 (180 mg, 64%) was obtained according to a similar synthesis method as intermediate J-1. 1 H NMR(400MHz,CD 3 OD)δ7.63(d,J＝8.5Hz,1H),7.43(dd,J＝7.6,1.5Hz,2H),7.36–7.26(m,3H),7.16(d,J＝2.2Hz,1H),7.11(dd,J＝8.5,2.4Hz,1H),3.82(s,3H). 13 C NMR(101MHz,CD 3 OD)δ173.27,160.32,145.92,140.53,127.97,127.95,126.12,125.45,118.24,112.81,88.97,54.53.ESI-MS:[M-H 2 O+H + ]:267.1
Starting from compound J-5 (80 mg,0.28 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-5-Na + (20mg,20％)。
Example 6: 1-hydroxy-3-methyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-6) and its sodium salt (J-6-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxypropionate (V-6)
Intermediate V-6 (650 mg, 50%) was obtained following a similar synthetic procedure to intermediate V-1 starting from methyl magnesium bromide (10 mmol,1M in THF), intermediate A (1.2 g,5 mmol).
Step 2: synthesis of methyl 1-hydroxy-3-methyl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-6)
Intermediate L-6 (280 mg, 54%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-6 (1.0 g,3.41 mmol).
Step 3: 1-hydroxy-3-methyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-6) and its sodium salt (J-6-Na) + ) Is synthesized by (a)
Starting from intermediate L-6 (280 mg,1.36 mmol), compound J-6 (50 mg, 19%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),9.42(s,1H),7.71(d,J＝7.2Hz,1H),7.49(s,2H),7.41(d,J＝6.7Hz,1H),1.66(s,3H). 13 C NMR(101MHz,DMSO-d6)δ173.83,156.76,131.51,130.94,128.47,121.97,84.68,25.83.MS:[M-H 2 O+H + ]:175.1
Starting from compound J-6 (80 mg,0.42 mmol), the compound J-1-Na was prepared + Similar synthesis method to obtain compound J-6-Na + (20mg,17％)。
Example 7: 1-hydroxy-3-thiophen-2-yl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-7) and its sodium salt (J-7-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2-thiophen-2-ylacetate (V-7)
Starting from intermediate G-M1 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-7 (1.38G, 84%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-2-thiophen-2-yl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-7)
Starting from intermediate V-7 (1.38 g,4.22 mmol), intermediate L-7 (500 mg, 43%) was obtained according to a similar synthetic method as intermediate L-1.
Step 3: 1-hydroxy-2-thiophen-2-yl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-7) and its sodium salt (J-7-Na) + ) Is synthesized by (a)
Starting from intermediate L-7 (500 mg,1.36 mmol), compound J-7 (254 mg, 72%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ13.53(s,1H),9.78(s,1H),7.74(dd,J＝7.5,3.1Hz,2H),7.58-7.54(m,1H),7.47-7.43(m,2H),7.21(dd,J＝3.5,1.1Hz,1H),7.00(dd,J＝5.0,3.7Hz,1H).MS:[M-H 2 O+H + ]:243.0
Starting from compound J-7 (80 mg,0.31 mmol), the compound J-1-Na was prepared + Similar synthesis method to obtain compound J-7-Na + (20mg,19％)。
Example 8: 1-hydroxy-3-thiophen-2-yl-1, 3-dihydrobenzo [ c ] ][1,2]Oxaborole-3-carboxylic acid (J-8) and its sodium salt (J-8-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-3-thiophen-2-ylacetate (V-8)
Starting from intermediate G-M15 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-8 (912 mg, 55%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-3-thiophen-2-yl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-8)
Intermediate L-8 (240 mg, 31%) was obtained by following a similar synthetic method to intermediate L-1 starting from intermediate V-8 (912 mg,2.79 mmol).
Step 3: 1-hydroxy-3-thiophen-2-yl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-8) and its sodium salt (J-8-Na) + ) Is synthesized by (a)
Starting from intermediate L-8 (240 mg,0.88 mmol), a similar synthesis of intermediate J-1 was performedThe method yielded compound J-8 (110 mg, 48%). 1 H NMR(400MHz,CD 3 OD)δ7.77(d,J＝7.8Hz,1H),7.67(d,J＝7.3Hz,1H),7.57–7.48(m,1H),7.42(t,J＝7.3Hz,1H),7.39–7.34(m,2H),7.21(dd,J＝4.5,1.8Hz,1H). 13 C NMR(101MHz,CD 3 OD)δ172.52,154.48,141.15,130.99,129.91,128.25,126.12,125.58,123.61,122.23,86.88.MS:[M-H 2 O+H + ]:243.0
Starting from compound J-8 (80 mg,0.31 mmol), the compound J-1-Na was prepared + Similar synthesis method to obtain compound J-7-Na + (25mg,24％)。
Example 9: 1-hydroxy-3-thiophen-2-yl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-9) and its sodium salt (J-9-Na) + )
Step 1: synthesis of methyl 2- (benzo [ b ] thiophen-3-yl) -2- (2-bromophenyl) -2-glycolate (V-9)
Starting from intermediate G-M13 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-13 (1.3G, 69%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- (benzo [ b ] thiophen-3-yl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-9)
Intermediate L-9 (268 mg, 24%) was obtained by following a similar synthetic method to intermediate L-1 starting from intermediate V-13 (1.3 g,3.44 mmol).
Step 3:3- (benzothien-3-yl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-9) and its sodium salt (J-9-Na) + ) Is synthesized by (a)
Starting from intermediate L-8 (268 mg,0.83 mmol), compound J-9 (50 mg, 19%) was obtained according to a similar synthetic method as intermediate J-1. MS [ M-H ] 2 O+H + ]:293.0
Starting from compound J-9 (80 mg,0.26 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-9-Na + (20mg,19％)。
Example 10: 1-hydroxy-3- (3-methylthiophene-2-yl) -1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-10) and its sodium salt (J-10-Na) + )
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Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2- (3-methylthiophene-2-yl) acetate (V-10)
Starting from intermediate G-M11 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-10 (780 mg, 46%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-3- (3-methylthiophene-2-yl) -1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-10) intermediate V-10 (780 mg,2.28 mmol) was used as a starting material, and intermediate L-10 (160 mg, 25%) was obtained according to a similar synthetic method as intermediate L-1.
Step 3: 1-hydroxy-3- (3-methylthiophene-2-yl) -1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-10) and its sodium salt (J-10-Na) + ) Is synthesized by (a)
Starting from intermediate L-10 (160 mg,0.56 mmol), compound J-10 (40 mg, 26%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,CD 3 OD)δ7.70(d,J＝7.7Hz,1H),7.59(d,J＝7.2Hz,1H),7.45(td,J＝7.5,1.1Hz,1H),7.38(t,J＝7.0Hz,1H),7.02(d,J＝5.2Hz,1H),6.78(d,J＝5.1Hz,1H),2.22(s,3H). 13 C NMR(101MHz,CD 3 OD)δ172.77,154.13,137.09,135.92,130.88,130.61,129.89,128.84,123.91,122.70,85.71,13.24.MS:[M-H 2 O+H + ]:257.1
Starting from compound J-10 (80 mg,0.29 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-10-Na + (20mg,19％)。
Example 11:3- (3, 5-dimethylphenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-11) and its sodium salt (J-11-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2- (3, 5-dimethylphenyl) -2-glycolate (J-11)
Starting from intermediate G-M11 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-11 (1.26G, 72%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- (3, 5-dimethylphenyl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-11)
Intermediate L-11 (210 mg, 20%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-11 (1.26 g,3.61 mmol).
Step 3: 1-hydroxy-3- (3-methylthiophene-2-yl) -1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-11) and its sodium salt (J-11-Na) + ) Is synthesized by (a)
Starting from intermediate L-10 (210 mg,0.71 mmol), compound J-10 (90 mg, 45%) was obtained according to a similar synthetic method as intermediate J-1. MS [ M-H ] 2 O+H + ]:265.1
Starting from compound J-11 (80 mg,0.28 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-11-Na + (20mg,19％)。
Example 12:3- (furan-2-yl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-12) and its sodium salt (J-12-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-furan-2-glycolate (V-12)
Starting from intermediate G-M14 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-12 (680 mg, 44%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- (furan-2-yl) -1-hydroxy-1, 3-dihydrobenzo [ C ] [1,2] oxaborole-3-carboxylate (L-12)
Intermediate L-12 (180 mg, 32%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-12 (680 g,2.19 mmol).
Step 3:3- (furan-2-yl) -1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-12) and its sodium salt (J-12-Na) + ) Is synthesized by (a)
Starting from intermediate L-12 (180 mg,0.7 mmol), compound J-12 (100 mg, 58%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ7.77(d,J＝7.2Hz,1H),7.69-7.67(m,1H),7.65-7.58(m,2H),7.49(t,J＝7.1Hz,1H),6.41(dd,J＝3.1,1.9Hz,1H),6.17(d,J＝3.2Hz,1H).MS:[M-H 2 O+H + ]:228.1
Starting from compound J-12 (80 mg,0.33 mmol), the compound J-1-Na was prepared + Similar synthesis method to obtain compound J-12-Na + (20mg,18％)。
Example 13: 1-hydroxy-3- (3-trifluoromethylphenyl) -1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-13) and its sodium salt (J-13-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2- (3-trifluoromethyl) phenyl) acetate (V-13)
Intermediate V-13 (1G, 51%) was obtained by a similar synthetic method to intermediate V-1 starting from intermediate G-M4 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol).
Step 2: synthesis of methyl 1-hydroxy-3- (3-trifluoromethylphenyl) -1, 3-dihydrobenzo [ c ] [1,2] oxaborolin-3-carboxylate (L-13)
Intermediate L-13 (300 mg, 35%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-13 (1 g,2.57 mmol).
Step 3: 1-hydroxy-3- (3-trifluoromethylphenyl) -1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-13) and its sodium salt (J-13-Na) + ) Is synthesized by (a)
Starting from intermediate L-13 (300 mg,0.89 mmol), compound J-13 (128 mg, 43%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,CD 3 OD)δ7.82-7.75(m,3H),7.71(d,J＝7.3Hz,1H),7.63(d,J＝7.7Hz,1H),7.60–7.51(m,2H),7.46(t,J＝7.3Hz,1H). 13 C NMR(101MHz,CD3OD)δ172.27,153.29,141.58,131.16,130.42,130.25,130.10,129.96,,128.97(s),128.62,124.84,124.80,124.76,124.73,,123.98,122.74,122.70,122.66,122.62,88.51.MS:[M-H 2 O+H + ]:305.1
Starting from compound J-13 (80 mg,0.25 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-13-Na + (20mg,20％)。
Example 14:3- (benzo [ b)]Thiophen-2-yl) -1-hydroxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-14) and its sodium salt (J-14-Na) + )
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Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2- (3-trifluoromethyl) phenyl) acetate (V-14)
Starting from intermediate G-M4 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-14 (1.36G, 72%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- (benzo [ b ] thiophen-2-yl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-14)
Intermediate L-14 (200 mg, 17%) was obtained by carrying out a similar synthesis of intermediate L-1 starting from intermediate V-14 (1.36 g,3.61 mmol).
Step 3:3- (benzo [ b)]Thiophen-2-yl) -1-hydroxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-14) and its sodium salt (J-14-Na) + ) Is synthesized by (a)
Starting from intermediate L-14 (200 mg,0.62 mmol), compound J-14 (65 mg, 34%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.91(d,J＝7.1Hz,1H),7.87–7.81(m,2H),7.78(d,J＝7.2Hz,1H),7.64–7.55(m,2H),7.49(t,J＝7.3Hz,1H),7.39–7.30(m,2H). 13 C NMR(101MHz,DMSO-d6)δ171.28,154.52,145.33,139.48,139.07,131.94,131.14,129.26,125.13,124.96,124.42,123.87,122.74,122.26,86.23.MS:[M-H 2 O+H + ]:293.1
Starting from compound J-14 (80 mg,0.26 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-14-Na + (20mg,20％)。
Example 15: 3-cyclopentyl-1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-15) and its sodium salt (J-15-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-cyclopentyl-2-glycolate (V-15)
Starting from intermediate G-M7 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-15 (560 mg, 36%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3-cyclopentyl-1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-15)
Intermediate L-15 (132 mg, 30%) was obtained by a similar synthesis method as intermediate L-1 starting from intermediate V-15 (560 mg,1.79 mmol).
Step 3: 3-cyclopentyl-1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-15) and its sodium salt (J-15-Na) + ) Is synthesized by (a)
Starting from intermediate L-145 (132 mg,0.54 mmol), compound J-15 (55 mg, 41%) was obtained according to a similar synthetic method as intermediate J-1. MS [ M-H ] 2 O+H + ]:229.1
Starting from compound J-15 (80 mg,0.33 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-15-Na + (20mg,18％)。
Example 16: 3-cyclobutyl-1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-Carboxylic acid (J-16) and sodium salt thereof (J-16-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-cyclobutyl-2-glycolate (V-16)
Starting from intermediate G-M16 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-16 (960 mg, 64%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3-cyclobutyl-1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-16)
Intermediate L-16 (240 mg, 30%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-16 (960 mg,3.21 mmol).
Step 3: 3-cyclobutyl-1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-16) and its sodium salt (J-16-Na) + ) Is synthesized by (a)
Starting from intermediate L-16 (240 mg,0.98 mmol), compound J-16 (116 mg, 51%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,CD 3 OD)δ7.61(d,J＝7.2Hz,1H),7.52(d,J＝7.7Hz,1H),7.45(t,J＝7.4Hz,1H),7.35(t,J＝7.2Hz,1H),3.39(p,J＝8.5Hz,1H),2.26–2.13(m,1H),2.04(dd,J＝19.3,10.8Hz,1H),1.92–1.78(m,1H),1.77–1.66(m,1H),1.44(dd,J＝16.0,8.5Hz,2H). 13 C NMR(101MHz,CD 3 OD)δ173.46,153.36,130.97,129.62,127.97,121.86,88.67,41.63,22.45,20.53,16.65.MS:[M-H 2 O+H + ]:215.1
Starting from compound J-16 (80 mg,0.34 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-16-Na + (20mg,19％)。
Example 17: 1-hydroxy-3- (3-methoxyphenyl) -1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-17) and its sodium salt (J-17-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2- (3-methoxyphenyl) acetate (V-17)
Starting from intermediate G-M6 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-17 (560 mg, 51%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of 1-hydroxy-3- (3-methoxyphenyl) -1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylic acid methyl ester (L-17) starting from intermediate V-17 (630 mg,2.53 mmol), intermediate L-17 (205 mg, 27%) was obtained according to a similar synthetic method as intermediate L-1.
Step 3: 1-hydroxy-3- (3-methoxyphenyl) -1, 3-dihydrobenzo [ c][1,2]E-oxaborole-3-carboxylic acid (J-17) and its sodium salt (J-17-Na) + ) Is synthesized by (a)
Starting from intermediate L-17 (205 mg,0.69 mmol), compound J-17 (40 mg, 20%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ13.24(s,1H),9.67(s,1H),8.05(s,1H),7.76-7.66(m,2H),7.61-7.51(m,1H),7.49-7.40(m,1H),7.34-7.24(m,1H),7.03(d,J＝6.1Hz,1H),6.98-6.86(m,1H),3.72(s,3H).MS:[M-H 2 O+H + ]:267.1
Starting from compound J-17 (80 mg,0.28 mmol), compound J-1-Na was prepared + Similar synthetic method to obtain compound J-17-Na + (20mg,19％)。
Example 18: 1-hydroxy-3- (4-methoxyphenyl) -1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-18) and its sodium salt (J-18-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2- (4-methoxyphenyl) acetate (V-18)
Starting from intermediate G-M5 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-18 (985 mg, 56%) was obtained according to a similar synthetic method to intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-3- (4-methoxyphenyl) -1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-18)
Intermediate L-18 (150 mg, 18%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-18 (985 mg,2.8 mmol).
Step 3: 1-hydroxy-3- (4-methoxyphenyl) -1, 3-dihydrobenzo [ c][1,2]E-oxaborole-3-carboxylic acid (J-18) and its sodium salt (J-18-Na) + ) Is synthesized by (a)
Starting from intermediate L-18 (150 mg,0.5 mmol), compound J-18 (80 mg, 56%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ9.30δ9.59(s,1H),7.75(d,J＝7.2Hz,2H),7.68(d,J＝7.7Hz,2H),7.55(t,J＝7.3Hz,2H),7.45(t,J＝7.2Hz,2H),7.32(d,J＝8.8Hz,4H),6.91(d,J＝8.8Hz,4H),3.73(s,6H). 13 C NMR(101MHz,DMSO-d6)δ172.75,159.39,154.70,133.25,131.45,130.92,128.71,127.85,124.68,114.09,88.32,55.60.MS:[M-H 2 O+H + ]:267.1
Starting from compound J-18 (80 mg,0.28 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-18-Na + (20mg,19％)。
Example 19: 1-hydroxy-3- (3-methylsulfanyl) phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-19) and its sodium salt (J-19-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2- (3-methylsulfanyl) phenyl) acetate (V-19)
Starting from intermediate G-M8 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-19 (776 mg, 42%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-3- (3-methylsulfanyl) phenyl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-19)
Intermediate L-19 (115 mg, 17%) was obtained by a similar synthesis method as intermediate L-1 starting from intermediate V-19 (776 mg,2.11 mmol).
Step 3: 1-hydroxy-3- (3-methylsulfanyl) phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-19) and its sodium salt (J-19-Na) + ) Is synthesized by (a)
Starting from intermediate L-19 (115 mg,0.37 mmol), compound J-19 (55 mg, 49%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,CD 3 OD)δ7.76(d,J＝7.5Hz,2H),7.58(t,J＝7.2Hz,1H),7.48(t,J＝7.1Hz,1H),7.39–7.20(m,4H),2.44(s,3H). 13 C NMR(101MHz,CD 3 OD)J20、 1 H NMR(400MHz,DMSO-d6)δ13.39(s,1H),9.71(s,1H),7.78(t,J＝7.0Hz,2H),7.68(s,1H),7.65-7.52(m,4H),7.51-7.43(m,5H),7.37(t,J＝7.2Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ171.40,153.33,140.70,139.72,139.39,130.57,129.98,128.46,127.80,127.05,126.10,125.96,124.52,123.60,123.55,87.38.MS:[M-H 2 O+H + ]:283.1
Starting from compound J-19 (80 mg,0.27 mmol), the compound J-1-Na was prepared + Similar synthetic method to obtain compound J-19-Na + (20mg,19％)。
Example 20:3- ([ 1,1' -biphenyl)]-3-yl) -1-hydroxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-20) and its sodium salt (J-20-Na) + )
Step 1: synthesis of methyl 2- ([ 1,1' -biphenyl ] -3-yl) -2- (2-bromophenyl) -2-glycolate (V-20)
Starting from intermediate G-M8 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-20 (1.08G, 54%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- ([ 1,1' -biphenyl ] -3-yl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-20)
Intermediate L-20 (320 mg, 30%) was obtained by a similar synthesis method as intermediate L-1 starting from intermediate V-20 (1.08 g,2.72 mmol).
Step 3:3- ([ 1,1' -biphenyl)]-3-yl) -1-hydroxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-20) and its sodium salt (J-20-Na) + ) Is synthesized by (a)
Starting from intermediate L-20 (320 mg,0.93 mmol), compound J-20 (165 mg, 54%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ13.39(s,1H),9.71(s,1H),7.78(t,J＝7.0Hz,2H),7.68(s,1H),7.64-7.52(m,4H),7.50-7.42(m,5H),7.37(t,J＝7.2Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ171.40,153.33,140.70,139.72,139.39,130.57,129.98,128.46,127.80,127.05,126.10,125.96,124.52,123.60,123.55,87.38.MS:[M-H 2 O+H + ]:313.1
Starting from compound J-20 (80 mg,0.24 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-20-Na + (20mg,20％)。
Example 21: 1-hydroxy-6-methoxy-3- (3-methoxyphenyl) -1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-21) and its sodium salt (J-21-Na) + )
Step 1: synthesis of methyl 2- (2-bromo-4-methoxyphenyl) -2-hydroxy-2- (3-methoxyphenyl) acetate (V-21)
Starting from intermediate G-M6 (10 mmol,1M in THF), intermediate D (1.36G, 5 mmol), intermediate V-21 (1.16G, 61%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- ([ 1,1' -biphenyl ] -3-yl) -1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-21)
Starting from intermediate V-21 (1.16 g,3.04 mmol), intermediate L-21 (282 mg, 28%) was obtained according to a similar synthetic method as intermediate L-1.
Step 3: 1-hydroxy-6-methoxy-3- (3-methoxyphenyl) -1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-21) and its sodium salt (J-21-Na) + ) Is synthesized by (a)
In the form of intermediatesL-21 (282 mg,0.86 mmol) starting from intermediate J-1 gave compound J-21 (136 mg, 50%). 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.62(s,1H),7.61(d,J＝8.5Hz,1H),7.32–7.23(m,2H),7.13(dd,J＝8.5,2.5Hz,1H),7.00(d,J＝8.1Hz,1H),6.96–6.87(m,2H),3.80(s,3H),3.72(s,3H). 13 C NMR(101MHz,DMSO-d6)δ172.57,159.99,159.51,146.38,142.82,129.92,125.81,118.72,118.70,114.10,113.33,112.57,87.94,55.73,55.54.MS:[M-H 2 O+H + ]:297.1
Starting from compound J-21 (80 mg,0.25 mmol), compound J-1-Na was prepared + Similar synthetic method to obtain compound J-21-Na + (20mg,20％)。
Example 22: 1-hydroxy-6-methoxy-3- (3-trifluoromethylphenyl) -1, 3-dihydrobenzo [ c ] ][1,2]Oxaborole-3-carboxylic acid (J-22) and its sodium salt (J-22-Na) + )
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Step 1: synthesis of methyl 2- (2-bromo-4-methoxyphenyl) -2-hydroxy-2- (3-trifluoromethyl) phenyl) acetate (V-22)
Starting from intermediate G-M4 (10 mmol,1M in THF), intermediate D (1.36G, 5 mmol), intermediate V-22 (990 mg, 47%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-6-methoxy-3- (3-trifluoromethylphenyl) -1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-22)
Intermediate L-22 (210 mg, 24%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-22 (990 mg,2.36 mmol).
Step 3: 1-hydroxy-6-methoxy-3- (3-trifluoromethylphenyl) -1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-22) and its sodium salt (J-22-Na) + ) Is synthesized by (a)
Starting from intermediate L-22 (210 mg,0.57 mmol), compound J-22 (60 mg, 30%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),7.84(d,J＝7.6Hz,1H),7.76-7.70(m,2H),7.65(t,J＝8.7Hz,2H),7.29(s,1H),7.18(d,J＝8.4Hz,1H),3.81(s,3H). 13 C NMR(101MHz,DMSO-d6)δ171.15,159.17,144.77,141.53,129.76,129.11,128.55,128.23,124.81,124.34,122.11,121.46,121.42,121.38,121.34,117.96,113.44,86.33,54.71.MS:[M-H 2 O+H + ]:335.1
Starting from compound J-22 (80 mg,0.23 mmol), the compound J-1-Na was prepared + Similar synthesis method to obtain compound J-22-Na + (20mg,20％)。
Example 23: 1-hydroxy-6-methoxy-3-thiophen-2-yl-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-23) and its sodium salt (J-23-Na) + )
Step 1: synthesis of methyl 2- (2-bromo-4-methoxyphenyl) -2-hydroxy-2- (thiophen-2-yl) acetate (V-23)
Starting from intermediate G-M1 (10 mmol,1M in THF), intermediate D (1.36G, 5 mmol), intermediate V-23 (760 mg, 43%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-6-methoxy-3- (3-trifluoromethylphenyl) -1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-23)
Intermediate L-23 (180 mg, 28%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-23 (760 mg,2.13 mmol).
Step 3: 1-hydroxy-6-methoxy-3-thiophen-2-yl-1, 3-dihydrobenzo [ c ]][1,2]Oxazoline-3-carboxylic acid (J-23) and its sodium salt (J-23-Na) + ) Is synthesized by (a)
Starting from intermediate L-23 (180 mg,0.59 mmol), compound J-23 (45 mg, 55%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6).δ7.64(d,J＝8.3Hz,1H),7.45(d,J＝4.7Hz,1H),7.23(d,J＝2.0Hz,1H),7.18(d,J＝2.0Hz,1H),7.15-7.10(m,1H),7.03–6.96(m,1H),3.79(s,3H). 13 C NMR(101MHz,DMSO-d6)δ171.79(s),160.18(s),147.18(s),144.93(s),127.32(s),126.17(s),125.71(s),124.98(s),118.95(s),114.10(s),85.59(s),55.77(s).MS:[M-H 2 O+H + ]:273.0
Starting from compound J-23 (80 mg,0.28 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-23-Na + (20mg,19％)。
Example 24: 1-hydroxy-6-methoxy-3- (3-methylthiophenyl) -1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-24) and its sodium salt (J-24-Na) + )
Step 1: synthesis of methyl 2- (2-bromo-4-methoxyphenyl) -2-hydroxy-2- (3-methylsulfanyl) phenyl) acetate (V-24)
Starting from intermediate G-M8 (10 mmol,1M in THF), intermediate D (1.36G, 5 mmol), intermediate V-24 (1.22G, 61%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-6-methoxy-3- (3-methylthiophenyl) -1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-24)
Intermediate L-24 (260 mg, 25%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-24 (1.22 g,3.07 mmol).
Step 3: 1-hydroxy-6-methoxy-3- (3-methylthiophenyl) -1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-24) and its sodium salt (J-24-Na) + ) Is synthesized by (a)
Starting from intermediate L-24 (260 mg,0.76 mmol), compound J-24 (80 mg, 32%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ7.61(d,J＝8.5Hz,1H),7.33(t,J＝7.7Hz,1H),7.27-7.19(m,4H),7.14(dd,J＝8.5,2.5Hz,1H),3.80(s,3H),2.44(s,3H). 13 C NMR(101MHz,DMSO-d6)δ172.49,160.05,146.18,141.99,138.67,129.53,125.82,125.73,123.83,123.15,118.78,114.21,87.84,55.74,15.19.MS:[M-H 2 O+H + ]:313.1
Starting from compound J-24 (80 mg,0.24 mmol)According to the implementation of the compound J-1-Na + Similar synthesis method to obtain compound J-24-Na + (20mg,20％)。
Example 25:3- ([ 1,1' -biphenyl)]-3-yl) -1-hydroxy-6-methoxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-25) and its sodium salt (J-25-Na) + )
Step 1: synthesis of methyl 2- ([ 1,1' -biphenyl ] -3-yl) -2- (2-bromo-4-methoxyphenyl) -2-glycolate (V-25)
Starting from intermediate G-M9 (10 mmol,1M in THF), intermediate D (1.36G, 5 mmol), intermediate V-25 (1.1G, 51%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- ([ 1,1' -biphenyl ] -3-yl) -1-hydroxy-6-methoxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-25)
Intermediate L-25 (195 mg, 20%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-25 (1.1 g,2.57 mmol).
Step 3:3- ([ 1,1' -biphenyl)]-3-yl) -1-hydroxy-6-methoxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-25) and its sodium salt (J-25-Na) + ) Is synthesized by (a)
Starting from intermediate L-25 (195 mg,0.52 mmol), compound J-25 (50 mg, 27%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,CD 3 OD)δ7.73–7.65(m,2H),7.59–7.49(m,3H),7.44–7.38(m,4H),7.31(t,J＝7.3Hz,1H),7.19(d,J＝2.3Hz,1H),7.14(dd,J＝8.5,2.5Hz,1H),3.83(s,3H). 13 C NMR(101MHz,CD 3 OD)δ173.25,160.38,145.77,141.28,141.11,140.74,128.53,127.16,126.68,126.60,125.45,125.08,124.81,118.30,112.95,88.97,54.54.MS:[M-H 2 O+H + ]:343.1
Starting from compound J-25 (80 mg,0.22 mmol), the compound J-1-Na was prepared + Similar synthetic method to obtain compound J-25-Na + (20mg,21％)。
Example 26:3- ([ 1,1' -biphenyl)]-3-yl) -1-hydroxy-6-methoxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-26) and its sodium salt (J-26-Na) + )
Step 1: synthesis of methyl 2- ([ 1,1' -biphenyl ] -3-yl) -2- (2-bromo-4-methoxyphenyl) -2-glycolate (V-26)
Starting from intermediate G-M10 (10 mmol,1M in THF), intermediate A (1.2G, 5 mmol), intermediate V-26 (840 mg, 47%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 3- ([ 1,1' -biphenyl ] -3-yl) -1-hydroxy-6-methoxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-26)
Intermediate L-26 (210 mg, 29%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-26 (840 mg,2.36 mmol).
Step 3:3- ([ 1,1' -biphenyl)]-3-yl) -1-hydroxy-6-methoxy-1, 3-dihydrobenzo [ c][1,2]Oxaborole-3-carboxylic acid (J-26) and its sodium salt (J-26-Na) + ) Is synthesized by (a)
Starting from intermediate L-26 (210 mg,0.69 mmol), compound J-26 (115 mg, 58%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ9.78(s,1H),7.76(dd,J＝13.6,7.5Hz,2H),7.62–7.55(m,1H),7.53–7.39(m,5H). 13 C NMR(101MHz,DMSO-d6)δ172.01,153.94,143.35,133.45,131.82,131.18,130.87,129.06,128.56,87.77.MS:[M-H 2 O+H + ]:271.0
Starting from compound J-26 (80 mg,0.28 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-26-Na + (20mg,19％)。
Example 27: 1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-27) and its sodium salt (J-27-Na) + )
Step 1: synthesis of methyl 2- (2-bromophenyl) -2-hydroxy-2-phenylacetate (V-27)
Starting from phenylmagnesium bromide (10 mmol,1M in THF), intermediate A (1.2 g,5 mmol), intermediate V-27 (820 mg, 51%) was obtained according to a similar synthetic method as intermediate V-1.
Step 2: synthesis of methyl 1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-27)
Intermediate L-27 (230 mg, 34%) was obtained by a similar synthetic method as intermediate L-1 starting from intermediate V-27 (630 mg,2.55 mmol).
Step 3: 1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-27) and its sodium salt (J-27-Na) + ) Is synthesized by (a)
Starting from intermediate L-26 (230 mg,0.86 mmol), compound J-26 (135 mg, 62%) was obtained according to a similar synthetic method as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ13.30(s,1H),9.64(s,1H),7.75(d,J＝7.1Hz,1H),7.70(d,J＝7.7Hz,1H),7.56(t,J＝7.4Hz,1H),7.48-7.39(m,3H),7.39-7.30(m,3H). 13 C NMR(101MHz,DMSO-d6)δ172.53,154.46,131.53,130.98,128.80,128.50,126.43,124.72,88.53.MS:[M-H 2 O+H + ]:237.1
Starting from compound J-27 (80 mg,0.31 mmol), the compound J-1-Na was prepared + Similar synthetic method to obtain compound J-27-Na + (20mg,19％)。
Example 28: 1-hydroxy-4, 6-dimethoxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid (J-28) and its sodium salt (J-28-Na) + )
Step 1: synthesis of methyl 1-hydroxy-4, 6-dimethoxy-3-phenyl-1, 3-dihydrobenzo [ c ] [1,2] oxaborole-3-carboxylate (L-28)
Compounds I (264 mg,2 mmol) and II (0.34 ml,3 mmol) were dissolved in dry chloroform (20 ml), triflic acid (0.18 ml,2 mmol) was added and reacted overnight at room temperature, after completion of TLC monitoring the reaction, the solvent was removed by evaporation and column chromatography gave intermediate L-28 (250 mg, 38%).
Step 2: 1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid methyl ester (L-27) and sodium salt (J-28-Na) thereof + ) Is synthesized by (a)
Intermediate L-27 (250 mg,0.76 mmol) was used as starting material to afford intermediate J-28 (160 mg, 67%) following a similar synthetic procedure as intermediate J-1. J28, 1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),9.53(s,1H),7.34(d,J＝6.7Hz,2H),7.31–7.22(m,3H),6.86(s,1H),6.68(s,1H),3.80(s,3H),3.71(s,3H). 13 C NMR(101MHz,DMSO-d6)δ171.88,161.98,155.58,140.06,135.72,127.1,127.81,127.79,102.72,88.31,55.87.MS:[M-H 2 O+H + ]:297.1
Starting from compound J-28 (80 mg,0.25 mmol), compound J-1-Na was prepared + Similar synthesis method to obtain compound J-28-Na + (20mg,24％)。
Example 29:2- (1-hydroxy-4, 6-dimethoxy-3-methyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborol-3-yl) acetic acid (J-29) and its sodium salt (J-29-Na) + )
Step 1: synthesis of methyl 2- (1-hydroxy-4, 6-dimethoxy-3-methyl-1, 3-dihydrobenzo [ c ] [1,2] oxaborol-3-yl) acetate (L-28)
Compounds I (264 mg,2 mmol) and III (0.34 ml,3 mmol) were dissolved in dry chloroform (20 ml), triflic acid (0.18 ml,2 mmol) was added and reacted overnight at room temperature, after completion of TLC monitoring the reaction, the solvent was removed by evaporation and column chromatography gave intermediate L-29 (220 mg, 39%).
Step 2: 1-hydroxy-3-phenyl-1, 3-dihydrobenzo [ c ]][1,2]Oxaborole-3-carboxylic acid methyl ester (L-29) and sodium salt (J-29-Na) thereof + ) Is synthesized by (a)
Intermediate L-29 (220 mg,0.79 mmol) was used as starting material and intermediate J-29 (170 mg, 81%) was obtained following a similar synthetic procedure as intermediate J-1. 1 H NMR(400MHz,DMSO-d6)δ11.78(s,1H),9.01(s,1H),6.75(d,J＝1.9Hz,1H),6.60(d,J＝1.9Hz,1H),3.80(s,3H),3.77(s,3H),2.82(d,J＝14.2Hz,1H),2.69(d,J＝14.2Hz,1H),1.51(s,3H). 13 C NMR(101MHz,DMSO-d6)δ171.39,161.13,154.67,139.72,105.12,101.93,82.27,55.91,55.70,43.95,27.03.MS:[M-H 2 O+H + ]:249.1
Starting from compound J-29 (80 mg,0.3 mmol), compound J-1-Na was prepared + Similar synthetic method to obtain compound J-29-Na + (20mg,20％)。
The beneficial effects of the compounds of the invention are demonstrated below by experimental examples.
Experimental example 1: in vitro inhibitory Activity of the Compounds of the invention against MBL and SBL enzymes
(1) Experimental materials:
WHB full black 96 well flat bottom light emitting plate (specification: WHB-96-02), WHB96 well cell culture plate (specification: WHB-96).
(2) The experimental method comprises the following steps:
the protein expression and purification steps are as follows: transferring the recombinant plasmid into Escherichia coli Transetta (DE 3) for expression, culturing at 37deg.C to OD 600 Reach toAfter decreasing the temperature to 20℃C (VIM-1, VIM-2, VIM-5, NDM-1, NDM-5, IMP-1, IMP-4 and CphA), 16℃C (Sfh-1, GOB-18, KPC-2, OXA-48) or 25℃C (L1), the target protein expression was induced by adding isopropyl beta-D-1-thiopyran galactoside (IPTG) at a final concentration of 0.5mM, and culturing was continued for 18-20 hours. The following day, cells were collected by centrifugation at 4000rpm for 15 minutes, resuspended in lysis Buffer A (class B1 Buffer A20 mM Tris-HCl,250mM NaCl,pH8.0;Sfh-I Buffer A50mM Hepes,400mM NaCl,PH8.0;CphA, GOB-18, L1 Buffer A40mM Hepes,200mM NaCl,PH7.4), and after lysis of the bacteria with a low temperature high pressure continuous flow cell disrupter (JNBIO), cell debris was removed by centrifugation at 15,000rpm for 30 minutes, and the supernatant was collected and purified using a Ni-NTA affinity chromatography column (Roche). Pretreatment of Ni-NTA column before protein purification: eluting residual protein with 10mL Buffer B (original Buffer A contains 500mM imidazole, with other components unchanged), and then 20mL m The illiQ water rinse was finally equilibrated with 20mL BufferA affinity column. The collected supernatant was fed into a Ni-NTA column, and after the supernatant was completely passed out of the Ni-NTA column, it was washed with Buffer C containing 5mM imidazole (the other components of the original Buffer A were unchanged, and 5mM imidazole was contained) in a large amount to remove non-specifically bound proteins and weakly bound proteins. Finally, buffer D containing 250mM imidazole (the other components of the original Buffer A are unchanged, and 250mM imidazole is contained) is used for eluting the target protein. Eluted target proteins were collected and concentrated using Amicon Ultra 10K (Millipore), and then the target proteins were replaced into the corresponding buffers using desalting column Hi Trap Desalting column (GE Healthcare), respectively. All steps in the purification process were monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAG), and the protein concentration was determined by Nanno Drop 2000 spectrophotometer (Thermo Scientific). Finally, the protein is frozen by liquid nitrogen and then stored at-80 ℃ for subsequent enzyme kinetics experiments.
The activity test experimental steps are as follows: all test compounds were dissolved in 100% DMSO solvent to prepare 100mM stock solutions, which were then diluted separately with buffer solution to compound working solutions. To each test well, 10. Mu.L of the compound working solution, 30. Mu.L of the buffer solution and 10. Mu.L of the enzyme solution were sequentially added, and after reacting at 25℃for 10 minutes, 10. Mu.L of the FC-5 substrate solution was added, and immediately after that, the fluorescence intensity during the enzymatic kinetic reaction was measured using a Thermo VARIOSKAN LUX microplate reader at an excitation light wavelength of 380nM and an emission light wavelength of 460 nM. B2 enzyme uses meropenem (MEM) as an activity test substrate, and ultraviolet absorption at 300nm wavelength in the enzyme kinetic reaction process is measured by using a Thermo VARIOSKAN LUX enzyme-labeling instrument. 3 parallel groups were set for each concentration.
With the best inhibitory activity on the B1 subclass MBL enzyme in the patent application No. 202110444405.4, compound 42 (structure) As a control compound, a compound which is a compound,
(3) Experimental results:
the inhibition activity of the compounds of the present invention and control compounds on MBL and SBL enzymes was tested by the above experimental methods, and the enzymes tested include VIM-1, VIM-2. VIM-5, NDM-1, NDM-5, IMP-1, IMP-4, sfh-I, cphA, L1, GOB-18, KPC-2 and OXA-48 enzymes. Half Inhibitory Concentrations (IC) of the compounds of the invention and control compounds against these enzymes 50 ) See tables 1 and 2.
TABLE 1 inhibitory Activity of the compounds of the invention on representative B1 subclasses of MBL enzymes (IC 50 ) a
a +：IC 50 ＞100μM；++：IC 50 IC is less than or equal to 100 mu M 50 ＞10μM；+++：IC 50 IC is less than or equal to 10 mu M 50 ＞1μM；++++：IC 50 IC is less than or equal to 1 mu M 50 ＞10nM；+++++：IC 50 ≤10nM。
The results in Table 1 show that the compounds of the invention have good and broad-spectrum inhibition activity on B1 subclass MBL enzymes, and can be used for preparing inhibitors of B1 subclass MBL enzymes.
As can be seen in Table 1 of the patent application No. 202110444405.4, the reported 3- (alpha-acrylic acid) substituted five-membered cyclic borate derivatives have an IC for the B1 subclass MBL enzymes VIM-2, NDM-1 50 Most are greater than 10 μm. Selecting compound 42 (structure of 202110444405.4) having the best inhibitory activity on MBL enzyme of subgroup B1 ) As a control compound, the test results under the same conditions show that the compound has inhibitory activity IC on VIM-2 50 IC with inhibitory activity against VIM-5 having a value ranging from 1. Mu.M to 10. Mu.M 50 IC having inhibitory activity against other B1 subclasses MBL, including VIM-1, NDM-5, IMP-1, IMP-4, in the range of 10. Mu.M to 100. Mu.M 50 The values are all greater than 100. Mu.M. IC of the inventive Compounds against the B1 subclass MBL enzyme VIM-2 50 Values of less than 1. Mu.M, part of compound IC 50 Values even below 10nM; IC of the inventive Compounds on NDM-1 50 The values were mostly below 1. Mu.M, with IC for NDM-1 for Compound J-6 alone 50 The activity is in the range of 1 mu M to 10 mu M; inhibitory Activity of the Compounds of the invention against VIM-1, NDM-5, IMP-1 IC 50 The values are all less than 100. Mu.M, most of the compound ICs 50 Values are less than 1. Mu.M, in part even less than 10nM. Thus, the compounds of the present invention inhibit the activity of the B1 subclass MBL enzyme more preferentially than the 3- (alpha-acrylic acid) substituted five-membered cyclic borate derivatives reported in the patent application No. 202110444405.4.
TABLE 2 inhibitory Activity of the compounds of the invention on representative B2 subclasses MBL, B3 subclasses MBL and SBL enzymes (IC 50 ) a
a +：IC 50 ＞100μM；++：IC 50 IC is less than or equal to 100 mu M 50 ＞10μM；+++：IC 50 IC is less than or equal to 10 mu M 50 ＞1μM；++++IC 50 IC is less than or equal to 1 mu M 50 ＞1nM；+++++：IC 50 ≤1nM。
The results in Table 2 show that the compounds of the present invention have good, broad-spectrum inhibitory activity against the B2 subclass MBL, the B3 subclass MBL and the SBL enzymes.
In conclusion, the compound has good broad-spectrum inhibition activity on the B1 subclass MBL, the B2 subclass MBL, the B3 subclass MBL and the SBL enzyme, and can be used for preparing inhibitors of the MBL and the SBL enzyme.
Experimental example 2: evaluation of clinically isolated drug-resistant bacterial Activity of the Compound of the present invention against meropenem
(1) Experimental materials:
transparent 96-well microtiter plates (purchased from corning principals); meropenem (product number purchased from Dalian Mei-ren Co., ltd.: D1204A).
(2) The experimental method comprises the following steps:
determination of the Compounds 2, 3, 5, 7, 8, 13, 14, 19, 20, 21, 22, 23, 24, 25, 26 of the invention (wherein Bla is defined for) by microdilution IMP-1 Measurement of only Compounds 2, 3, 5, 7, 8, 13, 14, 19, 20) and different concentrations of carbapenem antibiotics were performed(meropenem) Minimum Inhibitory Concentration (MIC) of clinically isolated enzyme-producing strains after combination. Bacterial strains used for testing included: coli 1541 (bla) IMP-1 ) Klebsiella pneumoniae 090567 (bla) NDM-1 ) Klebsiella pneumoniae 090571 (bla) NDM-1 )。
Experiments were performed in microtiter plates (Corning) and meropenem and a compound of the invention (dissolved in DMSO and diluted in Mueller Hinton (MH) broth, the inoculum was diluted to 0.5McFarland with 0.85% NaCl solution, meropenem (final concentration 128. Mu.g/mL to 0.25. Mu.g/mL, 2-fold dilution) and a compound of the invention (final concentration 10. Mu.M, 2. Mu.M) were added to the microtiter plates, and finally the test inoculum was added to ensure a final concentration of 5X 105CFU/mL. After incubation of the microtiter plates at 37℃for 16-20 hours, the minimum antimicrobial drug concentration (MIC) that was found to completely inhibit bacterial growth in the microtiter wells was observed and was the MIC value, and the experiment was repeated a total of two times.
(3) Experimental results:
the antibacterial activity of the combination of the compound of the invention and meropenem on drug-resistant bacteria expressing the B1 subclass MBL enzymes NDM-1 and IMP-1 was tested by the above experimental method, and the results are shown in Table 3.
Table 3. Antibacterial Activity of the compounds of the invention in combination with meropenem against resistant bacteria expressing the B1 subclass MBL enzymes NDM-1, IMP-1 (MIC, μg/mL). a
a ND, undetected.
The results show that the compound has excellent antibacterial activity on drug-resistant bacteria expressing B1 subclass MBL enzyme NDM-1 or IMP-1 when being combined with meropenem, and the compound can reverse the drug resistance of carbapenem drug-resistant bacteria.
In conclusion, the invention provides the benzo five-membered ring borate-3-carboxylic acid compound which has good broad-spectrum inhibition activity on MBL and/or SBL enzyme, particularly has half inhibition concentration on B1 subtype metal beta-lactamase reaching sodium mole or picomole level, and lays a material foundation for research and development of related medicines. In addition, the compound disclosed by the invention has excellent antibacterial activity on various drug-resistant bacteria, can reverse the drug resistance of carbapenem-resistant bacteria, and has great potential in preparing MBL/SBL dual inhibitors and drugs for reversing the drug resistance of carbapenem-resistant bacteria.
Claims (10)
1. The benzo five-membered ring boric acid ester-3-carboxylic acid compound, stereoisomer or salt thereof is characterized in that the structure of the benzo five-membered ring boric acid ester-3-carboxylic acid compound is shown as a formula I:
wherein R is 1 Selected from unsubstituted or R 3 The substituted following groups: c (C) 1-6 Alkyl, phenyl, heteroaryl, fused ring alkyl, heterofused ring group, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl; r is R 3 Selected from hydroxy, amino, amide, guanidino, mercapto, halogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, phenyl;
n is selected from 0, 1 or 2;
m is selected from 0, 1, 2, 3 or 4;
R 2 each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio groups.
2. The benzo five-membered ring borate-3-carboxylic acid compound, stereoisomer or salt thereof according to claim 1, wherein the structure of the benzo five-membered ring borate-3-carboxylic acid compound is as shown in formula II:
wherein R is 1 Selected from unsubstituted or R 3 The substituted following groups: c (C) 1-6 Alkyl, phenyl, heteroaryl, fused ring alkyl, heterofused ring group, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl; r is R 3 Selected from hydroxy, amino, amide, guanidino, mercapto, halogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, phenyl;
m is selected from 0, 1, 2, 3 or 4;
R 2 each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio groups.
3. The benzo five-membered ring borate-3-carboxylic acid compound, stereoisomer or salt thereof according to claim 2, wherein R is 1 Selected from unsubstituted or R 3 The substituted following groups: c (C) 1-4 Alkyl, phenyl,4-5 membered saturated cycloalkyl, 4-5 membered saturated heterocyclyl; r is R 3 Selected from halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl;
m is selected from 0, 1 or 2;
R 2 each independently selected from halogen, C 1-4 An alkoxy group.
4. The benzo five-membered ring borate-3-carboxylic acid compound, stereoisomer thereof or salt thereof according to claim 3, wherein the structure of the benzo five-membered ring borate-3-carboxylic acid compound is as shown in formula III:
wherein R is 3 Selected from hydroxy, amino, guanidino, amide, mercapto, halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl;
m is selected from 0, 1 or 2;
R 2 each independently selected from C 1-4 An alkoxy group;
preferably, the halogen substituted C 1-4 Alkyl is CF 3 。
5. The benzo five membered ring borate-3-carboxylic acid compound, stereoisomer or salt thereof according to claim 1, wherein the benzo five membered ring borate-3-carboxylic acid compound is selected from the group consisting of:
6. the benzo five membered ring borate-3-carboxylic acid compound, stereoisomer, or salt thereof according to claim 5, wherein the salt is a sodium salt and the salt of the benzo five membered ring borate-3-carboxylic acid compound is selected from the group consisting of:
7. a pharmaceutical composition, characterized in that it is a preparation prepared by using the benzo five-membered ring borate-3-carboxylic acid compound, stereoisomer or salt thereof as an active ingredient and pharmaceutically acceptable auxiliary materials as defined in any one of claims 1 to 6.
8. Use of a benzo five-membered ring borate-3-carboxylic acid compound, stereoisomer or salt thereof according to any one of claims 1 to 6 for the preparation of a β -lactamase inhibitor.
9. Use of a benzo five-membered ring borate-3-carboxylic acid compound, stereoisomer or salt thereof according to any one of claims 1 to 6 in combination with a carbapenem antibiotic for the manufacture of a medicament against carbapenem resistant bacteria; preferably, the carbapenem antibiotic is meropenem and/or the carbapenem-resistant bacterium is a beta-lactamase-expressing bacterium.
10. Use according to claim 8 or 9, characterized in that the beta-lactamase is a metallo beta-lactamase, a serine beta-lactamase or a metallo beta-lactamase and a serine beta-lactamase;
preferably, the metallo-beta-lactamase is a B1 subclass metallo-beta-lactamase, more preferably, the B1 subclass metallo-beta-lactamase is selected from the group consisting of VIM-1, VIM-2, VIM-5, NDM-1, NDM-5, IMP-1, IMP-4.
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